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HPLC-UV-guided fractionation of crude extract from the marine sediment-derived bacterium Streptomyces sp. CNP-944 has yielded two new pyrazine alkaloids, actinopolymorphols E and F (1 and 2), in addition to the previously reported biosynthetic product, actinopolymorphol G (3), and the known actinopolymorphol D (4). The chemical structures of 1-3 were determined based on the interpretation of the 1D, 2D NMR, and MS spectroscopic data. Compound 2 displayed weak antibacterial activities against Kocuria rhizophila, Bacillus subtilis, and Staphylococcus aureus with minimum inhibitory concentration (MIC) values of 16, 64, and 64 μg ml

FLT3 tyrosine kinase inhibitor (TKI) therapy evolved into a standard therapy in FLT3-mutated AML. TKI resistance, however, develops frequently with poor outcomes. We analyzed acquired TKI resistance in AML cell lines by multilayered proteome analyses. Leupaxin (LPXN), a regulator of cell migration and adhesion, was induced during early resistance development, alongside the tyrosine kinase PTK2B which phosphorylated LPXN. Resistant cells differed in cell adhesion and migration, indicating altered niche interactions. PTK2B and LPXN were highly expressed in leukemic stem cells in FLT3-ITD patients. PTK2B/FAK inhibition abrogated resistance-associated phenotypes, such as enhanced cell migration. Altered pathways in resistant cells, assessed by nascent proteomics, were largely reverted upon PTK2B/FAK inhibition. PTK2B/FAK inhibitors PF-431396 and defactinib synergized with different TKIs or daunorubicin in FLT3-mutated AML. Midostaurin-resistant and AML cells co-cultured with mesenchymal stroma cells responded particularly well to PTK2B/FAK inhibitor addition. Xenograft mouse models showed significant longer time to leukemia symptom-related endpoint upon gilteritinib/defactinib combination treatment in comparison to treatment with either drug alone. Our data suggest that the leupaxin-PTK2B axis plays an important role in acquired TKI resistance in AML. PTK2B/FAK inhibitors act synergistically with currently used therapeutics and may overcome emerging TKI resistance in FLT3-mutated AML at an early timepoint.

We hereby introduce a sensitive fast straightforward spectrofluorometric method for the estimation of remdesivir and favipiravir. The two drugs are prescribed in some regimens to treat COVID‐19 pandemic disease, which is caused by SARS‐CoV‐2. The method is based on the first derivative synchronous spectrofluorimetry approach for the measurement of remdesivir and favipiravir. This was accomplished at 251 nm and 335 nm respectively using the first derivative order at delta lambda of 140 nm. A linear response with a correlation coefficient 0.9994 was achieved between the concentration and the derivative amplitudes in the ranges of 20.0–100.0 ng ml−1 and 40.0–100.0 ng ml−1 for remdesivir and favipiravir, respectively. The methods were validated for different parameters as stated by the pharmacopeial rules and were applied successfully for estimation of the studied drugs in their synthetic mixtures and in spiked human plasma samples. No significant difference was observed between the proposed and comparison methods as revealed from the analysis of data.

Since the appearance of coronavirus disease 2019 (COVID-19), numerous studies have been conducted to find effective therapeutics. Favipiravir (FVP) is one of the repurposed drugs which has been authorized in a few countries on an emergency basis to treat COVID-19. Elderly individuals especially 65 years or older are more prone to develop severe illness. We aim to provide a short summary of the current knowledge of the antiviral efficacy of favipiravir with respect to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected elderly patients. We found that it is rather controversial whether favipiravir is effective against SARS-CoV-2 infection. Data regarding patients 65 years or older is not sufficient to support or reject the usage of favipiravir for COVD-19 treatment. Further studies would be advisable to elicit the efficiency of favipiravir in elderly COVID-19 patients.

Lipid droplets (LDs) are dynamic organelles which associated with many metabolic processes. Reliable long-term imaging of LD is of great importance in LD-based therapy and research. Conventional fluorescent probes suffer from poor photostability and difficulty of preparation, which compromise their LD imaging ability. In this study, we aim to provide a novel and universal fluorescent probe for LD-specific imaging in both eukaryotic and prokaryotic cells. The versatile and potential applications of the probe were also evaluated.We used one-step Suzuki coupling reaction to synthesize a fluoro-pyrazine-bridged donor-acceptor-donor fluorescent probe (T-FP-T). The fluorescent properties and stability of T-FP-T were detected. Then, LD-specific imaging and dynamic movement tracking capabilities of T-FP-T were studied in fungus, bacteria, plant and animal tissues. The biosafety and photodynamic toxicity of the probe under different light irradiation were characterized.T-FP-T showed large Stokes shift, superior brightness, excellent photostability, low toxicity. T-FP-T exhibited significant overlaps with adipophilin antibody or the commercial LD probe (LipidSpot™) in the cytoplasm, but not with Mitotracker red, Lysotracker red and Peroxisome Labeling dye. Moreover, T-FP-T also showed efficient superoxide anion generation capability under white LED light irradiation. The viability of Hela cells co-treated with T-FP-T and 1-h white LED light irradiation decreased to 62%.All these outstanding capabilities make T-FP-T a new efficient LD-specific imaging probe. The generated superoxide anion from T-FP-T under white LED light irradiation could cause obvious cell death, which will inspire broad study in LD-targeted photodynamic therapy.

Liver fibrosis is the common consequence of almost all liver diseases and has become an urgent clinical problem without efficient therapies. Recent evidence has shown that hepatocytes-derived extracellular vesicles (EVs) play important roles in liver pathophysiology, but little is known about the role of damaged hepatocytes-derived EVs in hepatic stellate cell (HSC) activation and following fibrosis. Tetramethylpyrazine (TMP) from Ligusticum wallichii Franchat exhibits a broad spectrum of biological activities including liver protection. In this study, we investigated whether TMP exerted liver-protective action through regulating EV-dependent intercellular communication between hepatocytes and HSCs. Chronic liver injury was induced in mice by CCl

The σ-hole interaction (type I), counterintuitive σ-hole interaction (type II) and type Ш noncovalent interaction system formed between three heterocyclic compounds (C4H4O, C5H5N and C4H4N2) and AtX (X = F, Cl and Br) have been investigated employing the MP2/aug-cc-pVTZ. For the C5H5N-AtX and C4H4N2-AtX complexes, the calculated interaction energy decreases according to the sequence type I > type II > type Ш. For the C4H4O-AtX complexes, the interaction energy decreases according to the sequence type II > type I > type Ш. For the same AtX, the interaction energy of type I and type Ш complexes decreases according to the sequence C5H5N > C4H4N2 > C4H4O. while for the type II complexes, the interaction energy decreases according to the sequence C4H4O > C5H5N > C4H4N2. SAPT analysis shows that the electrostatic energy are predominantly of the attraction for the typeⅠcomplexes while the type Ⅲ interactions are mainly electrostatic and dispersion energy. For the type Ⅱ complexes, the induction, dispersion and electrostatic term have been playing the same important in the total attractive interaction. NBO analysis have also been employed.

