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Recently, newly emerging halide perovskites have aroused intensive attention in photoelectric fields in virtue of their good properties, such as well-balanced carrier transport, large light absorption coefficient, tunable band gap, and low-temperature solution processing technique. Nevertheless, their future commercial development is severely hampered by lead toxicity and instability of such materials. In this work, one-dimensional Rb2CuBr3 single-crystal microwires (MWs) were prepared by antisolvent engineering, and they were further employed as absorbers to prepare sensitive ultraviolet (UV) photodetectors. The optical band gap of Rb2CuBr3 MWs is measured to be 3.83 eV, exhibiting an excellent UV absorption. The fabricated device demonstrates a remarkable UV light detection ability with a specific detectivity of 1.23 × 1011 Jones, responsivity of 113.64 mA W-1, and response speed of 69.31/87.55 ms under light illumination of 265 nm. Meanwhile, the proposed photodetector without any encapsulation shows outstanding stability and repeatability. After storing in ambient air for 2 weeks, the light detection ability remains basically unchanged. Further, a flexible photodetector was fabricated with the same structure, which demonstrates a remarkable bending endurance. These results confirm the great potential of Rb2CuBr3 for high-performance UV photodetectors, increasing the possibility for assembly of optoelectronic systems.

BACKGROUND Irisin is not only a myokine but also an adipokine that is critical in many diseases including in the development of such diseases as obesity, diabetes mellitus, metabolic syndrome, coronary artery disease, and chronic inflammation. However, the association between irisin and chronic kidney disease (CKD) is unclear. This systematic review aimed to assess circulating irisin levels in patients with CKD and compare them with those in non-CKD patients. METHODS PubMed, EMBASE, CENTRAL, ISI Web of Science, and CNKI were searched to identify observational studies of circulating irisin levels in patients with CKD. Two reviewers independently searched the databases and screened studies according to the inclusion criteria. Data were extracted using a standardized collection form. Meta-analysis was performed to compare the differences in circulating irisin levels between CKD and non-CKD patients. RESULTS A total of 9 studies (6 cross-sectional and 3 case controls) involving 859 CKD patients and 393 non-CKD individuals were selected. The pooled data indicated that circulating irisin concentrations were significantly lower in CKD nondialysis patients (WMD = - 84.79, 95% CI - 170.23, 0.50; p

Background In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose‐dense (DD) doxorubicin‐cyclophosphamide (AC)–paclitaxel regimen. Patients, Materials, and Methods In this prospective, single‐arm study, patients who completed four cycles of DD‐AC for stage I–III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3–4 HSRs. Results Among 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%–20.0%) patients had any‐grade HSRs, for a total of 22 (4.5%; 3.1%–6.4%) HSRs over 486 paclitaxel cycles. Any‐grade HSRs occurred in 1.6% (0.3%–5.0%), 6.5% (3.3%–11.3%), 7.4% (3.9%–12.5%), and 2.6% (0.7%–6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%–2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any‐grade HSRs occurred in 2.7% (3/111; 0.7%–6.8%) and 0.9% (1/109; 0.05%–4.3%) of patients in cycle 3 and 4, respectively. Conclusion Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose‐dense paclitaxel if HSRs are not observed during cycles 1 and 2. Implications for Practice Because of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care., To avoid hypersensitivity reactions, corticosteroids are routinely prescribed before each dose of paclitaxel. This article reports the results of a study that focused on whether corticosteroids could be safely omitted in later cycles of treatment if reactions did not occur during earlier cycles.

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659., A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

This study aimed to investigate the efficacy of the albumin/fibrinogen ratio (AFR) in the assessment of malnutrition and to compare its ability to predict early postoperative periprosthetic joint infection (PJI) in patients with aseptic revisions.Four hundred sixty-six patients undergoing revision total hip or knee arthroplasty between February 2017 and December 2019 were recruited in this retrospective study. We compared the differences in nutritional parameters between patients undergoing revision for septic and aseptic reasons. We used multivariate logistic regression and assessed the association between nutritional parameters and risk of PJI. 207 patients with aseptic revision were then evaluated for the incidence of acute postoperative infection within 90 days. The predictive ability of nutritional markers was assessed by receiver operating characteristic curves.In the multivariate logistic regression analysis, low albumin level (adjusted OR 1.56, 95% CI 1.16-2.08, P = .003), low prognostic nutritional index (PNI) (adjusted OR 1.57, 95% CI 1.01-2.43, P.043), and low AFR (adjusted OR 2.54, 95% CI 1.92-3.36, P.001) were independently associated with revision surgery for septic reasons. In accordance with the receiver operating characteristic analysis, the AFR exhibited a greater area under the curve value (0.721) than did the prognostic nutritional index and albumin. An elevated AFR (≥11.7) was significantly associated with old age, joint type, high Charlson comorbidity index, high American Society of Anesthesiologist, and diabetes (P.05).Our findings demonstrated AFR may be an effective biomarker to assess nutrition status and predict acute PJIs after revision TJA.

There are limited data on trastuzumab–pertuzumab (HP)-based treatments beyond the first-line, HER2+ metastatic breast cancer (MBC) setting. We conducted a phase II study of eribulin mesylate, which extends survival in MBC, with HP in patients with previously treated HER2+ MBC to evaluate efficacy, toxicity, and genomic alterations driving therapeutic response. After a run-in phase for eribulin dosing, two cohorts were enrolled (Cohort A-no prior pertuzumab; Cohort B-prior pertuzumab). All patients received eribulin 1.4 mg/m2 on days 1, 8 with standard-dose HP on day 1 (21-day cycles). The primary endpoint was objective response rate (ORR). Genomic characterization via whole exome sequencing (WES) was completed on tumor DNA and matched germline DNA from 19 patients. The six-patient run-in established a dose of eribulin 1.4 mg/m2 with HP. Cohorts A and B enrolled 17 and 7 patients, respectively. Accrual stopped early due to an evolving treatment landscape and slow enrollment. The ORR was 26.3% (95% Confidence Interval [CI] 9.2–51.2%) in Cohort A and 0% in Cohort B (95% CI 0–41.0%). WES revealed more frequent alterations in TP53 (p 0.05) in patients without clinical benefit (disease control for

The stability and lead toxicity are two fundamental problems which might impede the application of halide perovskite photodetectors (PDs), and all-inorganic lead-free double halide perovskites might solve the problems simultaneously. Herein, we report that through constructing a p–i–n heterostructure based on a double halide perovskite, Cs2AgBiBr6, a self-powered ultraviolet-blue PD was prepared. With a low dark current of 1.89 × 10–9 A, the device showed a photoresponsivity of 33 mA/W, a specific detectivity of 3.28 × 1011 Jones, an on/off ratio of 1.16 × 103, and a response speed of 151/215 μs under illumination of 365 nm at zero bias. The device shows good thermal, humidity and oxygen stability. The results indicate that Cs2AgBiBr6 might be an ideal active material for developing high-performance short-wavelength PDs with extended spectral response range.

The aim of the study is to identify, and present the CSR practices that have been, and are also currently being implemented by football clubs in the era of the Covid-19 pandemic. Moreover, it also strives to assess the impact of these practices on media coverage. The results of the research show that among the posts published by Zagłębie Sosnowiec on social media platforms, such as their official Facebook profile, and the posts about the results of the matches, tend to achieve the greatest reach. However, on the contrary, posts presenting the ongoing CSR initiatives for the local community come tend to take a backseat, and are considered to be secondary. Furthermore, when it comes to other posts that are related to sports activities or personalities (footballers' birthdays, match previews and information about sponsors), their reach does not tend to differ. From an empirical point of view, this study proves that CSR activities are an imperative element of building relationships with the club’s stakeholders.

