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The degradation behavior of biodegradable Mg alloys has become a research hotspot in the fields about biodegradable metallic materials. While the most of the related publications mainly focused on the degradation rate of Mg-based materials, but rare to care about the changes of their mechanical properties during the immersion period, which can significantly affect their service performance. The link between residual strength and Mg degradation is not appreciated enough. In this work, a series media were constructed based on Hanks’ solution, the effects of inorganic ions on the degradation rate and mechanical integrity of Mg-Zn-Y-Nd alloy were investigated. The results indicated that the degradation behavior of Mg alloy was mainly controlled by degradation products and there is no direct correspondence between the degradation rate change and mechanical integrity of Mg alloy. The relevant findings are beneficial for selecting the monitoring index in Mg corrosion tests and evaluating the service reliability of Mg alloys for biomedical applications.

Abstract Background F-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®). Methods This was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated. Results The mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 − 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim. Conclusions A single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC. Trial registration ClinicalTrials.gov: NCT04174599, on 22/11/2019.

Abstract Background This study was designed to evaluate the effect of progesterone receptor (PR) status on the prognosis of advanced estrogen receptor (ER)-high human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. Methods Advanced ER-high HER2-negative breast cancer patients who were admitted to Harbin Medical University Cancer Hospital and received cyclin-dependent kinase (CDK)4/6 inhibitor combined with endocrine as first-line therapy were included for analysis. Patients were divided into PR-high group (11-100%), PR-low group (1-10%), and PR-negative group (

Abstract Background Disitamab vedotin (DV; RC48‐ADC) is an antibody‐drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)‐directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2‐overexpression and HER2‐low advanced breast cancer (ABC). Methods In the phase I dose‐escalation study (C001 CANCER), HER2‐overexpression ABC patients received DV at doses of 0.5‐2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose‐range and expansion study (C003 CANCER) enrolled two cohorts: HER2‐overexpression ABC patients receiving DV at doses of 1.5‐2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2‐low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2‐low ABC. Results Twenty‐four patients with HER2‐overexpression ABC in C001 CANCER, 46 patients with HER2‐overexpression ABC and 66 patients with HER2‐low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%‐66.0%) and 33.3% (22/66; 95% CI: 22.2%‐46.0%), with median progression‐free survival (PFS) of 5.7 months (95% CI: 5.3‐8.4 months) and 5.1 months (95% CI: 4.1‐6.6 months) for HER2‐overexpression and HER2‐low ABC, respectively. Common (≥5%) grade 3 or higher treatment‐emergent adverse events included neutrophil count decreased (17.6%), gamma‐glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%). Conclusion DV demonstrated promising efficacy in HER2‐overexpression and HER2‐low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.

Abstract Spalling, a common failure mechanism of gear systems, greatly affects the dynamics of gears operation, which is reflected in the time-varying mesh stiffness (TVMS). Current TVMS models often overestimate the asymmetric spalling phenomenon and may lead to inaccuracy in identifying and predicting the spalling failure. To address this problem, in this paper, a new stiffness, namely torsional stiffness, is introduced to quantify the effect of asymmetric spalling defects, and an equivalent stiffness calculation method for different asymmetric shapes is proposed. Based on this, a shape-independent TVMS model is constructed, which can realize the fast calculation of TVMS for spalling defects with different shapes at arbitrary asymmetric locations. Furthermore, a FEM-based validation method is developed by considering diverse loading states and improving the current result extraction method. Case studies are presented to illustrate the proposed model and to analyze the effects of different types of asymmetric spalling defects on gear dynamics. The FEM validation has shown that the proposed model has a good effectiveness.

Resilience assessment and enhancement in distribution networks primarily focus on the ability to support and recover critical loads after extreme events. With the increasing integration of new energy sources and power electronics, distribution networks have gained a degree of resilience. However, the impact of power quality issues on these networks has become more severe. In some cases, even networks assessed as highly resilient by users suffer equipment damage and substantial economic losses due to power quality issues. To address this issue, this paper builds upon conventional distribution network resilience assessment methods by supplementing and modifying indices in the dimensions of resistance and recovery to account for power quality issues. Furthermore, an optimized energy storage system (ESS) configuration model is proposed as a technical means to minimize the total operational cost of the distribution network while enhancing comprehensive resilience indices. The proposed nonlinear optimization model is solved using second-order cone relaxation techniques. Finally, the proposed strategy is simulated on the IEEE 33-node distribution network. The simulation results demonstrate that the proposed strategy effectively improves the comprehensive resilience indices of the distribution network and reduces the total operational cost.

Summary: Grem1+ cancer-associated fibroblasts (CAFs) are crucial in colorectal cancer (CRC) development, yet technical challenges have limited understanding of their origins, spatiotemporal distribution, and potential roles. Here, we devised a custom mold, optimizing the gut Swiss-roll technique to create a single cryopreserved slide for comprehensive staining. Our integrated approach uncovered a marked increase in Grem1+ CAFs within ApcMin/+ mouse tumors at 12 weeks, compared to normal mucosa. Subsequent lineage tracing in Grem1-CreERT2; R26-LSL-tdTomato; ApcMin/+ mice revealed that most Grem1+ CAFs infiltrating the tumor core originated from Grem1+ intestinal reticular stem cells (iRSCs). A minor subset of Grem1+ CAFs, located in the submucosa, retained characteristics of Grem1+ intestinal sub-epithelial myofibroblasts (ISEMFs). Altogether, CAFs derived from Grem1+ iRSCs may serve as a principal stromal cell type driving early-stage CRC progression, while Grem1+ ISEMFs contribute less from a more distant location. Hence, targeting Grem1+ CAFs presents an early and promising therapeutic strategy in CRC.

Background In patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; Hi-CHOP) versus rituximab plus CHOP (R-CHOP) treatment regimens.Methods In a 2:1 ratio, eligible patients were assigned randomly to receive treatment of six cycles of either 375 mg/m2 zuberitamab or rituximab together with conventional CHOP chemotherapy. The objective response rate (ORR) at C6D50 served as the primary endpoint, and a non-inferiority margin of 10% was established. The secondary endpoints included the complete response (CR) rate at C6D50, duration of response (DOR), progression-free survival (PFS) and event-free survival (EFS) judged by blinded-independent review committee (BIRC), overall survival (OS) and safety outcomes.Results Of the 487 randomized patients, 423 patients including 287 in the Hi-CHOP and 136 in the R-CHOP groups completed the C6D50 assessment. For the full analysis set (FAS) and per-protocol set (PPS), BIRC-assessed ORR at C6D50 for the Hi-CHOP and R-CHOP groups were 83.5% versus 81.4% and 95.3% versus 93.7%, respectively. The non-inferiority was confirmed as the lower limit of the two-sided 95% CI for the intergroup differences of −5.2% and −3.3%; both were >−10% in the FAS and PPS. The BIRC-assessed CR rate of Hi-CHOP was significantly higher in PPS (85.7% vs 77.3%, p=0.038), but comparable in FAS (75.2% vs 67.9%, p=0.092). After a median follow-up of 29.6 months, patients in the Hi-CHOP group had a slight advantage with regard to the DOR (HR 0.74, p=0.173), PFS (HR 0.67, p=0.057), EFS (HR 0.90, p=0.517) and OS (HR 0.60, p=0.059). Patients with the germinal-center B cell-like subtype who received Hi-CHOP exhibited statistically significant improvements in ORR (p=0.034) and CR rate (p=0.038) at C6D50, EFS (p=0.046) and OS (p=0.014). Treatment-emergent adverse event occurrence rates were comparable across groups (all p>0.05). Infusion-related responses occurred more often in the Hi-CHOP group (32.1% vs 19.9%, p=0.006), all of grade 1–3 severity.Conclusions Zuberitamab (375 mg/m2) plus CHOP was non-inferior to R-CHOP regarding ORR but exhibited a higher CR rate and was well tolerated in CD20-positive, previously untreated Chinese patients with DLBCL.Trial registration number Chinese Clinical Trial Registry, ChiCTR2000040602, retrospectively registered.