Introduction In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag. Methods Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019. Results Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan–Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively. Conclusions These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen. Trial Registration ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306 Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01898-1.

Three-component reaction of aldehydes with 3-(1H-indol-3-yl)-3-oxopropanenitrile and 1H-1,2,4-triazol-5-amine under the solvent-free condition at 70 °C was effectively performed in the presence of 2 mg of polyionic magnetic nanoparticles with pyrazine bridge [Fe3O4@SiO2@(CH2)3]2-Pyrazinium-[TCM]2 as a catalyst for the synthesis of 7-aryl-5-(1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitriles via a cooperative anomeric-based oxidation. The polyionic magnetic nanoparticles catalyst was simply recovered and reused four successive runs. The morphology and structure of MNPs catalyst were investigated by numerous techniques such as XRD, FT-IR, EDX, WDX, FE-SEM, TEM, TGA, DTA, and VSM. The obtained products are reported for the first time that were identified by various analyses techniques such as melting point, FT-IR, 1H NMR, 13C NMR, and elemental analysis (CHN). A term entitled a cooperative geminal-vinylogous anomeric-based oxidation was introduced for the latter step of the reaction mechanism for the first time. Synthesis of 7-aryl-5-(1H-indol-3-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitriles by using [Fe3O4@SiO2@(CH2)3]2-Pyrazinium-[TCM]2 MNPs as a catalyst.

Data suggests that favipiravir (FVP) could be used against SARS-CoV-2. Our aim was to investigate the role of FVP in COVID-19 treatment. A prospective sequential cohort study was performed among adults hospitalized at our center between March and August 2020 with moderate-to-severe, PCR-confirmed COVID-19. For diagnosis and severity, ECDC and WHO definitions were utilized. Patients were screened for inclusion by a priori criteria and included in the FVP cohort if standard-of-care (SOC) + FVP or the non-FVP cohort if SOC ± other antivirals without FVP were administered for > 48 h from diagnosis. Treatment allocation was done per national guidelines, based on severity and drug availability. Primary endpoint was disease progression, a composite of 14-day all-cause death, need for mechanical ventilation, or immunomodulatory therapy. The impact of FVP exposure on disease progression was analyzed by binomial logistic regression. In all, 150 patients were included, 75 in each cohort. Disease progression (17/75, 22.7% vs. 10/75, 13.3%, p = 0.13), 14-day all-cause death (9/75, 12.0% vs. 10/75, 13.3%, p = 0.8), and need for mechanical ventilation (8/75, 10.7% vs. 4/75, 5.3%, p = 0.22) were similar, while immunomodulatory therapies were required more frequently among patients receiving FVP (10/75, 13.3% vs. 1/75, 1.3%, p

The maturation period of high-temperature Daqu (HTD) is usually 3-6 months, and the characteristics of HTD at different maturation stages were different. In this study, the microbial characteristics and metabolite profiles of HTD at different maturation stages were revealed with the combination of physicochemical detection, the third generation Pacific Biosciences (PacBio) single-molecule, real-time (SMRT) sequencing technology, gas chromatography-mass spectrometry (GC-MS), and gas chromatography-ion mobility spectrometry (GC-IMS). Results showed that HTD matured for 6 months (Mix_m6) had higher saccharification power but less culturable thermotolerant bacteria and fungi than HTD matured for 3 months (Mix_m3). The average relative abundances of Thermoactinomyces, Paenibacillus, and Rasamsonia in Mix_m3 were higher than that in Mix_m6, while the average relative abundances of Bacillus, Pseudomonas, Thermoascus increased obviously with the prolongation of the maturation period. Streptomyces and Thermoactinomyces were biomarkers in Mix_m3, while Burkholderia and Pseudomonas were regarded as biomarkers in Mix_m6. Differences in microbiota structure led to different enrichment of metabolic pathways in HTD at different maturation stages, resulting in different flavor profiles, especially in ethyl acetate, 1-octen-3-one, (E)-3-Hexen-1, 2,3,5-trimethy-6-ethylpyrazine, pyrazine, tetramethyl content. The microbiota and metabolite characteristics of HTD comprehensively reflected the HTD quality in different maturation stages, which provided a reference for determining the optimal maturation time.

Background Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P Methods We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. Results Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). Conclusion Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

We performed a systematic review and meta-analysis for the effectiveness of Favipiravir on the fatality and the requirement of mechanical ventilation for the treatment of moderate to severe COVID-19 patients. We searched available literature and reported it by using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Until June 1, 2021, we searched PubMed, bioRxiv, medRxiv, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar by using the keywords “Favipiravir” and terms synonymous with COVID-19. Studies for Favipiravir treatment compared to standard of care among moderate and severe COVID-19 patients were included. Risk of bias assessment was performed using Revised Cochrane risk of bias tool for randomized trials (RoB 2) and ROBINS-I assessment tool for non-randomized studies. We defined the outcome measures as fatality and requirement for mechanical ventilation. A total of 2702 studies were identified and 12 clinical trials with 1636 patients were analyzed. Nine out of 12 studies were randomized controlled trials. Among the randomized studies, one study has low risk of bias, six studies have moderate risk of bias, and 2 studies have high risk of bias. Observational studies were identified as having moderate risk of bias and non-randomized study was found to have serious risk of bias. Our meta-analysis did not reveal any significant difference between the intervention and the comparator on fatality rate (OR 1.11, 95% CI 0.64–1.94) and mechanical ventilation requirement (OR 0.50, 95% CI 0.13–1.95). There is no significant difference in fatality rate and mechanical ventilation requirement between Favipiravir treatment and the standard of care in moderate and severe COVID-19 patients.

Ligustrazine, an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort, has been clinically applied to treat the cerebrovascular diseases. Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD). Memory deficits can be caused by Hhcy via pathologies of AD-like tau and amyloid-β (Aβ) in the hippocampus. Here, we investigated whether homocysteine (Hcy) can induce AD-like pathologies and the effects of ligustrazine on these pathologies. The Hcy rat model was constructed by 14-day Hcy injection via vena caudalis, and rats were treated with daily intragastric administration of ligustrazine at the same time. We found that the pathologies of tau and Aβ were induced by Hcy in the hippocampus, while the Hcy-induced tau hyperphosphorylation and Aβ accumulation could be markedly attenuated by simultaneous ligustrazine treatment. Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced AD-like pathologies.