Simultaneously possessed high energy-storage and power density dielectric ceramics are promising materials for pulsed power capacitor applications. In this work, the (1 − x)K0.5Bi0.5TiO3–xCa0.7La0.2TiO3 ((1 − x)KBT–xCLT, x = 0, 0.24, 0.29, and 0.34) ceramics were prepared by conventional solid-state reaction method. The structural, dielectric, and energy storage properties of the ceramics were systematically studied. All ceramics exhibit a main perovskite phase with dense microstructure accompanied by little secondary phase. With the increasing of CLT content, relaxor behavior appears and gradually becomes notable in the samples. A high recoverable energy storage density of 2.57 J/cm3 together with outstanding power density of 47 MW/cm3 can be achieved simultaneously in the 0.66KBT–0.34CLT ceramic. In addition, the ceramic also shows a rapid discharge time of 41 ns. This study provides a strategy for achieving high recoverable energy storage and power density simultaneously for pulsed capacitor applications.

Hierarchical learning has been successful at learning generalizable locomotion skills on walking robots in a sample-efficient manner. However, the low-dimensional "latent" action used to communicate between two layers of the hierarchy is typically user-designed. In this work, we present a fully-learned hierarchical framework, that is capable of jointly learning the low-level controller and the high-level latent action space. Once this latent space is learned, we plan over continuous latent actions in a model-predictive control fashion, using a learned high-level dynamics model. This framework generalizes to multiple robots, and we present results on a Daisy hexapod simulation, A1 quadruped simulation, and Daisy robot hardware. We compare a range of learned hierarchical approaches from literature, and show that our framework outperforms baselines on multiple tasks and two simulations. In addition to learning approaches, we also compare to inverse-kinematics (IK) acting on desired robot motion, and show that our fully-learned framework outperforms IK in adverse settings on both A1 and Daisy simulations. On hardware, we show the Daisy hexapod achieve multiple locomotion tasks, in an unstructured outdoor setting, with only 2000 hardware samples, reinforcing the robustness and sample-efficiency of our approach., Accepted by RAL

With the increasing severity of global water scarcity, a myriad of scientific activities is directed toward advancing brackish water desalination and wastewater remediation technologies. Flow-electrode capacitive deionization (FCDI), a newly developed electrochemically driven ion removal approach combining ion-exchange membranes and flowable particle electrodes, has been actively explored over the past seven years, driven by the possibility of energy-efficient, sustainable, and fully continuous production of high-quality fresh water, as well as flexible management of the particle electrodes and concentrate stream. Here, we provide a comprehensive overview of current advances of this interesting technology with particular attention given to FCDI principles, designs (including cell architecture and electrode and separator options), operational modes (including approaches to management of the flowable electrodes), characterizations and modeling, and environmental applications (including water desalination, resource recovery, and contaminant abatement). Furthermore, we introduce the definitions and performance metrics that should be used so that fair assessments and comparisons can be made between different systems and separation conditions. We then highlight the most pressing challenges (i.e., operation and capital cost, scale-up, and commercialization) in the full-scale application of this technology. We conclude this state-of-the-art review by considering the overall outlook of the technology and discussing areas requiring particular attention in the future.

Objective: The purpose of this study was to investigate whether routine blood tests on admission and clinical characteristics can predict prognosis in patients with traumatic brain injury (TBI) combined with extracranial trauma. Methods: Clinical data of 182 patients with TBI combined with extracranial trauma from April 2018 to December 2019 were retrospectively collected and analyzed. Based on GOSE score one month after discharge, the patients were divided into a favorable group (GOSE 1-4) and unfavorable group (GOSE 5-8). Routine blood tests on admission and clinical characteristics were recorded. Results: Overall, there were 48 (26.4%) patients with unfavorable outcome and 134 (73.6%) patients with favorable outcome. Based on multivariate analysis, independent risk factors associated with unfavorable outcome were age (odds ratio [OR], 1.070; 95% confidence interval [CI], 1.018-1.124; p

Background To explore whether previous arthroscopic knee surgery affects future total knee arthroplasty (TKA) results or not. Methods A total of 56 patients with the previous arthroscopic treatment on one knee underwent subsequent bilateral total knee arthroplasty in our hospital from September 2012 to July 2018. Data on each patient were collected in regards to changes in postoperative clinical and functional scores, various other scores, as well as postoperative functional recovery and complications. We defined the knees with a previous arthroscopic history as group A, and the counter side as group B. The Knee Society clinical score, functional scores, range of motion (ROM), finger joint size (FJS), visual analogue scale (VAS) scores were assessed before and after surgery. Using the Kolmogorov-Smirnov Test to test the normality of continuous variables, and the chi-square test to compare the rate of reoperation and complications between two groups. For all statistical comparisons, P Results There were no statistically significance differences found in postoperative Knee Society clinical scores and functional scores between group A and group B, as well as in ROM, FJS, VAS scores and local complications. Conclusion There were no statistically significant differences found in postoperative functional recovery and complications in patients, who underwent total knee arthroplasty with previous knee arthroscopy.

Hemorrhagic transformation (HT) is a common complication after thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) in ischemic stroke. In this article, recent research progress of HT in vivo and in vitro studies was reviewed. We have discussed new potential mechanisms and possible experimental models of HT development, as well as possible biomarkers and treatment methods. Meanwhile, we compared and analyzed rodent models, large animal models and in vitro BBB models of HT, and the limitations of these models were discussed. The molecular mechanism of HT was investigated in terms of BBB disruption, rt-PA neurotoxicity and the effect of neuroinflammation, matrix metalloproteinases, reactive oxygen species. The clinical features to predict HT were represented including blood biomarkers and clinical factors. Recent progress in neuroprotective strategies to improve HT after stroke treated with rt-PA is outlined. Further efforts need to be made to reduce the risk of HT after rt-PA therapy and improve the clinical prognosis of patients with ischemic stroke.

Developing multifunctional carrier-free nanomedicine with high efficacy attracts tremendous attention in cancer treatment. Here, we develop selenium-containing carrier-free assemblies with aggregation-induced emission (AIE) property, which achieve the combination of cancer radiotherapy with chemotherapy. Under γ-radiation, diselenide bonds in the assemblies can be cleaved to form seleninic acid, which exhibits anticancer activity by upregulating the reactive oxygen species (ROS) levels in cancer cells. The incorporation of AIE groups further endows the selenium-containing assemblies with the ability of bioimaging. Their self-assembly behavior change under γ-radiation can be consequently observed in situ. The system combines cancer radiotherapy with chemotherapy, which exhibits improved anticancer activity.

Background: Armadillo repeat-containing 10 (ARMC10) is involved in the progression of multiple types of tumors. Pancreatic adenocarcinoma (PAAD) is a lethal disease with poor survival and prognosis.Methods: We acquired the data of ARMC10 in PAAD patients from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets and compared the expression level with normal pancreatic tissues. We evaluated the relevance between ARMC10 expression and clinicopathological factors, immune infiltration degree and prognosis in PAAD.Results: High expression of ARMC10 was relevant to T stage, M stage, pathologic stage, histologic grade, residual tumor, primary therapy outcome (PConclusions: Our research firstly discovered ARMC10 as a novel prognostic biomarker for PAAD patients and played a crucial role in immune regulation in PAAD.

