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Background: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. Methods: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. Results: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. Conclusions: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment. [ABSTRACT FROM AUTHOR]

The article offers information on voclosporin, a novel calcineurin inhibitor (CNI). Topics discussed include characterization of calcineurin, CNIs as a treatment for extrarenal disease, the potential of calcineurin to dephosphorylate intracellular molecules, synthesis of voclosporin and the efficacy of voclosporin as a treatment for lupus nephritis.

Simple Summary: Prognostic markers have become a promising tool for predicting response to a certain treatment and qualifying patients for a certain therapy; however, it is important to consider that they generally describe a probabilistic scenario. For instance, the analysis of programmed death ligand 1 expression on tumor cells or tumor mutational burden is commonly employed as a biomarker with relative predictive value for immunotherapy efficacy in non-small-cell lung cancer (NSCLC) patients. Cutting-edge techniques, such as next-generation sequencing of tumor tissue and flow cytometry analysis of lymphocyte subpopulations in the peripheral blood of patients, are used with the aim of increasing the predictive value, avoiding statistical weakness and discovering algorithms based on many biomarkers. To resolve the issues posed by these novel techniques, dynamic monitoring of biomarker changes can indicate resistance or response to immunotherapy during different points of the treatment. Hence, clinicians can flexibly modify the therapy course for the benefit of the patient, improving response rates, efficiency in laboratory routines, and the economic cost of the technique. Immune checkpoint immunotherapy alters the local (solid tumor infiltration) and systemic balance among several immune system cell populations. The usefulness of immune-cell-related soluble CD26 and its DPP4 activity in immunotherapy monitoring is discussed. Soluble CD26 (sCD26), a glycoprotein with dipeptidyl peptidase (DPP4) enzymatic activity, can contribute to early diagnosis of colorectal cancer and advanced adenomas and has been studied, including for prognostic purposes, across various other types of cancer and disease. The latest research in this field has confirmed that most, though not all, serum/plasma sCD26 is related to inflammation. The shedding and/or secretion of sCD26 from different immune cells are being investigated, and blood DPP4 activity levels do not correlate very strongly with protein titers. Some of the main substrates of this enzyme are key chemokines involved in immune cell migration, and both soluble and cell-surface CD26 can bind adenosine deaminase (ADA), an enzyme involved in the metabolism of immunosuppressor extracellular adenosine. Of note, there are T cells enriched in CD26 expression and, in mice tumor models, tumor infiltrating lymphocytes exhibited heightened percentages of CD26+ correlating with tumor regression. We employed sCD26 as a biomarker in the follow-up after curative resection of colorectal cancer for the early detection of tumor recurrence. Changes after treatment with different biological disease-modifying antirheumatic drugs, including Ig-CTLA4, were also observed in rheumatoid arthritis. Serum soluble CD26/DPP4 titer variation has recently been proposed as a potential prognostic biomarker after a phase I trial in cancer immunotherapy with a humanized anti-CD26 antibody. We propose that dynamic monitoring of sCD26/DPP4 changes, in addition to well-known inflammatory biomarkers such as CRP already in use as informative for immune checkpoint immunotherapy, may indicate resistance or response during the successive steps of the treatment. As tumor cells expressing CD26 can also produce sCD26, the possibility of sorting immune- from non-immune-system-originated sCD26 is discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes involved in the synthesis of retinoic acid, which is necessary for the normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. ALDH1A3, one of the enzymes that belong to the ALD1A subfamily, is also expressed at high levels in many human cancers like glioblastoma and mesothelioma. Herein, we review the role of ALDH1A3 in cancer, showing its relation with excessive proliferation, chemoresistance, and invasiveness. We also illustrate the current attempts to develop ALDH1A3-selective inhibitors and specific fluorescent probes that are potentially useful for cancer therapy and fluorescence-guided tumor resection. Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection. [ABSTRACT FROM AUTHOR]