Background: Abemaciclib was the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved globally in the adjuvant setting for high-risk hormone-receptor positive (HR+)/human epidermal growth factor 2 negative (HER2−) early breast cancer (EBC), based on the phase III monarchE trial. Objective: To report an exploratory Chinese population analysis based on the preplanned overall survival (OS) interim analysis with 5-year efficacy results of monarchE. Design and methods: Patients with HR+/HER2−, high-risk (⩾4 positive lymph nodes, or 1–3 nodes and either tumor size ⩾5 cm, histologic grade 3, or Ki-67 ⩾20%) EBC were randomized (1:1) to abemaciclib (150 mg twice daily for 2 years) plus endocrine therapy (ET), or ET alone. This analysis included Chinese patients enrolled in mainland China, Hong Kong, and Taiwan. The primary endpoint was invasive disease-free survival (IDFS); key secondary endpoints included distant relapse-free survival (DRFS), safety, and patient-reported outcomes (PROs). Results: Overall, 501 Chinese patients were included (abemaciclib + ET, n = 259; ET, n = 242). With a median follow-up of 53 months, the addition of abemaciclib to ET resulted in improvements in IDFS (estimated 5-year IDFS rate: 85.9% vs 79.1%; hazard ratio (HR), 0.65 (95% confidence interval (CI) 0.41–1.03)) and DRFS (estimated 5-year DRFS rate: 88.4% vs 82.3%; HR, 0.65 (95% CI, 0.39–1.07)). The most common grade ⩾3 treatment-emergent adverse events in the abemaciclib + ET versus ET groups were neutropenia (24.7% vs 0.8%) and leukopenia (22.4% vs 0.4%). Generally, no clinically meaningful difference in PROs (endocrine symptoms and fatigue) was observed between groups, except for diarrhea. Conclusion: At this prespecified OS interim analysis, which provides 5-year data, the addition of abemaciclib to ET in Chinese patients with high-risk HR+, HER2− EBC was associated with sustained and clinically meaningful improvements in IDFS and DRFS, with acceptable safety and tolerability profiles and minimal impact on PROs. These results represent the first full report of a CDK4/6 inhibitor in Chinese patients with EBC and support the positive benefit–risk profile of adjuvant abemaciclib + ET in Chinese patients. Trial registration: ClinicalTrials.gov identifier: NCT03155997 (first posted: May 16, 2017).

Conventional model-driven methods are hard to handle large-scale power flow with multivariate uncertainty, variable topology, and massive real-time repetitive calculations. With the ability to deal with non-Euclidean graph-structured power system data, graph deep learning shows great potential in modern power flow calculation. However, general graph deep learning based power flow calculation has limited adaptability because of its sole mapping of node information and black-box attributes. In this paper, an edge graph attention network based power flow calculation (EGAT-PFC) model is proposed with improved adaptability for power flow analysis of complex system scenarios. First, the dual-model structure of the node model and edge model is constructed to realize a complete power flow mapping covering all information in power systems. Second, an improved learnable attention coefficient mechanism fusing node and edge features is proposed to ensure global information can be completely considered. Third, mechanisms of extended first-order neighborhood, dynamic normalization, and regularization-based loss function are designed to improve training performance. Finally, visualized interpretability is developed to show valuable information of vulnerable nodes and lines of power system operation. The numerical simulation verifies that EGAT-PFC has high accuracy, fast mapping, as well as excellent adaptability to variable topologies.

Abstract Process industry suffers from production management in terms of efficiency promotion and waste reduction in large scale manufacturing due to poor organization of the intricate relational databases. In order to enhance the suitability of intelligent manufacturing systems in process industry, this study proposed an innovative top-down structure Knowledge Graph (KG) for process fault diagnosis, and papermaking was taken as a case study. The KG consists of a normalized seven-step-built ontology, which extracted instances of papermaking knowledge via Protégé software. The exported OWL file was imported into Neo4j software for visualization of the KG. The application in papermaking drying process for fault diagnosis shows that it can depict the material and energy flows throughout the process with a clearer relationship visualization than traditional measures. They also enable rationale search for faults and identification of their potential causes. The built KG efficiently manages the vast knowledge of the process, stores unstructured data, and promotes the intelligent development of process with high reusability and dynamicity that can rapidly import new production knowledge as well as flexibly self-updating.

Abstract On June 6, 2023, the Kakhovka Dam in Ukraine experienced a catastrophic breach that led to the loss of life and substantial economic values. Prior to the breach, the supporting structures downstream of the spillway had shown signs of being compromised. Here, we use multi-source satellite data, meteorological reanalysis, and dam design criteria to document the dam’s pre-failure condition. We find that anomalous operation of the Kakhovka Dam began in November 2022, following the destruction of a bridge segment, which led to persistent overtopping from late April 2023 up to the breach, contributing to the erosion of the spillway foundation. Moreover, our findings also highlight safety and risk-reduction measures pivotal in avoiding such scenarios. To help prevent future disasters, we advocate for greater transparency in the design parameters of key water structures to enable risk management, and conclude that remote sensing technology can help ensuring water infrastructure safety.