Interventions designed to limit the spread of coronavirus disease 2019 (COVID-19) are having profound effects on the delivery of health care, but data showing the impact on oncology clinical trial enrollment, treatment, and monitoring are limited. We prospectively tracked relevant data from oncology clinical trials at Dana-Farber Cancer Institute from January 1, 2018, to June 30, 2020, including the number of open trials, new patient enrollments, in-person and virtual patient visits, dispensed investigational infusions, dispensed or shipped oral investigational agents, research biopsies, and blood samples. We ascertained why patients came off trials and determined on-site clinical research staffing levels. We used 2-sided Wilcoxon rank sum tests to assess the statistical significance of the reported changes. Nearly all patients on interventional treatment trials were maintained, and new enrollments continued at just under one-half the prepandemic rate. The median number of investigational prescriptions shipped to patients increased from 0 to 74 (range = 22-107) per week from March to June 2020. The median number of telemedicine appointments increased from 0 to 107 (range = 33-267) per week from March to June 2020. Research biopsies and blood collections decreased dramatically after Dana-Farber Cancer Institute implemented COVID-19–related policies in March 2020. The number of research nurses and clinical research coordinators on site also decreased after March 2020. Substantial changes were required to safely continue clinical research during the pandemic, yet we observed no increases in serious adverse events or major violations related to drug dosing. Lessons learned from adapting research practices during COVID-19 can inform industry sponsors and governmental agencies to consider altering practices to increase operational efficiency and convenience for patients.

Background Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. Patients and methods This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). Results Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. Conclusion The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. Clinical Trial Registration NCT01921335.

Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle dilation and cardiac dysfunction, eventually developing into heart failure. Mzb1 (Marginal zone B and B1 cell specific protein 1) is a B-cell-specific and endoplasmic reticulum-localized protein. Mzb1 is an inflammation-associated factor that participates a series of inflammatory processes, including chronic periodontitis and several cancers. In this study we investigated the role of Mzb1 in experimental models of MI. MI was induced in mice by ligation of the left descending anterior coronary artery, and in neonatal mouse ventricular cardiomyocytes (NMVCs) by H(2)O(2) treatment in vitro. We showed that Mzb1 expression was markedly reduced in the border zone of the infarct myocardium of MI mice and in H(2)O(2)-treated NMVCs. In H(2)O(2)-treated cardiomyocytes, knockdown of Mzb1 decreased mitochondrial membrane potential, impaired mitochondrial function and promoted apoptosis. On contrary, overexpression of Mzb1 improved mitochondrial membrane potential, ATP levels and mitochondrial oxygen consumption rate (OCR), and inhibited apoptosis. Direct injection of lentiviral vector carrying Len-Mzb1 into the myocardial tissue significantly improved cardiac function and alleviated apoptosis in MI mice. We showed that Mzb1 overexpression significantly decreased the levels of Bax/Bcl-2 and cytochrome c and improved mitochondrial function in MI mice via activating the AMPK-PGC1α pathway. In addition, we demonstrated that Mzb1 recruited the macrophages and alleviated inflammation in MI mice. We conclude that Mzb1 is a crucial regulator of cardiomyocytes after MI by improving mitochondrial function and reducing inflammatory signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy.

Acute myocardial infarction (AMI) is the leading cause of death worldwide. Identifying the pathways that block cardiac cell death is a therapeutic strategy for ischemic heart disease. We found that long noncoding RNA (lncRNA) myocardial infarction-regulatory factor (MIRF) promoted ischemic myocardial injury by regulating autophagy through targeting miR-26a. However, the role of MIRF-miR-26a in apoptosis during AMI has not been delineated. In this study, we found the downregulation of miR-26a both in the heart of myocardial infarction (MI) mice and in H2O2-treated cardiomyocytes. miR-26a silencing resulted in apoptosis, whereas overexpression of miR-26a attenuated H2O2-induced apoptosis through promoting mitochondrial ATP content and increasing mitochondrial membrane potential (MMP). Moreover, forced expression of miR-26a protected against MI-induced cardiac injury and attenuated cardiac apoptosis. Further studies showed that miR-26a inhibited apoptosis through regulation of Bak1. Furthermore, MIRF decreased ATP content and MMP through regulating miR-26a, which then promoted the cardiomyocyte apoptosis. In contrast, deficiency of MIRF promoted mitochondrial ATP content and increased MMP, and then inhibited MI or H2O2-induced cardiac apoptosis, which was abolished by miR-26a inhibitor. Taken together, these results suggested that MIRF contributed to cardiomyocyte apoptosis through modulating Bak1 by regulation of miR-26a, which can be a potential therapeutic target for the treatment of ischemic heart disease., Graphical Abstract, Liang and colleagues showed that lncRNA MIRF contributed to cardiomyocyte apoptosis by modulating the miR-26a/Bak1 axis, which provides new insight into the roles of lncRNAs and miRNAs in the development of AMI.

Background: For patients (pts) with HR+ /HER2- MBC, the optimal regimen following disease progression on the combination of a CDK4/6i plus endocrine therapy (ET) is unknown, and there is a need to evaluate whether continued CDK 4/6 blockade is beneficial in subsequent lines of therapy. Methods: We developed an investigator initiated Phase I/II, open-label trial (NCT02871791) of triplet therapy: palbociclib (PALBO; CDK4/6i) + everolimus (EVE; mTOR inhibitor) + exemestane (EXE; ET) in men or postmenopausal women with measurable HR+ /HER2− MBC who had progressed on prior CDK4/6i and a non-steroidal aromatase inhibitor (NSAI). Pts may have received any number of prior lines of ET, and 0-1 prior line of chemotherapy. Exclusion criteria included prior use of mTORi or EXE. The primary objective was to estimate efficacy of the combination, defined as the clinical benefit rate (CR+PR+SD>6mo). With a one-sided alpha of 0.1, the study had 90% power to detect an improvement in CBR from 40% to 65%. The phase I determined RP2D to be PALBO 100 mg/day (21 of 28 days) + EVE 5mg/day + EXE 25mg/day (previously presented). For pts who entered into the phase IIa part of the study, a research biopsy at baseline and serial research blood collection for circulating tumor DNA (ctDNA) analysis were mandatory. The tumor tissue underwent whole exome sequencing and RNA sequencing and the ctDNA underwent whole exome sequencing. Here we present the first results of the phase 2 study of this triplet regimen. Results: As of June 29, 2019, after a median follow up of 3.8 (2.8-6.2) months, 32 patients were evaluable in the phase II portion of the study. The triplet combination was associated with a clinical benefit rate of 12.5% (n=4), which did not meet the predefined primary endpoint threshold (65%). There were no objective responses achieved. The median PFS was 3.8 (95%CI: 2.0-8.4) months and the 1-year PFS was 16.1% (95%CI: 3.1%-38.0%). The most common AEs were mucositis (all grades, 87.5%; grade 3/4, 15.6%), neutropenia (all grades 84.4%; grade 3/4, 71.9%), and fatigue (all grades 53.1%; grade 3/4, 0%). Data regarding genomic alterations and its association with outcomes will be presented. Conclusions: Among patients with metastatic HR+/HER2- MBC who had previous progression on a NSAI and a CDK 4/6i, there did not appear to be benefit from the addition of PALBO to EXE and EVE, but there were added toxicities. These findings suggest further evaluation of this triplet combination in patients with CDK 4/6i resistance is not warranted. Genomic data from baseline biopsies and circulating tumor DNA will be presented and may help us to explain why patients included in this study were intrinsically resistant to the triplet. Citation Format: Romualdo Barroso-Sousa, Tianyu Li, Lorenzo Trippa, Rebecca Rees, Chelsea Andrews, Arlindo R Ferreira, Karla Helvie, Ann H Partridge, Beth Overmoyer, Eric P Winer, Nikhil Wagle, Sara M Tolaney. A phase I/IIb study of palbociclib (PALBO) plus everolimus (EVE) and exemestane (EXE) in hormone-receptor positive (HR+)/HER2- metastatic breast cancer (MBC) after progression on a CDK4/6 inhibitor (CDK4/6i): Results of the phase II study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-04.