Simple Summary: KRAS mutations have critical roles in the etiology of cancers such as NSCLC, CRC, and PDAC. However, therapeutic targeting of KRAS has proven difficult due to the lack of typical drug-binding sites. Recent improvements have seen the emergence of inhibitors specially tailored for the p.G12C mutation, with Sotorasib showing promising results in NSCLC. Nonetheless, the CodeBreaK 200 study found no significant difference in overall survival between Docetaxel and Sotorasib. This study compares the structural configurations of KRAS isoforms KRAS4A and KRAS4B and analyzes the effects of mutations on drug binding. The present study reveals unique aggregation propensities in wild-type and mutant isoforms, highlighting the complexities of KRAS as a therapeutic target. Sotorasib's stable structure may allow for more effective binding to KRAS4B, despite the steric constraints imposed by KRAS4A and its mutations. This emphasizes the necessity for additional research into the complicated dynamics of KRAS targeting in cancer therapy. Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene variations are linked to the development of numerous cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The lack of typical drug-binding sites has long hampered the discovery of therapeutic drugs targeting KRAS. Since "CodeBreaK 100" demonstrated Sotorasib's early safety and efficacy and led to its approval, especially in the treatment of non-small cell lung cancer (NSCLC), the subsequent identification of specific inhibitors for the p.G12C mutation has offered hope. However, the CodeBreaK 200 study found no significant difference in overall survival (OS) between patients treated with Docetaxel and Sotorasib (AMG 510), adding another degree of complexity to this ongoing challenge. The current study compares the three-dimensional structures of the two major KRAS isoforms, KRAS4A and KRAS4B. It also investigates the probable structural changes caused by the three major mutations (p.G12C, p.G12D, and p.G12V) within Sotorasib's pocket domain. The computational analysis demonstrates that the wild-type and mutant isoforms have distinct aggregation propensities, resulting in the creation of alternate oligomeric configurations. This study highlights the increased complexity of the biological issue of using KRAS as a therapeutic target. The present study stresses the need for a better understanding of the structural dynamics of KRAS and its mutations to design more effective therapeutic approaches. It also emphasizes the potential of computational approaches to shed light on the complicated molecular pathways that drive KRAS-mediated oncogenesis. This study adds to the ongoing efforts to address the therapeutic hurdles presented by KRAS in cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Prior research has identified various prognostic markers in epithelial ovarian cancer (EOC), including BRCA mutation status and a response to platinum-based chemotherapy, to predict outcomes in patients undergoing PARP inhibitor maintenance therapy. The role of CA-125 elimination rate constant K (KELIM), although recognized as a prognostic indicator, has not been fully investigated. This study underscores the prognostic significance of KELIM, revealing that a favorable KELIM score significantly correlates with better PFS in patients treated with primary cytoreductive surgery (PCS) followed by PARP inhibitor therapy. It also shows that KELIM's predictive value varies with the timing of surgery, extending a different view of its utility in real-world practice. KELIM could be integrated into clinical decision-making processes, potentially informing future clinical guidelines and research into optimal treatment strategies for targeted use of PARP inhibitors in advanced EOC patients. Background: This multicenter retrospective study aimed to investigate the prognostic value of the CA-125 elimination rate constant K (KELIM) in EOC patients who received platinum-based chemotherapy followed by PARP inhibitors, in either upfront or interval treatment settings. Methods: Between July 2019 and November 2022, we identified stage III–IV EOC patients who underwent primary or interval cytoreductive surgery and received olaparib or niraparib. Individual KELIM values were assessed based on validated kinetics and classified into favorable and unfavorable cohorts. Results: In a study of 252 patients undergoing frontline maintenance therapy with olaparib or niraparib, favorable KELIM (≥1) scores were associated with a higher PFS benefit in the primary cytoreductive surgery (PCS) cohort (hazard ratio (HR) for disease progression or death 3.51, 95% confidence interval (CI); 1.37–8.97, p = 0.009). Additionally, within the interval cytoreductive surgery (ICS) cohort, a favorable KELIM score (≥1) significantly increased the likelihood of achieving complete resection following cytoreductive surgery, with 59.4% in the favorable KELIM group compared to 37.8% in those with unfavorable KELIM. Conclusions: A favorable KELIM score was associated with improved PFS in patients with advanced EOC undergoing PCS. Furthermore, in the ICS cohort, a favorable KELIM score increased the probability of complete cytoreduction. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with pediatric liver cancers hepatoblastoma and hepatocellular carcinoma very often develop lung metastases. These cancers can present with lung metastases and are at higher risk of relapse. Although cisplatin is very effective at clearing lung metastases, they can still relapse. Therefore, there is an urgent need to develop therapeutic approaches to prevent the development of lung metastases in patients with pediatric liver cancers. In this paper, we show that the metastatic microenvironment of HBL and HCC patients contains a heterogeneous cell population that formed tumor clusters. We found that both fresh primary tumors and generated primary cell cultures had increased the expression of HDAC1, a histone deacetylase, and the transcription factor Sp5. Sp5 and HDAC1 work in tandem by transporting HDAC1 to the promoters of genes and changing their expression. We analyzed the effects of the HDAC inhibitor, SAHA, on the metastasis-initiating cells in combination with cisplatin. We found that HDAC inhibition increases the efficacy of cisplatin to eliminate these metastasis-initiating cells. The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistant bacterial pathogens employ different mechanisms in evading the action of antibiotics. Multidrug resistance is wide spread among strains of Escherichia coli implicated in several infections including urinary tract infections, gastrointestinal infections, meningitis and bacteraemia. Aim/Objective: This study investigates the antibiotic resistance profile, efflux pump activity and biofilm formation ability of E. coli strains isolated from clinical samples. Methods: A total of 32 E. coli strains isolated from clinical samples were characterized and subjected to antibiotic susceptibility testing using standard methods. Isolates were screened phenotypically for biofilm formation and efflux pump activity. While molecular detection of genes encoding curli fimbriae and efflux pump activity was done by PCR. Results: All 32 (100%) E. coli isolates were resistant to ceftazidime, cefuroxime, cefixime, amoxicillin-clavulanate, ofloxacin and ciprofloxacin. While 30 (93.8%) were resistant to gentamicin, 27 (84.4%) were resistant to cefepime and the least resistance of 15.6% was to imipenem. Efflux pump encoding gene tolC was detected in 13(40.6%) of the isolates, while 1(3.1%) harboured acrA gene. acrB gene was not detected in any of the isolates. Seven (21.9%) of the isolates were strong biofilm formers, while 5 (15.6%) and 20 (62.5%) were moderate and weak biofilm formers respectively. csgA gene was detected in all E. coli isolates. Discussion: High antibiotic resistance of E. coli strains observed in this study is of public health significance.. It is therefore important to scale up efforts in regular monitoring of antibiotic resistance in both community and hospital settings. [ABSTRACT FROM AUTHOR]

Low-velocity penetrating brain injury (LVPBI) is a class of brain injury where a foreign object violates the skull and damages the brain. Such injuries are rare and consequently understudied. As such, we report an illustrative case of a 29-year-old female with a dense, plastic spike penetrating her right orbit and into her midbrain. After assessment with a CT scan and angiography, the object was removed with careful attention to possible vascular injury. The patient had an uncomplicated post-operative course and received antibiotic and antiepileptic prophylaxis. She was discharged on post-operative day 5, experiencing only mild left-sided weakness. Common concerns regarding LVPBI include infection, post-traumatic epilepsy, and vascular injury. A review of published LVPBI cases over the past 20 years demonstrated that most cases (55.2%) are due to accidents. Of patients undergoing surgery, 43.4% underwent a craniotomy, and 22.8% underwent a craniectomy. Despite the grave nature of LVPBI, only 13.5% of the patients died. Additionally, 6.5% of patients developed an infection over their clinical course. In all, more reported cases further paint a picture of the current state of management and outcomes regarding LVPBI, paving the way for more cohesive guidelines to ensure the best possible patient outcomes. [ABSTRACT FROM AUTHOR]

Infectious diseases have been jeopardized problem that threaten public health over a long period of time. The growing prevalence of drug‐resistant pathogens and infectious cases have led to a decrease in the number of effective antibiotics, which highlights the urgent need for the development of new antibacterial agents. Serine acetyltransferase (SAT), also known as CysE in certain bacterial species, and O‐acetylserine sulfhydrylase (OASS), also known as CysK in select bacteria, are indispensable enzymes within the cysteine biosynthesis pathway of various pathogenic microorganisms. These enzymes play a crucial role in the survival of these pathogens, making SAT and OASS promising targets for the development of novel anti‐infective agents. In this comprehensive review, we present an introduction to the structure and function of SAT and OASS, along with an overview of existing inhibitors for SAT and OASS as potential antibacterial agents. Our primary focus is on elucidating the inhibitory activities, structure–activity relationships, and mechanisms of action of these inhibitors. Through this exploration, we aim to provide insights into promising strategies and prospects in the development of antibacterial agents that target these essential enzymes. [ABSTRACT FROM AUTHOR]

