26,169 results on '"piperazines"'
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2. New psychoactive substances and the risks of consumption in children and adolescents
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Viorela Nitescu
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new psychoactive substances ,cannabinoids ,cathinones ,hallucinogens ,piperazines ,Medicine ,Pediatrics ,RJ1-570 - Abstract
According to the definition established by the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) a “new psychoactive substance is considered any narcotic or psychotropic substance in pure form or in preparations, which is not controlled by the Conventions regarding drugs of the United Nations and which represent a threat to human health comparable to that realized by the substances registered in these conventions considered illicit substances (1). There have been described 4 main classes of new psychoactive substances: synthetic cannabinoids (contained in plant mixtures) , synthetic cathinones (contained in various bath salt powders),natural hallucinogens and piperazines (contained in tablets or capsules). Synthetic cannabinoids are synthetic agonists of cannabinoid receptors, constituting a group of synthetic substances that mimic the effects of Δ 9 tetrahydrocannabinol (THC), the main product from cannabis, responsible for its psychoactive effects (4). Symptoms of poisoning are similar to those of cannabis poisoning but more severe, the clinical picture most commonly comprising: agitation, nausea, palpitations (9). Synthetic cathinones are compounds derived from cathinone - the main constituent of the Catha edulis plant known as KHAT (12). The effects of the consumption are similar to those of amphetamines, methamphetamines or cocaine. Natural hallucinogens are substances that in small doses have the main effect of altering the perception of thinking and mood with the preservation of lucidity along with minor effects on memory and orientation (23,24). Despite the name, these substances rarely produce true hallucinations. The most popular natural hallucinogens are: salvinorin A, psilocybin and psilocyn muscimol and ibotenic acid. Piperazines are synthetic compounds similar to amphetamines but with weaker effects. The best known are: benzylpiperazines and phenylpiperazines (28). Conclusions. The occasional consumption that can lead to acute intoxication or the chronic consumption of new psychoactive substances represents an important health problem occupying a place that should not be neglected in the pathology of adolescents and young people.
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- 2019
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3. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children
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Rajendra P. Singh, Kimberly K. Adkison, Mark Baker, Ridhi Parasrampuria, Allen Wolstenholme, Mark Davies, Nicola Sewell, Cindy Brothers, and Ann M. Buchanan
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Adult ,Microbiology (medical) ,Adolescent ,Anti-HIV Agents ,Pyridones ,Fixed-dose combination ,Administration, Oral ,Biological Availability ,Pharmacology ,Piperazines ,Young Adult ,chemistry.chemical_compound ,Pharmacokinetics ,Abacavir ,Single entity ,Oxazines ,medicine ,Humans ,Dosing ,Aged ,Acquired Immunodeficiency Syndrome ,business.industry ,Lamivudine ,Middle Aged ,Dideoxynucleosides ,Bioavailability ,Drug Combinations ,Infectious Diseases ,chemistry ,Pediatrics, Perinatology and Child Health ,Dolutegravir ,business ,Heterocyclic Compounds, 3-Ring ,Tablets ,medicine.drug - Abstract
BACKGROUND The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.
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- 2022
4. Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5
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L. Lepescheux, R. Gosmini, F. De Ceuninck, Thierry Christophe, E. van der Aar, I. Botez, Nele Vandervoort, Pierre Deprez, D. Amantini, Roland Blanque, D. Merciris, Robert Touitou, Philippe Clément-Lacroix, C. Cottereaux, S. Meurisse, Patrick Mollat, F. Brebion, D. Comas, Christopher B. Little, and Margaret M. Smith
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Metalloproteinase ,biology ,Chemistry ,Cartilage ,Biomedical Engineering ,Osteoarthritis ,Pharmacology ,medicine.disease ,Piperazines ,Rats ,Glycosaminoglycan ,Mice ,medicine.anatomical_structure ,Rheumatology ,Proteoglycan ,In vivo ,biology.protein ,medicine ,Animals ,Humans ,Orthopedics and Sports Medicine ,ADAMTS5 Protein ,Aggrecan ,Aggrecanase - Abstract
Summary Objective A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. Methods Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently-labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants, and on interleukin-1β-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. Results GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50 ± SD: 19 ± 2 nM and 5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 μM and 10 μM, respectively). In DMM mice, GLPG1972/S201086 (30–120 mg/kg b.i.d) versus vehicle reduced femorotibial cartilage proteoglycan loss (23–37%), cartilage structural damage (23–39%) and subchondral bone sclerosis (21–36%). In MNX rats, GLPG1972/S201086 (10–50 mg/kg b.i.d) versus vehicle reduced cartilage damage (OARSI score reduction, 6–23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77–110%). Conclusions GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.
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- 2022
5. Effects of the Moderate CYP3A4 Inhibitor Erythromycin on the Pharmacokinetics of Palbociclib
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Hilde Rosing, Stijn L.W. Koolen, Laura Molenaar-Kuijsten, Annelie J E Vulink, Niels de Vries, Ron H.J. Mathijssen, Stefanie L. Groenland, Marloes G J van Dongen, Alwin D. R. Huitema, C. Louwrens Braal, Neeltje Steeghs, Jos H. Beijnen, Medical Oncology, and Pharmacy
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Adult ,Pyridines ,Cmax ,Erythromycin ,Administration, Oral ,Antineoplastic Agents ,Breast Neoplasms ,Pharmacology ,Palbociclib ,Drug Administration Schedule ,Piperazines ,Cmin ,Pharmacokinetics ,SDG 3 - Good Health and Well-being ,Medicine ,Humans ,Pharmacology (medical) ,Drug Interactions ,Prospective Studies ,Protein Kinase Inhibitors ,Aged ,Netherlands ,Cross-Over Studies ,business.industry ,Middle Aged ,Crossover study ,Treatment Outcome ,Pharmacodynamics ,Concomitant ,Cytochrome P-450 CYP3A Inhibitors ,Female ,Drug Monitoring ,business ,medicine.drug - Abstract
Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0–24h), maximum plasma concentration (Cmax), and minimum plasma concentration (Cmin) were 1.46 × 103 ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103 ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0–24h, Cmax, and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24–1.66), 1.43 (1.20–1.69), and 1.46 (1.30–1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0–24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly.
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- 2022
6. Long-Term Safety and Efficacy of Blonanserin Oral Tablet in Adolescents with Schizophrenia: A 52-Week, Multicenter, Open-Label Extension Study
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Yohei Hyodo, Takuya Saito, Hiroshi Nakamura, Reiko Sakaguchi, and Jun Ishigooka
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Adult ,Pediatrics ,medicine.medical_specialty ,Adolescent ,business.industry ,Extension study ,Schizophrenia (object-oriented programming) ,Blonanserin ,Piperazines ,Psychiatry and Mental health ,Treatment Outcome ,Piperidines ,Tolerability ,Pediatrics, Perinatology and Child Health ,Schizophrenia ,medicine ,Humans ,Pharmacology (medical) ,Long term safety ,Open label ,business ,Antipsychotic Agents ,Tablets ,medicine.drug - Abstract
Objectives: To evaluate the long-term efficacy and safety/tolerability of oral blonanserin in adolescents with schizophrenia (Study registration number: JapicCTI-111725). Methods: This 52-week, mul...
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- 2022
7. Inhibiting Src-mediated PARP1 tyrosine phosphorylation confers synthetic lethality to PARP1 inhibition in HCC
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Xiaomin Ma, Yueke Lin, Lihui Zhu, Yeping Cheng, Weiqiang Jing, Xuecheng Shen, Lihui Han, Tao Li, Caiyu Sun, Xiaoting Lv, Dapeng Ma, Min Yang, Yunxue Zhao, Zhenzhi Qin, Gaozhong Xiong, and Haocheng Xuan
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Male ,Cancer Research ,Carcinoma, Hepatocellular ,Combination therapy ,medicine.medical_treatment ,Dasatinib ,Poly (ADP-Ribose) Polymerase-1 ,Synthetic lethality ,Poly(ADP-ribose) Polymerase Inhibitors ,Piperazines ,Targeted therapy ,Mice ,chemistry.chemical_compound ,PARP1 ,Mice, Inbred NOD ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans ,Medicine ,Dimethyl Sulfoxide ,Phosphorylation ,Zebrafish ,business.industry ,Liver Neoplasms ,Tyrosine phosphorylation ,Hep G2 Cells ,Xenograft Model Antitumor Assays ,digestive system diseases ,Up-Regulation ,Disease Models, Animal ,Adenosine diphosphate ,src-Family Kinases ,Oncology ,chemistry ,Cancer research ,Phthalazines ,business ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Hepatocellular carcinoma (HCC), a heterogeneous cancer with high mortality, is resistant to single targeted therapy; thus, combination therapy based on synthetic lethality is a promising therapeutic strategy for HCC. Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) is the most recognized target for synthetic lethality; however, the therapeutic effect of PARP1 inhibition on HCC is disappointing. Therefore, exploring new synthetic lethal partners for the efficient manipulation of HCC is urgently required. In this study, we identified Src and PARP1 as novel synthetic lethal partners, and the combination therapy produced significant anti-tumor effects without causing obvious side effects. Mechanistically, Src interacted with PARP1 and phosphorylated PARP1 at the Y992 residue, which further mediated resistance to PARP1 inhibition. Overall, this study revealed that Src-mediated PARP1 phosphorylation induced HCC resistance to PARP1 inhibitors and indicated a therapeutic window of the Y992 phosphorylation of PARP1 for HCC patients. Moreover, synthetic lethal therapy by co-targeting PARP1 and Src have the potential to broaden the strategies for HCC and might benefit HCC patients with high Src activation and resistance to PARP1 inhibitors alone.
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- 2022
8. Synthesis and Clinical Development of Palbociclib: An Overview
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Debabrata Konar, Kapil Kumar, Subhabrata Kar, and Saurabh Maru
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Oncology ,medicine.medical_specialty ,Pyridines ,Receptor, ErbB-2 ,medicine.medical_treatment ,Breast Neoplasms ,Palbociclib ,01 natural sciences ,Piperazines ,Targeted therapy ,03 medical and health sciences ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Drug Discovery ,medicine ,Humans ,Protein Kinase Inhibitors ,030304 developmental biology ,0303 health sciences ,Fulvestrant ,business.industry ,Cancer ,medicine.disease ,Metastatic breast cancer ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Receptors, Estrogen ,Female ,Skin cancer ,business ,Tamoxifen ,medicine.drug - Abstract
Breast cancer is the second most commonly identified cancer in women in the United States after skin cancer. The past few years have seen a substantial increase in breast cancer awareness campaigns and active research in fields of diagnosis and targeted therapy. These factors have led to a better mechanistic understanding of the disease, detection at earlier stages, and a more personalized approach to treatment, ultimately causing a crucial increase in the survival rates after detection. However, with the advances in treatment, cases of patients developing primary resistance and acquired resistance are increasing. Most of the breast cancers which develop resistance to therapy are ER+ and are typically treated with tamoxifen and fulvestrant. These drugs either lower the levels of estrogen or inhibit the receptors for estrogen and prevent the tumor from spreading. Around one-third of women treated with these drugs develop resistance to them, lowering their chances of survival. This has directed the search for newer drug therapies to target advanced breast cancer and resistance. One of these efforts has resulted in the development of Palbociclib, a first in class inhibitor of cyclin dependent kinases 4 and 6 (CDK4 and CDK6), which was granted accelerated approval from the FDA for combination therapy in postmenopausal women with ER+, HER2- metastatic breast cancer. This review is focused on the various aspects of “Palbociclib” including its synthesis, molecular modeling studies, and efficacy and safety profile with data obtained from various clinical trials.
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- 2022
9. AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1
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Ruing Zhao, Shenglin Ma, Qinghua Deng, Ke Zhang, Yanjiao Mao, Qingqing Yu, and Wei Yin
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Lung Neoplasms ,Applied Microbiology and Biotechnology ,Tyrosine-kinase inhibitor ,Receptor tyrosine kinase ,Piperazines ,Mice ,egfr mutant ,Carcinoma, Non-Small-Cell Lung ,Medicine ,Osimertinib ,Epidermal growth factor receptor ,Aniline Compounds ,Janus kinase 1 ,biology ,Brain Neoplasms ,jak1 ,Cell Cycle ,General Medicine ,Chemoradiotherapy ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,osimertinib ,azd3759 ,medicine.drug ,Research Article ,Research Paper ,Biotechnology ,medicine.drug_class ,Cell Survival ,Mice, Nude ,Bioengineering ,Gefitinib ,Cell Line, Tumor ,Animals ,Humans ,Lung cancer ,Cell Proliferation ,Acrylamides ,business.industry ,Janus Kinase 1 ,medicine.disease ,Xenograft Model Antitumor Assays ,respiratory tract diseases ,Apoptosis ,Cancer research ,biology.protein ,Quinazolines ,business ,nsclc ,TP248.13-248.65 - Abstract
AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.