Background: Immune checkpoint inhibitors (ICI), such as those targeting the PD-1/PD-L1 axis, have shown modest activity as monotherapy in both HR+ MBC and MOC. Strategies to improve ICI for these diseases are under investigation. In mouse models, CDK4/6 inhibitors boost anti-tumor immunity in part by increasing the infiltration and activation of cytotoxic T lymphocytes, and by suppressing regulatory T lymphocyte function, providing rationale for combining CDK4/6 inhibition and ICI. Methods: We conducted an open-label phase 1b dose escalation study with the primary objectives of determining the safety, tolerability, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ribociclib and spartalizumab in patients with HR+ MBC and MOC. Ribociclib was administered on days 1-21 and spartalizumab on day 1 of a 28-day cycle. The study used a 3 + 3 dose escalation design with dose-limiting toxicities (DLTs) formally defined during the first cycle. For the dose escalation there were no restrictions on prior chemotherapy or CDK4/6 inhibitor use but prior PD-1/PD-L1 inhibitor use was not allowed. Once the MTD/RP2D was determined, we conducted a safety run-in for the combination of ribociclib and spartalizumab with fulvestrant in patients with HR+ MBC. Results: During dose escalation, 9 patients with HR+ MBC and 1 patient with MOC were enrolled. Three patients each were enrolled to dose levels 1 and 2 (ribociclib 400 mg and 600 mg PO QD for 21/28 days, respectively, and spartalizumab 400 mg IV q28 days) and no DLTs were observed. Four additional patients were enrolled to dose level 2; one was deemed unevaluable due to drug compliance issues and was replaced. Among the 3 evaluable patients, 1 experienced a DLT of grade 3 atrial fibrillation and flutter, which were possibly related to both ribociclib and spartalizumab. Based on this experience, the MTD/RP2D was declared to be ribociclib 600mg PO QD for 21/28 days in combination with spartalizumab 400mg IV q28 days. For the safety run-in, evaluating the addition of fulvestrant to the combination of ribociclib and spartalizumab, 6 patients with HR+ MBC were enrolled and no additional DLTs were observed. Among all patients with MBC (n=15), the median number of prior hormonal therapies was 2 (range 0-4); 10 patients (67%) had previously received fulvestrant, and all patients had previously received a CDK4/6 inhibitor. For the entire group (n=16), 10 patients (63%) had received 4 or more prior lines of chemotherapy for metastatic disease. The most common grade 3 and 4 toxicities regardless of treatment attribution were neutropenia (n = 8, 50%), increased aspartate aminotransferase (n = 4, 25%), increased alanine aminotransferase (n = 4, 25%). Median follow-up for all patients was 3.5 months (95% CI: 2.8 - 5.1). Among the 16 patients treated, 1 breast cancer patient had a PR (ORR=6.25%, 95% CI: 0-30%) and 1 breast cancer patient had SD for > 24 weeks (6.25%, 95% CI 0-30%); CBR = 12.5% (95% CI: 1.6-38.3%): both of these patients received ribociclib and spartalizumab with fulvestrant. The median PFS for all patients was 3.1 months (95% CI: 1.9 - NR), and the median OS was 6.0 months (95% CI: 6.0 - NR). Conclusion: In this phase 1b study, the combination of ribociclib and spartalizumab was well tolerated with toxicity consistent with that expected from each agent alone and no new toxicities were observed. The RP2D for the combination is ribociclib 600mg PO QD for 21/28 days and spartalizumab 400mg IV q28 days with or without fulvestrant. Clinical benefit was achieved in 2 breast cancer patients who had previously received a CDK4/6 inhibitor combined with hormonal therapy. Dose expansion cohorts are currently enrolling for patients with HR+ MBC and MOC. Citation Format: Christina I Herold, Lorenzo Trippa, Tianyu Li, Khanh Do, Aditya Bardia, Leilani Anderson, Kamaneh Montazeri, Jessica Pittenger, Chelsea Andrews, Elizabeth A Mittendorf, Shom Goel, Eric P Winer, Geoffrey I Shapiro, Sara M Tolaney. A phase 1b study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with hormone receptor-positive metastatic breast cancer (HR+ MBC) and metastatic ovarian cancer (MOC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-03.

Background: Patients (pts) with mTNBC have a poor prognosis, and new therapies are needed. Cabozantinib is a multikinase inhibitor that blocks VEGF receptor 2, reduces myeloid-derived suppressor cells, and increases T cell infiltration, suggesting it may enhance the activity of the anti-PD-1 checkpoint blockade agent nivolumab. Here, we report the safety and efficacy of nivolumab plus cabozantinib in a phase II single-arm study in mTNBC pts. Methods: Eligible pts had metastatic breast cancer that was estrogen and progesterone receptor < 10% and HER2 negative, measurable disease, and received 0-3 prior lines of chemotherapy in the advanced setting. Pts received nivolumab (480 mg intravenously on day 1, every 28 days) plus cabozantinib (40 mg daily by mouth). The primary endpoint was objective response rate (ORR) by RECIST v1.1. Using the Simons “optimal” method, if ≥ 3/18 pts responded during the first stage, 17 more would be enrolled. If ≥ 7/35 responded, the null hypothesis (ORR=10%) would be rejected in favor of a 30% ORR. Predefined secondary endpoints included progression free survival (PFS), clinical benefit rate (CBR), and toxicity. CBR was defined as the fraction of pts with any objective response or stable disease (SD) ≥ 24 weeks. Analyses associating PD-L1 expression, tumor-infiltrating lymphocytes (TIL), and genomic alterations (assessed by next generation sequencing on archival tissue) with outcomes were exploratory. Results: From 12/15/2017 to 01/24/2019, 18 pts were enrolled into the first stage of the trial; one partial response was seen (ORR 5.6%; 95% CI: 0.3-29.4), and the study was closed to further accrual. The median age was 58y, all pts had ECOG PS 0, and 7 (38.9%) had liver metastases. The median number of prior cytotoxic therapies for mTNBC pts was 1 (range 0 to 3). Three pts had SD ≥24 weeks and two had progressive disease best response. The CBR was 22.2%. After a median follow up of 3.7 months, the median PFS was 4.4 months (95% CI: 1.9-12.8), and the median OS was 6.9 months (95% CI: 3.4-NR). All-cause adverse events occurred in 100% of pts (G3-4, 78%) including elevated liver enzymes (any 50%; G3-4 16.7%), hand-foot syndrome (any 38.9%; G3-4 16.7%), fatigue (any 38.9%; G3-4 11.1%), and hypothyroidism (any 33.3%; no G3-4). Of the 9 pts with available genomic data, none had tumor mutational burden ≥ 10 mutations per megabase. Updated data with TIL, PD-L1, whole exome sequencing and RNA-sequencing results will be presented. Conclusions: The combination of nivolumab plus cabozantinib was not associated with any unexpected adverse events, however, with an ORR of 5.6%, the study did not achieve its primary endpoint. Exploratory genomic and immunological correlative studies are ongoing. Clinical trial information: NCT03316586. Citation Format: Romualdo Barroso-Sousa, Lorenzo Trippa, Tianyu Li, Tanya E Keenan, Grace Winship, Chelsea Andrews, Wafa Osmani, Beth Overmoyer, Eric P Winer, Elizabeth A Mittendorf, Dan G Duda, Sara M Tolaney. A phase II study of nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-10.