Background Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. Methods We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. Results Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. Conclusions Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. Clinical trial identifier NCT02157792.

Background Preliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs. Objective To investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies. Patients and Methods In Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition. Results Seventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients. Conclusions The MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib. Trial registration: Clinicaltrials.gov; NCT02143466; 21 May 2014. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00806-5., Plain Language Summary For patients with epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors, like osimertinib, are the standard treatment. However, for most patients, these treatments eventually stop working, as tumors develop resistance to them. Early studies suggest that combining osimertinib with savolitinib can overcome this resistance. We report Part C of the four-part TATTON study, in which two groups of Japanese adult patients received treatment. One group received savolitinib 400 mg once daily, then 600 mg. The other group received osimertinib 80 mg with savolitinib 300/400/600 mg once daily. The main objective of the study was to determine the maximum dose of savolitinib that patients could receive (maximum tolerated dose) and to monitor the safety of the combination. Overall, 17 patients received savolitinib alone and 12 received the combination. The maximum tolerated dose of savolitinib was found to be 400 mg once daily in both groups of patients. The data demonstrated that savolitinib had acceptable safety outcomes either alone, or in combination with osimertinib. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00806-5.

Checkpoint kinase 1 (CHK1) has dual roles in both the DNA damage response and in the innate immune response to genotoxic stress. The combination of CHK1 inhibition and immune checkpoint blockade has the potential to enhance anti-tumoral T-cell activation. This was an open-label phase 1 study evaluating the CHK1 inhibitor prexasertib and the anti-PD-L1 antibody LY3300054. After a lead-in of LY3300054 (Arm A), prexasertib (Arm B) or the combination (Arm C), both agents were administered intravenously at their respective recommended phase 2 doses (RP2Ds) on days 1 and 15 of a 28-day cycle. Flow cytometry of peripheral blood was performed before and during treatment to analyze effects on immune cell populations, with a focus on T cell subsets and activation. Plasma cytokines and chemokines were analyzed using the Luminex platform. Among seventeen patients enrolled, the combination was tolerable at the monotherapy RP2Ds, 105 mg/m2 prexasertib and 700 mg LY3300054. Dose-limiting toxicities included one episode each of febrile neutropenia (Arm C) and grade 4 neutropenia lasting > 5 days (Arm B). One patient had immune-related AST/ALT elevation after 12 cycles. Three patients with CCNE1-amplified, high-grade serous ovarian cancer (HGSOC) achieved partial response (PR), 2 lasting > 12 months; a fourth such patient maintained stable disease > 12 months. Analysis of peripheral blood demonstrated evidence of CD8 + T-cell activation in response to treatment. Prexasertib in combination with PD-L1 blockade was tolerable and demonstrated preliminary activity in CCNE1-amplified HGSOC with evidence of cytotoxic T-cell activation in patient blood samples. ClinicalTrials.gov identifier: NCT03495323. Registered April 12, 2018.

Endotoxemia, a type of sepsis caused by gram-negative bacterial endotoxin [i.e., lipopolysaccharide (LPS)], is associated with manifestations such as cytokine storm; failure of multiple organs, including the liver; and a high mortality rate. We investigated the effect and mechanism of action of LGK974, a Wnt signaling inhibitor, in mice with LPS-induced endotoxemia, an animal model of sepsis. LGK974 significantly and dose-dependently increased the survival rate and reduced plasma cytokine levels in mice with LPS-induced endotoxemia. Transcriptome analysis of liver tissues revealed significant changes in the expression of genes associated with the Wnt pathway as well as cytokine and NF-κB signaling during endotoxemia. LGK974 treatment suppressed the activation of NF-κB signaling and cytokine expression as well as the Wnt/β-catenin pathway in the livers of endotoxemic mice. Coimmunoprecipitation of phospho-IκB and β-transducin repeat-containing protein (β-TrCP) was increased in the livers of endotoxemic mice but was reduced by LGK974 treatment. Moreover, LGK974 treatment decreased the coimmunoprecipitation and colocalization of β-catenin and NF-κB, which were elevated in the livers of endotoxemic mice. Our results reveal crosstalk between the Wnt/β-catenin and NF-κB pathways via interactions between β-TrCP and phospho-IκB and between β-catenin and NF-κB during endotoxemia. The results of this study strongly suggest that the crosstalk between the Wnt/β-catenin and NF-κB pathways contributes to the mutual activation of these two pathways during endotoxemia, which results in amplified cytokine production, liver damage and death, and that LGK974 suppresses this vicious amplification cycle by reducing the crosstalk between these two pathways., Inflammation: Stopping the out-of-control spiral A cancer drug called LGK974 may help treat sepsis, an exaggerated inflammatory response to infection leading to multiple organ failure and a leading cause of death in patients in intensive care. Sepsis can result when the body’s response to infection spirals out of control. Although the mechanism is poorly understood, the Wnt signaling pathway was recently reported to be involved. Yoosik Yoon at Chung-Ang University College of Medicine and Eek-hoon Jho at the University of Seoul, both in South Korea, investigated how LGK974, developed to fight cancers dependent on Wnt signaling, would affect sepsis, using a mouse model. They discovered that LGK974 interrupted feedback between Wnt and another signaling pathway, preventing uncontrolled amplification of inflammation. The mice showed decreased organ damage and increased survival. These results present a promising research direction for treating sepsis.

The Covid-19 pandemic is highly contagious and has spread rapidly across the globe. To date there have been no specific treatment options available for this life-threatening disease. During this medical emergency, target-based drug repositioning/repurposing with a continuous monitoring and recording of results is an effective method for the treatment and drug discovery. This review summarizes the recent findings on COVID-19, its genomic organization, molecular evolution through phylogenetic analysis and has recapitulated the drug targets by analyzing the viral molecular machinery as drug targets and repurposing of most frequently used drugs worldwide and their therapeutic applications in COVID-19. Data from solidarity trials have shown that the treatment with Chloroquine, hydroxychloroquine and lopinavir-ritonavir had no effect in reducing the mortality rate and also had adverse side effects. Remdesivir, Favipiravir and Ribavirin might be a safer therapeutic option for COVID-19. Recent clinical trial has revealed that dexamethasone and convalescent plasma treatment can reduce mortality in patients with severe forms of COVID-19.