Background Recent studies suggest that 5α-reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) result in abnormal retinal anatomical alteration. Objective To compare age-related macular degeneration (AMD) incidence in BPH patients receiving 5ARIs or tamsulosin. Design Retrospective, population-based cohort study using new-user and active-comparator design. Setting General population. Subjects Males with BPH, newly receiving 5ARIs or tamsulosin from 2010 to 2018. Methods Data were extracted from Taiwan's National Health Insurance Research Database. We used Cox proportional hazards model with 1:4 propensity score (PS) matching, based on intention-to-treat analysis to determine the risk of incident AMD. Sensitivity analyses included an as-treated approach and weighting-based PS methods. We also separately reported the risks of incident AMD in patients receiving finasteride and dutasteride to determine risk differences among different 5ARIs. Results We included 13 586 5ARIs users (mean age: 69 years) and 54 344 tamsulosin users (mean age: 68.37 years). After a mean follow-up of 3.7 years, no differences were observed in the risk of incident AMD between 5ARIs and tamsulosin users [hazard ratio (HR): 1.06; 95% confidence intervals (95% CI): 0.98–1.15], with similar results from sensitivity analyses. However, increased risk of incident age-related macular degeneration was observed in patients receiving dutasteride [HR: 1.13; 95% CI: 1.02–1.25], but not in those receiving finasteride [HR: 0.99; 95% CI: 0.87–1.12], in the subgroup analyses. Conclusions We found no difference between 5ARIs and tamsulosin regarding the incidence of AMD in BPH patients. However, the risk profiles for AMD differed slightly between dutasteride and finasteride, suggesting that the potency of androgen inhibition is a factor related to AMD incidence. [ABSTRACT FROM AUTHOR]

Two new sesquiterpenoid glycosides, 8α (H)-eudesmane-1,3,11 (13)-triene-2-one -12-O-β-D-glucopyranoside (1) and dmetelisproside B (2), together with ten known compounds (3–12) were isolated from calyces of Physalis alkekengi L. var. franchetii (Mast.) Makino (PAF). Their structures were unambiguously elucidated through HR-ESI-MS, UV, IR, and NMR spectral data. Compounds 1, 10, and 12 exhibited DPPH scavenging ability with IC50 values of 33.69 ± 6.65, 6.29 ± 0.06, and 25.66 ± 3.06 μM, respectively. Additionally, 10 and 12 demonstrated weak α-glucosidase inhibition activity with IC50 values of 250.9 ± 6.60 and 347.6 ± 2.48 μM, respectively. [ABSTRACT FROM AUTHOR]

Co-trimoxazole is a combination of two antimicrobial drugs, (trimethoprim and sulfamethoxazole), that are used to treat a wide variety of infections such as urinary tract infection, pneumocystis pneumonia and traveler's diarrhea. Hyperkalemia is a life-threatening electrolyte disturbance. Objectives: This study aimed to determine the incidence of hyperkalemia and its risk factors among hospitalized patients receiving intravenous co-trimoxazole at Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. Methods: This retrospective observational study included patients that were prescribed intravenous co-trimoxazole and identified using a computerized pharmacy system between January 2010 and December 2020. Patients' demographic and clinical characteristics were retrieved from their electronic medical records. The data were analyzed using descriptive and inferential statistical tests. Results: A total of 420 patients participated in this study. The median age of the patients was 51 (35-65) years and 55.5% were male. Hyperkalemia associated with co-trimoxazole was observed in (40.2%) of the patients. Around (44.2%) of patients who experienced hyperkalemia received a high dose of co-trimoxazole (15-20 mg/kg). Hyperkalemia occurred after the 5th day of co-trimoxazole treatment. Logistic regression analysis showed no relationship between hyperkalemia and age (adjusted odds ratio (AOR) 1.054, p=0.84), sex (AOR 1.167; p=0.471), dose (AOR 0.779; p=0.251), or use of concomitant medications (angiotensin-converting inhibitors, AOR 1.054, p=0.84; angiotensin receptor blockers, AOR 0.564; p=0.734; β-blockers, AOR 0.986; p=0.963; potassium supplements, AOR 0.59; p=0.175; nonsteroidal anti-inflammatory drugs, AOR 0.842, p=0.684; spironolactone AOR 0.748, p=0.629; heparin AOR 0.822, p=0.382; calcineurin inhibitor, AOR 1.537, p=0.406). Conclusion: Co-trimoxazole use was associated with a high incidence of hyperkalemia in this group of patients. No association between hyperkalemia and risk factors was observed. Serum potassium levels should be closely monitored, especially in the first week of co-trimoxazole treatment, to prevent the incidence of hyperkalemia, and clinical staff should adhere to serum monitoring guidelines. [ABSTRACT FROM AUTHOR]

Background Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. Methods To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1 , BRCA2 , ATM , BARD1 , BRIP1 , CHEK1 , CHEK2 , FANCA , FANCB , FANCC , FANCD2 , FANCE , FANCF , FANCG , FANCI , FANCL , FANCM , NBN , PALB2 , RAD51C , RAD51D , RAD50 , and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. Clinical Report and Results We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n  = 193) displayed 9 of all 31 BRCA2 alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2 alt (4.66%; q  < 0.001). All of 9 BRCA2 alt were represented by homDel, which related to a high fraction of genome altered. Conclusion uLMS displays a significant frequency of somatic BRCA2 alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations. [ABSTRACT FROM AUTHOR]

The first successful heart transplant was carried out in 1979, and there are now approximately 200 transplants undertaken in the UK each year. Many medications are used to prevent rejection of the transplanted organ, but this needs to be balanced with the risk of complications of immunosuppression, such as infection, organ dysfunction, graft dysfunction and vasculopathy. Patients must be able to adhere to the complex and vast regimen of medications started post-transplant, and extensive monitoring is required to ensure the correct balance of rejection risk and adverse effects, depending on where the patient is in their postoperative journey. Immediately after the transplant is when the patient is at highest risk of rejecting their new heart. Guidance is available to recommend regimens to prevent rejection, but needs to be adapted to each patient, taking into consideration their clinical picture, together with comorbidities, drug interactions and organ dysfunction. [ABSTRACT FROM AUTHOR]

Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N‐nitrosamine drug substance‐related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin‐converting enzyme inhibitors, identified by the suffix "pril," have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. N‐nitroso ramipril and N‐nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α‐position were non‐genotoxic in the in vivo liver comet assay and non‐mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non‐mutagenic and non‐carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for N‐nitroso ramipril and N‐nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar "pril" NDSRIs. [ABSTRACT FROM AUTHOR]