Immunotherapy has emerged as a promising new approach for cancer treatment. However, clinically available drugs have been limited until recently, and the antitumor efficacy of most cancer immunotherapies still needs to be improved. Herein, we develop diselenide-pemetrexed assemblies that combine natural killer (NK) cell-based cancer immunotherapy with radiotherapy and chemotherapy in a single system. The assemblies are prepared by co-assembly between pemetrexed and cytosine-containing diselenide through hydrogen bonds. Under γ-radiation, the hydrogen bonds are cleaved, resulting in the release of pemetrexed. At the same time, diselenide can be oxidized to seleninic acid, which suppresses the expression of human leukocyte antigen E (HLA-E) in cancer cells, thus activating the immune response of NK cells. In this way, cancer immunotherapy is combined with radiotherapy and chemotherapy, providing a new strategy for cancer treatment.

Performance optimization and cost reduction of a vanadium flow battery (VFB) system is essential for its commercialization and application in large-scale energy storage. However, developing a VFB stack from lab to industrial scale can take years of experiments due to the influence of complex factors, from key materials to the battery architecture. Herein, we have developed an innovative machine learning (ML) methodology to optimize and predict the efficiencies and costs of VFBs with extreme accuracy, based on our database of over 100 stacks with varying power rates. The results indicated that the cost of a VFB system (S-cost) at energy/power (E/P) = 4 h can reach around 223 $ (kW h)−1, when the operating current density reaches 200 mA cm−2, while the voltage efficiency (VE) and utilization ratio of the electrolyte (UE) are maintained above 90% and 80%, respectively. This work highlights the potential of the ML methodology to guide stack design and optimization of flow batteries to further accelerate their commercialization.

PURPOSE The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling. PATIENTS AND METHODS Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877 ). Our primary aim was to describe the proportion of patients with a qualifying ERBB2 mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of ERBB2 mutations, and survival. Associations were calculated using Fisher’s exact test. RESULTS We identified a total of 1,045 patients with metastatic breast cancer without ERBB2 amplification who had available genomic testing results. Of these, 42 patients were found to have ERBB2 mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing. CONCLUSION More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.

Cardiac fibrosis is a pathological reparative process that occurs subsequent to myocardial injury. It is associated with cardiac systolic and diastolic dysfunction and reduced cardiac compliance that eventually leads to heart failure. Delaying or inhibiting the progression of pathological myocardial fibrosis is of great significance for the treatment of many cardiovascular diseases. The Wnt signaling pathway is closely related to the occurrence of organ fibrosis, and Notum is a highly conserved secreted feedback inhibitor of Wnt signaling. It has been shown that Notum acts as a regulator in many organs, such as the aging intestinal epithelium, adult ventricular-subventricular zone neurogenesis, and mouse tooth root development. However, the role and mechanism of Notum on cardiac fibrosis are not well-understood. In this study, we found that Notum significantly increased survival rate and improved cardiac function following myocardial infarction in mice. More importantly, Notum inhibited the Wnt/β-catenin signaling pathway and senescence of cardiac fibroblasts, thereby decreasing the activation of cardiac fibroblasts, reducing the excessive deposition of extracellular matrix, and ultimately inhibiting the occurrence of cardiac fibrosis. Taken together, our findings demonstrated the anti-fibrotic effects of Notum on maladaptive cardiac fibrosis, and suggest that it may be a new strategy for the treatment of cardiac fibrosis.

Background: De-escalation of adjuvant therapy following pathologic complete response (pCR) to an abbreviated neoadjuvant regimen in HER2-positive (HER2+) breast cancer is the focus of a recently initiated national trial. However the feasibility of this approach, and its appeal to patients (pts) and providers, has not been formally investigated. Methods: We conducted a single arm pilot trial to determine the feasibility of de-escalated adjuvant therapy (HP-only) in patients with pCR following neoadjuvant THP. Eligible pts had clinical anatomic stage II-III treatment-naïve HER2+ breast cancer. All pts received weekly paclitaxel x12 doses, and HP every 3 weeks x4 doses (up to 6 doses allowed in case of surgical delay). The primary objective was to assess adherence to protocol-specified antibody doublet therapy (HP-only, without cytotoxic chemotherapy) in the adjuvant setting among pts with pCR (ypT0/isN0) following neoadjuvant THP; the primary endpoint was receipt of adjuvant cytotoxic chemotherapy, assessed 3 months post-operatively. Trastuzumab emtansine (T-DM1) was not considered cytotoxic chemotherapy. Among pts with pCR to THP, de-escalation would be deemed infeasible if the true rate of adherence to HP-only were 90% power to reject the null if the true rate of adherence were >95% (Binomial exact test; one-sided alpha=0.05). Questionnaires were administered and records were reviewed to assess pts’ and physicians’ decision-making about adjuvant systemic therapy following pCR and non-pCR. Results: 98 pts received at least one dose of THP on study. Median age was 50 yrs (range 24-78), pts were 99% female, 86% had stage II/14% stage III tumors, 32% ER/PR negative. No pts progressed during neoadjuvant THP. Five pts had incomplete clinical response following THP and received AC prior to surgery. They were classified as non-pCR and censored from further analyses. At the time of analysis, 93 pts were evaluable for response to neoadjuvant therapy (1 pt withdrew from study early; 4 pts had not reached surgery by the data cutoff). Overall pCR rate was 55% (51/93 pts); 10%, 28%, and 2% of pts had RCB I, II, and III responses, respectively (this excluded patients who received AC preoperatively). Of 51 pts who had pCR to THP, 40 had verified data available regarding adjuvant chemotherapy receipt at data cutoff. 39/40 pts (97.5%, 95% CI 86.8-99.9%) who had pCR did not receive adjuvant cytotoxic chemotherapy, meeting the trial’s prespecified threshold for declaring this a feasible approach (primary endpoint), though data remain pending for 11 pts with pCR and will be available at presentation. Of 30 pts who did not experience pCR to THP and had adjuvant chemotherapy status verified at data cutoff, 14/30 pts received adjuvant cytotoxic chemotherapy, and 16/30 pts did not receive adjuvant chemotherapy. The most common reasons cited by pts for non-receipt of adjuvant cytotoxic chemotherapy, despite residual disease at surgery, were (N=21): plan for adjuvant T-DM1 alone (67% of pts), good response to preop chemo (38% of pts), and plan for adjuvant hormonal therapy (24% of pts). The most common reason cited by treating physicians for non-administration of adjuvant chemotherapy, despite residual disease at surgery, was plan for adjuvant T-DM1 (17/21 (81%) physicians). With brief follow-up (median 10.2 mos), there were no breast cancer recurrences. Conclusions: De-escalation of adjuvant cytotoxic chemotherapy among pts who experience pCR in early stage HER2+ breast cancer appears to be an acceptable approach for both pts and physicians, though data are not yet complete and will be updated at the time of presentation. The long-term efficacy of this approach will be determined in the ongoing national CompassHER2-pCR trial. Citation Format: Adrienne G. Waks, Neelam V. Desai, Tianyu Li, Philip D. Poorvu, Ann H. Partridge, Natalie Sinclair, Laura M. Spring, Meredith Faggen, Michael Constantine, Jillian C. Alberti, Julia Deane, Shoshana M. Rosenberg, Sara M. Tolaney, Ian E. Krop, Nadine M. Tung, Nabihah Tayob, Tari A. King, Elizabeth A. Mittendorf, Eric P. Winer. The DAPHNE trial: A feasibility study of chemotherapy de-escalation based on response to neoadjuvant paclitaxel-HP (THP) in HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-05.

