Brugada syndrome in a patient with AKAP9 mutation: Case report and review of the literature.

Brugada syndrome (BrS) is a rare autosomal dominant inherited channel disorder characterized by a specific electrocardiographic pattern of right precordial ST-segment elevation. Clinically, patients may experience polymorphic ventricular tachycardia and ventricular fibrillation, leading to recurrent syncope and sudden cardiac death (SCD) in the absence of structural cardiomyopathy. The A-kinase anchor protein 9 (AKAP9) gene, located on chromosome 7, encodes the AKAP9 protein, which plays a crucial role in regulating the phosphorylation of slowly activating delayed rectifier potassium channels (IKs). Here, we present a rare case of BrS associated with an insertion mutation in AKAP9, resulting in a frameshift mutation.

An Innovative Bi12 SiO20 Multistage Cubic Nanospheres Cathode for High-Performance Bi//Zn Battery.

Alkaline Bi//Zn batteries with superb safety, low cost, and high power density are promising candidates for large-scale electrical energy storage. However, their developments are severely limited by the Bi-based cathode as the unsatisfying capacity and cycle life. Herein, an innovative multistage cubic nanospheres Bi12 SiO20 (MCS-Bi12 SiO20 ) is successfully synthesized by a simple calcination method, which shows excellent energy storage performances of superior specific capacity (294 mAh g-1 at 0.5 A g-1 ) and outstanding rate capability (134 mAh g-1 at 12 A g-1 ). When coupled with Zn anode a superior MCS-Bi12 SiO20 //Zn is fabricated, which delivers a high energy density of 247.5 Wh kg-1 at the power density of 375 W kg-1 . Additionally, the MCS-Bi12 SiO20 //Zn battery shows excellent cycle life, which reserves more than 100 % of its original capacity after 5000 cycles. Such performance is higher than previously reported Bi//Zn battery and most other Zn batteries. This is the first example of using Bi12 SiO20 as cathode for RAZBs, which may provide highly promising material towards better Bi//Zn battery.

Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression.

BACKGROUND: This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression. METHODS: In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP). RESULTS: In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26-0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib. CONCLUSIONS: Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression. TRIAL REGISTRATION: ClinicalTrials.gov NCT01988493.

Immunogenicity of avelumab in patients with metastatic Merkel cell carcinoma or advanced urothelial carcinoma.

Like other monoclonal antibodies, immune checkpoint inhibitors may be immunogenic in some patients, potentially affecting pharmacokinetics (PKs) and clinical outcomes. In post hoc analyses, we characterized antidrug antibody (ADA) development with avelumab monotherapy in patients with metastatic Merkel cell carcinoma (mMCC) from the JAVELIN Merkel 200 trial (first-line [1L; N = 116] and second-line or later [≥2L; N = 88] cohorts) or with advanced urothelial carcinoma (aUC) from the JAVELIN Bladder 100 (1L maintenance [N = 350]) and JAVELIN Solid Tumor (≥2L [N = 249]) trials. Treatment-emergent ADAs developed in a numerically higher proportion of patients with aUC (1L maintenance, 19.1%; ≥2L, 18.1%) versus mMCC (1L, 8.2%; ≥2L, 8.9%); incidences within tumor types were similar by line of therapy. In PK analyses, numerically lower avelumab trough concentration and higher baseline clearance were observed in treatment-emergent ADA+ versus ADA- subgroups; however, differences were not clinically relevant. Numerical differences in overall survival, progression-free survival, or objective response rate by ADA status were observed; however, no clinically meaningful trends were identified. Proportions of patients with treatment-emergent adverse events (TEAEs; any grade or grade 3/4), serious TEAEs, TEAEs leading to treatment discontinuation, or infusion-related reactions were similar, with overlapping 80% confidence intervals between ADA subgroups. Efficacy and safety observations were similar in subgroups defined by early development of ADA+ status during treatment. In conclusion, no meaningful differences in PKs, efficacy, and safety were observed between subgroups of avelumab-treated patients with different ADA status. Overall, these data suggest that ADAs are not relevant for treatment decisions with avelumab.

