Meta-Analysis of the Efficacy and Safety of Pembrolizumab in the Treatment of Advanced Gastric Cancer and Gastroesophageal Junction Cancer.

INTRODUCTION: Pembrolizumab has been approved for the first-line treatment of patients with advanced gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced GC/GEJ still needs to be precisely determined. PURPOSE: The aim of this meta-analysis was to assess the efficacy and safety of pembrolizumab in the treatment of advanced GC/GEJ. METHODS: We conducted computerized searches across multiple databases, including PubMed, Cochrane Library, Web of Science, and Embase. We established the inclusion criteria to comprise randomized clinical trials examining the efficacy of pembrolizumab in late-stage GC/GCJ cancer. We conducted a meta-analysis of outcome measures using STATA 14.0 software. RESULTS: A total of six studies involving 1,448 cases were included in this analysis. The results of the meta-analysis indicate that, when compared to chemotherapy, patients in the pembrolizumab group experienced a significant reduction in the risk of mortality in terms of overall survival (OS) (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.65-0.79, p < 0.01). In terms of progression-free survival (PFS), pembrolizumab was associated with a similar PFS as compared to chemotherapy (HR = 0.88, 95% CI: 0.73-1.07, p = 0.206). Subgroup analyses based on PD-L1 expression levels indicated a significantly longer PFS with pembrolizumab in subgroups of patients with PD-L1 CPS ≥10 but not in those with PD-L1 CPS ≥1 and PD-L1 CPS ≥5. Subgroup analyses based on distinct geographical regions revealed a comparable effect of PFS in patients residing in Asia or the USA Subgroup analysis based on tumor sites consistently demonstrated a similar effect of PFS in patients with EC/GEJ tumors and GC patients. CONCLUSION: Our findings demonstrated that pembrolizumab led to a significant extension in OS and objective response rate, along with a favorable tolerability profile compared to chemotherapy. Furthermore, the observed survival benefits were particularly pronounced in subgroup patients with a CPS of ≥10. Given the potential limitations inherent in our study, it is imperative to underscore the necessity for further large-scale RCTs to corroborate our results.

In Situ Self-Assembled Phytopolyphenol-Coordinated Intelligent Nanotherapeutics for Multipronged Management of Ferroptosis-Driven Alzheimer's Disease.

Ferroptosis is a vital driver of pathophysiological consequences of Alzheimer's disease (AD). High-efficiency pharmacological inhibition of ferroptosis requires comprehensive coordination of diverse abnormal intracellular events, which is an urgent problem and great challenge for its application in AD treatment. Herein, a triphenylphosphonium-modified quercetin-derived smart nanomedicine (TQCN) is developed for multipronged anti-ferroptosis therapy in AD. Taking advantage of the favorable brain-targeting and mitochondria-locating properties, TQCN can efficiently chelate iron through phytopolyphenol-mediated spontaneous coordination and self-assemble into metal-phenolic nanocomplexes in situ, exerting escalating exogenous offensive effects to attenuate iron overload and its induced free radical burst. Meanwhile, the Nrf2 signaling-mediated endogenous defensive system is reconstituted to restore iron metabolism homeostasis represented by iron export and storage and enhance cytoprotective antioxidant cascades represented by lipid peroxidation detoxification. Benefiting from the multifaceted regulation of pathogenic processes triggering ferroptosis, TQCN treatment can ameliorate various neurodegenerative manifestations associated with brain iron deposition and rescue severe cognitive decline in AD mice. This work displays great promise of in situ self-assembled phytopolyphenol-coordinated intelligent nanotherapeutics as advanced candidates against ferroptosis-driven AD progression.

Strain-modulated Ru-O Covalency in Ru-Sn Oxide Enabling Efficient and Stable Water Oxidation in Acidic Solution.

RuO2 is one of the benchmark electrocatalysts used as the anode material in proton exchange membrane water electrolyser. However, its long-term stability is compromised due to the participation of lattice oxygen and metal dissolution during oxygen evolution reaction (OER). In this work, weakened covalency of Ru-O bond was tailored by introducing tensile strain to RuO6 octahedrons in a binary Ru-Sn oxide matrix, prohibiting the participation of lattice oxygen and the dissolution of Ru, thereby significantly improving the long-term stability. Moreover, the tensile strain also optimized the adsorption energy of intermediates and boosted the OER activity. Remarkably, the RuSnOx electrocatalyst exhibited excellent OER activity in 0.1 M HClO4 and required merely 184 mV overpotential at a current density of 10 mA cm-2 . Moreover, it delivered a current density of 10 mA cm-2 for at least 150 h with negligible potential increase. This work exemplifies an effective strategy for engineering Ru-based catalysts with extraordinary performance toward water splitting.