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- 2022
10. Hyaluronic acid-coated and Olaparib-loaded PEI − PLGA nanoparticles for the targeted therapy of triple negative breast cancer
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Wenting Ji, Tingting Wu, Kaiping Wang, Chen Shi, Zhang Yu, Hao Mei, Huiping Hu, and Zihao He
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Pharmaceutical Science ,Triple Negative Breast Neoplasms ,Bioengineering ,Caspase 3 ,Piperazines ,Flow cytometry ,Olaparib ,Mice ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,In vivo ,Cell Line, Tumor ,Hyaluronic acid ,medicine ,Animals ,Humans ,Hyaluronic Acid ,Physical and Theoretical Chemistry ,Cytotoxicity ,Drug Carriers ,biology ,medicine.diagnostic_test ,Chemistry ,Cytochrome c ,Organic Chemistry ,Drug delivery ,biology.protein ,Cancer research ,Nanoparticles ,Phthalazines - Abstract
AIM To prepare the hyaluronic acid-coated Olaparib-loaded PEI - PLGA nanoparticles (HA-Ola-PPNPs) and investigate their tumor-targeted anticancer effect. METHODS The synthesis of HA-Ola-PPNPs was verified by DLS, TEM and SEM, followed was measured its cytotoxicity using CCK-8 assay. Confocal microscopy was used to observe the cellular uptake. Cell apoptosis was analyzed by flow cytometry, biological SEM and TEM. The expression of related proteins within the tumor site was investigated by immunostaining. RESULTS The prepared HA-Ola-PPNPs showed diameter of ∼160 nm with negatively charged surface (-16.9 ± 2.7 mV) and sustained drug release behavior. And the encapsulation efficiency of HA-Ola-PPNPs was 78.63 ± 5.29%. HA-Ola-PPNPs exhibited efficient in vitro and in vivo antitumor activities. HA-Ola-PPNPs induced cell apoptosis by upregulating Bax, Cytochrome C and Caspase 3, downregulating Bcl-2 in breast cancer-bearing mice. CONCLUSIONS According to the results, the Ola-loaded and HA-coated PEI - PLGA nanoparticles could be considered as a powerful tumor-targeted drug delivery system for TNBC treatment.
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- 2021
11. Adherence, resistance, and viral suppression on dolutegravir in sub-Saharan Africa: implications for the TLD era
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Suzanne M. McCluskey, Ravindra K. Gupta, Andrew Hill, Mark J. Siedner, Toby Pepperrell, and Willem D F Venter
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medicine.medical_specialty ,Efavirenz ,Sub saharan ,Anti-HIV Agents ,Pyridones ,Immunology ,HIV Infections ,Article ,Piperazines ,chemistry.chemical_compound ,Oxazines ,medicine ,Humans ,Immunology and Allergy ,Viral suppression ,Intensive care medicine ,business.industry ,Antiretroviral therapy ,VIROLOGIC FAILURE ,Clinical trial ,Infectious Diseases ,chemistry ,Dolutegravir ,business ,Heterocyclic Compounds, 3-Ring ,HIV drug resistance - Abstract
Dolutegravir (DTG) is now a component of preferred first-line antiretroviral therapy (ART) worldwide. ADVANCE and NAMSAL were two landmark clinical trials conducted exclusively in sub-Saharan Africa, which studied the effectiveness of DTG-based first-line regimens for ART-naive individuals. In this review, we examine the data from these studies to consider the contributions of adherence and HIV drug resistance to treatment failure on DTG-based ART, as compared with efavirenz (EFV)-based ART, which has a lower genetic barrier to resistance. We also discuss the implications of virologic failure on DTG and consolidate currently available data to conclude with recommendations for virologic monitoring on DTG-based ART.
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- 2021
12. Cost and cost-effectiveness of dolutegravir-based antiretroviral regimens: an economic evaluation of a clinical trial
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Gesine Meyer-Rath, Lise Jamieson, Leigh F. Johnson, Celicia Serenata, Godspower Akpomiemie, Willem D F Venter, Simiso Sokhela, Lebogang Makhubele, and Nkuli Mashabane
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Oncology ,medicine.medical_specialty ,Efavirenz ,Anti-HIV Agents ,Pyridones ,Cost effectiveness ,Cost-Benefit Analysis ,Immunology ,HIV Infections ,Emtricitabine ,Tenofovir alafenamide ,Piperazines ,chemistry.chemical_compound ,Internal medicine ,Oxazines ,medicine ,Humans ,Immunology and Allergy ,Clinical Trials as Topic ,business.industry ,Clinical trial ,Regimen ,Infectious Diseases ,chemistry ,Dolutegravir ,Economic evaluation ,business ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
BACKGROUND HIV programmes world-wide currently make decisions regarding new antiretroviral therapy (ART) regimens with less side-effects and higher resistance barriers, which may improve adherence and viral suppression. Economic evaluation helps inform these decisions. METHODS We conducted an economic evaluation of three ART regimens included in the ADVANCE trial from the provider's perspective: tenofovir alafenamide (TAF)/emtricitabine (FTC)+dolutegravir (DTG) and tenofovir disoproxil fumarate (TDF)/FTC+DTG, compared with TDF/FTC/efavirenz (EFV). We used top-down and bottom-up cost analysis with resource utilization based on trial data and adjusted to emulate routine care. We estimated the cost-effectiveness of each regimen as cost per person virally suppressed or retained and per life-year saved, at 48 and 96 weeks. RESULTS Though the DTG-based trial arms were 2% more costly than TDF/FTC/EFV, both had slightly lower cost-per-outcome ($9783 and $9929/patient virally suppressed for TDF/FTC+DTG and TAF/FTC+DTG, respectively) than TDF/FTC/EFV ($10 365). The trial cost per additional virally suppressed patient, compared with TDF/FTC/EFV, was lower in the TDF/FTC+DTG arm ($2967) compared with TAF/FTC+DTG ($3430). In routine care, cost per virally suppressed patient was estimated as similar between TDF/FTC+DTG ($426) and TDF/FTC/EFV ($424) but more costly under TAF/FTC+DTG. Similar results were seen in the cost per additional person retained across scenarios. When modelled over 20 years, TDF/FTC+DTG was more cost-effective than TAF/FTC+DTG ($10 341 vs $41 958/life-year saved). CONCLUSION TDF/FTC+DTG had similar costs per outcome as TDF/FTC/EFV in the routine care scenario but TDF/FTC+DTG was more cost-effective when modelled over 20 years.
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- 2021
13. Body mass index increase and weight gain among people living with HIV-1 initiated on single-tablet darunavir/cobicistat/emtricitabine/tenofovir alafenamide or bictegravir/emtricitabine/tenofovir alafenamide in the United States
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Prina Donga, Bruno Emond, David E. Anderson, Marie-Hélène Lafeuille, Aurélie Côté-Sergent, Brahim Bookhart, Carmine Rossi, and Patrick Lefebvre
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Adult ,Oncology ,medicine.medical_specialty ,Anti-HIV Agents ,Pyridones ,HIV Infections ,Weight Gain ,Emtricitabine ,Tenofovir alafenamide ,Piperazines ,Body Mass Index ,Internal medicine ,medicine ,Humans ,Tenofovir ,Darunavir ,Alanine ,Bictegravir ,business.industry ,Cobicistat ,Hazard ratio ,General Medicine ,Middle Aged ,Amides ,United States ,HIV-1 ,Female ,medicine.symptom ,business ,Heterocyclic Compounds, 3-Ring ,Weight gain ,Body mass index ,Tablets ,medicine.drug - Abstract
OBJECTIVE This study evaluated body mass index (BMI) and weight changes in people living with human immunodeficiency virus (HIV-1; PLWH) initiated on single-tablet darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/FTC/TAF) or bictegravir/FTC/TAF (BIC/FTC/TAF). METHODS Electronic medical records (EMR) data for treatment-naive or virologically suppressed adults with HIV-1 who initiated treatment with DRV/c/FTC/TAF or BIC/FTC/TAF (index date) were obtained from Decision Resources Group's EMR (7/17/2017-3/1/2020). Inverse probability of treatment weighting was used to account for differences in baseline characteristics between the two cohorts. BMI and weight changes from pre-index to 3, 6, 9, and 12 months following the index date were compared using weighted mean differences (MDs). The time until an increase in BMI or weight ≥5% or ≥10% was compared using weighted hazard ratios (HRs). RESULTS The weighted DRV/c/FTC/TAF and BIC/FTC/TAF cohorts comprised 1,116 and 1,134 PLWH, respectively (mean age=∼49 years, females: ∼28%). Larger increases in BMI and weight from pre-index to each post-index time points were observed in PLWH initiating BIC/FTC/TAF vs DRV/c/FTC/TAF (12 months: MD in BMI =1.23 kg/m2, p
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- 2021
14. Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial
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Rebecca Dent, Sung-Bae Kim, Matthew Wongchenko, Nicholas C. Turner, Zbigniew Nowecki, Carlos H. Barrios, Igor Bondarenko, Shigehira Saji, Mafalda Oliveira, Steven J. Isakoff, Bruno Kovic, Joyce O'Shaughnessy, Heather Hinton, Sarah-Jayne Reilly, Qinshu Lian, Aruna Mani, Institut Català de la Salut, [Turner N] Breast Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK. [Dent RA] Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore. [O'Shaughnessy J] Department of Medical Oncology, Texas Oncology, Baylor University Medical Center, US Oncology, Dallas, TX, USA. [Kim SB] Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. [Isakoff SJ] Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA. [Barrios C] Latin American Cooperative Oncology Group, Oncology Research Service, Hospital São Lucas, PUCRS, Porto Alegre, RS, Brazil. [Oliveira M] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Cancer Research ,medicine.medical_specialty ,Paclitaxel ,Class I Phosphatidylinositol 3-Kinases ,Receptor, ErbB-2 ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,medicine.medical_treatment ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Breast Neoplasms ,Neutropenia ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores] ,Gastroenterology ,Piperazines ,Medicaments antineoplàstics - Efectes secundaris ,Phosphatidylinositol 3-Kinases ,Breast cancer ,Double-Blind Method ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Other subheadings::Other subheadings::/adverse effects [Other subheadings] ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Chemotherapy ,Taxane ,business.industry ,Hazard ratio ,PTEN Phosphohydrolase ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,medicine.disease ,Metastatic breast cancer ,Hormones ,Pyrimidines ,Oncology ,Mama - Càncer - Tractament ,Female ,Neoplasm Recurrence, Local ,business ,Proto-Oncogene Proteins c-akt - Abstract
Purpose PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). Methods Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse 2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results Overall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). Conclusion Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects. Trial registration NCT03337724.
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- 2021
15. Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer
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Neil K. Taunk, Andrew R. Barsky, K. Kim, Sana Dastgheyb, Gary M. Freedman, Payal D. Shah, Amy S. Clark, and Alexandra Dreyfuss
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Oncology ,medicine.medical_specialty ,Pyridines ,medicine.medical_treatment ,Aminopyridines ,Breast Neoplasms ,Palbociclib ,CDK4/6 inhibitor ,Piperazines ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,Humans ,Protein Kinase Inhibitors ,RC254-282 ,Retrospective Studies ,Radiotherapy ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cyclin-Dependent Kinase 4 ,Cancer ,Common Terminology Criteria for Adverse Events ,Retrospective cohort study ,Cyclin-Dependent Kinase 6 ,General Medicine ,Metastatic breast cancer ,medicine.disease ,Palliation ,Radiation therapy ,Toxicity ,Original Article ,Benzimidazoles ,Female ,Surgery ,Safety ,business - Abstract
Introduction Cyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition. Methods We conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging. Results Thirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8–40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months. Conclusions The use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer., Highlights • CDK4/6 inhibitors with endocrine therapy is a preferred first line therapy for HR+, HER2-metastatic breast cancer. • Limited data exists on safety of combined radiotherapy and CDK4/6 inhibition in patients with metastatic breast cancer. • This retrospective cohort study included 30 patients who underwent palliative RT with combined CDK4/6 inhibitor use. • RT within 2 weeks of CDK4/6 inhibitor had low toxicity and high efficacy, supporting its safety in metastatic breast cancer.