A space-confined strategy towards stable α/ß-Bi2O3 heterojunction anode for high-energy aqueous battery.

It is very necessary to design a high-capacity and stable Bi2O3 anode for nickel-bismuth (Ni//Bi) batteries. In this work, a stable α- and ß- phase Bi2O3 heterojunction nanocomposite (α/ß - Bi2O3) was successfully prepared via a simple "space-confined" strategy and it was used as a superior anode for nickel-bismuth (Ni//Bi) battery. The α/ß-Bi2O3 obtained by using MCM-41 as a space-confined template possesses a stable structure and enhanced charge transfer capability. Such superior traits vest the designed α/ß-Bi2O3 electrode with high specific capacity (235 mAh g-1 at 1 A g-1), extraordinary rate performance (137 mAh g-1 at 40 A g-1, and ∼58% capacity retention vs 1 A g-1), and excellent cyclic durability (75% capacity retention after 5000 cycles). Such performances are far superior to that of mono-phase α-Bi2O3 and ß-Bi2O3 electrodes. Furthermore, an excellent Ni//Bi battery with outstanding energy density (∼155 Wh kg-1) and long cycle life was assembled using the obtained α/ß-Bi2O3 electrode and a NiC2O4 electrode as anode and cathode, respectively (NiC2O4//α/ß-Bi2O3). This work opens a new alternative strategy for the rational design of efficient electrodes for reliable aqueous rechargeable batteries.

Effects of norepinephrine­induced activation of rat vascular adventitial fibroblasts on proliferation and migration of BMSCs involved in vascular remodeling.

Vascular remodeling caused by vascular injury such as hypertension and atherosclerosis is a complex process involving a variety of cells and factors, and the mechanism is unclear. A vascular injury model was simulated by adding norepinephrine (NE) to culture medium of vascular adventitial fibroblasts (AFs). NE induced activation and proliferation of AFs. To investigate the association between the AFs activation and bone marrow mesenchymal stem cells (BMSCs) differentiation in vascular remodeling. BMSCs were cultured with supernatant of the AFs culture medium. BMSC differentiation and migration were observed by immunostaining and Transwell assay, respectively, while cell proliferation was measured using the Cell Counting Kit-8. Expression levels of smooth muscle actin (α-SMA), TGF-ß1 and SMAD3 were measured using western blot assay. The results indicated that compared with those in the control group, in which BMSCs were cultured in normal medium, expression levels of α-SMA, TGF-ß1 and SMAD3 in BMSCs cultured in medium supplemented with supernatant of AFs, increased significantly (all P<0.05). Activated AFs induced the differentiation of BMSCs into vascular smooth muscle-like cells and promoted proliferation and migration. AFs activated by NE may induce BMSCs to participate in vascular remodeling. These findings may help design and develop new approaches and therapeutic strategies for vascular injury to prevent pathological remodeling.

Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC.

Introduction: We present the results of a phase 2a trial of first-line avelumab (anti-programmed death-ligand 1 antibody) plus cetuximab (anti-EGFR antibody) in patients with advanced squamous NSCLC. Methods: Patients with recurrent or metastatic squamous NSCLC received avelumab 800 mg (d 1 and 8), cetuximab 250 mg/m2 (d 1) and 500 mg/m2 (d 8), cisplatin 75 mg/m2 (d 1), and gemcitabine 1250 mg/m2 (d 1 and 8) for four 3-week cycles, followed by avelumab 800 mg and cetuximab 500 mg/m2 every 2 weeks. The primary end point was the best overall response; the secondary end points were progression-free survival, duration of response, overall survival, and safety. Efficacy analyses were reported from an updated data cutoff. Results: A total of 43 patients were enrolled. The median follow-up was 6.6 months for the primary analyses and 9.2 months for the efficacy analyses. In the efficacy analyses, 15 patients had a confirmed partial response (objective response rate, 34.9% [95% confidence interval: 21.0%-50.9%]), and the median duration of response was 7.1 months (95% confidence interval: 4.2-12.5 mo). The median progression-free survival and overall survival were 6.1 months and 10.0 months, respectively. In the safety analyses (primary analysis), 38 patients (88.4%) had a treatment-related adverse event, of whom 24 (55.8%) had a grade 3 or higher treatment-related adverse event. Conclusions: The combination of avelumab + cetuximab and chemotherapy showed antitumor activity and tolerable safety; however, the ORR was not improved compared with those reported for current standards of care (NCT03717155).

Chinese- and French-Manufactured Immediate-Release Glucophage® Bioequivalence: A Randomized, Open-Label, Crossover Study.

OBJECTIVE: We aimed to assess the bioequivalence, safety, and tolerability of Chinese- and French-manufactured Glucophage® immediate-release (GIR) tablets under fasted and fed conditions in healthy volunteers. A bioequivalence study was proposed to support the manufacturing transfer. METHODS: This was an open-label, randomized, two-period, two-sequence, crossover study. Subjects were randomly assigned to receive the test product (one 500 mg GIR tablet manufactured in China) or reference product (one 500 mg GIR tablet manufactured in France). The primary study endpoint was the area under the plasma concentration-time curve from time zero to the last sampling time (AUCt) and maximum observed concentration (Cmax). RESULTS: In total, 96 subjects were screened and 44 subjects were randomly assigned to treatment (fasted group, 26 subjects; fed group, 18 subjects). All 44 subjects received the study drug, completed the study, and were included in the pharmacokinetic (PK) and safety analysis sets. Under fasted or fed conditions, the mean AUCt and Cmax (primary PK parameters) were comparable between the test and reference products. Point estimates for both parameters were close to 100% and the corresponding 90% confidence intervals were within the specified 80-125% bioequivalence boundary. There were no hypoglycemia-related adverse events (AEs) in either treatment group. All AEs in the present study were mild in severity. CONCLUSIONS: Bioequivalence between the test and reference GIR tablets was demonstrated under fasted and fed conditions and both were safe and well tolerated. CLINICAL TRIALS REGISTRATION: This study was registered at ClinicalTrials.gov under the identifying number NCT03393208.

Bioequivalence of China- and Germany-Manufactured Metformin Extended-Release Tablets Under Fed and Fasted Conditions in Healthy Volunteers: A Randomized, Open-Label, 2-Way Crossover Study.

We compared the bioequivalence, pharmacokinetics, and safety of metformin extended-release (MXR) tablets manufactured by Merck Pharmaceuticals Manufacturing (Jiangsu) Co., Ltd (Nantong, China) and Merck KGaA (Darmstadt, Germany) after a single oral dose under fasted/fed conditions. In this open-label phase 1 study, 54 healthy volunteers (fasted, n = 38; fed, n = 16) were randomly assigned to receive one 500-mg MXR tablet that was manufactured by Merck Pharmaceuticals Manufacturing (Jiangsu) Co. or Merck KGaA. Respectively, the mean terminal half-life was 7.5 and 6.8 hours in the fasted group, and 6.7 and 9.1 hours in the fed group. Median times to maximum observed concentration were 3 and 4 hours (fasted group) and 6 hours (both products, fed group). No significant differences were observed in the metformin plasma concentration-time curve (AUC) from time 0 to the last sampling time and maximum observed concentration between products. Geometric least square mean ratios for maximum observed concentration, AUC from time 0 to the last sampling time, and AUC from time 0 to infinity were nearly 100%; the corresponding 90%CIs for bioequivalence were within 80% to 125%. Diarrhea (26.4%), abdominal pain (5.7%), and nausea (3.8%) were the most common adverse events (AEs); AEs were mild. The mean AUC from time 0 to infinity (test and reference) was substantially increased by ≈45% in the fed condition (equivalent to a 1.5-fold dose increase); this means food increased net systemic availability but had no impact on AE incidence. This was considered in the study design, which included MXR administration with evening meals. MXR tablets were bioequivalent under fasted/fed conditions and were safe and well tolerated.

Avelumab for platinum-ineligible/refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck: phase Ib results from the JAVELIN Solid Tumor trial.

BACKGROUND: Recurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004). METHODS: Eligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety. RESULTS: Between April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0-6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths. CONCLUSION: Avelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.