V2G (Vehicle to Grid) technology can adjust the grid load through the unified control of the charging and discharging of electric vehicles, and achieve peak shaving and valley filling to smooth load fluctuations. Aiming at the random and uncertain problem of EV user travel and behavior decision-making, this paper proposes a V2G multi-objective dispatching strategy based on user behavior. First, a V2G behavior model was established based on user behavior questionnaire surveys, and the effective effect of EV load was simulated through Monte Carlo simulation. Secondly, combined with the regional daily load curve and peak-valley time-of-use electricity prices, with the goal of stabilizing grid load fluctuations and increasing the benefits of EV users, a multi-objective optimal dispatching model for electric vehicle cluster charging and discharging is established. Considering the needs of electric vehicles and the operation constraints of the distribution network, the genetic algorithm is used to obtain the Pareto optimal solution. The results show that when dispatching with the maximum benefit of users, the peak-to-valley ratio of the grid side can be reduced by 2.99%, and the variance can be reduced by 9.52%. The optimization strategy can use peak and valley time-of-use electricity prices to guide the intelligent charging and discharging of electric vehicles while meeting user needs, so as to achieve the optimal multi-objective benefit of V2G participation in power response.

Background: Despite substantial improvement in chronic total occlusions (CTO) revascularization technique, the long-term clinical outcomes in diabetic patients with revascularized CTO remain controversial. Our study aimed to investigate the 5-year cardiovascular survival for patients with or without type 2 diabetes mellitus (DM) who underwent successful percutaneous coronary intervention (PCI) for CTO.Methods: Data of the current analysis derived from a large single-center, prospective and observational cohort study, including 10,724 patients who underwent PCI in 2013 at Fuwai Hospital. Baseline, angiographic and follow-up data were collected. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which consisted of death, recurrent myocardial infarction (MI), stroke and target vessel revascularization (TVR). The secondary endpoint was all-cause mortality. Cox regression analysis and propensity-score matching was performed to balance the baseline confounders.Results: A total of 719 consecutive patients with ≥1 successful CTO-PCI were stratified into diabetic (n = 316, 43.9%) and non-diabetic (n = 403, 56.1%) group. During a median follow-up of 5 years, the risk of MACCE (adjusted hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.08–2.00, P = 0.013) was significantly higher in the diabetic group than in the non-diabetic group, whereas the adjusted risk of all-cause mortality (HR 2.37, 95% CI 0.94–5.98, P = 0.068) was similar. In the propensity score matched population, there were no significant differences in the risk of MACCE (HR 1.27, 95% CI 0.92–1.75, P = 0.155) and all-cause mortality (HR 2.56, 95% CI 0.91–7.24, P = 0.076) between groups. Subgroup analysis and stratification analysis revealed consistent effects on 5-year MACCE across various subgroups.Conclusions: In patients who received successful CTO-PCI, non-diabetic patients were related to better long-term survival benefit in terms of MACCE. The risk of 5-year MACCE appeared to be similar in less-controlled and controlled diabetic patients after successful recanalization of CTO. Further randomized studies are warranted to confirm these findings.

This single-arm phase II study investigated the efficacy and safety of cabozantinib combined with nivolumab in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was objective response rate (ORR) by RECIST 1.1. Biopsies at baseline and after cycle 1 were analyzed for tumor-infiltrating lymphocytes (TILs), PD-L1, and whole-exome and transcriptome sequencing. Only 1/18 patients achieved a partial response (ORR 6%), and the trial was stopped early. Toxicity led to cabozantinib dose reduction in 50% of patients. One patient had a PD-L1-positive tumor, and three patients had TILs > 10%. The responding patient had a PD-L1-negative tumor with low tumor mutational burden but high TILs and enriched immune gene expression. High pretreatment levels of plasma immunosuppressive cytokines, chemokines, and immune checkpoint molecules were associated with rapid progression. Although this study did not meet its primary endpoint, immunostaining, genomic, and proteomic studies indicated a high degree of tumor immunosuppression in this mTNBC cohort.

Radiation enteritis is the most common and serious complication of abdominal or pelvic radiation therapy. Mesenchymal stem cells (MSCs), as well as cell protection agents, inhibit apoptosis and promote the proliferation of injured tissues. 3 human umbilical cords MSCs (UCMSCs) were injected into the tail vein or peritoneal cavity of a rat model of radiation enteritis. The temporary protective effect was assessed by identification of donor cells, detection of cellular immune parameters and inflammatory cytokine levels, quantitation of jejunum mucosal preservation and examination of the rat remaining life. Only the rats in the intraperitoneal injection group exhibited a few positive donor cells 7 days after transplantation. CD4 +/CD8 + T cells, a cellular immune parameter, decreased in the abdominal exudate of intraperitoneal injection group, compared with the model-only control and tail vein groups (both P < .05). Both serum and abdominal exudate TNF-α and IL-6 levels in the intraperitoneally injected rats rapidly decreased and were significantly different from those in the model-only control and tail vein injection groups (all P < .05). Mucosal surface area and survival time increased in the intraperitoneal injection group compared with the vehicle and tail vein injection groups (all P = .000). Therefore, the administration of UCMSCs with intraperitoneal injection approach postponed death in a rat model of radiation enteritis, which was associated with reduced serum levels of proinflammatory cytokines (TNF-α, IL-6). However, UCMSCs injected via the tail vein triggered an intense cellular immune response in the serum that adversely affects their survival. This treatment failed to suppress circulating serum and abdominal exudate levels of TNF-α and IL-6 and could not provide a therapeutic benefit for prolonging life against acute radiation enteritis.

Autoencoder-based hybrid recommender systems have become popular recently because of their ability to learn user and item representations by reconstructing various information sources, including users' feedback on items (e.g., ratings) and side information of users and items (e.g., users' occupation and items' title). However, existing systems still use representations learned by matrix factorization (MF) to predict the rating, while using representations learned by neural networks as the regularizer. In this paper, we define the neural representation for prediction (NRP) framework and apply it to the autoencoder-based recommendation systems. We theoretically analyze how our objective function is related to the previous MF and autoencoder-based methods and explain what it means to use neural representations as the regularizer. We also apply the NRP framework to a direct neural network structure which predicts the ratings without reconstructing the user and item information. We conduct extensive experiments on two MovieLens datasets and two real-world e-commerce datasets. The results confirm that neural representations are better for prediction than regularization and show that the NRP framework, combined with the direct neural network structure, outperforms the state-of-the-art methods in the prediction task, with less training time and memory.

Accessing and updating data sharded across distributed machines safely and speedily in the face of failures remains a challenging problem. Most prominently, applications that share state across different nodes want their writes to quickly become visible to others, without giving up recoverability guarantees in case a failure occurs. Current solutions of a fast cache backed by storage cannot support this use case easily. In this work, we design a distributed protocol, called Distributed Prefix Recovery (DPR) that builds on top of a sharded cache-store architecture with single-key operations, to provide cross-shard recoverability guarantees. With DPR, many clients can read and update shared state at sub-millisecond latency, while receiving periodic prefix durability guarantees. On failure, DPR quickly restores the system to a prefix-consistent state with a novel non-blocking rollback scheme. We added DPR to a key-value store (FASTER) and cache (Redis) and show that we can get high throughput and low latency similar to in-memory systems, while lazily providing durability guarantees similar to persistent stores.