Characteristics and prognosis of EGFR mutations in small cell lung cancer patients in the NGS era.

PURPOSE: Targeted therapy has not been effective for small cell lung cancer (SCLC) patients. Although some studies have reported on EGFR mutations in SCLC, a systematic investigation into the clinical, immunohistochemical, and molecular characteristics and prognosis of EGFR-mutated SCLCs is lacking. METHODS: Fifty-seven SCLC patients underwent next-generation sequencing technology, with 11 in having EGFR mutations (group A) and 46 without (group B). Immunohistochemistry markers were assessed, and the clinical features and first-line treatment outcomes of both groups were analyzed. RESULTS: Group A consisted primarily of non-smokers (63.6%), females (54.5%), and peripheral-type tumors (54.5%), while group B mainly comprised heavy smokers (71.7%), males (84.8%), and central-type tumors (67.4%). Both groups showed similar immunohistochemistry results and had RB1 and TP53 mutations. When treated with tyrosine kinase inhibitors (TKIs) plus chemotherapy, group A had a higher treatment response rate with overall response and disease control rates of 80% and 100%, respectively, compared to 57.1% and 100% in group B. Group A also had a significantly longer median progression-free survival (8.20 months, 95% CI 6.91-9.49 months) than group B (2.97 months, 95% CI 2.79-3.15), with a significant difference (P = 0.043). Additionally, the median overall survival was significantly longer in group A (16.70 months, 95% CI 1.20-32.21) than in group B (7.37 months, 95% CI 3.85-10.89) (P = 0.016). CONCLUSION: EGFR-mutated SCLCs occurred more frequently in non-smoking females and were linked to prolonged survival, implying a positive prognostic impact. These SCLCs shared immunohistochemical similarities with conventional SCLCs, and both types had prevalent RB1 and TP53 mutations.

Combined small cell lung cancer: current progress and unmet needs.

Combined small cell lung cancer (CSCLC) is a specific subtype of lung cancer characterized by a pathological mixture of small cell lung cancer and any subtype of non-small cell lung cancer components. Currently, our understanding of the clinicopathological features, origin, molecular characterization, treatment, and prognosis of CSCLC remains limited. CSCLCs represent examples of intratumor heterogeneity and pose challenges for accurate diagnosis. Are there any distinct clinicopathologic and molecular differences between pure SCLC and CSCLC? Furthermore, the prognostic outcomes and optimal treatments for CSCLC are urgently needed. This article aims to summarize the current biological features and clinical management of CSCLC, providing a reference for further understanding of this heterogeneous form of small cell lung cancer.

mTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer's Disease Management.

Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer's disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and 18F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.

A retrospective real-world experience of immunotherapy in patients with extensive stage small-cell lung cancer.

BACKGROUND: The treatment of extensive stage small-cell lung cancer (ES-SCLC) has only made modest progress in the past decade, with two immune checkpoint inhibitors (ICIs), atezolizumab and durvalumab, approved for the treatment of SCLC by January 2022. However, currently, there is limited real-world data on ES-SCLC patients received immunotherapy. METHODS: We retrospectively collected and analyzed the demographic and treatment data of ES-SCLC patients at the First Affiliated Hospital of Guangzhou Medical University from January 2017 to January 2022. Survival and prognosis information was obtained through follow-up. RESULTS: A total of 353 ES-SCLC patients were included, of which 165 received immunotherapy combined with chemotherapy as the first-line (FL) treatment (chemo-immune group), and 188 received chemotherapy (chemotherapy group). The objective response rate (ORR) and disease control rate (DCR) of patients receiving immunotherapy as the FL treatment were better than the chemotherapy group (76.97% vs. 48.40%, p < 0.001, and 83.03% vs. 68.09%, p < 0.001). Moreover, the progression-free survival (PFS) and overall survival (OS) of ES-SCLC patients receiving immunotherapy as the FL treatment were better than the chemotherapy group (6.7 months vs. 5.1 months, p < 0.001, and 12.5 months vs. 11.2 months, p < 0.001). Furthermore, the OS of ES-SCLC patients who received immunotherapy as second-line treatment was better than that in the chemotherapy group (15.9 months vs. 12.9 months, p = 0.036). CONCLUSION: ICIs combined with chemotherapy as the FL treatment could be beneficial to the ORR, DCR, PFS, and OS of ES-SCLC patients. Furthermore, ES-SCLC patients can benefit from ICIs in the second-line treatment, even if they had not received ICIs in the FL treatment.