Background: Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC). Objectives: To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC. Design: A multicenter, open-label, phase Ib trial. Methods: Patients with locally recurrent or metastatic BC were enrolled in five cohorts. Patients without prior treatment for advanced disease (cohorts 1–2) were given dalpiciclib (125 or 150 mg) plus letrozole/anastrozole; patients who progressed after ET (cohorts 3–5) were given dalpiciclib (125, 150, or 175 mg) plus fulvestrant. Dalpiciclib was administered orally once daily in 3-weeks-on/1-week off schedule. The primary endpoint was safety. Results: A total of 58 patients received dalpiciclib with letrozole/anastrozole and 46 received dalpiciclib with fulvestrant. No maximum tolerated dose of dalpiciclib was reached with letrozole/anastrozole or fulvestrant. Across all cohorts, 86.7%–93.8% of patients had a grade ⩾3 adverse event, with the most common being neutropenia (grade 3, 40.0% for dalpiciclib 175 mg and 61.8%–87.5% for lower doses; grade 4, 46.7% and 4.2%–20.6%, respectively) and leukopenia (grade 3, 80.0% for 175 mg and 33.3%–54.2% for lower doses; grade 4, 0% for all doses). At tested dose levels, steady-state areas under the concentration curve and peak concentration of dalpiciclib increased with dose when combined with letrozole/anastrozole and fulvestrant. Dalpiciclib at 150 mg was associated with a numerically higher objective response rate in both patients untreated for advanced disease (67.6%; 95% confidence interval (CI) 49.5–82.6) and patients progressing after ET (53.3%; 95% CI 26.6–78.7); as of July 30, 2022, the median progression-free survival with dalpiciclib 150 mg was 24.1 months (95% CI 16.9–46.0) with letrozole/anastrozole and 16.7 months (95% CI 1.9–24.1) with fulvestrant. Conclusion: Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg. Trial registration: ClinicalTrials.gov identifier: NCT03481998.

PurposeThe aim of this study is to explore the interrelationships among body image perception, levels of psychological distress, and the quality of life (QOL) experienced by young breast cancer patients.MethodsThis study analyzed data from 339 young female breast cancer patients aged between 18 and 40 years (mean age was 33.47 years) from August 2023 to February 2024. Data on demographic characteristics, psychological distress, body image, medical coping, and QOL of young breast cancer patients were collected. Psychological distress, body image, medical coping, and QOL were measured using the Distress Thermometer (DT), Hospital Anxiety and Depression Scale (HADS), Body Image Scale (BIS), Medical Coping Modes Questionnaire (MCMQ), and Functional Assessment of Cancer Therapy-Breast (FACT-B), respectively. Multiple regression analysis was conducted to examine factors influencing QOL.ResultsAfter adjusting for covariates, significant predictors of QOL in young survivors included psychological distress (β = −3.125; p = 0.002), anxiety and depression (β = −4.31; p

The degradation of Mg alloys relates to the service performance of Mg alloy biodegradable implants. In order to investigate the degradation behavior of Mg alloys as vascular stent materials in the near service environment, the hot-extruded fine-grained Mg-Zn-Y-Nd alloy microtubes, which are employed to manufacture vascular stents, were tested under radial compressive stress in the dynamic Hanks’ Balanced Salt Solution (HBSS). The results revealed that the high flow rate accelerates the degradation of Mg alloy microtubes and its degradation is sensitive to radial compressive stress. These results contribute to understanding the service performance of Mg alloys as vascular stent materials.

Abstract This multicenter, phase II study (NCT03872791) aims to evaluate the efficacy and safety of the anti-PD-L1/CTLA-4 bispecific antibody KN046 combined with nab-paclitaxel in the first-line treatment of patients with metastatic triple-negative breast cancer (TNBC). The primary endpoints included objective response rate (ORR) and duration of response (DoR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) rate, safety, and the correlation of PD-L1 status with clinical efficacy. This trial met pre-specified endpoints. 27 female patients were enrolled sequentially to receive KN046 in two dose levels (3 mg/kg or 5 mg/kg). Among the 25 evaluable patients, the ORR achieved 44.0% (95% CI, 24.4% − 65.1%), and the median DoR was not mature. The median PFS reached 7.33 months (95%CI, 3.68 − 11.07 months), and the median OS was 30.92 months (95%CI, 14.75 - NE months). In PD-L1 positive patients, PFS was 8.61 months (versus 4.73 months) and the 2-year OS rate was 62.5% (versus 57.1%) compared to PD-L1 negative patients. Patients tolerated well the combination therapy. In general, KN046 combined with nab-paclitaxel showed favorable efficacy and survival benefits with tolerable toxicity in the first-line treatment of metastatic TNBC, especially PD-L1 positive, which is worth further investigation.

Abstract Background Chemoresistance presents a significant obstacle in the treatment of colorectal cancer (CRC), yet the molecular basis underlying CRC chemoresistance remains poorly understood, impeding the development of new therapeutic interventions. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) has emerged as a potential oncogenic factor implicated in various cancer types, where it fosters tumor growth and survival. However, its specific role in modulating the sensitivity of CRC cells to chemotherapy is still unclear. Methods Public dataset analysis and in-house sample validation were conducted to assess the expression of EFTUD2 in 5-fluorouracil (5-FU) chemotherapy-resistant CRC cells and the potential of EFTUD2 as a prognostic indicator for CRC. Experiments both in vitro, including MTT assay, EdU cell proliferation assay, TUNEL assay, and clone formation assay and in vivo, using cell-derived xenograft models, were performed to elucidate the function of EFTUD2 in sensitivity of CRC cells to 5-FU treatment. The molecular mechanism on the reciprocal regulation between EFTUD2 and the oncogenic transcription factor c-MYC was investigated through molecular docking, ubiquitination assay, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP). Results We found that EFTUD2 expression was positively correlated with 5-FU resistance, higher pathological grade, and poor prognosis in CRC patients. We also demonstrated both in vitro and in vivo that knockdown of EFTUD2 sensitized CRC cells to 5-FU treatment, whereas overexpression of EFTUD2 impaired such sensitivity. Mechanistically, we uncovered that EFTUD2 physically interacted with and stabilized c-MYC protein by preventing its ubiquitin-mediated proteasomal degradation. Intriguingly, we found that c-MYC directly bound to the promoter region of EFTUD2 gene, activating its transcription. Leveraging rescue experiments, we further confirmed that the effect of EFTUD2 on 5-FU resistance was dependent on c-MYC stabilization. Conclusion Our findings revealed a positive feedback loop involving an EFTUD2/c-MYC axis that hampers the efficacy of 5-FU chemotherapy in CRC cells by increasing EFTUD2 transcription and stabilizing c-MYC oncoprotein. This study highlights the potential of EFTUD2 as a promising therapeutic target to surmount chemotherapy resistance in CRC patients.

Visible Infrared Imaging Radiometer Suite (VIIRS) and Advanced Baseline Imager (GOES-R ABI) flood products have been widely used by the National Weather Service (NWS) for river flood monitoring, and by the Federal Emergency Management Agency (FEMA) for rescue and relief efforts. Some water bodies, like wetlands, are detected as water but not marked as permanent or normal water, which may result in their misclassification as floodwaters by VIIRS and GOES-R flood products. These water bodies generally do not cause significant property damage or fatalities, but they can complicate the identification of truly hazardous floods. This study utilizes the severe Louisiana flood event caused by Hurricane Ida to demonstrate how to differentiate wetlands from real-hazard flooding. Since Hurricane Ida made landfall in 2021, and there was no major flood event in 2022, VIIRS and ABI flood data from 2021 and 2022 were selected. The difference in annual total flooding days between 2021 and 2022 was calculated and combined with long-time flood frequency to distinguish non-hazard floodwaters due to wetlands identified from real-hazard floods caused by the hurricane. The results were compared with the wetlands from the change detection analysis. The confusion matrix analysis indicated an accuracy of 91.58%, precision of 89.97%, and F1-score of 76.63% for the VIIRS flood products. For the GOES-R ABI flood products, the confusion matrix analysis yielded an accuracy of 86.88%, precision of 97.49%, and F1-score of 75.21%. The accuracy and F1-score values for the GOES-R ABI flood products are slightly lower than those for the VIIRS flood products, possibly due to their lower spatial resolution, but still within a feasible range.