Embedding is a technology which permits to build highly integrated, compact power sections. It also helps to minimise parasitic elements within the power sections, this way facilitating the use of novel, fast switching devices like gallium-nitride (GaN) high electron mobility transistors (HEMTs). This paper deals with required processes and the development of a power section with GaN HEMTs for a three phase drive inverter with a nominal power in the lower kW range; a version with discrete devices has also been built as a benchmark for the embedded solution.

PURPOSE Human epidermal growth factor receptor 2 (HER2)–directed treatments improve outcomes for patients with HER2-positive metastatic breast cancer (MBC). Current identification of patients with HER2-positive disease relies on tumor tissue testing, which can be inaccurate because of tumor heterogeneity or tumor evolution. Circulating tumor cells (CTCs) are often present in patients with cancer. We hypothesized that HER2 assessment of CTCs in patients with HER2-negative breast cancer could identify a subset of patients with HER2-positive CTCs who could benefit from HER2-directed treatments. METHODS This was a single-arm, two-stage, phase II trial. Patients with HER2-negative progressive MBC with HER2-positive CTC (defined as HER2/CEP17 ratio ≥ 2.0 by fluorescence in situ hybridization), ≥ 1 prior chemotherapy regimen for MBC, and no prior vinorelbine received trastuzumab in combination with vinorelbine on days 1, 8, and 15 of a 21-day cycle. The primary end point was objective response rate. RESULTS From January 2013 to June 2014, we prospectively screened CTCs from patients with HER2-negative MBC. CTCs were detected in 201 of 311 patients (65%). The median number of CTCs was 10 (interquartile range, 3-57). Sixty-nine of 311 patients (22%) had HER2+ CTCs, with a median of three HER2+ CTCs (range 1-21). Twenty patients with HER2+ CTCs were treated on study. At data cutoff (January 13, 2017), no patients remained on study therapy. The objective response rate was 5% (95% CI, 0.1 to 24.9), with one of 20 patients experiencing a partial response. The clinical benefit rate was 20.0% (1 partial response and 3 stable diseases > 24 weeks, 95% CI, 5.7% to 43.7%). The median progression-free survival was 2.7 months. CONCLUSION CTC analysis of patients with HER2-negative MBC identifies a subset with HER2-amplified CTCs. However, clinical activity of an HER2-directed regimen in this population was low. The functional significance of HER2-positive CTCs remains uncertain.

The IGF2BP3 can affect cancer cells through the regulation of m6A. In this study, we combined the RNA sequencing and the RNA methylation sequencing to investigate the role and the mechanism of the IGF2BP3 in bladder cancer.TCGA data showed that the intersection genes of RBP differentially expressed and RBP involved in m6A modification were IGF2BP1 and IGF2BP3, only IGF2BP3 was significantly associated with short survival time (P

The optimization of power systems usually faces the trade-off between performance and cost. The 2021 Texas grid blackout reveals that the regionally centralized power grid has global risks, and the distributed energy structure has relative advantages in safety and flexibility. Household battery storage can balance the grid load and enhance the stability and flexibility of the grid. However, given its high cost, household battery storage is still not widespread nowadays. At present, research on enhancing the applicability of household battery storage is mainly focused on the optimizations of economic benefits, such as configuration, dispatch and subsidy policies, which rely relatively more on technological developments and financial support. Behavioral economics theory points out that consumers are not "rational people", and non-economic incentives can influence their decisions without increasing costs. Therefore, this paper proposes a household battery storage incentive method based on behavioral economics to guide users to purchase household battery storage to improve their power dispatch efficiency and economic benefits. In this paper, the utility model of behavioral economic incentives and purchase willingness is constructed through empirical research. Then, with grid-friendliness and economic benefits as the optimization goals, multi-objective genetic algorithm is used to optimize the dispatching of household battery storage. The result of this paper shows that the proposed incentive measures will increase users' willingness to purchase by 10.7% without increasing subsidies. Peak-load shifting coefficient and user revenue are improved by 4.2% and 10.6%, respectively, by optimizing the energy dispatching strategy.

In view of the load fluctuation caused by large-scale access of electric vehicles to the power grid, this paper proposes an electric vehicle cluster dispatching strategy considering demand response, which uses Vehicle to Grid (V2G) technology to control the charging and discharging behavior and provide auxiliary services for the power system. Firstly, the V2G model of EV is established according to the travel demand and regular characteristics of EV users. Secondly, combined with the regional daily load curve and time-of-use price, the multi-objective optimal dispatching model of EV cluster charging and discharging is established to stabilize the load fluctuation of power grid and increase the profit of EV users. Considering the demand of electric vehicles and the operation constraints of distribution network, the Pareto optimal solution is obtained by genetic algorithm. The case study results show that the optimization strategy can use peak-valley time-of-use electricity prices to guide the orderly charging and discharging of electric vehicles while meeting user needs, so as to achieve load peak-shaving and valley-filling. After increasing the V2G response subsidy under the tiered electricity price mode, when dispatching with the maximum profit of the user, the grid-side peak-to-valley ratio can be reduced by 2.99%, and the variance can be reduced by 9.52%, achieving the multi-objective optimization of V2G participation in power response.

Background: Despite substantial improvement in chronic total occlusions (CTO) revascularization technique, the long-term clinical outcomes in diabetic patients with revascularized CTO remain controversial. Our study aimed to investigate the five-year cardiovascular survival for patients with or without type 2 diabetes mellitus (DM) who underwent successful percutaneous coronary intervention (PCI) for CTO. Methods: Data of the current analysis derived from a large single-center, prospective and observational cohort study, including 10,724 patients who underwent PCI in 2013 at Fuwai Hospital. Baseline, angiographic and follow-up data were collected. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which consisted of death, recurrent myocardial infarction (MI), stroke and target vessel revascularization (TVR). The secondary endpoint was all-cause mortality. Cox regression analysis and propensity-score matching was performed to balance the baseline confounders. Results: A total of 719 consecutive patients with ≥ 1 successful CTO-PCI were stratified into diabetic (n=316, 43.9%) and non-diabetic (n=403, 56.1%) group. During a median follow-up of 5 years, the risk of MACCE (adjusted hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.08-2.00, P = 0.013) was significantly higher in the diabetic group than in the non-diabetic group, whereas the adjusted risk of all-cause mortality (HR 2.37, 95% CI 0.94-5.98, P = 0.068) was similar. In the propensity score matched population, there were no significant differences in the risk of MACCE (HR 1.27, 95% CI 0.92-1.75, P = 0.155) and all-cause mortality (HR 2.56, 95% CI 0.91-7.24, P = 0.076) between groups. Subgroup analysis revealed a consistent effect on five-year MACCE across various subgroups.Conclusions: In patients who received successful CTO-PCI, non-diabetic patients were related to better long-term survival benefit in terms of MACCE. Further randomized studies are warranted to confirm these findings.

Medullary sponge kidney (MSK) is a characteristic renal malformation, with a relatively low incidence. Radiologically, identification of MSK is sometimes ambiguous when compared to a renal mass. Here, we report a novel renal clear cell carcinoma in MSK, and discuss our approach to treatment. We recommended that a preoperative biopsy should be performed, followed by a comprehensive discussion regarding the appropriate perioperative preparations and careful surgical techniques that should be performed for this complex disease.