Deep convolutional neural networks using an active learning strategy for cervical cancer screening and diagnosis.

Cervical cancer (CC) is the fourth most common malignant tumor among women worldwide. Constructing a high-accuracy deep convolutional neural network (DCNN) for cervical cancer screening and diagnosis is important for the successful prevention of cervical cancer. In this work, we proposed a robust DCNN for cervical cancer screening using whole-slide images (WSI) of ThinPrep cytologic test (TCT) slides from 211 cervical cancer and 189 normal patients. We used an active learning strategy to improve the efficiency and accuracy of image labeling. The sensitivity, specificity, and accuracy of the best model were 96.21%, 98.95%, and 97.5% for CC patient identification respectively. Our results also demonstrated that the active learning strategy was superior to the traditional supervised learning strategy in cost reduction and improvement of image labeling quality. The related data and source code are freely available at https://github.com/hqyone/cancer_rcnn.

The relationship between major life events and non-suicidal self-injury among college students: the effect of rumination and body image.

Background: Non-suicidal self-injury (NSSI) poses a growing risk to public health worldwide. While numerous studies have identified major life events as key risk factors for NSSI, the mechanisms by which emotional and cognitive problems mediate or moderate this relationship remain unclear. To enhance the understanding of this field, we will draw upon the cascade theory of self-injury and the benefits and barriers model, to examine the relationship between major life events and NSSI, as well as the effect of rumination and body image. Methods: A sample of 2,717 college students (Mage = 19.81 years; SD = 1.09) participated in this study and anonymously completed the questionnaires. The moderated mediation model were conducted using Model 4 and Model 15 of the Process macro program in SPSS. Results: The results showed that rumination mediated the positive relationship between major life events and NSSI. Furthermore, body image was found to moderate both the relationship between major life events and NSSI, as well as the relationship between rumination and NSSI. Conclusion: The current findings suggest that rumination is an important mediator in the relationship between major life events and NSSI among college students. Teachers, parents, and researchers should recognize the important role of body image self-perceptions of college students and actively promote a healthy and accurate body image.

In Situ Fabrication and Static Contact Resistance of CdMoO4 Reinforced Cu Matrix Composites.

Particle-reinforced Cu-based electrical contact materials prepared by traditional powder metallurgical methods suffer the same critical problem, where the agglomeration of the addition phases in the Cu matrix significantly deteriorates the performance of the composites and restricts their application. In this work, CdMoO4/Cu matrix composites were fabricated by an in situ method and followed by a powder metallurgical process. Firstly, CdMoO4/particles formed a nucleus and grew up based on the surfaces of Cu particles, realizing the controllable in situ synthesis of mixed powders with homogeneously dispersed CdMoO4 nanoparticles via a one-step reaction. Secondly, the bulk CdMoO4/Cu composites were fabricated by pressing and sintering and then densified by hot-extrusion and cold rolling processes. The microstructures and properties of the extruded and rolled specimens were characterized, respectively. The results indicated that the rolled CdMoO4/Cu composite exhibited excellent comprehensive properties of electrical conductivity and mechanical properties for electrical contact materials. Moreover, the effects of the contact force on the static contact resistance of the extruded and rolled composites were evaluated in the closed state of the contact materials. It was found that the rolled CdMoO4/Cu contact materials possessed a stable electrical contact characteristic with low and steady contact resistance. This work designed ternary CdMoO4 particles to reinforce Cu-based composites with well-balanced performances by an in situ synthesis method and this strategy can be extended to the design of ternary oxide/metal composites utilized as electrical contact materials.