Introduction: Oxidative stress is involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, and multiple sclerosis. It seems that the intake of exogenous antioxidants may be effective in preventing, treating, and reducing the complications of these diseases. Astaxanthin is a carotenoid pigment with antioxidant and anti-inflammatory properties, protecting the nervous system. The present study aimed to assess the effect of astaxanthin on the amount of malondialdehyde and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) after oxidative stress with hydrogen peroxide in the human neuroblastoma cell line BE (2)-C. Material & Methods: Human neuroblastoma cells were treated in this study with different concentrations of astaxanthin (25, 50, and 100 μM) or 50 μM ascorbic acid (positive control) for 24 h. To induce oxidative stress, they were exposed to hydrogen peroxide at a concentration of 400 μM for 2 h. There was also a control group without treatment and without inducing oxidative stress. The amount of malondialdehyde as an index of oxidative stress and the activity of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were measured using calorimetric methods. Results: The obtained results demonstrated that the malondialdehyde concentration was significantly reduced in the groups treated with different concentrations of astaxanthin and ascorbic acid compared to the hydrogen peroxide group (P<0.05). The activities of superoxide dismutase, catalase, and glutathione peroxidase also increased significantly in these groups compared to the group with oxygenated water (P<0.05). Discussion & Conclusion: Astaxanthin appears to counteract the oxidative stress caused by hydrogen peroxide by lowering malondialdehyde levels and increasing the activity of antioxidant enzymes in BE (2)C cells, thereby protecting the cells from the impact of oxidative stress. [ABSTRACT FROM AUTHOR]

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There is a growing interest in the discovery of novel xanthine oxidase inhibitors for gout prevention and treatment with fewer side effects. This study aimed to identify the xanthine oxidase (XO) inhibitory potential and drug-likeness of the metabolites present in the methanolic leaf extract of Anastatica (A.) hierochuntica L. using in vitro and in silico models. The extract-derived metabolites were identified by liquid-chromatography–quadrupole-time-of-flight-mass-spectrometry (LC-QTOF-MS). Molecular docking predicted the XO inhibitory activity of the identified metabolites and validated the best scored in vitro XO inhibitory activities for experimental verification, as well as predictions of their anticancer, pharmacokinetic, and toxic properties; oral bioavailability; and endocrine disruption using SwissADMET, PASS, ProTox-II, and Endocrine Disruptome web servers. A total of 12 metabolites, with a majority of flavonoids, were identified. Rutin, quercetin, and luteolin flavonoids demonstrated the highest ranked docking scores of −12.39, −11.15, and −10.43, respectively, while the half-maximal inhibitory concentration (IC50) values of these metabolites against XO activity were 11.35 µM, 11.1 µM, and 21.58 µM, respectively. In addition, SwissADMET generated data related to the physicochemical properties and drug-likeness of the metabolites. Similarly, the PASS, ProTox-II, and Endocrine Disruptome prediction models stated the safe and potential use of these natural compounds. However, in vivo studies are necessary to support the development of the prominent and promising therapeutic use of A. hierochuntica methanolic-leaf-extract-derived metabolites as XO inhibitors for the prevention and treatment of hyperuricemic and gout patients. Furthermore, the predicted findings of the present study open a new paradigm for these extract-derived metabolites by revealing novel oncogenic targets for the potential treatment of human malignancies. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) significantly increases the risk of cardiovascular diseases. Despite advances in glycemic control, managing cardiovascular risk remains a critical challenge. This systematic review aims to assess and compare the cardiovascular outcomes associated with three classes of antidiabetic medications: sulfonylureas, Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with T2DM. A systematic review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases, including PubMed, Embase, Cochrane Library, and Google Scholar, were searched for relevant studies published between 2019 and 2023. Inclusion criteria were adults (=18 years) with T2DM, studies assessing cardiovascular outcomes with the specified medications, randomized controlled trials, observational studies, or meta-analyses. Two independent reviewers performed data extraction and risk of bias assessments. From the initial 1,543 records, 12 studies were included involving 61,534 patients. As a result, GLP-1 RAs demonstrated favorable cardiovascular safety and efficacy, particularly in reducing major adverse cardiovascular events and all-cause mortality. DPP-4 inhibitors were associated with neutral cardiovascular outcomes but indicated an elevated risk of cardiac failure in some studies. In recent studies, sulfonylureas, previously associated with cardiovascular concerns, showed no consistent evidence of increased cardiovascular risk. These findings highlight the importance of personalized treatment strategies to optimize cardiovascular outcomes in patients with T2DM. [ABSTRACT FROM AUTHOR]

Purpose: The skin and mucous membrane of cancer patients can be directly or indirectly impaired during the treatment of cancers, bringing about not physical but also psychological damages to cancer patients. A practical guideline is of great significance to improve the quality of life for patients suffered from cutaneous adverse events. Methods: This guideline was generated based on up-to-date evidence and the consensus of experts specialized in dermatology. Results: The current guideline include the baseline screening of skin and mucosal membranes, the manifestations of injuries on skin, mucosa and appendages, along with the treatment of them. The causal anti-tumor management include chemotherapy, radiotherapy, immune therapy and surgery. Conclusion: This guideline can be helpful to reduce the risk of cutaneous adverse events during anti-cancer treatment and improve the quality of life of patients suffered from these adverse events. [ABSTRACT FROM AUTHOR]

Simple Summary: The diagnosis of hairy-cell leukemia (HCL) and HCL-like disorders including the variant form of HCL (HCL-V), splenic diffuse red pulp lymphoma (SDRPL) and splenic marginal zone lymphoma (SMZL) is a challenge in clinical practice. We discuss the major points for the diagnosis of HCL and HCL-like disorders and we propose recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients. Introduction: Hairy-cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder (B-CLPD), whose favorable prognosis has changed with the use of purine nucleoside analogs (PNAs), such as cladribine (CDA) or pentostatin (P). However, some patients eventually relapse and over time HCL becomes resistant to chemotherapy. Many discoveries have been made in the pathophysiology of HCL during the last decade, especially in genomics, with the identification of the BRAFV600E mutation and cellular biology, including the importance of signaling pathways as well as tumor microenvironment. All of these new developments led to targeted treatments, especially BRAF inhibitors (BRAFis), MEK inhibitors (MEKis), Bruton's tyrosine kinase (BTK) inhibitors (BTKis) and recombinant anti-CD22 immunoconjugates. Results: The following major changes or additions were introduced in these updated guidelines: the clinical relevance of the changes in the classification of splenic B-cell lymphomas and leukemias; the increasingly important diagnostic role of BRAFV600E mutation; and the prognostic role of the immunoglobulin (IG) variable (V) heavy chain (H) (IGHV) mutational status and repertory. We also wish to insist on the specific involvement of bones, skin, brain and/or cerebrospinal fluid (CSF) of the disease at diagnosis or during the follow-up, the novel targeted drugs (BRAFi and MEKi) used for HCL treatment, and the increasing role of minimal residual disease (MRD) assessment. Conclusion: Here we present recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients as well as for HCL-like disorders including HCL variant (HCL-V)/splenic B-cell lymphomas/leukemias with prominent nucleoli (SBLPN) and splenic diffuse red pulp lymphoma (SDRPL). [ABSTRACT FROM AUTHOR]