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- 2021
16. Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models
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Robert L. Coleman, Emine Bayraktar, Paola Amero, Cristina Ivan, Katelyn F. Handley, Cristian Rodriguez-Aguayo, Prahlad T. Ram, Deanna Glassman, Clifford Stephan, Anil K. Sood, Mark Seungwook Kim, Mary Sobieski, Elaine Stur, Nghi Nguyen, Shaolin Ma, Sujanitha Umamaheswaran, Yunfei Wen, Santosh K. Dasari, Reid T. Powell, Robiya Joseph, Yosef Landesman, and Shannon N. Westin
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Drug ,Cancer Research ,media_common.quotation_subject ,Poly ADP ribose polymerase ,Mice, Nude ,Article ,Piperazines ,Olaparib ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,media_common ,Ovarian Neoplasms ,business.industry ,Triazoles ,medicine.disease ,In vitro ,High-Throughput Screening Assays ,Disease Models, Animal ,Hydrazines ,Oncology ,chemistry ,Cell culture ,PARP inhibitor ,Cancer research ,Phthalazines ,Female ,Ovarian cancer ,business - Abstract
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
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- 2021
17. Palbociclib in combination with aromatase inhibitors in patients ≥ 75 years with oestrogen receptor-positive, human epidermal growth factor receptor 2 negative advanced breast cancer: A real-world multicentre UK study
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Richard Simcock, Yatri Shah, Thomas Pigott, Maung Maung Myat Moe, Simon Dixon, Alicja Synowiec, Pavel Bezecny, Bilal A Tahir, Kirsty Balachandran, Salma El Badri, Catherine Harper-Wynne, Marianna Theodoulou, Fiona Britton, Anna Stansfeld, Karen Desouza, Andrew Proctor, Anshu Wadhawan, M. Davies, Daniel Hills, Mark Verrill, and Caroline Wilson
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Oncology ,medicine.medical_specialty ,Pyridines ,Receptor, ErbB-2 ,Breast Neoplasms ,Palbociclib ,Neutropenia ,Piperazines ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Cost analysis ,Humans ,RC254-282 ,Aged ,Retrospective Studies ,Toxicity ,business.industry ,Aromatase Inhibitors ,Incidence (epidemiology) ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Retrospective cohort study ,General Medicine ,medicine.disease ,Frail elderly ,United Kingdom ,Tolerability ,Receptors, Estrogen ,Real-world ,Treatment efficacy ,Surgery ,Female ,Original Article ,business ,Febrile neutropenia - Abstract
Background Breast cancer incidence increases with age and real-world data is essential to guide prescribing practices in the older population. The aim of this study was to collect large scale real-world data on tolerability and efficacy of palbociclib + AI in the first line treatment of ER+/HER2-advanced breast cancer in those aged ≥75 years. Methods 14 cancer centres participated in this national UK retrospective study. Patients aged ≥75 years treated with palbociclib + AI in the first line setting were identified. Data included baseline demographics, disease characteristics, toxicities, dose reductions and delays, treatment response and survival data. Multivariable Cox regression was used to assess independent predictors of PFS, OS and toxicities. Results 276 patients met the eligibility criteria. The incidence of febrile neutropenia was low (2.2%). The clinical benefit rate was 87%. 50.7% of patients had dose reductions and 59.3% had dose delays. The 12- and 24- month PFS rates were 75.9% and 64.9%, respectively. The 12- and 24- month OS rates were 85.1% and 74.0%, respectively. Multivariable analysis identified PS, Age-adjusted Charlson Comorbidity Index (ACCI) and number of metastatic sites to be independent predictors of PFS. Dose reductions and delays were not associated with adverse survival outcomes. Baseline ACCI was an independent predictor of development and severity of neutropenia. Conclusion Palbociclib is an effective therapy in the real-world older population and is well-tolerated with low levels of clinically significant toxicities. The use of geriatric and frailty assessments can help guide decision making in these patients., Highlights • Palbociclib is a safe and effective treatment in patients ≥75 years. • Higher rates of treatment discontinuation and dose reductions were noted. • Dose delays and reductions were not associated with a worse survival outcome. • ACCI is a predictor of PFS and also for development and severity of neutropenia.
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- 2021
18. Recent advances in drug repurposing using machine learning
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Sean Ekins, Fabio L. Urbina, and Ana C. Puhl
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2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Antineoplastic Agents ,Disease ,Machine learning ,computer.software_genre ,Antiviral Agents ,Biochemistry ,Article ,Piperazines ,Analytical Chemistry ,Machine Learning ,Piperidines ,Alzheimer Disease ,Neoplasms ,Humans ,Medicine ,Clemastine ,Lenalidomide ,Protein Kinase Inhibitors ,Drug discovery ,business.industry ,Drug Repositioning ,Computational Biology ,Dipyridamole ,COVID-19 Drug Treatment ,Drug repositioning ,Neuroprotective Agents ,Artificial intelligence ,business ,computer ,Hydroxychloroquine - Abstract
Drug repurposing aims to find new uses for already existing and approved drugs. Normally this has occurred through serendipity while high throughput screening of FDA approved drug libraries has been responsible for increasing its popularity. Computational repurposing is a newer credible approach to drug discovery that has been steadily building a foundation with applications and examples of experimental validation. One particular area of computational repurposing is using machine learning. We now provide a brief overview of recent developments in drug repurposing using machine learning alongside other computational approaches for comparison. In addition, we will highlight several applications of computational drug repurposing using machine learning for cancer indications targeting kinase inhibitors, Alzheimer’s disease as well as COVID-19 from many different groups as well as our own. This overview should serve to rebalance the ‘repurposing hype’ of the past year, set expectations of what is possible as well as suggest areas for future development.
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- 2021
19. Evaluation of Erastin as a Therapeutic Agent Under Hypoxic Conditions in Pancreatic Cancer Cells
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Yukari Shida, Takaaki Kinoue, Hiroyuki Furuya, Satoshi Owada, Masayuki Tatemichi, and Hitoshi Endo
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Cancer Research ,Programmed cell death ,Cell Survival ,Antineoplastic Agents ,Apoptosis ,Piperazines ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Humans ,Viability assay ,Hypoxia ,Cytotoxicity ,Cell Proliferation ,chemistry.chemical_classification ,Reactive oxygen species ,General Medicine ,Hypoxia (medical) ,medicine.disease ,Cell Hypoxia ,Pancreatic Neoplasms ,Oncology ,chemistry ,Cancer research ,medicine.symptom ,Reactive Oxygen Species ,Oxidation-Reduction ,Intracellular - Abstract
Background/aim In pancreatic cancer tissues, hypoxic areas exist due to poor blood flow. Attenuation of the pharmacological efficacy of existing anticancer drugs in these hypoxic areas necessitates the search for novel anticancer compounds. We aimed to determine whether erastin exhibits anticancer effects in a hypoxic environment. Materials and methods Pancreatic cancer cell lines were subjected to cobalt chloride, a hypoxia-mimicking agent. Cell viability assay, measurement of reactive oxygen species, and western blotting analysis were conducted to investigate the efficacy of erastin under hypoxic environments. Results Erastin exhibited remarkable cytotoxicity and induced apoptosis under hypoxic conditions. Furthermore, erastin triggered the intracellular accumulation of reactive oxygen species in a hypoxic environment. Subsequent treatment with N-acetylcysteine, an antioxidant, markedly attenuated cytotoxicity, and apoptosis. Conclusion Erastin induces cell death by accumulation of intracellular reactive oxygen species and inducing apoptosis under hypoxic conditions, proving its potential for further development as a novel anticancer compound.
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- 2021
20. AZD4547 targets the FGFR/Akt/SOX2 axis to overcome paclitaxel resistance in head and neck cancer
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Michael Ittmann, Neslisah Barlak, Betul Gundogdu, Omer Faruk Karatas, Abdulmelik Aytatli, Hasan Onur Caglar, Arzu Tatar, and Fatma Sanli
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Cancer Research ,Paclitaxel ,Fibroblast growth factor ,Piperazines ,Phosphatidylinositol 3-Kinases ,stomatognathic system ,SOX2 ,Cell Line, Tumor ,medicine ,Humans ,Receptor ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Glycogen Synthase Kinase 3 beta ,Chemistry ,SOXB1 Transcription Factors ,General Medicine ,medicine.disease ,Receptors, Fibroblast Growth Factor ,Head and neck squamous-cell carcinoma ,stomatognathic diseases ,Oncology ,Drug Resistance, Neoplasm ,Head and Neck Neoplasms ,Fibroblast growth factor receptor ,Benzamides ,embryonic structures ,Cancer research ,Pyrazoles ,Molecular Medicine ,biological phenomena, cell phenomena, and immunity ,Stem cell ,Proto-Oncogene Proteins c-akt - Abstract
Development of chemoresistance is one of the major obstacles to the treatment of head and neck squamous cell carcinoma (HNSCC). The PI3K/Akt pathway, involved in drug resistance, has been found to be overactivated in > 90% of HNSCCs. Aberrant activation of the FGF receptors (FGFRs) has been reported to cause overactivation of the PI3K/Akt pathway and to be associated with the maintenance of stem cell features, which is controlled via SOX2 expression. In this study, we aimed at investigating the potential of using AZD4547, an orally bioavailable FGFR inhibitor, to overcome taxol-resistance by targeting the FGFR/Akt/SOX2 axis in HNSCC. We initially evaluated FGFR2 and SOX2 expression using in silico tools. We analyzed the FGFR/Akt/SOX2 axis in normal/tumor tissue pairs and in recombinant FGF2 treated HNSCC cells. Next, we explored the effects of AZD4547 alone and in combination with taxol on the proliferation, migration and colony forming capacities of parental/taxol-resistant cells using in vitro models. We found that the p-FGFR, p-AKT, p-GSK-3β and SOX2 expression levels were higher in tumor tissues than in its corresponding normal tissues, and that AZD4547 effectively suppressed the expression of FGFR and its downstream targets in recombinant FGF2 treated HNSCC cells. We also found that AZD4547 diminished the viability, migration and colony forming capacity of HNSCC cells, and that co-treatment with taxol potentiated the impact of taxol on these cells. Finally, we found that AZD4547 inhibited the overexpressed FGFR/Akt/SOX2 axis and profoundly suppressed cancer-related phenotypes in taxol-resistant HNSCC cells. From our data we conclude that AZD4547 may increase the impact of taxol during HNSCC treatment. We suggest AZD4547 as a therapeutic agent to overcome taxol-resistance.
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- 2021
21. Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer
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Lei Huang, Qian-Wen Lin, Shuping Wang, Qihua Zhu, Qin Sun, Yungen Xu, Shi-Qi Wu, Shi-Hui Huang, Ling-Li Gao, Liu-Qiong Meng, Yi Zou, and Yu Li
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DNA Repair ,DNA repair ,Poly ADP ribose polymerase ,Genes, BRCA1 ,Antineoplastic Agents ,Cell Cycle Proteins ,Poly(ADP-ribose) Polymerase Inhibitors ,medicine.disease_cause ,Piperazines ,Olaparib ,chemistry.chemical_compound ,PARP1 ,Breast cancer ,Pancreatic cancer ,Drug Discovery ,Autophagy ,medicine ,Humans ,Mutation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,chemistry ,Cancer research ,Phthalazines ,Molecular Medicine ,Rad51 Recombinase ,Homologous recombination ,DNA Damage ,Transcription Factors - Abstract
Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.
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- 2021
22. Real‐World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men
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Norihiko Oharu, Patrick Schnell, Keith D. Wilner, Jack Mardekian, Michelle Yu-Kite, Diane D. Wang, Jillian Motyl Rockland, Dongrui R. Lu, Todd VanArsdale, Jennifer M. Tursi, Albert L. Kraus, Cynthia Huang Bartlett, Matthew J. Cotter, Kenneth R. Carson, Jaclyn Decembrino, Sindy T. Kim, Anala Gossai, and Tamara Snow
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Databases, Factual ,Combination therapy ,Pyridines ,Antineoplastic Agents ,Pharmacy ,Kaplan-Meier Estimate ,Palbociclib ,Piperazines ,Breast Neoplasms, Male ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Electronic Health Records ,Humans ,Pharmacology (medical) ,Neoplasm Metastasis ,Aged ,Retrospective Studies ,Pharmacology ,Aromatase Inhibitors ,business.industry ,Letrozole ,Endocrine therapy ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,Confidence interval ,Clinical trial ,Observational Studies as Topic ,business ,Administrative Claims, Healthcare ,medicine.drug - Abstract
This report examined the benefits and risks of palbociclib plus endocrine therapy (ET) in men with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib was evaluated using three independent data sources: real-world data from pharmacy and medical claims, a de-identified real-world data source derived from electronic health records (EHRs), and a global safety database. From medical and pharmacy records, 1,139 men with MBC were identified; in the first-line setting, median duration of treatment was longer with palbociclib plus ET (n = 37, 8.5 months, 95% confidence interval (CI), 4.4-13.0) than ET alone (n = 214, 4.3 months, 95% CI, 3.0-5.7) and specifically, was longer with palbociclib plus letrozole (n = 26, 9.4 months, 95% CI, 4.4-14.0) than letrozole alone (n = 63, 3.0 months, 95% CI, 1.8-4.8). In the EHR-derived database, 59 men received treatment for MBC; real-world response across all lines of therapy in the metastatic setting was reported in 4 of 12 patients (33.3%) in the palbociclib plus ET group vs. 1 of 8 (12.5%) patients in the ET group. Review of the global safety database did not identify any new safety signals in palbociclib-treated men. Real-world data indicated that men with MBC benefit from palbociclib plus ET, with a safety profile consistent with previous observations in women with MBC. Collective data on palbociclib in women and men in this report, including clinical trial data, real-world data, and a well-established risk/benefit profile, led to US approval of an expansion of the palbociclib indication to include men with MBC.