Background Epidemiological evidence has shown that lower salt intake reduces hypertension-related disease mortality. Japan has experienced a drastic decrease in cardiovascular mortality, although this varies across regions. This regional variation does not necessarily match the local patterns of reported average salt intake. In this study, we examined population-level risk factors for hypertension-related disease mortality, focussing on the average household dietary consumption of salt intake sources. Methods We prepared an ecological panel dataset, with prefecture as the unit of analysis, by referring to public statistics and market research data from 2012 to 2015. We collected prefectural averages of household dietary consumption related to salt intake and other nutrients that may affect hypertension control. We used demographic characteristics, medical care availability and local economy indices as covariates. Panel data analysis with fixed-effects modelling was performed, regressing prefectural-level mortality from ischaemic heart diseases, subarachnoid and intracerebral haemorrhage and cerebral infarction on dietary consumption and the selected covariates. Results We confirmed the average household consumption of salt equivalents of discretional salt intake sources to be positively but only weakly associated with mortality from ischaemic heart diseases and cerebral infarction. Household expenditure on processed foods was positively associated with ischaemic heart disease mortality. Conclusions These findings may suggest that the reduction of salt in processed foods, in addition to individual behavioural change, could be useful for decreasing mortality from ischaemic heart diseases in the Japanese population. Ecological factors related to decreasing cerebrovascular disease mortality in the context of the ageing Japanese population require further investigation.

Utilising solar thermal energy for membrane distillation desalination represents a green and sustainable solution for building environments in regions with a high correlation between water shortage and high solar irradiance. Today’s solar thermal-driven membrane distillation systems are designed with physically separated solar thermal collectors (e.g. flat plate or evacuated solar thermal collectors) and membrane distillation modules. In these systems, a thermal storage tank, a heat exchanger, and complex plumbing arrangements are required to control the heat and mass transfer between the solar collectors and the membrane distillation unit(s). Due to their high complexity and high capital/operational costs, these systems are rarely installed in buildings. To overcome these weaknesses, the present work conducts an experimental and numerical feasibility study of an integrated solar membrane distillation prototype (with the membrane distillation modules built directly into the evacuated solar tubes) for both potable water and/or thermal energy production. To the best of the authors’ knowledge, this elegant combination of an evacuated tube solar collector and a membrane distillation unit represents an innovative approach which couples two well-developed technologies into an efficient, yet relatively low cost, hybrid energy-water production system. Our experimental results revealed that 4–10 L per square meter of membrane area per hour of permeate flux is achievable when the feed temperature ranges from 50 to 70 °C, achieving a salinity level of 10–200 ppm from a 35,000 ppm (e.g. the salinity of seawater) feed. It was found that a system with a solar absorbing area of 1.6 m2 integrated with ∼0.2 m2 of membranes can produce ∼4 L of drinkable water and ∼4.5 kWh of heat energy (at 45 °C) per day (with an average daily solar exposure of 4 kWh/m2). We envision that this design could be beneficially deployed on the rooftops of residential and commercial buildings—buildings which require a continual supply of both potable water and domestic hot water.

With the construction of the “3-level, 3-vertical-line, and 1-circle” power backbone in China, it's stricter and stricter on relay protection system and security and stability control system (SSCS) for reliable power transmission. Lots of blackouts in the world had happened, one main reason for which is the hidden failures of relay protection system or SSCS. Much work had been done about the hidden failure of relay protection, including classification, probability model, analysis methods of effects on power grid, and monitoring measures, which was summarized in the paper. The operation experiences of SSCS indicated that there might be hidden failures in five links of the security and stability control device (SSCD), e.g. measuring, control strategy, setting, communication and voting pattern. In addition, the coordination hidden failure among relay protection system, SSCS, and power plant's parameters related to the power grid was pointed out for more attention. In the future, amounts of work will be expected to be conducted on hidden failure: model building, assessment methods, application of research achievements, operation management of secondary equipment, and coordination problem between the relay protection system and the SSCS.

Objective To perform a comprehensive histopathologic review of sporadic resected solitary cT1 renal masses comparing those with and without radiographic involvement of the hilum. Materials and Methods A prospectively maintained database was queried for all cT1 renal masses undergoing resection classified per the R.E.N.A.L. nephrometry score. Hilar masses were defined as tumors that abut the main renal artery or vein on cross-sectional imaging. Demographic, treatment, renal mass, and histopathologic characteristics were compared between hilar and nonhilar renal masses. Multivariate regression model analyses were performed to assess factors associated with renal mass upstaging and disease recurrence. Results A total of 1324 stage 1 renal masses met criteria for analysis of which 226 (17.1%) were defined as hilar. Hilar masses were larger, scored with higher complexity, and more likely to undergo a radical nephrectomy. On histopathologic analysis, we found no difference between hilar and nonhilar masses regarding the incidence of malignancy, presence of high nuclear grade, or risk of upstaging. On multivariate analysis, a tumor's hilar location was not associated with upstaging or disease recurrence. Conclusion We present a comprehensive histopathologic review of a large cohort of cT1 hilar lesions noting no difference in the risk of malignancy, high nuclear grade, upstaging, or recurrence when compared to nonhilar lesions. Together, these data suggest that there is no compelling cancer-specific rationale to perform a radical nephrectomy when managing renal hilar tumors.

Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.

Two types of stiffened sandwich plate structures are analyzed and compared. The first is surface-immersed stiffened sandwich plate, in which the stiffener’s top surface is bonded to the bottom surface of the sandwich plate. The second is body-immersed stiffened sandwich plate, in which the stiffener is immersed into the 3-D space of core soft layer. The immersed discontinuous semi-discrete finite element method is developed and applied to study the stiffened plates. The results are compared with ANSYS to verify the accuracy of the method. The convergence study is also given: an exponential convergence is observed. The stiffening efficiency is compared between the two types of stiffened sandwich plates. It is observed that the body-immersed stiffened plate has better strength and stability. The motivation to develop this method is to use a much smaller number of degree-of-freedom to analyze those stiffened plates, for which traditional finite element methods may not be convenient because of the difficulty in the generation of high-quality compatible mesh.

Guidelines recommend surveillance after resection of colorectal cancer (CRC), but rates of adherence to surveillance are variable and have not been studied at National Cancer Institute (NCI)‐designated Comprehensive Cancer Centers. The aim of this study was to determine rates of adherence to standard postresection CRC surveillance recommendations including physician visits, carcinoembryonic antigen (CEA), computed tomography (CT), and colonoscopy after CRC resection at three NCI‐designated centers. Data on patients with resected CRC from 2010 to 2017 were reviewed. Adherence to physician visits was defined as having at least two visits within 14 months after surgical resection. CEA adherence was defined as having at least four CEA levels drawn within 14 months. CT and colonoscopy adherence were defined as completing each between 10 and 14 months from surgical resection. Chi‐square test and logistic regression analyses were performed for overall adherence and adherence to individual components. A total of 241 CRC patients were included. Overall adherence was 23%. While adherence to physician visits was over 98%, adherence to CEA levels, CT, and colonoscopy were each less than 50%. Center was an independent predictor of adherence to CEA, CT, and/or colonoscopy. Stage III disease predicted CT adherence, while distance traveled of 40 miles or less predicted colonoscopy adherence. Overall adherence to postresection CRC guideline‐recommended care is low at NCI‐designated centers. Adherence rates to surveillance vary by center, stage, and distance traveled for care. Understanding factors associated with adherence is critical to ensure CRC patients benefit from postresection surveillance.