An abstract of the study by Kim et al examining the brain distributional kinetics of SAR405838, and correlate the observed changes in delivery with efficacy in glioblastoma (GBM) models is presented. ...In this study, a GBM PDX-model overexpressing MDM2 (G108) was modified with lentiviral transduction with either empty vector (G108-EV) or vector containing VEGFA transcript (G108-VEGF). Results, the tumor distribution of SAR405838 was greater and more homogeneous in G108-VEGFA tumors, based on the results of MALDI-Mass Spectrometry Imaging. Furthermore, brain delivery of SAR405838 is limited due to p-glyco-protein-mediated active efflux at the BBB.
Being able to replicate scientific findings is crucial for scientific progress
. We replicate 21 systematically selected experimental studies in the social sciences published in Nature and Science ...between 2010 and 2015
. The replications follow analysis plans reviewed by the original authors and pre-registered prior to the replications. The replications are high powered, with sample sizes on average about five times higher than in the original studies. We find a significant effect in the same direction as the original study for 13 (62%) studies, and the effect size of the replications is on average about 50% of the original effect size. Replicability varies between 12 (57%) and 14 (67%) studies for complementary replicability indicators. Consistent with these results, the estimated true-positive rate is 67% in a Bayesian analysis. The relative effect size of true positives is estimated to be 71%, suggesting that both false positives and inflated effect sizes of true positives contribute to imperfect reproducibility. Furthermore, we find that peer beliefs of replicability are strongly related to replicability, suggesting that the research community could predict which results would replicate and that failures to replicate were not the result of chance alone.
Medical‐refractory severe alcoholic hepatitis (AH) has a high mortality. The national frequency, longer term outcomes and regional practices of AH liver transplantation (LT) in the United States are ...not well described, despite the increasing mortality from alcohol‐associated liver disease. We analyzed the trends in frequency and outcomes of UNOS data on 39 455 adult patients who underwent LT from 2014 to 2019, including AH LT recipients. LTs for AH increased 5‐fold, from 28 in 2014 to 138 in 2019, varying 8‐fold between UNOS regions. Three transplant centers accounted for 50%‐90% of AH LTs within each region. The number of transplant centers performing AH LTs increased from 14 in 2014 to 47 in 2019. AH patients were younger (mean = 39.4 years), had higher MELD scores (mean = 36.8), and were more often on dialysis (46.0%) and in ICU (38.4%), compared to other indications (all P < .05). One‐ and 5‐year graft survivals for AH LT recipients were 91.7% and 81.9%, respectively. The frequency of AH LT is increasing rapidly, with excellent medium‐term outcomes. An impact of AH recurrence on patient or graft survival is not apparent in this national analysis. There are marked geographic variations in practices, highlighting the lack of selection criteria standardization.
This analysis of the US national transplant database shows that liver transplantation for alcoholic hepatitis has dramatically increased in recent years with excellent outcomes despite profound geographic variation in this practice. See the editorial from Maddur and Asrani on page 921.
This work proposes gallium oxide grown by plasma‐enhanced atomic layer deposition, as a surface passivation material at the CdS buffer interface of Cu(In,Ga)Se2 (CIGS) solar cells. In preliminary ...experiments, a metal‐insulator‐semiconductor (MIS) structure is used to compare aluminium oxide, gallium oxide, and hafnium oxide as passivation layers at the CIGS‐CdS interface. The findings suggest that gallium oxide on CIGS may show a density of positive charges and qualitatively, the least interface trap density. Subsequent solar cell results with an estimated 0.5 nm passivation layer show an substantial absolute improvement of 56 mV in open‐circuit voltage (VOC), 1 mA cm−2 in short‐circuit current density (JSC), and 2.6% in overall efficiency as compared to a reference (with the reference showing 8.5% under AM 1.5G).
This work proposes gallium oxide as a surface passivation layeron the photovoltaic material in Cu(In,Ga)Se2 (CIGS) solar cells. A metal‐insulator‐semiconductor (MIS) structure is used to compare aluminium oxide, gallium oxide, and hafnium oxide for this purpose. Solar cells fabricated with gallium oxide deposited between the CIGS and CdS buffer layer interface, show better performance than reference cells.
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in ...genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) Aversa , Biaryl amide compounds as kinase inhibitors and their preparation. WO 2014151616, 2014 , a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor ...overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and ...outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours.
Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure.
In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96).
Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes.
Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival.
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•Liver injury related to immune checkpoint inhibitors (irLI) is significantly more common in patients with HCC than other malignancies.•IrLI does not negatively affect outcomes of patients with HCC in terms of treatment discontinuation and hepatic decompensation.•Patients with HCC experiencing grade 1-2 irLI exhibit significantly better overall survival and objective response rates.
Background&aims: Unlike other malignancies, hepatic functional reserve competes with tumour progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative ...contribution of hepatic decompensation over tumour progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients. Approach&Results: From the AB-real observational study(n=898), we accrued 571 patients with advanced/unresectable HCC, Child-Pugh A class treated with frontline atezolizumab+bevacizumab(AB). Hepatic decompensation and tumour progression during follow-up were studied in relationship to patients’ OS using time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95%CI 5.1-19.7), 293 patients(51.3%) developed tumour progression without decompensation and 94(16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation(hazard ratioHR 19.04, 95%CI 9.75-37.19), HCC progression(HR 9.91, 95%CI 5.85-16.78), albumin-bilirubin(ALBI) grade 2/3(HR 2.16, 95%CI 1.69-2.77) and number of nodules>3(HR 1.63, 95%CI 1.28-2.08) were independently associated with OS. Pre-treatment ALBI grade 2/3(subdistribution HR sHR 3.35, 95%CI 1.98-5.67) was independently associated with decompensation, whereas viral aetiology was protective(sHR 0.55, 95%CI 0.34-0.87). Among patients with viral aetiology, effective antiviral treatment was significantly associated with lower risk of decompensation (sHR 0.48, 95%CI 0.25-0.93). Conclusions: Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI>1 and non-viral aetiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with non-viral aetiologies and the importance of multi-disciplinary management to maximise OS.
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