T-006, a small-molecule compound derived from tetramethylpyrazine (TMP), has potential for the treatment of neurological diseases. In order to investigate the effect of T-006 prophylactic treatment on an Alzheimer's disease (AD) model and identify the target of T-006, we intragastrically administered T-006 (3 mg/kg) to Alzheimer's disease (AD) transgenic mice (APP/PS1-2xTg and APP/PS1/Tau-3xTg) for 6 and 8 months, respectively. T-006 improved cognitive ability after long-term administration in two AD mouse models and targeted mitochondrial-related protein alpha-F1-ATP synthase (ATP5A). T-006 significantly reduced the expression of phosphorylated-tau, total tau, and APP while increasing the expression of synapse-associated proteins in 3xTg mice. In addition, T-006 modulated the JNK and mTOR-ULK1 pathways to reduce both p-tau and total tau levels. Our data suggested that T-006 mitigated cognitive decline primarily by reducing the p-tau and total tau levels in 3xTg mice, supporting further investigation into its development as a candidate drug for AD treatment.

Macropinocytosis is a type of endocytosis accompanied by actin rearrangement-driven membrane deformation, such as lamellipodia formation and membrane ruffling, followed by the formation of large vesicles, macropinosomes. Ras-transformed cancer cells efficiently acquire exogenous amino acids for their survival through macropinocytosis. Thus, inhibition of macropinocytosis is a promising strategy for cancer therapy. To date, few specific agents that inhibit macropinocytosis have been developed. Here, focusing on the mechanosensitive ion channel Piezo1, we found that Yoda1, a Piezo1 agonist, potently inhibits macropinocytosis induced by epidermal growth factor (EGF). The inhibition of ruffle formation by Yoda1 was dependent on the extracellular Ca2+ influx through Piezo1 and on the activation of the calcium-activated potassium channel KCa3.1. This suggests that Ca2+ ions can regulate EGF-stimulated macropinocytosis. We propose the potential for macropinocytosis inhibition through the regulation of a mechanosensitive channel activity using chemical tools.

A novel electrochemical sensor is reported for the detection of the antiviral drug favipiravir based on the core-shell nanocomposite of flower-like molybdenum disulfide (MoS

Purpose Berzosertib (formerly M6620) is the first-in-class inhibitor of ataxia–telangiectasia and Rad3-related protein, a key component of the DNA damage response, and being developed in combination with chemotherapy for the treatment of patients with advanced cancers. The objectives of this analysis were to characterize the pharmacokinetics (PK) of berzosertib across multiple studies and parts, estimate inter-individual variability, and identify covariates that could explain such variability. Methods A population PK analysis was performed using the combined dataset from two phase I clinical studies (NCT02157792, EudraCT 2013-005100-34) in patients with advanced cancers receiving an intravenous infusion of berzosertib alone or in combination with chemotherapy. The analysis included data from 240 patients across 11 dose levels (18–480 mg/m2). Plasma concentration data were modeled with a non-linear mixed-effect approach and clinical covariates were evaluated. Results PK data were best described by a two-compartment linear model. For a typical patient, the estimated clearance (CL) and intercompartmental CL were 65 L/h and 295 L/h, respectively, with central and peripheral volumes estimated to be 118 L and 1030 L, respectively. Several intrinsic factors were found to influence berzosertib PK, but none were considered clinically meaningful due to a very limited effect. Model simulations indicated that concentrations of berzosertib exceeded p-Chk1 (proximal pharmacodynamic biomarker) IC50 at recommended phase II doses in combination with carboplatin, cisplatin, and gemcitabine. Conclusions There was no evidence of a clinically significant PK interaction between berzosertib and evaluated chemo-combinations. The covariate analysis did not highlight any need for dosing adjustments in the population studied to date. Clinical Trial information NCT02157792, EudraCT 2013-005100-34

Currently, minimally invasive approach is preferred for the treatment of ventral hernias. After the introduction of extended view totally extraperitoneal (e-TEP) technique, there has been a constant debate over the choice of better approach. In this study, we compare the short-term outcomes of e-TEP and laparoscopic IPOM Plus repair for ventral hernias. This is a comparative, prospective single-center study done at GEM Hospital and research center Coimbatore, India from July 2018 to July 2019. All patients who underwent elective ventral hernia surgery with defect size of 2 to 6 cm were included. Patient demographics, hernia characteristics, operative and perioperative findings, and postoperative complications were systematically recorded and analyzed. We evaluated 92 cases (n = 92), 46 in each group. Mean age, sex, BMI, location of hernia, primary and incisional hernia, and comorbidity were comparable in both the groups. Mean defect size for IPOM Plus and e-TEP was 4 cm and 3.89 cm, respectively. Operative time was significantly higher for e-TEP, while postoperative pain (VAS), analgesic requirement, and postoperative hospital stay were significantly less as compared to IPOM Plus. However, 2 cases (4.35%) of e-TEP had recurrence but none in IPOM Plus group. e-TEP is an evolving procedure and comparable to IPOM Plus in terms of postoperative pain, analgesic requirement, cost of mesh, and length of hospital stay. More randomized controlled and multicentric studies are required with longer follow-up to validate our findings.

AIMS/HYPOTHESIS: Growth hormone (GH) causes insulin resistance that is linked to lipolysis, but the underlying mechanisms are unclear. We investigated if GH-induced insulin resistance in skeletal muscle involves accumulation of diacylglycerol (DAG) and ceramide as well as impaired insulin signalling, or substrate competition between fatty acids and glucose.METHODS: Nine GH-deficient male participants were randomised and examined in a 2 × 2 factorial design with and without administration of GH and acipimox (an anti-lipolytic compound). As-treated analyses were performed, wherefore data from three visits from two patients were excluded due to incorrect GH administration. The primary outcome was insulin sensitivity, expressed as the AUC of the glucose infusion rate (GIRAUC), and furthermore, the levels of DAGs and ceramides, insulin signalling and the activity of the active form of pyruvate dehydrogenase (PDHa) were assessed in skeletal muscle biopsies obtained in the basal state and during a hyperinsulinaemic-euglycaemic clamp (HEC).RESULTS: Co-administration of acipimox completely suppressed the GH-induced elevation in serum levels of NEFA (GH versus GH+acipimox, p CONCLUSIONS/INTERPRETATION: GH-induced insulin resistance in skeletal muscle is: (1) causally linked to lipolysis; (2) not associated with either accumulation of DAGs and ceramides or impaired insulin signalling; (3) likely to involve substrate competition between glucose and lipid intermediates.TRIAL REGISTRATION: ClinicalTrials.gov NCT02782208 FUNDING: The work was supported by the Grant for Growth Innovation (GGI), which was funded by Merck KGaA, Darmstadt, Germany. Graphical abstract.