The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper understanding of the metabolic mechanisms associated with TKI resistance is critical for refining therapeutic strategies. In this study, we established resistance to sunitinib and pazopanib by exposing a parental Caki-1 cell line to increasing concentrations of sunitinib and pazopanib. The intracellular and extracellular metabolome of sunitinib- and pazopanib-resistant mRCC cells were investigated using a nuclear magnetic resonance (NMR)-based metabolomics approach. Data analysis included multivariate and univariate methods, as well as pathway and network analyses. Distinct metabolic signatures in sunitinib- and pazopanib-resistant RCC cells were found for the first time in this study. A common metabolic reprogramming pattern was observed in amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolism. Sunitinib-resistant cells exhibited marked alterations in metabolites involved in antioxidant defence mechanisms, while pazopanib-resistant cells showed alterations in metabolites associated with energy pathways. Sunitinib-resistant RCC cells demonstrated an increased ability to proliferate, whereas pazopanib-resistant cells appeared to restructure their energy metabolism and undergo alterations in pathways associated with cell death. These findings provide potential targets for novel therapeutic strategies to overcome TKI resistance in mRCC through metabolic regulation. [ABSTRACT FROM AUTHOR]

Objective: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. Methods: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. Results: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. Conclusion: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies. [ABSTRACT FROM AUTHOR]

Alkaptonuria is an inborn error of metabolism inherited as an autosomal recessive disorder due to a mutation in the homogentisic acid dioxygenase gene. It occurs rarely (global prevalence of alkaptonuria is 1 in 100,000 to 250,000), and mainly affects the joints and connective tissue of the body due to deposition of homogentisic acid giving affected areas a blue-black discoloration (ochronosis). In this case report, we present a male patient, aged 47 years, with joint and scleral involvement. He had been diagnosed many years ago with the disease by gas chromatography. His symptoms kept progressively worsening since he was recently prescribed physiotherapy and vitamin C for his disease, which has not been shown to be an effective treatment. A main reason for his disease deterioration was also the lack of nitisinone availability in his home country, as well as in the subcontinent region generally. We also presen a summary of some previously reported cases and treatment regimens to compare our case and present the comparison as a learning source for future physicians. [ABSTRACT FROM AUTHOR]

We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals. [ABSTRACT FROM AUTHOR]

Methionine biosynthesis in most microorganisms proceeds in two alternative ways. Each pathway is catalyzed by independent enzymes and is tightly regulated by methionine. The transulfurylation pathway involves the formation of a cystathionine, and cysteine acts as a source of sulfur. The enzymes of this metabolic pathway are characterized in detail. The direct sulfhydrylation pathway involves the synthesis of homocysteine with the participation of an inorganic sulfur source directly from O-acetylhomoserine and is predominant in most classes of bacteria. The subject of this review is the properties and functioning of one of the least studied enzymes of the direct sulfhydrylation pathway—O-acetylhomoserine sulfhydrylase. A deep understanding of the mechanisms controlling the substrate and reaction specificity of O-acetylhomoserine sulfhydrylase is a necessary step in the rational redesign of the enzyme in order to create a promising catalyst for the synthesis of methionine and its derivatives, as well as, in combination with crystallographic data, for the development of new antimicrobial compounds based on effective enzyme inhibitors. [ABSTRACT FROM AUTHOR]

In enzyme kinetic chemical reaction, inhibitors are working as a regulators of the metabolism of the systems and the biochemical activities as well. The main focus of this study is to explore the fractional dynamics of enzyme kinetic biochemical reactions with competitive and uncompetitive inhibitors. Further, the analysis continuous with the optimal controls on the system which accelerate biochemical reactions and maximize product generation. Eventually, the numerical analysis have been done by the Adams predictor–corrector method and the forward–backward sweep method for the dynamics and optimal control study, respectively. [ABSTRACT FROM AUTHOR]

Purpose of Review: On 1 July 2023, the Therapeutic Goods Administration approved 3,4‐methylenedioxymethamphetamine (MDMA)‐assisted psychotherapy for the treatment of post‐traumatic stress disorder (PTSD). Accordingly, the purpose of this review is to provide an overview of MDMA and what pharmacists should know as this treatment emerges. Sources of Information: EMBASE, MEDLINE, and CINAHL databases were searched to provide an overview narrative synthesis of the literature on MDMA, relevant to pharmacists. Key Findings: Cytochrome P450 2D6 is involved in the metabolic pathway of MDMA, an enzyme inhibited by a number of drugs used in the pharmacological management of PTSD (e.g. selective serotonin reuptake inhibitors). Co‐administration of these drugs with MDMA can lead to increases in plasma MDMA concentrations. Additionally, inhibition of the serotonin transporter can inhibit the uptake of MDMA into the presynaptic terminal, dampening the effects of MDMA and potentially, limiting the effectiveness of MDMA‐assisted psychotherapy. Accordingly, these drugs are typically withdrawn prior to treatment with MDMA. While selective serotonin reuptake inhibitor/serotonin noradrenaline reuptake inhibitor drugs with MDMA are unlikely to cause serotonin toxicity, monoamine oxidase inhibitors can. Other drugs, such as caffeine, alcohol, over‐the‐counter medicines, and complimentary/alternative medicines, can also interact with MDMA. Conclusion: With a detailed knowledge of the pharmacology of MDMA, pharmacists may play a role in MDMA‐assisted psychotherapy by collecting a detailed medication history and assisting clinicians in the withdrawal of interacting medicines. [ABSTRACT FROM AUTHOR]