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- 2021
23. High-Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Noncovalent Inhibitor
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Andre Merzky, Ryan Chard, Jurgen G. Schmidt, Zhuozhao Li, Srinivas C. Chennubhotla, Heng Ma, Li Tan, Mikhail Titov, Vlimos Kertesz, Austin Clyde, Daniel W. Kneller, Hyungro Lee, Alexander Brace, Rick Stevens, Darin Hauner, Leighton Coates, Shantenu Jha, Kyle Chard, Andrey Kovalevsky, Arvind Ramanathan, Thomas Brettin, Neeraj Kumar, Ben Blaiszik, Stephanie Galanie, Hubertus J. J. van Dam, Matteo Turilli, Martha S Head, Yadu Babuji, Ian Foster, and Anda Trifan
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General Chemical Engineering ,medicine.medical_treatment ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Context (language use) ,Computational biology ,Molecular Dynamics Simulation ,Library and Information Sciences ,medicine.disease_cause ,Antiviral Agents ,Article ,Piperazines ,medicine ,Humans ,Protease Inhibitors ,Binding site ,Coronavirus 3C Proteases ,Coronavirus ,Orotic Acid ,Virtual screening ,Protease ,SARS-CoV-2 ,Chemistry ,COVID-19 ,General Chemistry ,Ligand (biochemistry) ,Computer Science Applications ,Molecular Docking Simulation ,Docking (molecular) - Abstract
Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel noncovalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro inhibitor with an inhibition constant (Ki) of 2.9 μM (95% CI 2.2, 4.0). Furthermore, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mpro forming stable hydrogen bond and hydrophobic interactions. We then used multiple μs-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro and offers a springboard for further therapeutic design.
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- 2021
24. Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis
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Jifang Tu, Jinghan Wang, Yungui Wang, Min Yang, Jiansong Huang, Wenle Ye, Xin Huang, Fenglin Li, Daqiang He, Xia Li, Huanping Wang, Xiangjie Lin, Yang Li, Jie Jin, and Xiao Yan
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Blood Platelets ,Acrylamides ,biology ,Chemistry ,Megakaryocyte differentiation ,Janus kinase 3 ,Cell Differentiation ,General Medicine ,Piperazines ,Cell biology ,Mice, Inbred C57BL ,Mice ,Haematopoiesis ,Pyrimidines ,medicine.anatomical_structure ,Megakaryocyte ,medicine ,biology.protein ,Animals ,Bruton's tyrosine kinase ,Thrombopoiesis ,Megakaryocytes ,Tyrosine kinase ,Megakaryopoiesis - Abstract
Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton’s tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.
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- 2021
25. The Sigma‐2 Receptor/TMEM97 Agonist PB28 Suppresses Cell Proliferation and Invasion by Regulating the PI3K‐AKT‐mTOR Signalling Pathway in Renal Cancer
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Yuanjun Jiang, Xiao Dong, Bo Zhan, Chiyuan Piao, Chuize Kong, Yang Du, and Zhe Zhang
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medicine.drug_class ,Drug Resistance ,Sigma-2 receptor ,PI3K‐AKT‐mTOR pathway ,Piperazines ,Mice ,Phosphatidylinositol 3-Kinases ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptors, sigma ,Receptor ,Carcinoma, Renal Cell ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Dose-Response Relationship, Drug ,Chemistry ,Cell growth ,TOR Serine-Threonine Kinases ,EMT ,Membrane Proteins ,Cancer ,Original Articles ,Cell Biology ,Receptor antagonist ,medicine.disease ,Xenograft Model Antitumor Assays ,Sigma‐2/TMEM97 ,Disease Models, Animal ,Renal cancer ,PB28 ,Cancer cell ,Cancer research ,Molecular Medicine ,Original Article ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Sigma‐2 receptor/TMEM97 is overexpressed in many tumours, and sigma‐2 receptor ligands are under investigation for cancer therapy. We intended to evaluate the effect of PB28 on renal cancer in proliferation, migration and invasion in vitro and in vivo. Invasive renal cancer cell lines treated with PB28 (or sigma‐2 receptor antagonist 1) were subjected to cell proliferation, migration and invasion assays. The therapeutic effect of PB28 was performed on nude mice. Western blot for proteins in the PI3K‐AKT‐mTOR signalling pathway was conducted. A CCK‐8 assay was used to examine the effect of the combination of PB28 and cisplatin on renal cancer cells. Significant inhibitory effects were observed on proliferation, migration and invasion of 786‐O and ACHN cells after culturing with PB28. But, the outcomes of sigma‐2 receptor antagonist 1 presented the opposite tendency. PB28 significantly inhibited the proliferative and invasive ability of OS‐RC‐2 cells in vivo. Treatment resulted in decreased phosphorylation of constituents of the PI3K‐AKT‐mTOR pathway. The combination of PB28 and cisplatin showed enhanced efficacy in the inhibition of renal cancer cell proliferation. Taken together, PB28 inhibited the tumorigenic behaviours of renal cancer cells by regulating the PI3K‐AKT‐mTOR signalling pathway and was expected to be a sensitizer of cisplatin.
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- 2021
26. Diverse alterations associated with resistance to KRAS(G12C) inhibition
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Chuanchuan Li, Britta Weigelt, Mark Li, Elisa de Stanchina, Yonina R. Murciano-Goroff, Kanika Arora, Lee P. Lim, Jorge S. Reis-Filho, Jenny Y. Xue, Dongsung Kim, Rohan S. Roy, Yulei Zhao, Michael F. Berger, Amber Bahr, Ann E. Sisk, Brian Loomis, Deanna Mohn, Pragathi Achanta, Trang Thi Mai, Agnes Ang, Bob T. Li, Arnaud Da Cruz Paula, Gregory J. Riely, Kathryn C. Arbour, Jessica Lucas, Piro Lito, J. Russell Lipford, and Anne Y. Saiki
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Proto-Oncogene Proteins B-raf ,MAPK/ERK pathway ,Neuroblastoma RAS viral oncogene homolog ,Acetonitriles ,Lineage (genetic) ,endocrine system diseases ,MAP Kinase Signaling System ,Pyridines ,Mutant ,Antineoplastic Agents ,Biology ,medicine.disease_cause ,Article ,Piperazines ,Cell Line ,GTP Phosphohydrolases ,Cohort Studies ,Proto-Oncogene Proteins p21(ras) ,Mice ,Carcinoma, Non-Small-Cell Lung ,Neoplasms ,medicine ,Animals ,Humans ,Extracellular Signal-Regulated MAP Kinases ,neoplasms ,Gene ,Allele frequency ,Multidisciplinary ,Membrane Proteins ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,Pyrimidines ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,Female ,KRAS - Abstract
Inactive state-selective KRAS(G12C) inhibitors1–8 demonstrate a 30–40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials. Multiple treatment-emergent alterations appear in patients with advanced-stage cancer who were treated with a KRAS inhibitor.
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- 2021
27. Permeabilized Cryopreserved Human Hepatocytes as an Exogenous Metabolic System in a Novel Metabolism-Dependent Cytotoxicity Assay for the Evaluation of Metabolic Activation and Detoxification of Drugs Associated with Drug-Induced Liver Injuries: Results with Acetaminophen, Amiodarone, Cyclophosphamide, Ketoconazole, Nefazodone, and Troglitazone
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Hong Wei and Albert P. Li
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Drug ,media_common.quotation_subject ,Amiodarone ,Pharmaceutical Science ,Pharmacology ,Piperazines ,Activation, Metabolic ,Troglitazone ,Cytochrome P-450 Enzyme System ,Detoxification ,medicine ,Humans ,Cyclophosphamide ,Acetaminophen ,media_common ,Chemistry ,Triazoles ,Glutathione ,HEK293 Cells ,Ketoconazole ,Drug development ,Toxicity ,Hepatocytes ,Chemical and Drug Induced Liver Injury ,Drug metabolism ,medicine.drug - Abstract
We report here a novel in vitro experimental system, the metabolism-dependent cytotoxicity assay (MDCA), for the definition of the roles of hepatic drug metabolism in toxicity. MDCA employs permeabilized cofactor-supplemented cryopreserved human hepatocytes (MetMax Human Hepatocytes, MMHH), as an exogenous metabolic activating system, and human embryonic kidney 293 (HEK293) cells, a cell line devoid of drug-metabolizing enzyme activity, as target cells for the quantification of drug toxicity. The assay was performed in the presence and absence of cofactors for key drug metabolism pathways known to play key roles in drug toxicity: NADPH/NAD+ for phase 1 oxidation, uridine 5'-diphosphoglucuronic acid (UDPGA) for uridine 5'-diphospho-glucuronosyltransferase (UGT) mediated glucuronidation, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for cytosolic sulfotransferase (SULT) mediated sulfation, and glutathione (GSH) for glutathione S-transferase (GST) mediated GSH conjugation. Six drugs with clinically significant hepatoxicity, resulting in liver failure or a need for liver transplantation: acetaminophen, amiodarone, cyclophosphamide, ketoconazole, nefazodone, and troglitazone were evaluated. All six drugs exhibited cytotoxicity enhancement by NADPH/NAD+, suggesting metabolic activation via phase 1 oxidation. Attenuation of cytotoxicity by UDPGA was observed for acetaminophen, ketoconazole, and troglitazone, by PAPS for acetaminophen, ketoconazole, and troglitazone, and by GSH for all six drugs. Our results suggest that MDCA can be applied toward the elucidation of metabolic activation and detoxification pathways, providing information that can be applied in drug development to guide structure optimization to reduce toxicity and to aid the assessment of metabolism-based risk factors for drug toxicity. GSH detoxification represents an endpoint for the identification of drugs forming cytotoxic reactive metabolites, a key property of drugs with idiosyncratic hepatotoxicity. SIGNIFICANCE STATEMENT: Application of the metabolism-dependent cytotoxicity assay (MDCA) for the elucidation of the roles of metabolic activation and detoxification pathways in drug toxicity may provide information to guide structure optimization in drug development to reduce hepatotoxic potential and to aid the assessment of metabolism-based risk factors. Glutathione (GSH) detoxification represents an endpoint for the identification of drugs forming cytotoxic reactive metabolites that may be applied toward the evaluation of idiosyncratic hepatotoxicity.
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- 2021
28. Ferroptosis Promotes Cyst Growth in Autosomal Dominant Polycystic Kidney Disease Mouse Models
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Linda Xiaoyan Li, Chen Yu, Xiaogang Li, Xiaoqin Zhang, Hao Ding, and Vicente E. Torres
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Male ,Programmed cell death ,TRPP Cation Channels ,Iron ,Ferroportin ,Autosomal dominant polycystic kidney disease ,Phenylenediamines ,urologic and male genital diseases ,GPX4 ,Piperazines ,Mice ,Spheroids, Cellular ,medicine ,Animals ,Ferroptosis ,Humans ,Cells, Cultured ,Mice, Knockout ,Cyclohexylamines ,Mice, Inbred BALB C ,Kidney ,biology ,PKD1 ,Cell Cycle ,Autophagy ,Epithelial Cells ,Lipid metabolism ,General Medicine ,Polycystic Kidney, Autosomal Dominant ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Basic Research ,medicine.anatomical_structure ,Gene Expression Regulation ,Nephrology ,Disease Progression ,biology.protein ,Cancer research ,Female ,RNA Interference ,Lipid Peroxidation ,Transcriptome - Abstract
Background Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, is regulated by different forms of cell death, including apoptosis and autophagy. However, the role in ADPKD of ferroptosis, a recently discovered form of cell death mediated by iron and lipid metabolism, remains elusive. Methods To determine a pathophysiologic role of ferroptosis in ADPKD, we investigated whether the absence of Pkd1 (encoding polycystin-1) affected the expression of key factors involved in the process of ferroptosis, using Western blot and qRT-PCR analysis in Pkd1 mutant renal cells and tissues. We also examined whether treatment with erastin, a ferroptosis inducer, and ferrostain-1, a ferroptosis inhibitor, affected cyst growth in Pkd1 mutant mouse models. Results We found that kidney cells and tissues lacking Pkd1 exhibit extensive metabolic abnormalities, including reduced expression of the system Xc- amino acid antiporter (critical for import of cystine), of iron exporter (ferroportin), and of GPX4 (a key and negative regulator of ferroptosis). The abnormalities also include increased expression of iron importers (TfR1, DMT1) and HO-1, which in turn result in high iron levels, low GSH and GPX4 activity, increased lipid peroxidation, and propensity to ferroptosis. We further found that erastin increased, and ferrostatin-1 inhibited ferroptotic cell death and proliferation of Pkd1-deficient cells in kidneys from Pkd1 mutant mice. A lipid peroxidation product increased in Pkd1-deficient cells, 4HNE, promoted the proliferation of survived Pkd1 mutant cells via activation of Akt, S6, Stat3, and Rb during the ferroptotic process, contributing to cyst growth. Conclusion These findings indicate that ferroptosis contributes to ADPKD progression and management of ferroptosis may be a novel strategy for ADPKD treatment.