Gilteritinib (Xospata®), a next-generation tyrosine kinase inhibitor (TKI), is approved in several countries/regions worldwide for the treatment of relapsed or refractory acute myeloid leukaemia (AML) in adults with FMS-like tyrosine kinase 3 (FLT3) mutations. In this patient population, oral gilteritinib significantly improved overall survival (OS) and the response rate for complete remission with full or partial haematological recovery compared with salvage chemotherapy in the phase III ADMIRAL trial. In an integrated safety analysis of patients with relapsed or refractory AML, the most commonly reported grade ≥ 3 treatment-related adverse events (AEs) in gilteritinib recipients included anaemia, febrile neutropenia and thrombocytopenia. Clinically relevant AEs of special interest (AESIs) with gilteritinib therapy included differentiation syndrome, posterior reversible encephalopathy syndrome, QT interval prolongation and pancreatitis. AEs, including AESIs, were generally manageable with dose reduction, interruption or discontinuation. All patients of reproductive potential should use contraception during gilteritinib treatment due to the risk of embryo-foetal toxicity. Given its convenient oral regimen, along with the poor prognosis and paucity of treatment options for adults with relapsed or refractory FLT3-mutated AML, gilteritinib represents a valuable first-line targeted monotherapy in these patients.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell development, differentiation and B-cell receptor (BCR) signaling. The use of Bruton's tyrosine kinase inhibitors (BTKi) in the treatment of lymphoid malignancies has dramatically increased, owing to both impressive efficacy and ease of administration. However, BTKi have a range of drug-drug and drug-food interactions, which may alter drug efficacy and/or increase toxicity. Healthcare professionals should be aware of the probability of drug interactions with BTKi and make recommendations accordingly. In this article, we discuss the relevant drug-drug and drug-food interactions associated with ibrutinib, acalabrutinib, and zanubrutinib, and provide clinical practice recommendations for managing these interactions based on the available literature.

Background Novel coronavirus disease 2019 (COVID-19) refers to infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, and has spread to pandemic levels since its inception in December 2019. While several risk factors for severe presentation have been identified, the clinical course for end-stage renal disease (ESRD) patients on maintenance hemodialysis with COVID-19 has been unclear. Previous studies have revealed that some antiviral agents may be effective against COVID-19 in the general population, but the pharmacokinetics and pharmacodynamics of these agents in ESRD patients remain under investigation. Favipiravir, an antiviral agent developed for treatment of influenza, is one candidate treatment for COVID-19, but suitable dosages for patients with renal insufficiency are unknown. Here we provide a first report on the efficacy of favipiravir in a patient with ESRD undergoing hemodialysis. Case presentation The case involved a 52-year-old woman with COVID-19 who had been undergoing maintenance hemodialysis three times a week for 3 years due to diabetic nephropathy. She had initially been treated with lopinavir/ritonavir and ciclesonide for 5 days, but developed severe pneumonia requiring invasive positive-pressure ventilation. Those antiviral agents were subsequently switched to favipiravir. She recovered gradually, and after 2 weeks was extubated once the viral load of SARS-CoV-2 fell below the limit of detection. Although concentrations of several biliary enzymes were elevated, no major adverse events were observed. Conclusion Favipiravir may be an effective option for the treatment of COVID-19-infected patients with ESRD.

Drug toxicity and efficacy are difficult to predict partly because they are both poorly defined, which I aim to remedy here from a transcriptomic perspective. There are two major categories of drugs: (1) restorative drugs aiming to restore an abnormal cell, tissue, or organ to normal function (e.g., restoring normal membrane function of epithelial cells in cystic fibrosis), and (2) disruptive drugs aiming to kill pathogens or malignant cells. These two types of drugs require different definition of efficacy and toxicity. I outlined rationales for defining transcriptomic efficacy and toxicity and illustrated numerically their application with two sets of transcriptomic data, one for restorative drugs (treating cystic fibrosis with lumacaftor/ivacaftor aiming to restore the cellular function of epithelial cells) and the other for disruptive drugs (treating acute myeloid leukemia with prexasertib). The conceptual framework presented will help and sensitize researchers to collect data required for determining drug toxicity. Electronic supplementary material The online version of this article (10.1007/s10565-020-09552-2) contains supplementary material, which is available to authorized users.

Noroviruses are the main causative agents of acute viral gastroenteritis worldwide. However, no vaccine or specific antiviral treatment is available, imposing a heavy global health burden. The nucleoside analogue 2’-fluoro-2’-deoxycytidine (2’-FdC) has been reported to have broad antiviral activity. Here, we report that 2’-FdC significantly inhibits murine norovirus replication in macrophages. This effect was partially reversed by exogenous supplementation of cytidine triphosphate. The combination of 2’-FdC with mycophenolic acid, ribavirin or favipiravir (T705) exerts synergistic antiviral effects. These results indicate that 2’-FdC is a potential candidate for antiviral drug development against norovirus infection. Electronic supplementary material The online version of this article (10.1007/s00705-020-04759-4) contains supplementary material, which is available to authorized users.

Neuroblastoma, a common childhood tumor, remains one of the most elusive diseases to treat. To date, high-risk neuroblastoma is associated with low survival rates. To address this, novel and more effective therapeutic strategies must continue to be explored. We employed a bioinformatics approach corroborated with in vitro and in vivo data. Samples from neuroblastoma patients were retrieved and immuno-stained for Bruton’s tyrosine kinase (BTK). To evaluate its effect on cellular functions, BTK expression in SK-N-BE(2) and SH-SY5Y neuroblastoma cells was downregulated using gene silencing or inhibition with ibrutinib or acalabrutinib. Xenograft mouse models were used to investigate the in vivo role of BTK in neuroblastoma tumorigenesis. We found that BTK was highly expressed in primary neuroblastoma samples, preferentially in MYCN-amplified neuroblastoma cases, and was associated with a poor prognosis. Immunohistochemical staining of tissues from our neuroblastoma cohort revealed a strong BTK immunoreactivity. We also found that neuroblastoma SK-N-BE(2) and SH-SY5Y cells were sensitive to treatment with ibrutinib and acalabrutinib. Pharmacologic or molecular inhibition of BTK elicited a reduction in the migratory and invasive abilities of neuroblastoma cells, and ibrutinib considerably attenuated the neurosphere-forming ability of neuroblastoma cells. Both inhibitors showed synergism with cisplatin. In vivo assays showed that acalabrutinib effectively inhibited neuroblastoma tumorigenesis. From our data we conclude that BTK is a therapeutically targetable driver of neuroblastoma.