Human serum carnosinase is an enzyme that operates the preferential hydrolysis of dipeptides with a C-terminus histidine. Only higher primates excrete such an enzyme in serum and cerebrospinal fluid. In humans, the serum hydrolytic rate has high interindividual variability owing to gene polymorphism, although age, gender, diet, and also diseases and surgical interventions can modify serum activity. Human genetic diseases with altered carnosinase activity have been identified and associated with neurological disorders and age-related cognitive decline. On the contrary, low peripheral carnosinase activity has been associated with kidney protection, especially in diabetic nephropathy. Therefore, serum carnosinase is a druggable target for the development of selective inhibitors. However, only one molecule (i.e., carnostatine) has been discovered with the purpose of developing serum carnosinase inhibitors. Bestatin is the only inhibitor reported other than carnostatine, although its activity is not selective towards serum carnosinase. Herein, we present a review of the most critical findings on human serum carnosinase, including enzyme expression, localization and substrate selectivity, along with factors affecting the hydrolytic activity, its implication in human diseases and the properties of known inhibitors of the enzyme. [ABSTRACT FROM AUTHOR]

Objective: Short peptides play a significant role in exploring drugs with higher selectivity and fewer side effects in cancer and COVID-19 therapies. This study evaluated the anticancer and anti-COVID-19 activities of Glu-Arg-Gln (ERQ) tripeptide for the first time. To discover the potentiality of the tripeptide as an anticancer and as a SARS-CoV-2 inhibitor, molecular docking analysis of ERQ tripeptide with DNA (PDB ID: 1BNA) and a variety of SARS-CoV-2 enzymes, namely. Main protease (PDB IDs: 6M03, 6LU7) and Spike glycoprotein (PDB ID: 6VXX) were performed. Materials and Methods: To determine the binding efficiency of ERQ to target DNA and proteins, molecular docking processes were carried out using the Autodock Vina program. The sorts of bonds and interacting residues in ERQ/DNA and ERQ/protein complexes were determined. Results: Molecular docking simulations of ERQ tripeptide against 1BNA, 6M03, 6LU7, and 6VXX were performed, and the interactions between the docked ligand and target residues were determined. The binding mechanisms of ERQ with the receptors were clarified. The binding affinities of ERQ towards the targets were predicted to be between -6.3 and -6.7 kcal/mol. ERQ showed the highest binding affinity to Spike glycoprotein (6VXX), with an estimated binding energy of -6.7 kcal/mol. Conclusion: Molecular docking simulations revealed the potential of ERQ tripeptide as an anticancer and anti-COVID-19 agent. High binding affinity against 1BNA (-6.4 kcal/mol), 6M03 (-6.3 kcal/mol), 6LU7 (-6.6 kcal/mol), and 6VXX (-6.7 kcal/mol) indicated that ERQ could be an excellent new natural therapy for the treatment of cancer and COVID-19. [ABSTRACT FROM AUTHOR]

Simple Summary: This review discusses the enzymatic processes governing the initial stages of the synthesis of glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine) and triacylglycerol. The key enzymes analyzed include glycerol-3-phosphate acyltransferases (GPAT) and 1-acylglycerol-3-phosphate acyltransferases (AGPAT). Additionally, because most AGPATs have lysophospholipid acyltransferase (LPLAT) activity, enzymes involved in the Lands cycle with similar functions were also included. The review further explores the potential therapeutic implications of inhibiting these enzymes in the treatment of metabolic diseases and cancer. By elucidating the enzymatic pathways involved in lipid synthesis and their impact on various pathological conditions, the article contributes to the understanding of these processes and their potential as therapeutic targets. This review delves into the enzymatic processes governing the initial stages of glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine) and triacylglycerol synthesis. The key enzymes under scrutiny include GPAT and AGPAT. Additionally, as most AGPATs exhibit LPLAT activity, enzymes participating in the Lands cycle with similar functions are also covered. The review begins by discussing the properties of these enzymes, emphasizing their specificity in enzymatic reactions, notably the incorporation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid and docosahexaenoic acid (DHA) into phospholipids. The paper sheds light on the intricate involvement of these enzymes in various diseases, including obesity, insulin resistance, and cancer. To underscore the relevance of these enzymes in cancer processes, a bioinformatics analysis was conducted. The expression levels of the described enzymes were correlated with the overall survival of patients across 33 different types of cancer using the GEPIA portal. This review further explores the potential therapeutic implications of inhibiting these enzymes in the treatment of metabolic diseases and cancer. By elucidating the intricate enzymatic pathways involved in lipid synthesis and their impact on various pathological conditions, this paper contributes to a comprehensive understanding of these processes and their potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Mutation of the SMARCB1 gene can cause one of the most aggressive and lethal cancers of early childhood and infancy, malignant rhabdoid tumor (MRT). Despite the standard multimodal therapy (resection, conventional chemotherapy, and radiotherapy), the outlook for young children with MRT is poor. For infants, the disease can also preclude the use of radiotherapy. Numerous experimental treatments explore epigenetic mechanisms, but the DNA damage response has not yet been extensively evaluated as a therapeutic approach for MRT. We report a new therapeutic strategy for SMARCB1-deficient MRTs, combining PARP1 inhibition and DNA damage induction. The observed synergy between the PEGylated PARP1 inhibitor talazoparib (PEG~TLZ) and the DNA alkylating agent temozolomide (TMZ) may lead to improved therapeutic strategies for patients with this challenging cancer. We identified a new potential biomarker of response to PEG~TLZ+TMZ, O6-methylguanine methyltransferase (MGMT), and uncovered dysregulated signaling pathways involved in the response. Additionally, we elucidated the pro-survival role of SMARCB1 loss in MRT cells. Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)—a pivotal component of the SWI/SNF chromatin remodeling complex—is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD), a chronic inflammatory, pruritic skin disorder, is seen primarily in the pediatric population but can be found among all age groups. The symptoms of AD can cause embarrassment in patients and can interrupt daily activities and productivity, potentially resulting in avoidance of social situations. In addition to nonpharmacologic management, mainstay pharmacologic treatments for AD are topical medications including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and topical Janus kinase (JAK) inhibitors. Promising new drugs—oral JAK inhibitors and monoclonal antibodies—have emerged as new treatment options for moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Thyroid cancer is a common endocrine malignancy with increasing incidence globally. Although most cases can be treated effectively, some cases are more aggressive and have a higher risk of mortality. Inhibiting RET and BRAF kinases has emerged as a potential therapeutic strategy for the treatment of thyroid cancer, particularly in cases of advanced or aggressive disease. However, the development of resistance mechanisms may limit the efficacy of these kinase inhibitors. Therefore, developing precise strategies to target thyroid cancer cell metabolism and overcome resistance is a critical area of research for advancing thyroid cancer treatment. In the field of cancer therapeutics, researchers have explored combinatorial strategies involving dual metabolic inhibition and metabolic inhibitors in combination with targeted therapy, chemotherapy, and immunotherapy to overcome the challenge of metabolic plasticity. This review highlights the need for new therapeutic approaches for thyroid cancer and discusses promising metabolic inhibitors targeting thyroid cancer. It also discusses the challenges posed by metabolic plasticity in the development of effective strategies for targeting cancer cell metabolism and explores the potential advantages of combined metabolic targeting. [ABSTRACT FROM AUTHOR]