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- 2021
29. Synthesis, Biological Evaluation, and QPLD Studies of Piperazine Derivatives as Potential DPP-IV Inhibitors
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Tariq Al-Qirim, Reema Abu Khalaf, Haya Abu Jarad, and Dima A. Sabbah
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Blood Glucose ,Male ,Dipeptidyl Peptidase 4 ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Incretin ,Pharmacology ,Crystallography, X-Ray ,Ligands ,Piperazines ,Diabetes Mellitus, Experimental ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Diabetes mellitus ,Drug Discovery ,medicine ,Animals ,Dipeptidyl-Peptidase IV Inhibitors ,Mice, Inbred BALB C ,Binding Sites ,Insulin ,Streptozotocin ,medicine.disease ,In vitro ,Molecular Docking Simulation ,Piperazine ,chemistry ,Docking (molecular) ,Hyperglycemia ,medicine.drug - Abstract
Background: Diabetes mellitus is a serious global health issue, currently affecting 425 million people and is set to affect over 690 million people by 2045. It is a chronic disease characterized by hyperglycemia due to relative or absolute insulin hormone deficiency. Dipeptidyl peptidase- IV (DPP-IV) inhibitors are hypoglycemic agents augmenting the action of the incretin hormones that stimulate insulin secretion from the pancreatic beta cells. Objectives: In this study, synthesis and biological evaluation of seven piperazine derivatives 3a-g was carried out. Methods: The synthesized molecules were characterized using proton-nuclear magnetic resonance, carbon-nuclear magnetic resonance, infrared spectroscopy and mass spectrometry. Results: In vitro biological evaluation study showed comparable DPP-IV inhibitory activity for the targeted compounds ranging from 19%-30% at 100 μM concentration. Furthermore, the in vivo hypoglycemic activity of 3d was evaluated using streptozotocin-induced diabetic mice. It was found that compound 3d significantly decreased the blood glucose level when the diabetic group treated with 3d was compared to the control diabetic group. Quantum–Polarized Ligand Docking (QPLD) studies demonstrate that 3a-g fit the binding site of DPP-IV enzyme and form H-bonding with the backbones of R125, E205, E206, K554, W629, Y631, Y662, R669, and Y752. Conclusion: Piperazine derivatives were successfully found to be new scaffolds as potential DPP-IV inhibitors.
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- 2021
30. Population-adjusted indirect treatment comparison of the SOLO1 and PAOLA-1/ENGOT-ov25 trials evaluating maintenance olaparib or bevacizumab or the combination of both in newly diagnosed, advanced BRCA-mutated ovarian cancer
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Guilherme Cantuaria, Paul DiSilvestro, Kirsty Rhodes, Lucy Gilbert, Johanna Mäenpää, Christian Marth, Maria Jesus Rubio Pérez, Koji Matsumoto, Claire Garnier-Tixidre, Ayumi Shikama, Isabelle Ray-Coquard, Philipp Harter, Daniel M. Anderson, Magdalena Sikorska, Francesco Raspagliesi, Ignace Vergote, Mario Ouwens, Robert Hettle, Domenica Lorusso, Kathleen N. Moore, Andres Poveda, Nicoletta Colombo, Ronnie Shapira-Frommer, Vergote, I, Ray-Coquard, I, Anderson, D, Cantuaria, G, Colombo, N, Garnier-Tixidre, C, Gilbert, L, Harter, P, Hettle, R, Lorusso, D, Maenpaa, J, Marth, C, Matsumoto, K, Ouwens, M, Poveda, A, Raspagliesi, F, Rhodes, K, Rubio Perez, M, Shapira-Frommer, R, Shikama, A, Sikorska, M, Moore, K, Disilvestro, P, Tampere University, Clinical Medicine, and Department of Gynaecology and Obstetrics
- Subjects
Oncology ,Cancer Research ,Piperazines ,Placebos ,chemistry.chemical_compound ,Olaparib ,Maintenance therapy ,3123 Gynaecology and paediatrics ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Ovarian Neoplasms ,education.field_of_study ,BRCA1 Protein ,BRCA mutation ,Hazard ratio ,Middle Aged ,Newly diagnosed ,Progression-Free Survival ,Bevacizumab ,Female ,Life Sciences & Biomedicine ,medicine.drug ,medicine.medical_specialty ,3122 Cancers ,Population ,Poly(ADP-ribose) Polymerase Inhibitors ,Placebo ,Maintenance Chemotherapy ,Double-Blind Method ,Ovarian cancer ,Internal medicine ,Humans ,education ,Response Evaluation Criteria in Solid Tumors ,Aged ,Neoplasm Staging ,BRCA2 Protein ,Science & Technology ,business.industry ,medicine.disease ,chemistry ,Mutation ,Phthalazines ,business ,Follow-Up Studies - Abstract
BACKGROUND: In the absence of randomised head-to-head trials, we conducted a population-adjusted indirect treatment comparison (PA-ITC) of phase III trial data to evaluate the relative efficacy and safety of maintenance olaparib and bevacizumab alone and in combination in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation (BRCAm). METHODS: An unanchored PA-ITC was performed on investigator-assessed progression-free survival (PFS) data. Individual patient data from SOLO1 (olaparib versus placebo) and from BRCA-mutated patients in PAOLA-1/ENGOT-ov25 (olaparib plus bevacizumab versus placebo plus bevacizumab) were pooled. Each arm of PAOLA-1 was weighted so that key baseline patient characteristics were similar to the SOLO1 cohort. Analyses were performed in patients with complete baseline data. Weighted Cox regression analysis was used to estimate the comparative efficacy of different maintenance therapy strategies, supplemented by weighted Kaplan-Meier analyses. RESULTS: Data from SOLO1 patients (olaparib, n = 254; placebo, n = 126) were compared with data from BRCA-mutated PAOLA-1 patients (olaparib plus bevacizumab, n = 151; placebo plus bevacizumab, n = 71). Adding bevacizumab to olaparib was associated with a numerical improvement in PFS compared with olaparib alone (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.45-1.09). Statistically significant improvements in PFS were seen with olaparib alone versus placebo plus bevacizumab (HR 0.48; 95% CI 0.30-0.75), olaparib plus bevacizumab versus placebo (0.23; 0.14-0.34), and placebo plus bevacizumab versus placebo (0.65; 0.43-0.95). CONCLUSIONS: Results of this hypothesis-generating PA-ITC analysis support the use of maintenance olaparib alone or with bevacizumab in patients with newly diagnosed, advanced ovarian cancer and a BRCAm. ispartof: EUROPEAN JOURNAL OF CANCER vol:157 pages:415-423 ispartof: location:England status: published
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- 2021
31. Safety but Limited Efficacy of Ensartinib in ROS1-Positive NSCLC: A Single-Arm, Multicenter Phase 2 Study
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Cheng Huang, Yang Wang, Yan Wang, Xiaoqing Liu, Tao Wang, Jianhua Chen, Xinghao Ai, Jiuwei Cui, Yun Fan, Helong Zhang, Shun Lu, Hongke Cheng, Lieming Ding, Jianying Zhou, Xiaorong Dong, Beili Gao, Ziping Wang, Cuimin Ding, Qiming Wang, Lejie Cao, Gongyan Chen, Xiaobin Yuan, Xingya Li, and Ying Cheng
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Lung Neoplasms ,business.industry ,Incidence (epidemiology) ,Phases of clinical research ,Protein-Tyrosine Kinases ,Rash ,Piperazines ,Confidence interval ,Pyridazines ,Oncology ,Response Evaluation Criteria in Solid Tumors ,Proto-Oncogene Proteins ,Internal medicine ,Concomitant ,Clinical endpoint ,Humans ,Medicine ,medicine.symptom ,business ,Adverse effect ,Protein Kinase Inhibitors - Abstract
Introduction Some ALK inhibitors with good inhibition of ROS1 in preclinical studies have been reported to be possibly beneficial in ROS1-positive NSCLC. In this work, we studied the efficacy and safety of ensartinib in the treatment of patients with ROS1-positive NSCLC. Methods The exploratory study was a phase 2, single-arm, multicenter design (NCT03608007). Patients with ROS1-positive NSCLC with a previous chemotherapy line number of less than or equal to 1 who received ensartinib at the dose of 225 mg once daily were enrolled. The primary end point was objective response rate evaluated by an investigator per Response Evaluation Criteria in Solid Tumors version 1.1. Results From June 2018 to July 2019, a total of 59 patients were enrolled at 23 centers in the People’s Republic of China. At the time of data cutoff, the median follow-up was 19.8 months (range: 0.8–22.5). The median objective response rate was 27.0 % (95 % confidence interval [CI]: 13.8–44.1) with 10 partial responses. Median duration of response was 4.8 months (95 % CI: 1.8–10.8). The median progression-free survival was 4.6 months (95 % CI: 4.0–6.4). The median overall survival was not estimable (95 % CI: 14.9–not estimable). Of four patients with brain metastases, intracranial disease control was reported in three (75.0 %, 95 % CI: 19.4–99.4). The most common treatment-related adverse events (TRAEs) were rash and liver enzyme abnormalities, with good prognosis after adjustment for dosage and concomitant medication. Most of the TRAEs were of grades 1 to 2, and incidence of grade greater than or equal to 3 TRAEs was 25.4 %. Conclusions Ensartinib had a modest efficacy in patients with ROS1-positive NSCLC with an acceptable safety profile.
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- 2021
32. Five Years With Dolutegravir Plus Lamivudine as a Switch Strategy: Much More Than a Positive Finding
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Andrea Giacometti, Gabriella d'Ettorre, Amedeo Capetti, William Gennari, Stefano Rusconi, Gaetana Sterrantino, Andrea Giacomelli, Vanni Borghi, Gianmaria Baldin, Alessandra Latini, Andrea De Vito, Cristina Mussini, Arturo Ciccullo, Simona Di Giambenedetto, Giordano Madeddu, and Maria Vittoria Cossu
- Subjects
Male ,medicine.medical_specialty ,HAART ,Anti-HIV Agents ,Pyridones ,HIV Infections ,3-Ring ,Settore MED/17 - MALATTIE INFETTIVE ,Piperazines ,chemistry.chemical_compound ,Heterocyclic Compounds ,Interquartile range ,Internal medicine ,HIV Seropositivity ,Oxazines ,medicine ,Humans ,Pharmacology (medical) ,Survival analysis ,Retrospective Studies ,business.industry ,HIV ,Lamivudine ,Retrospective cohort study ,Middle Aged ,dolutegravir ,Discontinuation ,Regimen ,Infectious Diseases ,Tolerability ,chemistry ,Dolutegravir ,RNA ,Female ,business ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
BACKGROUND Results from clinical trials and observational studies suggest that dolutegravir plus lamivudine could be an effective and well-tolerated option for simplification in HIV-1-positive patients. We aimed to assess long-time efficacy and safety in our multicenter cohort. METHODS This was a retrospective study enrolling HIV-1-infected, virologically suppressed patients switching to dolutegravir + lamivudine. We performed survival analysis to evaluate time to virological failure (VF, defined by a single HIV-RNA ≥1000 copies/mL or by 2 consecutive HIV-RNA ≥ 50 copies/mL) and treatment discontinuation (defined as the interruption of either 3TC or dolutegravir), assessing predictors via Cox regression analyses. RESULTS Seven-hundred eighty-five patients were considered for the analysis: 554 were men (70.6%), with a median age of 52 years (interquartile range 45-58 years). Estimated probabilities of maintaining virological suppression at weeks 96, 144, and 240 were 97.7% (SD ±0.6), 96.9% (SD ±0.8), and 96.4% (SD ±0.9), respectively. A non-B HIV subtype (P = 0.014) and a previous VF (P = 0.037) resulted predictors of VF. We did not observe differences in probability of VF in people living with HIV with an M184V resistance mutation (P = 0.689); however, in a deeper analysis, M184V mutation was a predictor of VF (P = 0.038) in patients with time of virological suppression
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- 2021
33. Patient experiences of switching from Efavirenz- to Dolutegravir-based antiretroviral therapy: a qualitative study in Uganda
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Andrew Mujugira, Agnes N. Kiragga, Anne Katahoire, Mohammed Lamorde, Miriam Laker, Henry Onen, Mari Armstrong-Hough, Noela Owarwo, Florence Ajok, Kay Seden, Barbara Castelnuovo, Adelline Twimukye, Eva Agnes Laker Odongpiny, Ivan Kalule, and Phoebe Kajubi
- Subjects
Adult ,Cyclopropanes ,medicine.medical_specialty ,Efavirenz ,Anti-HIV Agents ,Pyridones ,HIV Infections ,Infectious and parasitic diseases ,RC109-216 ,Piperazines ,chemistry.chemical_compound ,Interquartile range ,Qualitative research ,Oxazines ,medicine ,Humans ,Uganda ,Medical prescription ,Adverse effect ,business.industry ,Research ,HIV ,Benzoxazines ,Patient Outcome Assessment ,Regimen ,Infectious Diseases ,Drug switching ,chemistry ,Dolutegravir ,Alkynes ,Pill ,Family medicine ,Anxiety ,Female ,medicine.symptom ,business ,Heterocyclic Compounds, 3-Ring - Abstract
Background In 2019, the World Health Organisation (WHO) recommended Dolutegravir (DTG) as the preferred first-line antiretroviral treatment (ART) for all persons with HIV. ART regimen switches may affect HIV treatment adherence. We sought to describe patient experiences switching from EFV to DTG-based ART in Kampala, Uganda. Methods Between July and September 2019, we purposively sampled adults living with HIV who had switched to DTG at the Infectious Diseases Institute HIV clinic. We conducted in-depth interviews with adults who switched to DTG, to explore their preparation to switch and experiences on DTG. Interviews were audio-recorded, transcribed and analysed thematically using Atlas ti version 8 software. Results We interviewed 25 adults: 18 (72%) were women, and the median age was 35 years (interquartile range [IQR] 30–40). Median length on ART before switching to DTG was 67 months (IQR 51–125). Duration on DTG after switching was 16 months (IQR 10–18). Participants reported accepting provider recommendations to switch to DTG mainly because they anticipated that swallowing a smaller pill once a day would be more convenient. While most participants initially felt uncertain about drug switching, their providers offer of frequent appointments and a toll-free number to call in the event of side effects allayed their anxiety. At the same time, participants said they felt rushed to switch to the new ART regimen considering that they had been on their previous regimen(s) for several years and the switch to DTG happened during a routine visit when they had expected their regular prescription. Some participants felt unprepared for new adverse events associated with DTG and for the abrupt change in treatment schedule. Most participants said they needed additional support from their health providers before and after switching to DTG. Conclusion and recommendations Adults living with HIV stable on an EFV-based regimen but were switched to DTG in a program-wide policy change found the duration between counselling and drug switching inadequate. DTG was nonetheless largely preferred because of the small pill size, once daily dosing, and absence of EFV-like side effects. Community-engaged research is needed to devise acceptable ways to prepare participants for switching ART at scale.