7511 Background: Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment (tx) of CLL and are associated with partial restoration of immune function with ongoing tx. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized. Methods: CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline (bl) and outcome data were collected including incidence (inc) of Richter’s transformation (RT), non-melanoma skin cancer (NMSC), and SPN. Standard inc ratio (SIR) with 95% confidence intervals (CI) were calculated using expected inc rates from the Surveillance, Epidemiology, and End Results Program, assuming a Poisson distribution for the observed inc. Cumulative inc (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow-up (f/u). SPN was correlated with bl data using the Fine-Gray model. Results: 691 pts were included; median age was 64 years (y), median prior lines of treatment (tx) was 2 (20% tx-naïve, 66% with prior chemo-immunotherapy), and 56% were never smokers. At median f/u of 44 months, 68 pts (10%) were diagnosed (dx) with SPN (SIR 2.4, CI 1.9-3.0) including 13 lung (SIR 3.2, CI 1.7-5.5), 9 melanoma (SIR 6.9, CI 3.1-13), 9 prostate (SIR 1.4, CI 0.6-2.6), 7 bladder (SIR 5.2, CI 2.1-10.6) cancers. CIR of SPN at 3 y was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7-5.0, p < .01) and low bl CD8 count (HR 0.9 for 2-fold increase, CI 0.8-0.9, p < .01) were associated with higher inc of SPN. RT was dx in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 y overall survival of 79% (CI 76-82); the most common causes of death were CLL/RT (57%) and SPN (13%). Conclusions: The inc of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 y CIR of NMSC and SPN of 23% and 12%, these data support consideration of intensive cancer screening for CLL pts receiving BTKi. [Table: see text]

We previously reported that tetramethylpyrazine (TMP) alleviates experimental autoimmune encephalomyelitis (EAE) by decreasing glia activation. Activated microglia has been shown to mediate blood-spinal cord barrier (BSCB) disruption, which is a primary and continuous pathological characteristic of multiple sclerosis (MS). Therefore, in this study, we further investigated whether TMP protects the BSCB integrity by inhibition of glia activation to alleviate EAE. Extravasation of evans blue was used to detect the BSCB disruption. Tumor necrosis factor-α (TNF-α)/interlukine-1β (IL-1β) and interlukine-4 (IL-4)/interlukine-10 (IL-10) were determined by enzyme-linked immunosorbent assay. BV2 glial cells stimulated by interferon-γ (IFN-γ) were co-cultured with human brain microvascular endothelial cells to investigate the effect of TMP on the BSCB disruption. Flow cytometry was used to analyze the microglia phenotype. Western blot was performed to reveal the signaling pathways involved in the microglia activation. In this study, most importantly, we found that TMP protects the BSCB integrity by modulating microglia polarization from M1 phenotype to M2 phenotype through activation of STAT3/SOCS3 and inhibition of NF-кB signaling pathways. Moreover, TMP significantly preserves the tight junction proteins, reduces the secretion of pro-inflammatory cytokines (TNF-α, IL-1β) and increases the secretion of anti-inflammatory cytokines (IL-4, IL-10) from IFN-γ-stimulated BV2 microglia cells. Consequently, protection of the BSCB integrity leads to alleviation of clinical symptoms and demyelination in EAE mice. Therefore, TMP might be an effective therapeutic agent for cerebral disorders with BBB or BSCB disruption, such as ischemic stroke, MS, and traumatic brain injury.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.

Patients with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML) respond to conventional induction chemotherapy, with remission rates similar to those seen in other subtypes; however, they are much more likely to relapse and relapse is rapid. For this reason, eligible patients receive consolidation therapy with early allogenic transplantation, but the recurrence rate remains high, even after transplantation. Moreover, the optimal therapy for patients with FLT3-ITD AML who relapse after allogeneic hematopoietic stem cell transplantation remains unclear. Here, we report a case in which graft-versus-leukemia (GVL) effects were induced by gilteritinib administration after a second transplant from the same donor, resulting in sustained remission of early FLT3-ITD AML relapse after allogeneic transplantation. Several studies suggest that the benefits of FLT3 tyrosine kinase inhibitors (FLT3-TKI) after allogeneic transplantation are attributable to GVL induction, as well as direct effects on FLT3 mutation-positive leukemia cells. With this in mind, we induced lymphodepletion using L-PAM to further enhance GVL induction by donor lymphocytes and FLT3-TKI. We believe that enhancement of GVL induction by lymphodepletion should be considered before FLT3-TKI use, if the prognosis is very poor, such as in patients with recurrence following allogeneic transplantation.

Isocyanides as key intermediates and magic reactants have been widely applied in organic reactions for direct access to a broad spectrum of remarkable organic compounds. Although the history of these magical compounds dates back more than 100 years, it still has been drawing widespread attention of chemists who confirmed their versatility and effectiveness. Because of their wide spectrum of pharmacological, industrial and synthetic applications, many reactions with the utilization of isocyanides are reported in the literature. In this context, Iranian scientist played a significant role in the growth of isocyanides chemistry. The present review article covers literature from the period starting from 2010 onward and encompasses new synthetic routes and organic transformation involving isocyanides by Iranian researchers. During this period, a diverse range of isocyanide-based multi-component reactions (I-MCRs) has been reported such as a new modification of Ugi, post-Ugi, Passerini and Groebke-Blackburn-Bienayme condensation reactions, isocyanide-based [1 + 4] cycloaddition reactions, isocyanide-acetylene-based MCRs, isocyanide and Meldrum's acid-based MCRs, several unexpected reactions besides green mediums and novel catalytic systems for the synthesis of diverse kinds of pharmaceutically and industrially remarkable heterocyclic and linear organic compounds. This review also emphasizes the neoteric applications of I-MCR for the synthesis of valuable peptide and pseudopeptide scaffolds, enzyme immobilization and functionalization of materials with tailorable properties that can play important roles in the plethora of applications.

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in approximately one third of patients with acute myeloid leukemia (AML), either by internal tandem duplications (FLT3-ITD), or by a point mutation mainly involving the tyrosine kinase domain (FLT3-TKD). Patients with FLT3-ITD have a high risk of relapse and low cure rates. Several FLT3 tyrosine kinase inhibitors have been developed in the last few years with variable kinase inhibitory properties, pharmacokinetics, and toxicity profiles. FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) based on their potency and specificity of FLT3 inhibition. These diverse FLT3 inhibitors have been evaluated in myriad clinical trials as monotherapy or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front-line, relapsed or refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. In this practical question-and-answer-based review, the main issues faced by the leukemia specialists on the use of FLT3 inhibitors in AML are addressed.