Background: Older adults with diabetes mellitus require drug treatment considering their frailty, cognitive function, and hypoglycemia. Objective: We investigated the association between diabetic pharmacologic therapy and both diabetic complications and frailty across eight diabetes-specific outpatient clinics nationwide. Methods: Participants (aged 60–80 years) who had type 2 diabetes and did not require nursing care were included in the study. Basic attributes, patient background, complications, hypoglycemic status, body weight, body composition, blood tests, grip strength, and Kihon Checklist (a frailty index) and self-care scores were obtained. Descriptive statistics, t-test, chi-square test, and regression analyses were employed for evaluation. Results: Overall, 417 participants were included (224 men, 193 women, mean age 70.1 ± 5.4 years, diabetes duration 14.9 ± 10.9 years, body mass index 24.5 ± 3.8, glycated hemoglobin 7.22 ± 0.98%, proportion of individuals with frailty and prefrailty, 19.9% and 41.0%, respectively). All drugs were used more frequently in prefrailty conditions. Each diabetes medication was related to complications, body composition, and frailty, as follows: sulfonylurea (lower hypoglycemia); glinide (severe hypoglycemia, retinopathy, weaker grip strength, high Kihon Checklist score, decreased physical activities); alpha-glucosidase inhibitors (no association); biguanide (high body mass index, high body fat, stronger grip strength); thiazolidinedione (decreased instrumental activities of daily living); dipeptidyl‐peptidase‐4 inhibitors (no association); sodium-glucose cotransporter 2 inhibitors; retinopathy, high body mass index and Kihon Checklist score, and depressive mood); glucagon-like peptide-1 receptor agonists (high body mass index and body fat and poor nutritional status); and insulin preparations (hypoglycemia, retinopathy, neuropathy, nephropathy, cardiovascular diseases, weaker grip strength, and high Kihon Checklist score and physical inactivity). Conclusions: Some formulations, such as glinide, sodium-glucose cotransporter 2 inhibitors, and insulin, are associated with an increased frequency of frailty, warranting careful and individualized diabetes treatment. [ABSTRACT FROM AUTHOR]

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an effective way to initiate an immune response against tumors, and the research on agonists targeting STING has become a new hotspot in the development of antitumor drugs. However, as a novel STING agonist, the limited bioavailability and activation routes of manganese ions (Mn2+) significantly hinder its antitumor effects. To address these challenges, we have designed a metal-coordinated nucleoside metabolic inhibitor (gemcitabine, Gem)-induced metal nanotheranostic (MGP) with PEGylation. This formulation synergistically enhanced the immune response against cancer cells by sensitizing the cGAS-STING pathway and promoting immunogenic cell death (ICD). Modified with PEG derivatives, MGP was efficiently delivered to the tumor site and was internalized by cancer cells. Upon internalization, the release of Mn2+ triggered the activation of the cGAS-STING pathway, while the release of Gem induced DNA damage. On the one hand, the damaged DNA caused by Gem leaked into the cytoplasm, synergistically amplified Mn2+-induced activation of the cGAS-STING pathway, and induced the production of the tumor cytotoxic factor IFN-β. On the other hand, Mn2+-mediated chemodynamic therapy (CDT) exhibited an ICD effect, which further synergized with the activation of the cGAS-STING pathway to promote dendritic cells (DCs) maturation and antigen-specific T cells infiltration. Both in vitro and in vivo studies have demonstrated that MGP nanotheranostics could elicit a robust antitumor effect, especially when combined with anti-PD-1. This study provided a new paradigm for intensifying immune activation by constructing metal coordination nanotheranostics. [Display omitted] • Metal coordination nanotheranostics for tumor immunotherapy. • Mn2+ induces chemodynamic therapy and activates the STING pathway. • Chemotherapy-elicited damaged DNA sensitizes the STING pathway activation. [ABSTRACT FROM AUTHOR]

A number of new conjugates of dehydroabiethylamine and adamantane was obtained using a three-step synthetic scheme in order to study the effect of linker type and length on biological activity. The inhibitory activity of the synthesized compounds toward the DNA repair enzyme Tyrosyl-DNA phosphodiesterase 1 was studied. The compounds are potent inhibitors, exhibiting activity in micromolar concentrations. [ABSTRACT FROM AUTHOR]

A method comprising the use of a fluorinating agent, the Ishikawa's reagent, at one of its steps was developed for the synthesis of 1,3,5-trifluoroadamantane-7-isocyanate from 3,5,7-trifluoroadamantane-1-carboxylic acid and diphenylphosphoryl azide. The reaction of 1,3,5-trifluoroadamantane-7-isocyanate with fluoroanilines gave 1,3-disubstituted ureas in the yields of 58–73%. The influence of number of the fluorine atoms in the adamantyl moiety on the melting point, lipophilicity, and water solubility of ureas was estimated, which allows one to intentionally tune these important properties of ureas as promising enzyme inhibitors. The molecular docking revealed the effectiveness of 4-({4-[3-(3,5,7-trifluoroadamantan-1-yl)ureido]cyclohexyl}oxy)benzoic acid in the inhibition of p38 MAPK, c-Raf and hsEH. [ABSTRACT FROM AUTHOR]

Background To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer. Methods This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy. Results Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of −73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation. Conclusions Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted. Clinical Trial Registration ChiCTR2100046678. [ABSTRACT FROM AUTHOR]

This study aimed to explore the potential of Urtica dioica (U. dioica) ethanolic leaf extract for cancer treatment by identifying its components, evaluating its effects on cancer cell lines, and analyzing its molecular docking. The objective of this study was to investigate the anticancer properties of U. dioica ethanolic leaf extract and assess its potential as a therapeutic strategy for cancer treatment. This study utilized high-performance liquid chromatography (HPLC) to analyze the chemical composition of U. dioica ethanolic leaf extract. The anticancer effects of the extract were evaluated by assessing cell viability, determining IC50 values, and conducting ADMET analysis after oral administration. U. dioica ethanolic leaf extract was found to contain methyl hexadecanoate as its primary component, along with flavonoids and polyphenols. It effectively reduced cell viability in various tested cancer cell lines, with IC50 values varying for each cell line. The duration of treatment significantly influenced cell viability, with the most significant reduction observed after 48 h. Molecular docking studies suggested that catechin, kaempferol, and quercetin-3-O-rutinoside may have potential as inhibitors of the MTHFD2 enzyme. This study revealed the potential of U. dioica and its compounds in cancer treatment. Ethanolic leaf extract has been shown to have anticancer effects on various cancer cell lines, with catechin and kaempferol showing promise as inhibitors of the MTHFD2 enzyme. Further research is warranted to explore the therapeutic implications of U. dioica in cancer treatment. [ABSTRACT FROM AUTHOR]