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- 2021
34. Lack of a Clinically Meaningful Drug Interaction Between the HIV‐1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate
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Danielle Armas, Sabrina Fox-Bosetti, Saijuan Zhang, Deanne Jackson Rudd, Evan J. Friedman, Randolph P. Matthews, Kerry L. Fillgrove, S. Aubrey Stoch, and Marian Iwamoto
- Subjects
Adult ,Pyridones ,Pharmaceutical Science ,Pharmacology ,Piperazines ,law.invention ,chemistry.chemical_compound ,ANTIRETROVIRAL AGENTS ,Acquired immunodeficiency syndrome (AIDS) ,Pharmacokinetics ,law ,Oxazines ,Humans ,Medicine ,Drug Interactions ,Pharmacology (medical) ,Tenofovir ,Clinical pharmacology ,Deoxyadenosines ,business.industry ,Drug interaction ,medicine.disease ,Clinical trial ,Anti-Retroviral Agents ,Tolerability ,chemistry ,Dolutegravir ,HIV-1 ,business ,Heterocyclic Compounds, 3-Ring - Abstract
Islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, is in clinical development for the treatment and prevention of HIV-1 infection. Because islatravir may be coadministered with other antiretroviral agents, assessment of potential drug-drug interactions are warranted. This phase 1, open-label, fixed-sequence, 2-period trial in adults without HIV (N = 12) assessed the safety and pharmacokinetic interactions of islatravir administered with dolutegravir and tenofovir disoproxil fumarate (TDF). In period 1, participants received a single oral dose of islatravir (20 mg). In period 2, participants received oral doses of dolutegravir (50 mg) and TDF (300 mg) once daily on days 1 through 11, with a single oral dose of islatravir (20 mg) coadministered on day 8. There were no clinically significant changes in islatravir, dolutegravir, or TDF pharmacokinetics following coadministration. Islatravir was generally well tolerated when administered alone or in combination with dolutegravir and TDF. Coadministration of islatravir, dolutegravir, and TDF is supported, with no clinically meaningful effect on pharmacokinetics, safety, or tolerability in participants without HIV.
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- 2021
35. Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma
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Harold N. Keer, John Lyons, Joanne M. Munck, Harpreet K Saini, George Ward, Nicola Ferrari, Roberta Ferraldeschi, Martin Sims, Simone Jueliger, Christina Gewinner, Tomoko Smyth, and Matthew Davis
- Subjects
Programmed cell death ,Skin Neoplasms ,business.industry ,Morpholines ,Immunity ,Apoptosis ,Hematology ,Lymphoma, T-Cell ,Inhibitor of apoptosis ,medicine.disease ,Piperazines ,In vitro ,Immune system ,Mechanism of action ,In vivo ,Cancer research ,Humans ,Medicine ,T-cell lymphoma ,Pyrroles ,Neoplasm Recurrence, Local ,medicine.symptom ,business - Abstract
Tolinapant (ASTX660) is a potent, nonpeptidomimetic antagonist of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) and X-linked IAP, which is currently being evaluated in a phase 2 study in T-cell lymphoma (TCL) patients. Tolinapant has demonstrated evidence of single-agent clinical activity in relapsed/refractory peripheral TCL and cutaneous TCL. To investigate the mechanism of action underlying the single-agent activity observed in the clinic, we have used a comprehensive translational approach integrating in vitro and in vivo models of TCL confirmed by data from human tumor biopsies. Here, we show that tolinapant acts as an efficacious immunomodulatory molecule capable of inducing complete tumor regression in a syngeneic model of TCL exclusively in the presence of an intact immune system. These findings were confirmed in samples from our ongoing clinical study showing that tolinapant treatment can induce changes in gene expression and cytokine profile consistent with immune modulation. Mechanistically, we show that tolinapant can activate both the adaptive and the innate arms of the immune system through the induction of immunogenic forms of cell death. In summary, we describe a novel role for IAP antagonists as immunomodulatory molecules capable of promoting a robust antitumor immune response in TCL.
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- 2021
36. Polyphyllin I, a lethal partner of Palbociclib, suppresses non-small cell lung cancer through activation of p21/CDK2/Rb pathway in vitro and in vivo
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Zhiwei Zhang, Aixue Zuo, Jihong Shen, Zhengchao Shen, Qingyu Zhang, Xuhua Li, Rong Chen, Enli Cai, Kunbin Ke, Xinan Shi, Hao Fu, Weiping Wan, Rongping Zhang, Jian Wang, Na Song, and Xingxing Xie
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Lung Neoplasms ,Pyridines ,Antineoplastic Agents ,Diosgenin ,Palbociclib ,Retinoblastoma Protein ,Piperazines ,In vivo ,Cyclin-dependent kinase ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Lung cancer ,Molecular Biology ,biology ,Kinase ,Cyclin-Dependent Kinase 2 ,Cyclin-Dependent Kinase 4 ,Cancer ,Cell Biology ,medicine.disease ,Apoptosis ,Cancer cell ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Research Paper ,Signal Transduction ,Developmental Biology - Abstract
Cyclin-dependent kinases (CDKs) are hyperactive in many cancers and have served as cancer therapeutic targets for decades. Palbociclib (Palb) is the first approved CDK4/6 inhibitor to treat hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Acquired drug resistance is one obstacle of Palb be utilized in other cancer. CDK2 compensation of CDK4/6 loss is one of the causes that cancer cells are resistant to Palb. Hence, targeting multiple CDKs could be a novel strategy to prevent the drug resistance of cancer cells and expand the application of Palb in other cancer. In this study, we initially indicated Polyphyllin I (PPI) significantly inhibits non-small lung cancer cell (NSCLC) proliferation, promotes cell apoptosis in vitro and in vivo. Mechanistically, PPI can inhibit Rb through the p21/CDK2/Rb signaling pathway in NSCLC. A combination of PPI and Palb exerts a significant synergistic anti-cancer ability on NSCLC. Of note, PPI can reverse Palb drug resistance. Herein, we first time demonstrated PPI can disturb CDK2 function through upregulation of p21. The PPI effect on CDK2 provides a choice for a chemotherapeutic strategy for the elimination of NSCLC. Our study highlighted the clinical significance of simultaneously blocking of CDK2 and CDK4/6 for NSCLC treatment.
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- 2021
37. Dual Akt and Bcl-2 inhibition induces cell-type specific modulation of apoptotic and autophagic signaling in castration resistant prostate cancer cell lines
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Ferda Kaleağasıoğlu, Fikrettin Şahin, Duygu Turan, Martin R. Berger, Hüseyin Abdik, Ezgi Avşar Abdik, İstinye Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, and Kaleagasioglu, Ferda
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Male ,EXPRESSION ,CROSSTALK ,Antineoplastic Agents ,Apoptosis ,Piperazines ,Flow cytometry ,Nitrophenols ,Phosphatidylinositol 3-Kinases ,Cell Line, Tumor ,Autophagy ,Genetics ,medicine ,Humans ,MYELOGENOUS LEUKEMIA-CELLS ,COMBINATION ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cancer ,Cell Proliferation ,Castration-resistant prostate cancer ,DOCETAXEL ,Sulfonamides ,ABT-737 ,medicine.diagnostic_test ,Chemistry ,Biphenyl Compounds ,General Medicine ,Castration-resistant Prostate ,Organophosphates ,Quaternary Ammonium Compounds ,Prostatic Neoplasms, Castration-Resistant ,Erufosine ,Proto-Oncogene Proteins c-bcl-2 ,Cell culture ,ALKYLPHOSPHOCHOLINE ,Cancer cell ,Cancer research ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Background Cancer cell survival depends on the cross-regulation between apoptosis and autophagy which share common signaling pathways including PI3K/Akt/mTOR and Bcl-2. The aim of this study was to elucidate the modulation patterns between apoptosis and autophagy following dual inhibition by Akt inhibitor erufosine and Bcl-2 inhibitor ABT-737 in castration-resistant prostate cancer (CRPC) cell lines, PC-3 (Bax+) and DU-145 (Bax-). Methods and Results Cell cycle progression, apoptotic and autophagic signaling were examined by flow cytometry, multi-caspase assay, Hoechst staining, acridine orange staining of acidic vesicular organelles (AVOs), qRT-PCR and Western Blot. Dual inhibition increased G2/M arrest in PC-3 and DU-145, but not in the healthy prostate epithelium cells, PNT-1A. Only in PC-3, dual inhibition induced synergistic apoptotic and additive autophagic effects. In DU-145 and PNT-1A cells, ABT-737 did not display any remarkable effect on multicaspase activity and erufosine and ABT-737, neither alone nor in combination induced AVOs. By dual inhibition, AKT, BCL-2 and NF-kappa B gene expressions were downregulated in PC-3, both ATG-5 and BECLIN-1 gene expressions were upregulated in DU-145 but Beclin-1 protein expression was substantially reduced in both CRPC cells. Dual inhibition-induced synergistic multicaspase activation in PC-3 degrades and disrupts autophagic activity of Beclin-1, enhancing caspase-dependent apoptosis. However, in DU-145, following dual inhibition, rate of multicaspase induction and apoptosis are lower but autophagy is completely abolished despite markedly increased BECLIN-1 gene expression. Conclusion In conclusion, antineoplastic drug combinations may display cell-type specific modulation of apoptotic and autophagic signaling and lack of protective autophagy may not necessarily indicate increased chemotherapeutic sensitivity in heterogenous tumor subpopulations. Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [315S039] This study was funded by the Scientific and Technological Research Council of Turkey (TUBITAK), Project No: 315S039.
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- 2021
38. The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer’s disease: a randomized, triple-blind, placebo-controlled trial
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Mônica V. Silva, Guilherme A Ribeiro, Dayde Lane Mendonça-Silva, Bruno S B Gonçalves, Luciana L. Louzada, Juliana Lima Quintas, Einstein Francisco Camargos, Otávio de Toledo Nóbrega, and Flávio V. Machado
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Zolpidem ,medicine.medical_specialty ,Sedation ,Placebo-controlled study ,Placebo ,Article ,Piperazines ,Double-Blind Method ,Alzheimer Disease ,Sleep Initiation and Maintenance Disorders ,Internal medicine ,Insomnia ,medicine ,Clinical endpoint ,Humans ,Hypnotics and Sedatives ,Aged, 80 and over ,Pharmacology ,Zopiclone ,business.industry ,Psychiatry and Mental health ,medicine.symptom ,Sleep onset ,business ,Azabicyclo Compounds ,medicine.drug - Abstract
No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer's dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores ≥ 2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10 mg/day, zopiclone 7.5 mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81 min increase in MNSD (95% confidence interval (CI): -0.8, 163.2), a 26 min reduction in WASO (95% CI: -56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: -4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22 min reduction in WASO (95% CI: -52.5, 8.3) and a reduction of 1 awakening each night (95% CI: -3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: -4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: -21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.