AIMS/HYPOTHESIS: Sodium–glucose cotransporter 2 (SGLT2) inhibitors, which prevent the renal reabsorption of glucose, decrease blood glucose levels in an insulin-independent manner. We previously reported creating a mouse model of systemic inhibition of target receptors for both insulin and IGF-1 by treating animals with OSI-906, a dual insulin/IGF-1 receptor inhibitor, for 7 days. The OSI-906-treated mice exhibited an increased beta cell mass, hepatic steatosis and adipose tissue atrophy, accompanied by hyperglycaemia and hyperinsulinaemia. In the present study, we investigated the effects of an SGLT2 inhibitor, luseogliflozin, on these changes in OSI-906-treated mice. METHODS: We treated C57BL/6J male mice either with vehicle, luseogliflozin, OSI-906 or OSI-906 plus luseogliflozin for 7 days, and phenotyping was performed to determine beta cell mass and proliferation. Subsequently, we tested whether serum-derived factors have an effect on beta cell proliferation in genetically engineered beta cells, mouse islets or human islets. RESULTS: SGLT2 inhibition with luseogliflozin significantly ameliorated hyperglycaemia, but not hyperinsulinaemia, in the OSI-906-treated mice. Liver steatosis and adipose tissue atrophy induced by OSI-906 were not altered by treatment with luseogliflozin. Beta cell mass and proliferation were further increased by SGLT2 inhibition with luseogliflozin in the OSI-906-treated mice. Luseogliflozin upregulated gene expression related to the forkhead box M1 (FoxM1)/polo-like kinase 1 (PLK1)/centromere protein A (CENP-A) pathway in the islets of OSI-906-treated mice. The increase in beta cell proliferation was recapitulated in a co-culture of Irs2 knockout and Insr/IR knockout (βIRKO) beta cells with serum from both luseogliflozinand OSI-906-treated mice, but not after SGLT2 inhibition in beta cells. Circulating factors in both luseogliflozin- and OSI-906-treated mice promoted beta cell proliferation in both mouse islets and cadaveric human islets. CONCLUSIONS/INTERPRETATION: These results suggest that luseogliflozin can increase beta cell proliferation through the activation of the FoxM1/PLK1/CENP-A pathway via humoral factors that act in an insulin/IGF-1 receptor-independent manner.

Background Older adults (≥65 years) with diabetes and multiple chronic conditions (MCC) (> 2 chronic conditions) experience reduced function and quality of life, increased health service use, and high mortality. Many community-based self-management interventions have been developed for this group, however the evidence for their effectiveness is limited. This paper presents the protocol for a randomized controlled trial (RCT) comparing the effectiveness and implementation of the Aging, Community and Health Research Unit-Community Partnership Program (ACHRU-CPP) to usual care in older adults with diabetes and MCC and their caregivers. Methods We will conduct a cross-jurisdictional, multi-site implementation-effectiveness type II hybrid RCT. Eligibility criteria are: ≥65 years, diabetes diagnosis (Type 1 or 2) and at least one other chronic condition, and enrolled in a primary care or diabetes education program. Participants will be randomly assigned to the intervention (ACHRU-CPP) or control arm (1:1 ratio). The intervention arm consists of home/telephone visits, monthly group wellness sessions, multidisciplinary case conferences, and system navigation support. It will be delivered by registered nurses and registered dietitians/nutritionists from participating primary care or diabetes education programs and program coordinators from community-based organizations. The control arm consists of usual care provided by the primary care setting or diabetes education program. The primary outcome is the change from baseline to 6 months in mental functioning. Secondary outcomes will include, for example, the change from baseline to 6 months in physical functioning, diabetes self-management, depressive symptoms, and cost of use of healthcare services. Analysis of covariance (ANCOVA) models will be used to analyze all outcomes, with intention-to-treat analysis using multiple imputation to address missing data. Descriptive and qualitative data from older adults, caregivers and intervention teams will be used to examine intervention implementation, site-specific adaptations, and scalability potential. Discussion An interprofessional intervention supporting self-management may be effective in improving health outcomes and client/caregiver experience and reducing service use and costs in this complex population. This pragmatic trial includes a scalability assessment which considers a range of effectiveness and implementation criteria to inform the future scale-up of the ACHRU-CPP. Trial registration Clinical Trials.gov Identifier NCT03664583. Registration date: September 10, 2018.

Gestational diabetes mellitus (GDM) is a disease characterized by insufficient insulin secretion and glucose metabolic disorder during pregnancy. Tetramethylpyrazine has been reported to inhibit endoplasmic reticulum (ER) stress and high glucose-induced inflammation, which are closely associated with GDM. This study aimed to investigate the effects of tetramethylpyrazine on inflammatory responses, ER stress and oxidative stress of the placenta in a mouse model of GDM. Our results showed that tetramethylpyrazine treatment significantly alleviated the GDM symptoms characterized by low body weight and serum insulin levels, high blood glucose, and decreased β-cell function in pregnant C57BL/KsJdb/+ mice. In addition, tetramethylpyrazine reduced the level of malondialdehyde, and increased the levels of superoxide dismutase, glutathione peroxidase and glutathione. Moreover, tetramethylpyrazine decreased the total serum cholesterol, serum triglyceride, and serum low-density lipoprotein levels and increased the high-density lipoprotein level. Further, tetramethylpyrazine regulated the levels of serum and placental inflammatory factors and the expression of ER stress related proteins. Taken together, the present study demonstrated that tetramethylpyrazine attenuated placental oxidative stress, inflammatory responses and ER stress in GDM mice.

Graphical abstract A novel and sensitive voltammetric nanosensor was developed for the first time for trace level monitoring of favipiravir based on gold/silver core–shell nanoparticles (Au@Ag CSNPs) with conductive polymer poly (3,4-ethylene dioxythiophene) polystyrene sulfonate (PEDOT:PSS) and functionalized multi carbon nanotubes (F-MWCNTs) on a glassy carbon electrode (GCE). The formation of Au@Ag CSNPs/PEDOT:PSS/F-MWCNT composite was confirmed by various analytical techniques, including X-ray diffraction (XRD), ultraviolet–visible spectroscopy (UV–Vis), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), and field-emission scanning electron microscopy (SEM). Under the optimized conditions and at a typical working potential of + 1.23 V (vs. Ag/AgCl), the Au@Ag CSNPs/PEDOT:PSS/F-MWCNT/GCE revealed linear quantitative ranges from 0.005 to 0.009 and 0.009 to 1.95 µM with a limit of detection 0.46 nM (S/N = 3) with acceptable relative standard deviations (1.1-4.9 %) for pharmaceutical formulations, urine, and human plasma samples without applying any sample pretreatment (1.12–4.93%). The interference effect of antiviral drugs, biological compounds, and amino acids was negligible, and the sensing system demonstrated outstanding reproducibility, repeatability, stability, and reusability. The findings revealed that this assay strategy has promising applications in diagnosing FAV in clinical samples, which could be attributed to the large surface area on active sites and high conductivity of bimetallic nanocomposite. Supplementary Information The online version contains supplementary material available at 10.1007/s00604-021-05107-2.