ObjectiveTo systematically evaluate and explore the factors influencing depressive symptoms in female breast cancer patients in China through meta-analysis.MethodsRelevant data were retrieved from cross-sectional studies or cohort studies on depressive symptoms of Chinese breast cancer within the following databases: PubMed, Embase, Cohrane Library, Web of 105 Science, Database of Medical Literature (CBM), Wan Fang Data, CNKI, and VIP databases. The literature screening, data extraction and literature quality evaluation were performed by two researchers by carefully reading the title, abstract and full text, and meta-analysis was performed using Stata 1.5 software after extracting relevant data.ResultsFourteen papers were finally included, with a cumulative total of 3,071 people surveyed, and a total of 1,298 breast cancer patients were detected with depression, with a detection rate of depressive symptoms of 42.26%; meta analysis showed that age less than 40 years old, unmarried, less than undergraduate education, monthly income

Abstract Poor selectivity, low bioavailability and serious systemic side-effects have limited the application of traditional chemotherapy method for treatment of prostate cancer. Stimuli-responsive drug delivery systems for chemotherapy are mainly based on the unique characteristics of tumor microenvironment. In this study, the GSH-sensitive poly-TTG-SS@DTX NPs (DTX-loaded poly-Tetraethylene glycol nanoparticles) were designed and synthesized, which were characterized with nanosized diameter (92.8 ± 2.5 nm) and negatively charged surface charge (−24.7 ± 5.56 mV). Experiments in vitro showed that poly-TTG-SS@DTX NPs had good compatibility to healthy cells and strong anti-tumor effect because of rapid and sustained drug release of DTX from poly-TTG-SS@DTX NPs under the tumor-microenvironment condition. The cellular activity remained greater than 90% when the concentration of poly-TTG-SS NPs reached as high as 100 µg/mL treated on healthy cells. The killing effect of DTX loading NPs group on C4-2 cells was stronger than that of free anti-tumor drug and free DTX combined with the blank nano-carrier (25.21% vs 19.93% vs 20.96%). In conclusion, poly-TTG-SS@DTX NPs may provide a new therapeutic strategy for the chemotherapy of prostate cancer. Graphical Abstract

Abstract Some triple-negative breast cancer (TNBC) patients evaluated as Miller-Payne 4 with ypN0 after neoadjuvant chemotherapy (NACT) who have better prognoses should avoid escalation of therapy. We aim to identify these patients by evaluating pretherapeutic spatial distributions of immunophenotypes. Our retrospective study in patients with TNBC assessed as Miller-Payne grade 4/5 with ypN0 showed that Miller-Payne 4 with ypN0 group had poorer 5-year disease-free survival (DFS, 63.8% vs. 83.0%, p = 0.003) and the 5-year overall survival (OS, 71.0% vs. 85.5%, p = 0.007) than Miller-Payne 5 with ypN0 group. High TILs were significantly associated with better DFS and OS in patients with Miller-Payne 4 and ypN0 (both p = 0.016). Spatially, detected by multiplexed ion beam imaging by the time of flight combined with proteomics, tumors assessed as Miller-Payne 4 and ypN0 with good prognosis exhibited an inflamed phenotype, with dominant CD8+ T cells on tumor center, few scattered CD68+ myeloid-derived cells far away from T cells, and deposit of increased activated molecules of lymphocyte. While those with poor prognoses presented excluded phenotypes, with few CD8+ T cells restricted to invasive margins and a high density of CD14+CD68+CD11c+ myeloid cells. A good classifier model based on 29 spatial immunophenotypes was established by the random forest algorithm (AUC = 0.975), for identifying patients with Miller-Payne 4 and ypN0 who had favorable prognoses. We also observed similar signatures in patients with Miller-Payne 5 and ypN0. Taken together, spatial immunophenotypes may assess the prognosis in TNBC patients with Miller-Payne 4 and ypN0 after NACT.

BackgroundAs a therapy to prevent and treat essential hypertension (EH), traditional Chinese exercises (TCEs) were widely used in clinical practice. However, there is a lack of strictly comparison of the antihypertensive efficacy of different TCEs, which not conducive to the selection of the best and most optimal treatment. This study aimed to perform a network meta-analysis to objectively evaluate which TCE has the best effects in assisting with lowering blood pressure.MethodsPubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), VIP, SinoMed and Wanfang Data were searched for all randomized controlled trials (RCTs) on TCEs for the treatment of EH published up to July 10, 2023. RoB2.0 tool was utilized to evaluate the quality of the RCTs. The network meta-analysis was performed by R 4.1.2 and Stata 17.0. Weighted mean difference (WMD) was calculated for continuous outcomes.ResultsA total of 29 studies, including 2,268 patients were included to analyze 6 different interventions. The network meta-analysis results presented that in comparison with control group, Tai Chi + antihypertensive medication [WMD = −10.18, 95% CI, (−14.94, −5.44)] is the most effective intervention for lowering systolic blood pressure (SBP), and Wuqinxi + antihypertensive medication [WMD = −10.36, 95% CI (−18.98, −1.66)] is the most effective intervention for lowering diastolic blood pressure (DBP).ConclusionTCEs combined with antihypertensive medication may be able to achieve more prominent antihypertensive effects with Tai Chi and Wuqinxi potentially being the higher-priority options. However, well-designed randomized studies are warranted to further verify currently conclusion.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with antitumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/refractory mature Bcell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase 2 dose (RP2D). Overall, 134 Chinese patients were enrolled (dose escalation, n=27; dose expansion, n=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d. The primary efficacy end point of independent review committee–assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% CI, 37.5–64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the doseexpansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased doseproportionally with ascending dose levels from 200–800 mg, without observed saturation. Sovleplenib showed antitumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Abstract Aim The number of breast cancer patients is increasing, but there are insufficient sources of information for their family caregivers. The purpose of this systematic review was to elaborate the psychologically realistic experiences and corresponding needs of family members of patients with breast cancer in the course of their experience in the disease which may provide them with effective, targeted intervention strategies to improve their quality of life. Design Protocol for a meta‐synthesis. Methods We will search the Chinese databases (i.e., China National Knowledge Infrastructure, VIP Database and Wanfang Database) and the English databases (i.e., PubMed, Embase, Web of Science, the Cochrane Library, CINAHL and PsycINFO). Qualitative studies from the above databases, studying the psychological experiences of family members of patients with breast cancer, will be searched comprehensively. The quality of the study will be evaluated by two reviewers independently using the Joanna Briggs Institute (JBI) critical appraisal tools for qualitative study, and any disagreements will be discussed and judged by the third reviewer. Data will be extracted using JBI standardized data extraction tool. Then, the literature will be compared and analysed, and the raw results summarized using the JBI meta‐aggregation tool. The reliability and credibility of the overall quality of the included studies will be assessed by using the JBI ConQual approach. Results N/A. No Patient or Public Contribution. PROSPERO registration number REDACTED.