Given that novel anticancer therapies have different toxicity profiles and mechanisms of action, it is important to reconsider the current approaches for dose selection. In an effort to move away from considering the maximum tolerated dose as the optimal dose, the Food and Drug Administration Project Optimus points to the need of incorporating long-term toxicity evaluation, given that many of these novel agents lead to late-onset or cumulative toxicities and there are no guidelines on how to handle them. Numerous methods have been proposed to handle late-onset toxicities in dose-finding clinical trials. A summary and comparison of these methods are provided. Moreover, using PI3K inhibitors as a case study, we show how late-onset toxicity can be integrated into the dose-optimization strategy using current available approaches. We illustrate a re-design of this trial to compare the approach to those that only consider early toxicity outcomes and disregard late-onset toxicities. We also provide proposals going forward for dose optimization in early development of novel anticancer agents with considerations for late-onset toxicities. [ABSTRACT FROM AUTHOR]

Optimal recovery of muscle function after proximal nerve injuries remains a complex and challenging problem. After a nerve injury, alterations in the affected muscles lead to atrophy, and later degeneration and replacement by fat-fibrous tissues. At present, several different strategies for the preservation of skeletal muscle have been reported, including various sets of physical exercises, muscle massage, physical methods (e.g. electrical stimulation, magnetic field and laser stimulation, low-intensity pulsed ultrasound), medicines (e.g. nutrients, natural and chemical agents, anti-inflammatory and antioxidants, hormones, enzymes and enzyme inhibitors), regenerative medicine (e.g. growth factors, stem cells and microbiota) and surgical procedures (e.g. supercharge end-to-side neurotization). The present review will focus on methods that aimed to minimize the damage to muscles after denervation based on our present knowledge. [ABSTRACT FROM AUTHOR]

Background: Ceftazidime-Avibactam (CAZ-AVI) is one of the new antibiotics available to treat infections due to carbapenem-resistant gram-negative bacteria (CRB). Our aim was to describe the use of CAZ-AVI in children admitted to pediatric intensive care units (PICUs), with suspected or proven CRB infections. Methods: A retrospective descriptive study was conducted in two PICUs of Rio de Janeiro, Brazil, between January 2020 and January 2024. Children aged 0 to 18 years who received CAZ-AVI for more than 24 h were included. Results: CAZ-AVI was used in 37 patients. The median age was 28 months (range 1–215), 17 (45.9%) being male. The median time from the patient admission to the initial prescription of CAZ-AVI was 39.9 days (range 1–138). Thirty-four (91.9%) children had at least one comorbidity at admission and (91.9%) used at least one invasive device prior to the CAZ-AVI prescription, and 89.2% had received carbapenem before; and fifteen (40.5%) had healthcare-associated infection (HAI) prior to CAZ-AVI use. The mean time of CAZ-AVI use was 11 days (range 1–22). Gram-negative bacteria were isolated in cultures from 12 (32.4%) patients in the 24 h prior to prescription or on the day of prescription. In five patients, CRB was confirmed in cultures, and in four (80%) of them, microbiological clearance was verified after 7 days of treatment. The 30-day mortality rate was 37.8%. Conclusion: Almost all patients who used CAZ-AVI were critically ill children with multiple comorbidities and previous use of carbapenems. Among CRB confirmed infections, microbiology clearance in 7 days was high. [ABSTRACT FROM AUTHOR]

Objective: Postprandial hyperglycemia is considered an early sign of diabetes. Enzyme inhibitors, such as α-amylase and α-glucosidase inhibitors, are currently being studied as potential drugs for preventing postprandial hyperglycemia. Methods: In this study, we investigated the effects of four purified 7-hydroxycoumarine derivatives from Ferula assafoetida: umbelliprenin, farnesiferol A, farnesiferol C, and samarcandin. We evaluated cell toxicity using the MTT method and also examined glucose uptake and inhibition of α-amylase and α-glucosidase enzymes in vitro. Additionally, we conducted a molecular docking study to investigate the mechanism of enzyme inhibition. Results: The cell toxicity of the terpenoid coumarin derivatives (umbelliprenin, farnesiferol A, farnesiferol C, and samarcandin) on HepG2 cells was found to be approximately 28 to 37 µg/ml. The glucose uptake assay showed that these compounds (at a concentration of 25 µg/ml) were able to increase glucose consumption by HepG2 cells to a level comparable to that of the positive control (metformin at 50 µg/ml). Furthermore, umbelliprenin significantly inhibited the activity of α-amylase and α-glucosidase (by 35.07% and 4.98%, respectively). Molecular docking results indicated that umbelliprenin, with a farnesyl chain, had a more potent inhibitory effect. Conclusion: Our findings suggest that umbelliprenin may be a valuable compound for controlling postprandial hyperglycemia and diabetes. However, further in vivo studies and clinical trials are necessary to validate these effects. While this research offers potential for the development of more effective compounds with coumarin structures, further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

The present study screened various fungal species for inhibitors of alpha-glucosidase, alpha-amylase, and DPP-4, enzymes that are crucial in carbohydrate metabolism. Ethanolic extracts exhibited superior inhibitory activity compared to water extracts, suggesting their potential as sources of anti-diabetic agents. Further fractionation revealed fomentariol from Fomes fomentarius as a potent inhibitor of alpha-glucosidase and DPP-4, with higher activity against alpha-glucosidase than acarbose. Fomentariol presents a novel avenue for diabetes management, demonstrating the simultaneous inhibition of key enzymes in glucose metabolism. However, comprehensive clinical studies are needed to evaluate its safety and efficacy in humans. [ABSTRACT FROM AUTHOR]

BackgroundIsocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.MethodsIn a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.ResultsA total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P

A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered 17, which showed excellent potency toward both rat (Ki 15 nM) and human nNOS (Ki 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. 17 also showed excellent permeability (Pe = 13.7 × 10-6 cm s-1), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and >60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors.