Noise robust automatic charge state recognition in quantum dots by machine learning and pre-processing, and visual explanations of the model with Grad-CAM

Charge state recognition in quantum dot devices is important in preparation of quantum bits for quantum information processing. Towards auto-tuning of larger-scale quantum devices, automatic charge state recognition by machine learning has been demonstrated. In this work, we propose a simpler method using machine learning and pre-processing. We demonstrate the operation of the charge state recognition and evaluated an accuracy high as 96%. We also analyze the explainability of the trained machine learning model by gradient-weighted class activation mapping (Grad-CAM) which identifies class-discriminative regions for the predictions. It exhibits that the model predicts the state based on the change transition lines, indicating human-like recognition is realized.Comment: 15 pages, 6 figure

Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2

Background & Aims: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH‐2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha‐fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post‐hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). Methods: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH‐2. Kaplan‐Meier and Cox proportional hazards regression methods (stratified by study) assessed OS, progression‐free survival (PFS), time to progression (TTP) and patient‐reported outcomes (Functional Hepatobiliary System Index‐8 [FHSI‐8] score). Results: A total of 542 patients (<65 years: n = 302; ≥65 to <75 years: n = 160; ≥75 years: n = 80) showed similar baseline characteristics between ramucirumab and placebo. Older subgroups had higher hepatitis C and steatohepatitis incidences, and lower AFP levels, than the <65 years subgroup. Ramucirumab prolonged OS in patients <65 years (hazard ratio [HR], 0.753; 95% CI 0.581‐0.975), ≥65 to <75 years (0.602; 0.419‐0.866) and ≥75 years (0.709; 0.420‐1.199), PFS and TTP irrespective of age. Ramucirumab showed similar overall safety profiles across subgroups, with a consistent median relative dose intensity ≥97.8%. A trend towards a delay in symptom deterioration in FHSI‐8 with ramucirumab was observed in all subgroups. Conclusions: In this post‐hoc analysis, ramucirumab showed a survival benefit across age subgroups with a tolerable safety profile, supporting its use in advanced HCC with elevated AFP, irrespective of age, including ≥75 years

Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2

Background & Aims: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC. Methods: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2weeks. Datawere analysed by trial and as a meta-analysis of individual patientlevel data (pooled population) from REACH (alpha-fetoprotein>− 400 ng/ml) and REACH-2. Patients from REACHwith Child-Pugh class Bwere analysed as a separate cohort. The ALBI grades and scoreswere calculated at baseline and before each treatment cycle. Results: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]. Conclusions: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade

Reinvestigation of the Oxidative Folding Pathways of Hen Egg White Lysozyme: Switching of the Major Pathways by Temperature Control

Abstract: It has been well established that in the oxidative folding of hen egg white lysozyme (HEL), which has four SS linkages in the native state (N), three des intermediates, i.e., des[76–94], des[64–80], and des [6–127], are populated at 20 °C and N is dominantly formed by the oxidation of des[64–80] and des[6–127]. To elucidate the temperature effects, the oxidative folding pathways of HEL were reinvestigated at 5–45 °C in the presence of 2 M urea at pH 8.0 by using a selenoxide reagent, DHS ox. When reduced HEL was reacted with 1–4 equivalents of DHS ox, 1S, 2S, 3S, and 4S intermediate ensembles with 1–4 SS linkages, respectively, were produced within 1 min. After the oxidation, 3S was slowly converted to the des intermediates with formation of the native structures through SS rearrangement. At 5 °C, des[76–94] was populated in the largest amount, but the oxidation to N was slower than that of des[64–80] and des[6–127]. At 35 °C, on the other hand, des[64–80] and des[6–127] were no longer stable, and only des[76–94] was populated. The results suggested that the major folding pathways of HEL can be switched from one to the other by temperature control

Mechanistic studies of gene delivery into mammalian cells by electrical short-circuiting via an aqueous droplet in dielectric oil.

We have developed a novel methodology for the delivery of cell-impermeable molecules, based on electrical short-circuiting via a water droplet in dielectric oil. When a cell suspension droplet is placed between a pair of electrodes with an intense DC electric field, droplet bouncing and droplet deformation, which results in an instantaneous short-circuit, can be induced, depending on the electric field strength. We have demonstrated successful transfection of various mammalian cells using the short-circuiting; however, the molecular mechanism remains to be elucidated. In this study, flow cytometric assays were performed with Jurkat cells. An aqueous droplet containing Jurkat cells and plasmids carrying fluorescent proteins was treated with droplet bouncing or short-circuiting. The short-circuiting resulted in sufficient cell viability and fluorescent protein expression after 24 hours' incubation. In contrast, droplet bouncing did not result in successful gene transfection. Transient membrane pore formation was investigated by uptake of a cell-impermeable fluorescence dye YO-PRO-1 and the influx of calcium ions. As a result, short-circuiting increased YO-PRO-1 fluorescence intensity and intracellular calcium ion concentration, but droplet bouncing did not. We also investigated the contribution of endocytosis to the transfection. The pre-treatment of cells with endocytosis inhibitors decreased the efficiency of gene transfection in a concentration-dependent manner. Besides, the use of pH-sensitive dye conjugates indicated the formation of an acidic environment in the endosomes after the short-circuiting. Endocytosis is a possible mechanism for the intracellular delivery of exogenous DNA

The prevalence of gene mutations in homologous recombination repair pathways in Japanese patients with metastatic castration‐resistant prostate cancer in real‐world clinical practice: The multi‐institutional observational ZENSHIN study

Abstract Background Metastatic castration‐resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC. Methods This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR‐related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate‐specific antigen progression‐free survival (PSA‐PFS) and overall survival (OS). Results Of the 143 patients analyzed, HRR‐related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first‐line therapy for mCRPC was next‐generation hormonal agents (NHA, 44.4%), followed by first‐generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first−/second‐line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA‐PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA‐PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations. Conclusions In conclusion, approximately one‐third of Japanese patients with mCRPC carried mutations in HRR‐related genes in this study. The real‐world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease

High-power test and thermal characteristics of a new radio-frequency quadrupole cavity for the Japan Proton Accelerator Research Complex linac

We performed a high-power test of a new radio-frequency quadrupole (RFQ II) for the J-PARC linac. RFQ II was developed as a spare RFQ because the operating J-PARC RFQ has suffered from a sparking problem. First, the conditioning of RFQ II was carried out; after 50 h of conditioning, RFQ II became very stable with a nominal power and duty of 330 kW and 3%, respectively. Next the thermal properties were measured because the resonant frequency of RFQ II is tuned by changing the temperature of the cooling water. The frequency response was measured and compared to finite-element method simulation results, confirming that the simple two-dimensional model reproduces the experimental data well. The differences in the field distribution with changes in the rf loading and the cooling-water temperature were also measured, and no serious field distortion was observed. Therefore, we conclude that RFQ II can perform well as a high-power rf cavity