Abstract Background Tumor necrosis (TN) was associated with poor prognosis. However, the traditional classification of TN ignored spatial intratumor heterogeneity, which may be associated with important prognosis. The purpose of this study was to propose a new method to reveal the hidden prognostic value of spatial heterogeneity of TN in invasive breast cancer (IBC). Methods Multiphoton microscopy (MPM) was used to obtain multiphoton images from 471 patients. According to the relative spatial positions of TN, tumor cells, collagen fibers and myoepithelium, four spatial heterogeneities of TN (TN1-4) were defined. Based on the frequency of individual TN, TN-score was obtained to investigate the prognostic value of TN. Results Patients with high-risk TN had worse 5-year disease-free survival (DFS) than patients with no necrosis (32.5% vs. 64.7%; P

Entinostat plus exemestane in hormone receptor-positive (HR+) advanced breast cancer (ABC) previously showed encouraging outcomes. This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR + ABC that relapsed/progressed after ≥1 endocrine therapy. Patients were randomized (2:1) to oral exemestane 25 mg/day plus entinostat (n = 235) or placebo (n = 119) 5 mg/week in 28-day cycles. The primary endpoint was the independent radiographic committee (IRC)-assessed progression-free survival (PFS). The median age was 52 (range, 28–75) years and 222 (62.7%) patients were postmenopausal. CDK4/6 inhibitors and fulvestrant were previously used in 23 (6.5%) and 92 (26.0%) patients, respectively. The baseline characteristics were comparable between the entinostat and placebo groups. The median PFS was 6.32 (95% CI, 5.30–9.11) and 3.72 (95% CI, 1.91–5.49) months in the entinostat and placebo groups (HR, 0.76; 95% CI, 0.58–0.98; P = 0.046), respectively. Grade ≥3 adverse events (AEs) occurred in 154 (65.5%) patients in the entinostat group versus 23 (19.3%) in the placebo group, and the most common grade ≥3 treatment-related AEs were neutropenia [103 (43.8%)], thrombocytopenia [20 (8.5%)], and leucopenia [15 (6.4%)]. Entinostat plus exemestane significantly improved PFS compared with exemestane, with generally manageable toxicities in HR + ABC (ClinicalTrials.gov #NCT03538171).

Abstract Background RecQ‐mediated genome instability 2 (RMI2) maintains genome stability by promoting DNA damage repair. It has been reported to accelerate the progression of several tumors. However, the functional mechanism of RMI2 in breast cancer remains unclear. Methods Gene expression profiles were obtained from TCGA, GTEx, and GEO databases. The expression of RMI2 and its prognostic value in breast cancer was explored. In addition, we calculated pooled standardized mean deviation (SMD) and performed a summary receiver operating characteristic (sROC) curve analysis to further determine RMI2 expression status and diagnostic significance. The functions and related signaling pathways were investigated based on GO and KEGG analyses. The PPI network was constructed by combining the STRING database and Cytoscape software. Subsequently, in vitro assays were conducted to detect the effect of RMI2 on the proliferation and migration of breast cancer cells. Results The expression of RMI2 was markedly upregulated in breast cancer tissues relative to that in normal tissues. Moreover, pooled SMD further confirmed the overexpression of RMI2 in breast cancer (SMD = 1.29, 95% confidence interval (CI): 1.18–1.41, p = 0.000). The sROC curve analysis result suggested that RMI2 had a relatively high diagnostic ability in breast cancer (AUC = 0.87, 95% CI: 0.84–0.90). High RMI2 expression was associated with poor prognosis. GO and KEGG analyses revealed that RMI2 was closely related to cell adhesion, various enzyme activities, and PI3K/AKT signaling pathway. PPI analysis showed that RMI2 had interactions with proteins involved in DNA damage repair. knockdown of RMI2 remarkably inhibited the proliferation and migration of breast cancer cells, while overexpression of RMI2 exerted the opposite effects. Furthermore, we identified that RMI2 accelerates the proliferation and migration of breast cancer cells via activation of the PI3K/AKT pathway. Conclusion The results suggest that RMI2 is a potential diagnostic and prognostic biomarker associated with cell proliferation and migration, and may be used as a novel therapeutic target for breast cancer in the future.

In this paper, a new reliability assessing method for structures influenced by both aleatory and epistemic uncertainty simultaneously is developed. To handle hybrid types of uncertainties, chance theory is introduced to define a new hybrid reliability index. By mathematical derivation and theorems proofs, the new index is showed to be effective and compatible with hybrid types of uncertainties. Correspondingly, a generalized first-order second-moment (GFOSM) algorithm is established for practical reliability assessment of structures with hybrid uncertainties. Based on the first two moments of basic variables, the GFOSM method can perform fast and effective reliability assessment without large-scale integration operations and can be considered as an extension and expansion of the traditional FOSM method. Two numerical cases further illustrate the effectiveness and practicability of the proposed method from different perspectives.

The reliability of circuit systems is primarily affected by cascading failures due to their complex structural and functional coupling. Causes of cascading failure during circuit operation include the continuous degradation process of components and external random shocks. Circuit systems can exhibit asymmetric structural changes and functional loss during cascading failure propagation due to the coupling of degradation and shock and their uncertainty effects. To tackle this issue, this paper abstracts the circuit into an impedance network and constructs a component failure behavior model that considers the correlation between degradation and shock. The interactions between soft and hard failure processes among different components are discussed. Two types of cascading failure propagation processes are described: slow propagation associated with continuous degradation and damage shock, and fast propagation due to fatal shock. Based on this, a cascading failure simulation algorithm is developed. This article presents a case study to demonstrate the proposed models and to analyze the reliability of a typical circuit system.

Abstract Background Sirtuin 3 (Sirt3) is a controversial regulator of carcinogenesis. It residents in the mitochondria and gradually decays during aging. In this study, we tried to investigate the role of Sirt3 in carcinogenesis and to explore its involvement in metabolic alteration. Methods We generated conditional intestinal epithelium Sirt3-knockout mice by crossing Apc Min/+; Villin-Cre with Sirt3 fl/fl (AVS) mice. The deacetylation site of Lon protease-1 (LONP1) was identified with Mass spectrometry. The metabolic flux phenotype was determined by Seahorse bioanalyzer. Results We found that intestinal epithelial cell-specific ablation of Sirt3 promotes primary tumor growth via stabilizing mitochondrial LONP1. Notably, we newly identified that Sirt3 deacetylates human oncogene LONP1 at N terminal residue lysine 145 (K145). The LONP1 hyperacetylation-mutant K145Q enhances oxidative phosphorylation to accelerate tumor growth, whereas the deacetylation-mutant K145R produces calorie-restriction like phenotype to restrain tumorigenesis. Sirt3 deacetylates LONP1 at K145 and subsequently facilitates the ESCRT0 complex sorting and K63-ubiquitination that resulted in the degradation of LONP1. Our results sustain the notion that Sirt3 is a tumor-suppressor to maintain the appropriate ubiquitination and degradation of oncogene LONP1. Conclusion Sirt3 represents a targetable metabolic checkpoint of oncogenesis, which produces energy restriction effects via maintaining LONP1 K145 deacetylation and subsequent K63 ubiquitination.

Abstract In this post hoc subgroup analysis of 200 patients enrolled in China from the phase III PHOENIX trial (N = 838, NCT01855750), addition of ibrutinib to rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) did not improve event‐free survival (EFS) versus placebo+R‐CHOP in the intent‐to‐treat (ITT; n = 200, hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0·509–1.349; p = 0.4495) or activated B‐cell‐like (ABC; n = 141 [based on available gene‐expression profiling data], HR = 0.86, 95% CI: 0.467–1.570; p = 0.6160) subpopulations. However, ibrutinib+R‐CHOP improved EFS (HR = 0·50, 95% CI: 0.251–1.003) and progression‐free survival (PFS; HR = 0.48, 95% CI: 0.228–1.009) versus placebo+R‐CHOP in patients aged

Abstract Background Strategies to improve activity of immune checkpoint inhibitors for triple-negative breast cancer (TNBC) are needed. Preclinical studies showed that antiangiogenic agents and poly (ADP-ribose) polymerase (PARP) inhibitors might sensitize tumors to immunotherapy. Here, we investigated the tolerability, safety, and preliminary antitumor activity of camrelizumab, an anti-PD-1 antibody, in combination with apatinib, a vascular endothelial growth factor receptor-2 inhibitor, and fuzuloparib, a PARP inhibitor, in patients with recurrent or metastatic TNBC. Methods This phase Ib study included a dose-finding part and a dose-expansion part. In the dose-finding part, a 3 + 3 dose escalation scheme was introduced. Patients were given camrelizumab (200 mg every 2 weeks) plus apatinib (375 mg or 500 mg once daily) and fuzuloparib (starting dose 100 mg twice daily) every 28-day cycle. After evaluation of the tolerability and safety of the dosing regimens, a clinical recommended dose was determined for the dose-expansion part. The primary endpoint was dose-limiting toxicity (DLT). Results A total of 32 patients were enrolled. Three patients received camrelizumab 200 mg + apatinib 375 mg + fuzuloparib 100 mg, and 29 received camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg (clinical recommended dose). No DLTs were observed in either group. The most common grade ≥ 3 treatment-related adverse events were decreased white blood cell count (20.7%), hypertension (13.8%), decreased neutrophil count (10.3%), and increased aspartate aminotransferase (10.3%). Two patients discontinued study treatment due to immune-mediated hepatitis (n = 1) and anemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, increased aspartate aminotransferase, and increased γ-glutamyltransferase (n = 1). One patient died of unknown cause. Two (6.9% [95% CI, 0.9–22.8]) of 29 patients with camrelizumab 200 mg + apatinib 500 mg + fuzuloparib 100 mg had objective response. The disease control rate was 62.1% (95% CI, 42.3–79.3). The median progression-free survival was 5.2 months (95% CI, 3.6–7.3), and the 12-month overall survival rate was 64.2% (95% CI, 19.0–88.8). Conclusions Combination of camrelizumab plus apatinib and fuzuloparib showed manageable safety profile and preliminary antitumor activity in patients with recurrent or metastatic TNBC. Trial registration ClinicalTrials.gov NCT03945604 (May 10, 2019).

Cancer prognosis using multiregion sampling is costly and not completely reliable due to the required biomarker homogenisation step. Here, the authors develop an intratumor graph neural network for prognosis in multiregion cancer samples based on in situ biomarkers and gene expression that does not need homogenisation.

ObjectiveWe performed a systematic review and meta-analysis of the cognitive effectiveness and safety of lecanemab on subjects with Alzheimer's disease (AD).MethodsWe screened the literature published before February 2023 in PubMed, Embase, Web of Science, and Cochrane that were searched for randomized controlled trials testing lecanemab for the treatment of cognitive decline in patients with MCI or AD. Outcomes measured were CDR Sum of Boxes (CDR-SB), Alzheimer's Disease Composite Score (ADCOMS), AD Assessment Scale–Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating (CDR), amyloid PET Standardized Uptake Volume Ratio (SUVr), amyloid burden on PET, and risks for adverse events.ResultsA total of four randomized controlled trials were included, involving 3,108 AD patients (1,695 lecanemab groups and 1,413 placebo groups) to synthesize evidence. Baseline characteristics of the two groups were similar in all outcomes except that ApoE 4 status and higher MMSE score were observed in the lecanemab group. It is reported that lecanemab was beneficial to stabilize or slow down the decrease in CDR-SB (WMD: −0.45; 95% CI: −0.64, −0.25; p < 0.00001), ADCOMS (WMD: −0.05; 95% CI: −0.07, −0.03; p < 0.00001), ADAS-cog (WMD: −1.11; 95% CI: −1.64, −0.57; p < 0.0001), amyloid PET SUVr (WMD: −0.15; 95% CI: −0.48, 0.19; p = 0.38), amyloid burden on PET (WMD:−35.44; 95% CI: −65.22,−5.67; p = 0.02), adverse events (subjects with any TEAE) (OR: 0.73; 95% CI: 0.25, 2.15; p = 0.57), ARIA-E (OR:8.95; 95% CI: 5.36, 14.95; p < 0.00001), and ARIA-H (OR:2.00; 95% CI: 1.53, 2.62; p < 0.00001) in early AD patients.ConclusionOur analysis found that lecanemab showed significant positive statistical efficacy with respect to cognition, function, and behavior in patients with early AD though the actual clinical significance is yet to be establishedSystematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD42023393393.

Background: The involvement of glycolysis in carcinogenesis and the tumor microenvironment is being increasingly supported by the available data. The aim of this work was to develop a triple-negative breast cancer predictive model based on glycolysis. Methods: Glycolysis mediated pattern clusters were created using the R “ConsensusClusterPlus” package. The variations in the tumor microenvironment between the pattern clusters were examined using the R “GSVA”, “ESTIMATE”, and “CIBERSORT” package. The risk score and nomogram were established to assess clinical outcomes of patients. Results: Substantial differences were observed in the immunological landscape between the glycolysis-mediated pattern clusters. When it came to predicting survival and immunotherapy response, the developed risk score showed promising predictive power. Nomogram was designed to be used in therapeutic settings due to its remarkable predictive accuracy. Conclusions: The immune microenvironment varied among cases of triple-negative breast cancer. The nomogram and the risk score based on glycolysis could both be used to help create more effective treatments.

Objective: Chinese herbal medicine formula and calcium antagonist are commonly used medicines for hypertension in China. This study aims to examine the efficacy and safety of for the treatment of Chinese herbal medicine formula combined calcium antagonist hypertension. Methods: PubMed, the Cochrane library, CNKI, VIP, Sinomed, and Wanfang Database were searched up to January 31, 2021. Data analysis was performed using the Recman 5.3. The source of clinical heterogeneity used stata16.0 for sensitivity analysis. Results: 17 RCTs and 1587 cases were finally included. The results shows that the traditional Chinese medicine decoction combined with calcium antagonists is better than calcium antagonists alone in the treatment of hypertension. In addition, it can effectively alleviate the adverse reactions caused by calcium antagonists. However, due to the low quality of methodology and the small-scale research, more high-quality clinical trials are still needed for verification.

Abstract. Backgrounds:. GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China. Methods:. Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety. Results:. Overall, 58 patients with FL were randomized to the G-chemo (n = 25) and R-chemo arms (n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09–1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography [PET]) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%). Conclusions:. The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit–risk profile in patients from China with FL. Trial registration:. ClinicalTrials.gov, No. NCT01332968.

Abstract Objective To investigate the prognostic value of derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) in patients with advanced HER2 positive breast cancer treated with trastuzumab emtansine. Methods Fifty one patients with advanced HER2 positive breast cancer who received T-DM1 treatment in Harbin Medical University Cancer Hospital were selected. The clinical data and blood test indexes were collected, and the ROC curve determined the optimal cut-off value. Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of dNLR,LDH,LNI (dNLR combined with LDH index) before and after T-DM1 treatment on the survival of patients. Results The median PFS and OS of the patients with advanced HER2 positive breast cancer who received T-DM1 treatment were 6.9 months and 22.2 months, respectively. The optimal cut-off value of LDH and dNLR before T-DM1 treatment was 244 U / L (P = 0.003) and 1.985 (P = 0.013), respectively. Higher LDH and dNLR were significantly correlated with shorter median PFS and OS (P 244 U / L, dNLR > 1.985, LNI > 0, ECOG ≥1 and HER-2 (IHC2 +, FISH+) before the T-DM1 treatment were the poor prognostic factors. LDH uptrend after the T-DM1 treatment also predicted poor prognosis. Conclusion Serum LDH > 244 U / L and dNLR > 1.985 before the T-DM1 treatment were prognostic risk factors for patients with advanced HER2 positive breast cancer receiving T-DM1 treatment. The higher LNI score was significantly associated with shorter PFS and OS. LDH uptrend after T-DM1 treatment was also related to the poor prognosis.

Abstract The currently available materials cannot meet the requirements of human thermal comfort against the hot and cold seasonal temperature fluctuations. In this study, a dual‐mode Janus film with a bonded interface to gain dual‐mode functions of both highly efficient radiative cooling and solar heating for year‐round thermal management is designed and prepared. The cooling side is achieved by embedding NaH2PO2 particles with high infrared radiation (IR) emittance into a porous polymethyl methacrylate (PMMA) film during pore formation process, which is reported for the first time to the knowledge. A synergistic enhancement of NaH2PO2 and 3D porous structure leads to efficient radiant cooling with high solar reflectance (R̅solar ≈ 92.6%) and high IR emittance (ε̅IR ≈ 97.2%), especially the ε̅IR value is much greater than that of the reported best porous polymer films. In outdoor environments under 750 mW cm−2 solar radiation, the dual‐mode Janus film shows subambient cooling temperature of ≈8.8 °C and heating temperature reaching ≈39.3 °C, indicating excellent thermal management capacity. A wide temperature range is obtained only by flipping the dual‐mode Janus film for thermal management. This work provides an advanced zero‐energy‐consumption human thermal management technique based on the high‐performance dual‐mode integrated Janus film material.

Summary: Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.

Objective: Follicular lymphoma (FL) occurring progression within 24 months (POD24) after initial immunochemotherapy has poor prognosis. GLUT1 affects glycolysis within tumor microenvironment (TME) and promotes tumor progression. However, its specific mediated mechanism remains unclear in FL. Methods: Baseline GLUT1 expression, infiltrations of M2 macrophage, and CD8+ T-cells were assessed by immunohistochemistry in FL with POD24 and long-term remission respectively. The spatial features of TME were assessed by MIBI-TOF and proteomics. Predictive immunophenotypes for POD24 occurrence was analyzed by random forest algorithm. The lactate production and the induction of M2 macrophages were detected when GLUT1 was transfected or knocked down in DOHH2. The activation of PI3K/Akt/mTOR signaling in DOHH2 and WSU-FSCCL cells co-cultured with induced inhibitory immunocytes was tracked by western blotting. Results: The FL with POD24 exhibited higher baseline GLUT1 expression and increased infiltration of various inhibitory immunocytes. Spatial signatures of 69 immunophenotypes could predict POD24 occurrence. The activation of PI3K/ Akt /mTOR signaling pathway was not significant in both groups. The supernatant of DOHH2-GLUT1 cells which had more lactate content could induce more M2-type macrophages than that of DOHH2/siRNA GLUT1 cells. When co-cultured with exhausted CD8+ T cells, M2-type macrophages and Tregs, compared with WSU-FSCCL cells, DOHH2 cells with high GLUT1 expression induced more M2-type macrophages and was triggered activation of PI3K/ Akt /mTOR signaling pathway. Conclusion: Tumor cells overexpressing GLUT1 could domesticate immunocytes to form an immunosuppressive TME, which promotes occurrence of POD24 and gradually activates PI3K/ Akt /mTOR pathway of tumor cells in FL. Significance: Tumor cells overexpressing GLUT1 could domesticate immunocytes to form an immunosuppressive microenvironment, which in turn promoted the growth of tumor cells and was related to the progression of disease within 24 months in FL. Suppressive immunocytes gradually activated PI3K/ Akt /mTOR pathway of tumor cells in later stage. Distinguishing spatial features of immunocytes could well predict POD24 occurrence, hoping to benefit these patients from early anti-metabolism therapy based on GLUT1 in the future.