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- 2021
39. Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial
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Gabe S. Sonke, Cara Mathews, Carol Aghajanian, Nicoletta Colombo, Alexandra Leary, Ana Oaknin, Joyce F. Liu, Giovanni Scambia, William H. Bradley, Elizabeth S. Lowe, Jae Weon Kim, Alla Lisyanskaya, Antonio González-Martín, Anne Floquet, Michael Friedlander, Kathleen N. Moore, Ralph Bloomfield, Amit M. Oza, Charlie Gourley, Susana Banerjee, Paul DiSilvestro, Colombo, N, Moore, K, Scambia, G, Oaknin, A, Friedlander, M, Lisyanskaya, A, Floquet, A, Leary, A, Sonke, G, Gourley, C, Banerjee, S, Oza, A, Gonzalez-Martin, A, Aghajanian, C, Bradley, W, Kim, J, Mathews, C, Liu, J, Lowe, E, Bloomfield, R, Disilvestro, P, Institut Català de la Salut, [Colombo N] University of Milan-Bicocca and IEO European Institute of Oncology IRCCS, Milan, Italy. [Moore K] Stephenson Cancer Center at the University of Oklahoma, Oklahoma City, OK, United States. [Scambia G] Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica, Rome, Italy. [Oaknin A] Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Friedlander M] University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, Australia. [Lisyanskaya A] St Petersburg City Oncology Dispensary, St Petersburg, Russia, and Vall d'Hebron Barcelona Hospital Campus
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medicine.medical_specialty ,Nausea ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES] ,Neutropenia ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Piperazines ,Olaparib ,chemistry.chemical_compound ,Double-Blind Method ,Ovarian cancer ,Internal medicine ,Humans ,Medicine ,Adverse effect ,BRCA2 Protein ,Ovarian Neoplasms ,BRCA1 Protein ,business.industry ,Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES] ,BRCA mutation ,Obstetrics and Gynecology ,Ovaris - Càncer - Tractament ,Middle Aged ,Tolerability ,medicine.disease ,Newly diagnosed ,Discontinuation ,Oncology ,chemistry ,Mutation ,Avaluació de resultats (Assistència sanitària) ,Vomiting ,Phthalazines ,Female ,Safety ,medicine.symptom ,business - Abstract
Olaparib; Ovarian cancer; Tolerability Olaparib; Cáncer de ovarios; Tolerabilidad Olaparib; Càncer d'ovaris; Tolerabilitat Objectives In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1. Methods Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130). Results Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was
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- 2021
40. Efficacy and safety of palbociclib in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer with preexisting conditions: A post hoc analysis of PALOMA-2
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Reshma Mahtani, Janice M. Walshe, Eustratios Bananis, Meghan Sri Karuturi, D. Lu, Sindy T. Kim, Patrick Schnell, Anil A. Joy, Karen A. Gelmon, Patrick Neven, and Lee S. Schwartzberg
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Oncology ,medicine.medical_specialty ,Pyridines ,Receptor, ErbB-2 ,MedDRA ,Estrogen receptor ,Breast Neoplasms ,Palbociclib ,Placebo ,Piperazines ,Internal medicine ,Post-hoc analysis ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Adverse effect ,Preexisting condition ,RC254-282 ,Science & Technology ,business.industry ,Letrozole ,Obstetrics & Gynecology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,General Medicine ,Receptors, Estrogen ,OLDER WOMEN ,Surgery ,Female ,Original Article ,Advanced breast cancer ,Safety ,COMORBIDITY ,business ,Life Sciences & Biomedicine ,medicine.drug - Abstract
Objective In the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods Postmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup. Results At baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups. Conclusion This post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427)., Highlights • Preexisting conditions can affect the safety and efficacy of breast cancer therapies. • This is a post hoc analysis of patients with preexisting conditions from PALOMA-2. • Palbociclib prolonged median PFS, regardless of preexisting condition. • Within each treatment arm, AEs were similar regardless of preexisting condition.
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- 2021
41. High FAS expression correlates with a better prognosis and efficacy of taxanes and target regents in breast cancer
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Danying Xu, Xuan Shao, Zhigang Chen, Xuan Zhu, Chen-Yi Gao, Yi Zhang, and Jun Wu
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cell ,Datasets as Topic ,Breast Neoplasms ,Kaplan-Meier Estimate ,Disease-Free Survival ,Piperazines ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,Breast ,Everolimus ,fas Receptor ,Taxane ,Tissue microarray ,Oncogene ,business.industry ,General Medicine ,Prognosis ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Chemotherapy, Adjuvant ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Phthalazines ,Female ,Taxoids ,Neoplasm Recurrence, Local ,Breast carcinoma ,business ,medicine.drug - Abstract
BACKGROUND: FAS can serve as both an oncogene and a suppresser in different malignancies, and the prognostic value of FAS remains controversial. METHODS: The Oncomine database, KM-Plotter and bc-GenExMiner platform were adopted to analyze the prognostic value of FAS in breast cancer. Breast cancer tissue microarrays were further used to verify these data. The Cell Miner Tool was used to predict the value of FAS mRNA expression in predicting the efficacies of clinical drugs. RESULTS: We found that both FAS mRNA and protein expression level significantly reduced in breast carcinoma. In addition, high FAS expression indicates a better metastatic relapse-free survival. Interestingly, FAS was associated with a better prognosis in different subtypes of breast cancer patients, namely, only in grade II and III, lymph nodal positive or p53 wild-type patients. The data from the Cell Miner Tool revealed that FAS mRNA expression was correlated with the efficacy of the first-line chemotherapeutic taxane agents and target drugs including olaparib and everolimus. CONCLUSIONS: FAS expression correlates with a better prognosis in breast cancer and may provide an effective clinical strategy to predict the sensitivity of taxanes and targeted drugs.
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- 2021
42. Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy – naive adults with HIV-1 infection
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Martin Gartland, Juan Sierra Madero, Andrea Antinori, Brian Wynne, Jean van Wyk, Pedro Cahn, Keith A. Pappa, Choy Y. Man, Pierre-Marie Girard, Mark R. Underwood, Daisy J. Brandon, Lloyd Curtis, Roberto Ortiz, Jose R. Arribas, Chien-Ching Hung, Jürgen K. Rockstroh, Michael Aboud, Jörg Sievers, Amanda Clarke, Rimgaile Urbaityte, Kimberly Y. Smith, and UAM. Departamento de Medicina
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Adult ,medicine.medical_specialty ,Medicina ,Anti-HIV Agents ,Pyridones ,Immunology ,Human immunodeficiency virus (HIV) ,nucleoside reverse transcriptase inhibitor ,integrase strand transfer inhibitor ,HIV Infections ,Emtricitabine ,medicine.disease_cause ,Gastroenterology ,Piperazines ,chemistry.chemical_compound ,Internal medicine ,Oxazines ,medicine ,Humans ,Immunology and Allergy ,two-drug regimen ,Adverse effect ,business.industry ,treatment-naive ,Lamivudine ,Clinical Science ,Antiretroviral therapy ,dolutegravir ,Treatment Outcome ,Infectious Diseases ,chemistry ,Tolerability ,Relative risk ,Dolutegravir ,HIV-1 ,Drug Therapy, Combination ,business ,Heterocyclic Compounds, 3-Ring ,medicine.drug - Abstract
To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2.Design:Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks).Methods:Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC.Results:At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA, This study was funded by ViiV Healthcare
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- 2021
43. ATARI trial: ATR inhibitor in combination with olaparib in gynecological cancers with ARID1A loss or no loss (ENGOT/GYN1/NCRI)
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Saira Khalique, Judith M Bliss, Katherine Vroobel, Christopher James Lord, Alexandra Leary, Rachael Natrajan, Ayoma D. Attygalle, Nuria Porta, Jeremy Tai, C. Toms, Stephanie Lheureux, James Stewart, and Susana Banerjee
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Oncology ,medicine.medical_specialty ,endometrial neoplasms ,Indoles ,Combination therapy ,cervical cancer ,Morpholines ,Poly(ADP-ribose) Polymerase Inhibitors ,Piperazines ,Olaparib ,chemistry.chemical_compound ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Multicenter Studies as Topic ,Protein Kinase Inhibitors ,Ovarian Neoplasms ,Cervical cancer ,Sulfonamides ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Clinical Trial ,DNA-Binding Proteins ,ovarian cancer ,Pyrimidines ,chemistry ,PARP inhibitor ,Clear cell carcinoma ,Phthalazines ,Female ,Neoplasm Recurrence, Local ,business ,Ovarian cancer ,Ataxia telangiectasia and Rad3 related ,Transcription Factors - Abstract
BackgroundARID1A (AT-rich interactive domain containing protein 1A) loss-of-function mutations have been reported in gynecological cancers, including rarer subtypes such as clear cell carcinoma. Preclinical studies indicate that ARID1A mutant cancers display sensitivity to ATR inhibition while tumors without ARID1A mutations may be sensitive to Ataxia telangiectasia and Rad3 related (ATR) inhibitors in combination with poly-ADP ribose polymerase (PARP) inhibitors.Primary ObjectiveTo determine whether the ATR inhibitor, ceralasertib, has clinical activity as a single agent and in combination with the PARP inhibitor, olaparib, in patients with ARID1A ‘loss’ and ‘no loss’ clear cell carcinomas and other relapsed gynecological cancers.Study HypothesisARID1A deficient clear cell carcinoma of the ovary or endometrium is sensitive to ATR inhibition, while the combination of ATR and PARP inhibition has activity in other gynecological tumors, irrespective of ARID1A status.Trial DesignATARI (ENGOT/GYN1/NCRI) is a multicenter, international, proof-of-concept, phase II, parallel cohort trial assessing ceralasertib activity as a single agent and in combination with olaparib in ARID1A stratified gynecological cancers. Patients with relapsed ovarian/endometrial clear cell carcinoma with ARID1A loss will receive ceralasertib monotherapy (cohort 1A). Relapsed ovarian/endometrial clear cell carcinoma patients with no ARID1A loss (cohort 2) or patients with other histological subtypes (endometrioid, carcinosarcoma, cervical) (cohort 3) will receive combination therapy (olaparib/ceralasertib). Treatment will continue until disease progression.Major Inclusion/Exclusion CriteriaPatients with histologically confirmed recurrent clear cell (ovarian, endometrial, or endometriosis related), endometrioid (ovarian, endometrial, or endometriosis related), cervical (adenocarcinomas or squamous), or carcinosarcomas (ovarian or endometrial) are eligible. Patients progressing after ≥1 prior platinum with evidence of measurable (RECIST v1.1) radiological disease progression since last systemic anticancer therapy and prior to trial entry are eligible. Previous ATR or PARP inhibitor treatment is not permissible.Primary EndpointBest overall objective response rate (RECIST v1.1).Sample SizeA minimum of 40 and a maximum of 116.Estimated Dates for Completing Accrual and Presenting ResultsAccrual is anticipated to be complete by the second quarter of 2022, with reporting of results by the fourth quarter of 2022. Overall accrual targets and reporting timelines are dependent on individual cohort progression to stage 2.Trial Registration NumberNCT0405269.
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- 2021
44. Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment
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Jacques Gasnault, Pierre-Hadrien Becker, Lionelle Nkam, Antoine Cheret, Anne-Marie Taburet, Aurélie Barrail-Tran, Valérie Furlan, Pilartxo Catalan, Cécile Goujard, Thibaut Gelé, Hélène Gouget, Coralie Pallier, Alicia Castro Gordon, Service de pharmacie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Service de Virologie [Villejuif], Hôpital Paul Brousse, Service de Biochimie [AP-HP Hôpital Bicêtre], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculté de Médecine Paris-Saclay, and AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay
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Microbiology (medical) ,medicine.medical_specialty ,Anti-HIV Agents ,Pyridones ,[SDV]Life Sciences [q-bio] ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,Emtricitabine ,Gastroenterology ,Tenofovir alafenamide ,Piperazines ,Cerebrospinal fluid ,Tandem Mass Spectrometry ,Internal medicine ,Oxazines ,medicine ,Humans ,Pharmacology (medical) ,In patient ,Tenofovir ,Aged ,Pharmacology ,Alanine ,Total plasma ,Bictegravir ,business.industry ,Adenine ,Middle Aged ,Amides ,Emtricitabine/Tenofovir ,Infectious Diseases ,HIV-1 ,Female ,business ,Heterocyclic Compounds, 3-Ring ,Chromatography, Liquid ,medicine.drug - Abstract
Objectives The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study. Methods Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range). Results Twenty-four patients (nine women) were enrolled. The age was 45 (26–68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6–9.6), 84.4 (28.6–337.4) and 1.6 (0.7–4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%–82%) versus 0.33% (0.11%–0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir). Conclusions We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age.