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy [1,2,3,4,5]. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitors may address some limitations.

Multiple myeloma (MM) is a hematological cancer resulting from accumulated abnormal plasma cells. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and the platelet-derived growth factor receptor. Generally, the mechanism of inhibition of non-receptor tyrosine kinase c-Abl has played an essential role in the inhibition of cancer progression. However, little is known regarding the effects of the c-Abl inhibitor, radotinib on MM cells. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Interestingly, radotinib caused apoptosis in MM cells including RPMI-8226, MM.1S, and IM-9 cells, even in the absence of c-kit expression in 2 of these lines. Radotinib treatment significantly increased the number Annexin V-positive cells and decreased the mitochondrial membrane potential in MM cells. Additionally, we observed that cytochrome C was localized in the cytosol of radotinib-treated MM cells. Moreover, radotinib decreased the expression of Bcl-2 and Bcl-xL, and increased the expression of Bax and Bak in MM cells. Furthermore, radotinib promoted caspase pathway activation by inducing the expression and activity of caspase-3, -7, and -9. Expression of cleaved PARP-1 was also increased by radotinib treatment in various MM cells. In addition, radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells, and killed ex vivo myeloma cells from patients. In conclusion, radotinib may play an important role as a candidate agent or chemosensitizer for the treatment of MM.

About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.

Purpose The primary objective was to determine the recommended Phase 2 dose (RP2D) of checkpoint kinase 1 inhibitor, prexasertib, in combination with the p38 mitogen-activated protein kinase inhibitor, ralimetinib, which may be safely administered to patients with advanced cancer. Methods This Phase 1, nonrandomized, open-label, dose-escalation study of prexasertib+ralimetinib included patients with advanced and/or metastatic cancer, followed by a planned cohort expansion in patients with colorectal or non-small-cell lung cancer with KRAS and/or BRAF mutations. Intravenous prexasertib was administered at 60 mg/m2 (days 1 and 15 of a 28-day cycle), together with oral ralimetinib every 12 h (days 1 to 14 at 100 mg [Cohort 1, n = 3] or 200 mg [Cohort 2, n = 6]). Dose escalations for each agent were planned using a model-based 3 + 3 escalation paradigm. Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0X. Tumor response was determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results Nine patients were treated; 3 experienced dose-limiting toxicities, all in Cohort 2, prohibiting further dose escalation. The most common ≥Grade 3 adverse event was neutrophil count decreased; other reported ≥Grade 3 hematological toxicities included febrile neutropenia and anemia. The pharmacokinetics of prexasertib+ralimetinib was comparable to the monotherapy population profile for each agent. One patient achieved a best overall response of stable disease (for 2 cycles); there were no complete/partial responses. Conclusions This study did not achieve its primary objective of establishing an RP2D of combination prexasertib + ralimetinib that could be safely administered to patients with advanced cancer.

Background Severe fever and thrombocytopenia syndrome (SFTS) is an acute illness with a high mortality (16.2–29.1%). Unfortunately, there is no specific cure or vaccine for SFTS. Methods In this open-label study, two patients with SFTS were treated with favipiravir, a new antiviral drug. Results Patients had a sustainable virologic, immunologic and symptomatic recovery. Conclusions Favipiravir may be a prosiming drug for the treatment of SFTS. Electronic supplementary material The online version of this article (10.1007/s15010-019-01364-9) contains supplementary material, which is available to authorized users.

Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials.

Background Up to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression. We asked whether ATM-deficient lung cancer cell lines are sensitive to poly-ADP ribose polymerase (PARP) inhibitors and determined the mechanism of action of olaparib in ATM-deficient A549 cells. Methods We analysed drug sensitivity data for olaparib and talazoparib in lung adenocarcinoma cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) project. We deleted ATM from A549 lung adenocarcinoma cells using CRISPR/Cas9 and determined the effects of olaparib and the ATM/Rad3-related (ATR) inhibitor VE-821 on cell viability. Results IC50 values for both olaparib and talazoparib positively correlated with ATM mRNA levels and gene amplification status in lung adenocarcinoma cell lines. ATM mutation was associated with a significant decrease in the IC50 for olaparib while a similar trend was observed for talazoparib. A549 cells with deletion of ATM were sensitive to ionising radiation and olaparib. Olaparib induced phosphorylation of DNA damage markers and reversible G2 arrest in ATM-deficient cells, while the combination of olaparib and VE-821 induced cell death. Conclusions Patients with tumours characterised by ATM-deficiency may benefit from treatment with a PARP inhibitor in combination with an ATR inhibitor.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized in part by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The main pathological hallmark of PD is the intraneuronal accumulation of misfolded α-synuclein (α-syn) aggregates. Mutations in the SNCA gene (encoding α-syn) and variations in its copy number are associated with some forms of familial PD. In the present study, T-006, a new tetramethylpyrazine (TMP) derivative with recently reported anti-Alzheimer activity, is shown to significantly promote α-syn degradation in a cellular PD model. Moreover, we illustrate that T-006 inhibits the accumulation of both Triton-soluble and -insoluble forms of α-syn and protects against α-syn-induced neurotoxicity in A53T-α-syn transgenic mice. The mechanism of action of T-006 was verified by evaluation of a potential protein degradation pathway. We found that T-006 promotes α-syn degradation in a proteasome-dependent and autophagy-independent manner. We further confirmed that T-006 enhances proteasome activity by upregulating 20S proteasome subunit β5i (LMP7) protein expression. A functional study revealed that T-006 activates the PKA/Akt/mTOR/p70S6K pathway to trigger LMP7 expression and enhance chymotrypsin-like proteasomal activity. These findings indicate that T-006 is a potent proteasome activator and a potential therapeutic agent for the prevention and treatment of PD and related diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00759-8) contains supplementary material, which is available to authorized users.