Abstract Background Collagen fibers play an important role in tumor initiation, progression, and invasion. Our previous research has already shown that large-scale tumor-associated collagen signatures (TACS) are powerful prognostic biomarkers independent of clinicopathological factors in invasive breast cancer. However, they are observed on a macroscale and are more suitable for identifying high-risk patients. It is necessary to investigate the effect of the corresponding microscopic features of TACS so as to more accurately and comprehensively predict the prognosis of breast cancer patients. Methods In this retrospective and multicenter study, we included 942 invasive breast cancer patients in both a training cohort (n = 355) and an internal validation cohort (n = 334) from one clinical center and in an external validation cohort (n = 253) from a different clinical center. TACS corresponding microscopic features (TCMFs) were firstly extracted from multiphoton images for each patient, and then least absolute shrinkage and selection operator (LASSO) regression was applied to select the most robust features to build a TCMF-score. Finally, the Cox proportional hazard regression analysis was used to evaluate the association of TCMF-score with disease-free survival (DFS). Results TCMF-score is significantly associated with DFS in univariate Cox proportional hazard regression analysis. After adjusting for clinical variables by multivariate Cox regression analysis, the TCMF-score remains an independent prognostic indicator. Remarkably, the TCMF model performs better than the clinical (CLI) model in the three cohorts and is particularly outstanding in the ER-positive and lower-risk subgroups. By contrast, the TACS model is more suitable for the ER-negative and higher-risk subgroups. When the TACS and TCMF are combined, they could complement each other and perform well in all patients. As expected, the full model (CLI+TCMF+TACS) achieves the best performance (AUC 0.905, [0.873–0.938]; 0.896, [0.860–0.931]; 0.882, [0.840–0.925] in the three cohorts). Conclusion These results demonstrate that the TCMF-score is an independent prognostic factor for breast cancer, and the increased prognostic performance (TCMF+TACS-score) may help us develop more appropriate treatment protocols.

Abstract Purpose In clinical practice, the risk factors for pegylated liposomal doxorubicin-related hand-foot syndrome remain unclear. The purpose of this study was to determine the risk factors associated with hand-foot syndrome in patients with lymphoma using pegylated liposomal doxorubicin. Methods This retrospective descriptive analysis included patients with lymphoma who received PLD treatment (≥ 2 cycles of chemotherapy) at our cancer centre and had complete follow-up data from January 2016 to February 2020. Clinical, laboratory data, as well as the occurrence of hand-foot syndrome (incidence, location, severity, impact on follow-up chemotherapy) were obtained. The primary end point was the incidence of hand-foot syndrome, which was classified according to the “Common Terminology Criteria for Adverse Events” (Version 4.0). A multivariate logistic regression analysis was used to identify risk factors for hand-foot syndrome in patients with lymphoma using doxorubicin liposomes. Findings A total of 167 patients met the inclusion criteria. 58 developed HFS, of which 45 occurred after the second course of chemotherapy. The multivariate logistic regression analysis revealed that a dose increase of pegylated liposomal doxorubicin and hepatobiliary dysfunction were significantly associated with an increased risk for hand-foot syndrome(dose intensity, OR = 6.479; 95% CI, 1.431–29.331 [P = 0.015]; history of gallstones, OR = 14.144, 95% CI, 1.512–132.346 [P = 0.020]; alanine aminotransferase, OR = 1.194, 95% CI, 1.056–1.350 [P = 0.005]; aspartate aminotransferase, OR = 1.162, 95% CI, 1.010–1.336 [P = 0.035]; and glutamine transpeptidase, OR = 1.092, 95% CI, 1.016–1.174 [P = 0.018]). Implications These findings contribute to the risk assessment of patients with lymphoma before using pegylated liposomal doxorubicin. For patients with the above risk factors, preventive measures should be taken in advance to reduce the incidence of HFS.

Background: Triple-negative breast cancer remains a highly malignant disease due to the lack of specific targeted therapy and immunotherapy. A growing body of evidence supports the role of pyroptosis in tumorigenesis and prognosis, but further exploration is needed to improve our understanding of the tumor microenvironment in patients with triple-negative breast cancer.Methods: Consensus clustering analysis was performed to construct pattern clusters. A correlation analysis was conducted between the pattern clusters and the tumor microenvironment using GSVA, ESTIMATE, and CIBERSORT. Then, a risk score and a nomogram were constructed and verified to predict overall survival.Results: Two pyro-clusters and three pyro-gene clusters that differed significantly in terms of prognosis, biological processes, clinical features, and tumor microenvironment were identified. The different clusters corresponded to different immune expression profiles. The constructed risk score predicted patient prognosis and response to immunotherapy. Patients with low risk scores exhibited favorable outcomes with increased immune cell infiltration and expression of immune checkpoint molecules. Compared to other models, the nomogram was extremely effective in predicting prognosis.Conclusion: In the landscape of the immune microenvironment, pyroptosis-mediated pattern clusters differed markedly. Both the developed risk score and the nomogram were effective predictive models. These findings could help develop customized treatment for patients with triple-negative breast cancer.

BackgroundNearly all anti-PD-1 antibodies are of the IgG4 isotype, and thus possess residual FcR effector functions. Such anti-PD-1 antibodies are also associated with immune tolerance and escape due to instability of the CH3 domain and Fc-Fc interaction. In this trial, we examined the efficacy and safety of penpulimab, a novel IgG1 anti-PD-1 antibody that does not bind to the Fc receptor, in patients with refractory or relapsed classical Hodgkin lymphoma (R/R cHL).MethodsAdult patients (≥18 years of age) with R/R cHL received 200 mg penpulimab once biweekly until disease progression or unacceptable toxicities for a maximum of 24 months. The primary endpoint was objective response rate (ORR) based on the Independent Radiology Review Committee per Lugano 2014 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs).ResultsA total of 94 patients were enrolled. The median follow-up was 15.8 months. The ORR was 89.4% (95% CI 80.8%, 95.0%) in the full analysis set (85 patients). Forty (47.1%) patients achieved complete remission, 36 (42.4%) patients achieved partial remission. The 12-month PFS rate was 72.1% (95% CI 60.5%, 80.8%) and the 18-month OS rate was 100%. Totally 97.9% (92/94) of patients experienced at least one TRAE. The rate of grade 3 and above TRAEs was 26.6% (25/94). In addition, 51 (54.3%) patients experienced an irAE, and 4 (4.3%) patients developed grade 3 or above irAEs. No irAE-related death occurred.ConclusionsPenpulimab was effective and safe in patients with R/R cHL.

Abstract Endocrine therapy is the standard treatment for estrogen receptor (ER)-positive breast cancer, but tumors eventually develop resistance. However, endocrine therapy resistance mechanisms mediated through interactions between breast cancer cells and tumor-associated macrophages (TAMs) are still unclear. Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1α/signal transducer and activator of transcription-3 pathway. In turn, M2-like TAMs activate breast cancer cells through EGFR/PI3K/Akt signaling, providing feedback to upregulate SGLT1 and promote tamoxifen resistance and accelerate tumor growth in vitro and in vivo. Higher expression of SGLT1 and CD163+ TAMs was associated with endocrine-resistant ER-positive breast cancers. Our study identifies a novel vicious cycle of metabolic reprogramming, M2-like TAM polarization, and endocrine therapy resistance, which involves SGLT1, proposing SGLT1 as a therapeutic target to overcome endocrine therapy resistance in breast cancer.