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- 2021
45. Therapeutic Potential of Olaparib in Combination With Pembrolizumab in a Young Patient With a Maternally Inherited BRCA2 Germline Variant: A Research Report
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Ravi Salgia, Stacy W. Gray, Rebecca Pharaon, Hannah Romo, Jeremy Fricke, Bassam Ghanem, Isa Mambetsariev, Angel Ray Baroz, and Thomas Waddington
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Adult ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,endocrine system diseases ,medicine.medical_treatment ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Piperazines ,Article ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Germline mutation ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,skin and connective tissue diseases ,Lung cancer ,Germ-Line Mutation ,BRCA2 Protein ,business.industry ,Immunotherapy ,medicine.disease ,Precision medicine ,Treatment Outcome ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Phthalazines ,Drug Therapy, Combination ,Female ,Maternal Inheritance ,Ovarian cancer ,business - Abstract
Clinical Practice Points • Familial history of lung cancer is concerning in the clinical setting and often, germline testing is warranted. • Individuals with germline alterations in BRCA1 and BRCA2 have increased susceptibility to hereditary cancers such as breast, ovarian, and prostate cancers. • We present a clinical case of a young female patient with a notable germline mutation in BRCA2 gene (BRCA2 S497*), concomitantly diagnosed with widespread non–small cell lung cancer (NSCLC). The patient is currently treated with Pembrolizumab, an anti-PD-1 antibody, and Olaparib, a poly-ADP ribose polymerase (PARP) inhibitor, with positive treatment response. • Olaparib has been shown to have potent anti-tumor activity in patients with BRCA-mutated breast cancer and in ovarian cancer. Although there is evidence of Olaparib's effectiveness on lung cancer in the preclinical setting, ongoing investigation is underway to evaluate efficacy and safety of Olaparib alone or in combination with chemotherapy or immunotherapy as a promising therapeutic strategy in patients with NSCLC.
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- 2021
46. Indirect treatment comparison of olaparib and talazoparib in germline BRCA-mutated HER2-negative metastatic breast cancer
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Robert Hettle, Preety Rajora, Charles McCrea, Ankush Taneja, and Poonam Gulati
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Nausea ,Breast Neoplasms ,Piperazines ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,Humans ,Talazoparib ,skin and connective tissue diseases ,Adverse effect ,Germ-Line Mutation ,business.industry ,Health Policy ,Bayes Theorem ,medicine.disease ,Metastatic breast cancer ,Germ Cells ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,PARP inhibitor ,Vomiting ,Phthalazines ,Female ,medicine.symptom ,business - Abstract
Aim: Two poly(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib are approved for patients with germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer. Methods: A Bayesian fixed-effects indirect treatment comparison (ITC) analysis was performed to simulate the comparative efficacy (primary outcome of progression-free survival [PFS]) and safety of PARP inhibitor monotherapy. Results: ITC of data from the OlympiAD (olaparib) and EMBRACA (talazoparib) studies suggested no significant difference in efficacy (PFS) between olaparib and talazoparib. However, there were differences in specific adverse events; patients receiving olaparib had a higher rate of nausea and vomiting, while those receiving talazoparib had a higher rate of alopecia and anemia. Discussion: These data support the benefit of the PARP inhibitor class in gBRCAm HER2-negative metastatic breast cancer.
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- 2021
47. Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior
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John G. Keilp, Ainsley K. Burke, Mohammad Lesanpezeshki, J. John Mann, Jeffrey M. Miller, Francesca Zanderigo, M. Elizabeth Sublette, Elizabeth Bartlett, Nadine M. Melhem, Madison Newell, R. Todd Ogden, Yongqi Zhong, and David A. Brent
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Adult ,Male ,Hypothalamo-Hypophyseal System ,AcademicSubjects/MED00415 ,Hydrocortisone ,Pyridines ,Pituitary-Adrenal System ,suicidal behavior ,Suicide, Attempted ,[11C]CUMI-101 PET imaging ,Regular Research Articles ,Piperazines ,Suicidal Ideation ,cortisol response to stress ,Medicine ,Humans ,Pharmacology (medical) ,Family history ,familial risk ,Depression (differential diagnoses) ,5-HT1A Receptor ,Second-degree relative ,Pharmacology ,Social stress ,Depressive Disorder, Major ,Suicide attempt ,business.industry ,AcademicSubjects/SCI01870 ,Brain ,Psychiatry and Mental health ,Mood ,Positron-Emission Tomography ,Receptor, Serotonin, 5-HT1A ,5-HT1A receptor ,Female ,Serotonin ,business ,Stress, Psychological ,Clinical psychology - Abstract
BackgroundThe serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters with depression. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to familial risk and resilience for suicidal behavior.Methods[11C]CUMI-101 positron emission tomography imaging to quantify regional brain 5-HT1A receptor binding was conducted in individuals considered to be at high risk for mood disorder or suicidal behavior on the basis of having a first- or second-degree relative(s) with an early onset mood disorder and history of suicidal behavior. These high-risk individuals were subdivided into the following groups: high risk resilient having no mood disorder or suicidal behavior (n = 29); high risk with mood disorder and no suicidal behavior history (n = 31); and high risk with mood disorder and suicidal behavior (n = 25). Groups were compared with healthy volunteers without a family history of mood disorder or suicidal behavior (n = 34). Participants underwent the Trier Social Stress Task (TSST). All participants were free from psychotropic medications at the time of the TSST and PET scanning.ResultsWe observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND for all participants and BPp in a subset of the sample) and definitions of regions of interest (ROIs; standard or serotonin system-specific ROIs). We also found no group differences on TSST outcomes. Within the high risk with mood disorder and suicidal behavior group, lower BPp binding (β = −0.084, SE = 0.038, P = .048) and higher cortisol reactivity to stress (β = 9.25, 95% CI [3.27,15.23], P = .004) were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes.Conclusions5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how hypothalamic-pituitary-adrenal axis function influences such risk.
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- 2021
48. Zopiclone to treat insomnia in older adults: A systematic review
- Author
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Flávio V. Machado, Luciana L. Louzada, Otávio de Toledo Nóbrega, and Einstein Francisco Camargos
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medicine.medical_specialty ,Piperazines ,03 medical and health sciences ,0302 clinical medicine ,Sleep Initiation and Maintenance Disorders ,medicine ,Insomnia ,Humans ,Hypnotics and Sedatives ,Pharmacology (medical) ,Effects of sleep deprivation on cognitive performance ,Biological Psychiatry ,Aged ,Pharmacology ,Zopiclone ,business.industry ,030227 psychiatry ,Clinical trial ,Psychiatry and Mental health ,Cross-Sectional Studies ,Neurology ,Tolerability ,Physical therapy ,Observational study ,Neurology (clinical) ,Sleep onset ,medicine.symptom ,business ,Azabicyclo Compounds ,030217 neurology & neurosurgery ,Cohort study ,medicine.drug - Abstract
Considering the global increase in use of Z-drugs to treat insomnia, the study objective was to conduct a systematic review on the efficacy and safety of zopiclone to treat sleep disorders in older adults compared to other sedative-hypnotics, to placebo or to non-pharmacological interventions. The literature search for original reports — clinical trials, cohort studies and cross-sectional, observational investigations — was done in eleven databases and web search engines followed PRISMA guidelines, and methodological quality was assessed using the Risk of Bias tool in the Cochrane Reviewers’ Handbook. The search resulted in 12 randomized, placebo-controlled clinical trials along with 2 open studies and 2 observational reports. Overall, the studies suggest that zopiclone is effective to treat insomnia by reducing sleep latency, nocturnal awakenings and wake time after sleep onset while increasing total sleep time, with probable effects on sleep architecture. Zopiclone was found to be fairly tolerated, to induce a low rate of adverse events with non-severe impact on psychomotor or cognitive performance and to produce no major harm to the overall well-being and daily living abilities. However, the quality of most studies was classified as low or unclear. Though the studies available support benefits from zopiclone use, there is still a need for further evidence on long-term effects, tolerability and safety in the treatment of older adults by means of high-quality trials.
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- 2021
49. Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties
- Author
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Maciej Pawłowski, Xavier Bantreil, Natalia Malikowska-Racia, Ryszard Bugno, Joanna Golebiowska, Jean Martinez, Frédéric Lamaty, Séverine Chaumont-Dubel, Gilles Subra, Paweł Zajdel, Grzegorz Satała, Piotr Popik, Katarzyna Grychowska, Andrzej J. Bojarski, Philippe Marin, Szczepan Mogilski, Rafał Kurczab, Agnieszka Nikiforuk, Tomasz Kos, Lamaty, Frédéric, Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Polish Academy of Sciences (PAN), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,medicine.medical_treatment ,[CHIM.THER] Chemical Sciences/Medicinal Chemistry ,Guinea Pigs ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Pharmacology ,Article ,Piperazines ,Rats, Sprague-Dawley ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Drug Discovery ,medicine ,Inverse agonist ,Animals ,Humans ,Serotonin 5-HT3 Receptor Antagonists ,Cognitive Dysfunction ,Receptor ,Antipsychotic ,Phencyclidine ,Nootropic Agents ,030304 developmental biology ,0303 health sciences ,Sulfonamides ,Molecular Structure ,Chemistry ,Antagonist ,medicine.disease ,Ondansetron ,3. Good health ,Rats ,Drug Combinations ,Schizophrenia ,Receptors, Serotonin ,5-HT6 receptor ,Microsomes, Liver ,Molecular Medicine ,Receptors, Serotonin, 5-HT3 ,Antagonism ,030217 neurology & neurosurgery ,medicine.drug ,Antipsychotic Agents - Abstract
International audience; In line with recent clinical trials demonstrating that ondansetron, a 5-HT3 receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.
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- 2021
50. UBE2S promotes the progression and Olaparib resistance of ovarian cancer through Wnt/β-catenin signaling pathway
- Author
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Min Li, Xinxian Gu, Wenjing Hu, and Youguo Chen
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endocrine system ,endocrine system diseases ,Poly(ADP-ribose) Polymerase Inhibitors ,Piperazines ,Metastasis ,Olaparib ,chemistry.chemical_compound ,Downregulation and upregulation ,medicine ,Humans ,Clonogenic assay ,Wnt Signaling Pathway ,beta Catenin ,Ovarian Neoplasms ,Wnt/β-catenin ,business.industry ,Research ,Wnt signaling pathway ,Obstetrics and Gynecology ,Transfection ,Gynecology and obstetrics ,Middle Aged ,UBE2S ,medicine.disease ,female genital diseases and pregnancy complications ,Ovarian Cancer ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Ubiquitin-Conjugating Enzymes ,Cancer research ,Disease Progression ,RG1-991 ,Phthalazines ,Female ,Signal transduction ,Ovarian cancer ,business - Abstract
Background Ovarian cancer is the most lethal gynecologic malignancy worldwide. Olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), is becoming widely used in ovarian cancer treatment. The overall survival of ovarian cancer has not been significantly changed over the past decades and ovarian cancer has become increasingly resistant to the Olaparib. Ubiquitin-conjugating enzyme E2S (UBE2S) has been proved to promote malignant behaviors in many cancers. However, the function of UBE2S in the development and Olaparib resistance of ovarian cancer are unclear. Materials and methods In this study, we detected the expression of UBE2S in normal fallopian tube (FT) and HGSOC tissues. A2780 and SKOV3 cells were stably transfected with PCMV-UBE2S, PCMV-UBE2S-C95S, UBE2S shRNAs, and negative controls. The CCK8 assay and clonogenic assay were conducted to analyze ovarian cancer proliferation and Olaparib resistance. The transwell assay was performed to determine the migration and invasion of ovarian cancer cells. The relative protein levels of the Wnt/β-catenin signaling pathway were tested using western blot. The ovarian cancer cells were treated with XAV-939 to investigate the role of Wnt/β-catenin signaling pathway in Olaparib resistance. Moreover, we repeated some above procedures in the xenograft model. Results The results demonstrated that UBE2S was highly upregulated in HGSOC and that high UBE2S expression was correlated with poor outcomes in HGSOC. UBE2S promoted ovarian cancer proliferation and drived the migration and invasion of ovarian cancer cells. UBE2S activated the Wnt/β-catenin signaling pathway in ovarian cancer resulting in Olaparib resistance in vitro and in vivo. Furthermore, UBE2S enhanced the proliferation and Olaparib resistance of ovarian cancer in its enzymatic activity dependent manner. Conclusions These data suggest a possible molecular mechanism of proliferation and metastasis of ovarian cancer and highlight the potential role of UBE2S as a therapeutic target in ovarian cancer.
- Published
- 2021
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