Compact and explicit physical model for lateral metal-oxide-semiconductor field-effect transistor with nanoelectromechanical system based resonant gate

International audienceWe propose a simple analytical model of a metal-oxide-semiconductor field-effect transistor with a lateral resonant gate based on the coupled electromechanical equations, which are self-consistently solved in time. All charge densities according to the mechanical oscillations are evaluated. The only input parameters are the physical characteristics of the device. No extra mathematical parameters are used to fit the experimental results. Theoretical results are in good agreement with the experimental data in static and dynamic operation. Our model is comprehensive and may be suitable for any electromechanical device based on the field-effect transduction

Presynaptic adenosine receptor-mediated regulation of diverse thalamocortical short-term plasticity in the mouse whisker pathway

Short-term synaptic plasticity (STP) sets the sensitivity of a synapse to incoming activity and determines the temporal patterns that it best transmits. In “driver” thalamocortical (TC) synaptic populations, STP is dominated by depression during stimulation from rest. However, during ongoing stimulation, lemniscal TC connections onto layer 4 neurons in mouse barrel cortex express variable STP. Each synapse responds to input trains with a distinct pattern of depression or facilitation around its mean steady-state response. As a result, in common with other synaptic populations, lemniscal TC synapses express diverse rather than uniform dynamics, allowing for a rich representation of temporally varying stimuli. Here, we show that this STP diversity is regulated presynaptically. Presynaptic adenosine receptors of the A1R type, but not kainate receptors (KARs), modulate STP behavior. Blocking the receptors does not eliminate diversity, indicating that diversity is related to heterogeneous expression of multiple mechanisms in the pathway from presynaptic calcium influx to neurotransmitter release

Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study

Purpose: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization. Patients and methods: NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naïve to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS). Results: 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1). Conclusions: The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT

Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events.

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. CONCLUSION: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib

CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis.

Background & Aims Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3–5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. Methods This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7–B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Results Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5–25%) with 6 patients responding; disease control rate was 55% (95% CI 40–69%). Median time to response was 2.7 months (interquartile range, 1.4–4.2), and median duration of response was 9.9 months (95% CI 9.7–9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Conclusions Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. Lay summary In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. Clinical trial number NCT01658878

Radiological response to nivolumab in patients with hepatocellular carcinoma: A multicenter analysis of real-life practice

Background and aims: Immune-checkpoint inhibitors are effective in many advanced tumors. However, there is scarce information regarding the radiological response to these agents in hepatocellular carcinoma outside clinical trials. We aimed to describe the radiological response in a retrospective cohort of hepatocellular carcinoma patients treated with nivolumab and to analyze the radiological evolution according to tumor response at first post-treatment radiological assessment. Methods: We reviewed pre-treatment and post-treatment images (CT or MRI) obtained at different time-points in patients with hepatocellular carcinoma treated with nivolumab outside clinical trials at seven Spanish centers, assessing the response according to RECIST 1.1 and iRECIST and registering atypical responses. We also analyzed the imaging findings on subsequent assessments according to tumor status on the first posttreatment imaging assessment. Results: From the 118 patients with hepatocellular carcinoma treated with nivolumab, we finally analyzed data from 31 patients (71 % Child-Pugh A; 74 % BCLC-C). Median follow-up was 8.39 months [IQR 5.00-10.92]; median overall survival was 12.82 months (95 %CI 10.92-34.79). According to RECIST 1.1, the objective response rate was 16 % and according to iRECIST, the objective response rate was 22.6 %. Findings at the first post-treatment assessment varied, showing stable disease in 44.8 % of patients; findings during follow-up also varied widely, including 4 hyperprogressions and 3 pseudoprogressions. Conclusion: Imaging findings during nivolumab treatment are heterogeneous between and within patients. Progression of disease does not always signify treatment failure, and surrogate end-points may not reflect survival outcomes, making the management of hepatocellular carcinoma patients under immunotherapy challengin

Genetic association study of coronary collateral circulation in patients with coronary artery disease using 22 single nucleotide polymorphisms corresponding to 10 genes involved in postischemic neovascularization

Background: collateral growth in patients with coronary artery disease (CAD) is highly heterogeneous. Although multiple factors are thought to play a role in collateral development, the contribution of genetic factors to coronary collateral circulation (CCC) is largely unknown. The goal of this study was to assess whether functional single nucleotide polymorphisms (SNPs) in genes involved in vascular growth are associated with CCC. Methods: 677 consecutive CAD patients were enrolled in the study and their CCC was assessed by the Rentrop method. 22 SNPs corresponding to 10 genes involved in postischemic neovascularization were genotyped and multivariate logistic regression models were adjusted using clinically relevant variables to estimate odds ratios and used to examine associations of allelic variants, genotypes and haplotypes with CCC. Results: statistical analysis showed that the HIF1A rs11549465 and rs2057482; VEGFA rs2010963, rs1570360, rs699947, rs3025039 and rs833061; KDR rs1870377, rs2305948 and rs2071559; CCL2 rs1024611, rs1024610, rs2857657 and rs2857654; NOS3 rs1799983; ICAM1 rs5498 and rs3093030; TGFB1 rs1800469; CD53 rs6679497; POSTN rs3829365 and rs1028728; and LGALS2 rs7291467 polymorphisms, as well as their haplotype combinations, were not associated with CCC (p < 0.05). Conclusions: we could not validate in our cohort the association of the NOS3 rs1799983, HIF1A rs11549465, VEGFA rs2010963 and rs699947, and LGALS2 rs7291467 variants with CCC reported by other authors. A validated SNP-based genome-wide association study is required to identify polymorphisms influencing CCC

The opposing homeobox genes Goosecoid and Vent1/2 self-regulate Xenopus patterning

We present a loss-of-function study using antisense morpholino (MO) reagents for the organizer-specific gene Goosecoid (Gsc) and the ventral genes Vent1 and Vent2. Unlike in the mouse Gsc is required in Xenopus for mesodermal patterning during gastrulation, causing phenotypes ranging from reduction of head structures—including cyclopia and holoprosencephaly—to expansion of ventral tissues in MO-injected embryos. The overexpression effects of Gsc mRNA require the expression of the BMP antagonist Chordin, a downstream target of Gsc. Combined Vent1 and Vent2 MOs strongly dorsalized the embryo. Unexpectedly, simultaneous depletion of all three genes led to a rescue of almost normal development in a variety of embryological assays. Thus, the phenotypic effects of depleting Gsc or Vent1/2 are caused by the transcriptional upregulation of their opposing counterparts. A principal function of Gsc and Vent1/2 homeobox genes might be to mediate a self-adjusting mechanism that restores the basic body plan when deviations from the norm occur, rather than generating individual cell types. The results may shed light on the molecular mechanisms of genetic redundancy

Assessing the impact of COVID-19 on liver cancer management (CERO-19).

BACKGROUND & AIMS: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic. METHODS: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. RESULTS: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37). CONCLUSIONS: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making. LAY SUMMARY: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes