SynergyX: a multi-modality mutual attention network for interpretable drug synergy prediction.

Discovering effective anti-tumor drug combinations is crucial for advancing cancer therapy. Taking full account of intricate biological interactions is highly important in accurately predicting drug synergy. However, the extremely limited prior knowledge poses great challenges in developing current computational methods. To address this, we introduce SynergyX, a multi-modality mutual attention network to improve anti-tumor drug synergy prediction. It dynamically captures cross-modal interactions, allowing for the modeling of complex biological networks and drug interactions. A convolution-augmented attention structure is adopted to integrate multi-omic data in this framework effectively. Compared with other state-of-the-art models, SynergyX demonstrates superior predictive accuracy in both the General Test and Blind Test and cross-dataset validation. By exhaustively screening combinations of approved drugs, SynergyX reveals its ability to identify promising drug combination candidates for potential lung cancer treatment. Another notable advantage lies in its multidimensional interpretability. Taking Sorafenib and Vorinostat as an example, SynergyX serves as a powerful tool for uncovering drug-gene interactions and deciphering cell selectivity mechanisms. In summary, SynergyX provides an illuminating and interpretable framework, poised to catalyze the expedition of drug synergy discovery and deepen our comprehension of rational combination therapy.

Monovalent SARS-COV-2 mRNA vaccine using optimal UTRs and LNPs is highly immunogenic and broadly protective against Omicron variants.

The emergence of highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that are resistant to the current COVID-19 vaccines highlights the need for continued development of broadly protective vaccines for the future. Here, we developed two messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines, TU88mCSA and ALCmCSA, using the ancestral SARS-CoV-2 spike sequence, optimized 5' and 3' untranslated regions (UTRs), and LNP combinations. Our data showed that these nanocomplexes effectively activate CD4+ and CD8+ T cell responses and humoral immune response and provide complete protection against WA1/2020, Omicron BA.1 and BQ.1 infection in hamsters. Critically, in Omicron BQ.1 challenge hamster models, TU88mCSA and ALCmCSA not only induced robust control of virus load in the lungs but also enhanced protective efficacy in the upper respiratory airways. Antigen-specific immune analysis in mice revealed that the observed cross-protection is associated with superior UTRs [Carboxylesterase 1d (Ces1d)/adaptor protein-3ß (AP3B1)] and LNP formulations that elicit robust lung tissue-resident memory T cells. Strong protective effects of TU88mCSA or ALCmCSA against both WA1/2020 and VOCs suggest that this mRNA-LNP combination can be a broadly protective vaccine platform in which mRNA cargo uses the ancestral antigen sequence regardless of the antigenic drift. This approach could be rapidly adapted for clinical use and timely deployment of vaccines against emerging and reemerging VOCs.

Impact of Removal of Lymph Nodes on Survival in Stage I-III Gastric Signet-Ring Cell Cancer: The More, the Better?

BACKGROUND: There is an ongoing debate over the prognostic value of the number of examined lymph nodes (ELNs) in cases of gastric signet-ring cell cancer (GSRCC). In this study, we sought to evaluate the correlation between the number of ELNs and the prognosis of GSRCC and identify the optimal number of ELNs. METHODS: A total of 1020 patients diagnosed with GSRCC between 2011 and 2018 in the National Cancer Center database were identified. Clinicopathological characteristics were retrospectively collected, and optimal cutoff values of ELNs were calculated by using X-tile. The impact of different ELNs on overall survival (OS) was compared by using Kaplan-Meier curves. We used univariate and multivariate Cox and subgroup analyses to explore the relationship between ELNs and OS. Furthermore, nonlinear correlations were investigated by using restricted cubic splines (RCSs). RESULTS: X-tile showed that the optimal cutoff value of ELNs was 22. The 5-year OS was higher for patients with ELNs > 22 (vs. ELNs ≤ 22, 66.9% vs. 74.9%, P = 0.026). Multivariate Cox analyses showed that high ELNs were associated with superior OS (hazard ratio = 0.56, 95% confidence interval 0.43-0.74, P < 0.001). In subgroup analyses, the significant association between tumor size > 4 cm, and TNM III stage was still observed. The RCS regression model showed a U-shaped dose-response nonlinear relationship between ELNs and OS; the inflection point, as well as the lowest risk points, corresponded to 44-52 ELNs. CONCLUSIONS: A U-shaped, nonlinear correlation with inflection points of 44-52 ELNs between ELNs and prognosis in GSRCC was identified.

Large-Scale Production and Integrated Application of Micro-Supercapacitors.

Micro-supercapacitors, emerging as promising micro-energy storage devices, have attracted significant attention due to their unique features. This comprehensive review focuses on two key aspects: the scalable fabrication of MSCs and their diverse applications. The review begins by elucidating the energy storage mechanisms and guiding principles for designing high-performance devices. It subsequently explores recent advancements in scalable fabrication techniques for electrode materials and micro-nano fabrication technologies for micro-devices. The discussion encompasses critical application domains, including multifunctional MSCs, energy storage integration, integrated power generation, and integrated applications. Despite notable progress, there are still some challenges such as large-scale production of electrode material, well-controlled fabrication technology, and scalable integrated manufacture. The summary concludes by emphasizing the need for future research to enhance micro-supercapacitor performance, reduce production costs, achieve large-scale production, and explore synergies with other energy storage technologies. This collective effort aims to propel MSCs from laboratory innovation to market viability, providing robust energy storage solutions for MEMS and portable electronics.

Reperfusion Injury Is Associated With Poor Outcome in Patients With Recanalization After Thrombectomy.

BACKGROUND: The existence of cerebral reperfusion injury in human beings remains controversial. Thus, we aimed to explore the presence of reperfusion injury in acute ischemic stroke patients with recanalization after mechanical thrombectomy and analyzed its impact on neurological outcome. METHODS: We reviewed our prospectively collected database CIPPIS (Comparison Influence to Prognosis of CTP and MRP in AIS Patients, NCT03367286), and enrolled anterior circulation large artery occlusion patients with recanalization after mechanical thrombectomy who underwent (1) computed tomography (CT) perfusion on admission and immediately after recanalization to determine reperfusion region, and (2) CT and/or magnetic resonance imaging (MRI) immediately and 24 hours after recanalization to determine lesion areas. The expansion of lesion between recanalization and 24 hours within reperfusion region was potentially caused by reperfusion, thus termed as radiological observed reperfusion injury (RORI). Based on the imaging modality immediately after recanalization, RORI was further divided into RORICT and RORIMRI. We first included a small cohort who had performed both CT and MRI immediately after recanalization to validate the consistency between RORICT and RORIMRI (Study 1). Then the association with RORICT and poor outcome, defined as 3-month modified Rankin Scale score of 3 to 6, was explored in a larger cohort (Study 2). RESULTS: Study 1 included 23 patients and good consistency was found between RORICT and RORIMRI (intraclass correlation=0.97, P<0.001). Among 226 patients included in Study 2, a total of 106 (46.9%) were identified with RORI. The ratio of RORI to reperfusion region was 30.1 (16.2, 51.0)% and was independently associated with poor outcome (odds ratio=1.55 per 10% [95% CI' 1.30-1.84]; P<0.001). CONCLUSIONS: Our findings suggested that RORI was relatively frequent in stroke patients with recanalization after mechanical thrombectomy and associated with poor outcome despite successful recanalization. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03367286.

BRD4 as a potential target for human papillomaviruses associated cancer.

Around 99% of cervical cancer and 5%-10% of human cancer are associated with human papillomaviruses (HPV). Notably, the life-cycle of HPV begins by low-level infection of the basal cells of the stratified epithelium, where the viral genomes are replicated and passed on to the daughter proliferating basal cells. The production of new viral particles remains restricted to eventually differentiated cells. HPVs support their persistent infectious cycle by hijacking pivotal pathways and cellular processes. Bromodomain-containing protein 4 (BRD4) is one of the essential cellular factors involved in multiple stages of viral transcription and replication. In this review, we demonstrate the role of BRD4 in the multiple stages of HPV infectious cycle. Also, we provide an overview of the intense research about the cellular functions of BRD4, the mechanism of action of bromodomain and extra terminal inhibitors, and how it could lead to the development of antiviral/anticancer therapies.

Lonidamine liposomes to enhance photodynamic and photothermal therapy of hepatocellular carcinoma by inhibiting glycolysis.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has great promise in the treatment of cancer. However, there are many obstacles that can restrict the therapeutic efficacy of phototherapy. The hypoxic tumor microenvironment can restrict the production of reactive oxygen species (ROS) in PDT. As for PTT, the thermotolerance of cancer cells may lead to ineffective PTT. In this study, IR780 and glycolysis inhibitor lonidamine (LND)-encapsulated liposomes are prepared for photodynamic and photothermal therapy of hepatocellular carcinoma. IR780 can be used as a photosensitizer and photothermal agent for simultaneous PDT and PTT after being irradiated with 808 nm laser. LND can reduce the oxygen consumption of cancer cells by inhibiting glycolysis, which will relieve tumor hypoxia and produce more ROS for PDT. On the other hand, energy supply can be blocked by LND-induced glycolysis inhibition, which will inhibit the production of heat shock proteins (HSPs), reduce the thermotolerance of tumor cells, and finally enhance the therapeutic efficacy of PTT. The enhanced PTT is studied by measuring intracellular HSPs, ATP level, and mitochondrial membrane potential. The antitumor effect of IR780 and LND co-loaded liposomes is extensively investigated by in vitro and in vivo experiments. This research provides an innovative strategy to simultaneously enhance the therapeutic efficacy of PDT and PTT by inhibiting glycolysis, which is promising for future creative approaches to cancer phototherapy.

WHITE AND LESION-MIMIC LEAF1, encoding a lumazine synthase, affects reactive oxygen species balance and chloroplast development in rice.

The riboflavin derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are essential cofactors for enzymes in multiple cellular processes. Characterizing mutants with impaired riboflavin metabolism can help clarify the role of riboflavin in plant development. Here, we characterized a rice (Oryza sativa) white and lesion-mimic (wll1) mutant, which displays a lesion-mimic phenotype with white leaves, chlorophyll loss, chloroplast defects, excess reactive oxygen species (ROS) accumulation, decreased photosystem protein levels, changes in expression of chloroplast development and photosynthesis genes, and cell death. Map-based cloning and complementation test revealed that WLL1 encodes lumazine synthase, which participates in riboflavin biosynthesis. Indeed, the wll1 mutant showed riboflavin deficiency, and application of FAD rescued the wll1 phenotype. In addition, transcriptome analysis showed that cytokinin metabolism was significantly affected in wll1 mutant, which had increased cytokinin and δ-aminolevulinic acid contents. Furthermore, WLL1 and riboflavin synthase (RS) formed a complex, and the rs mutant had a similar phenotype to the wll1 mutant. Taken together, our findings revealed that WLL1 and RS play pivotal roles in riboflavin biosynthesis, which is necessary for ROS balance and chloroplast development in rice.

Evaluation of a multicomponent intervention to shorten thrombolytic door-to-needle time in stroke patients in China (MISSION): A cluster-randomized controlled trial.

BACKGROUND: Rapid intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is crucial for improving outcomes. However, few randomized trials of interventions aimed at reducing in-hospital delay have been carried out in China. We aimed to evaluate the effect of a multicomponent intervention on thrombolytic door-to-needle time (DNT) of AIS patients via video teleconference based on the Behavior Change Wheel (BCW) method. METHODS AND FINDINGS: This cluster-randomized trial, conducted between January 1, 2019 and December 31, 2019, randomly allocated 22 hospitals equally to PEITEM (Persuasion Environment reconstruction Incentivization Training Education Modeling) intervention or routine care plus stroke registry and subsequently enrolled 1,634 AIS patients receiving IVT within 4.5 hours upon stroke onset from participant hospitals. The PEITEM group received a 1-year PEITEM 6-component intervention based on the behavioral theory monthly via video teleconference. The primary outcome was the proportion of patients with a DNT of 60 minutes or less. A total of 987 patients participated in the PEITEM group (mean age, 69 years; female, 411 [41.6%]) and 647 patients in the control group (mean age, 70 years; female, 238 [36.8%]). Of all participants, the proportion of DNT ≤60 minutes in the PEITEM group was higher than in the control group (82.0% versus 73.3%; adjusted odds ratio, 1.77; 95% confidence interval (CI), 1.17 to 2.70; ICC, 0.04; P = 0.007). Among secondary outcomes, the average DNT was 43 minutes in the PEITEM group and 50 minutes in the control group (adjusted mean difference: -8.83; 95% CI, -14.03 to -3.64; ICC, 0.12; P = 0.001). Favorable functional outcome (score of 0 to 1 on the modified Rankin scale (mRS)) was achieved in 55.6% patients of the PEITEM group and 50.4% of the control group (adjusted odds ratio, 1.38; 95% CI, 1.00 to 1.90; ICC, 0.01; P = 0.049). Main study limitations include non-blinding of clinicians, and that specific interventions component responsible for the observed changes could not be determined. CONCLUSIONS: The teleconference-delivered PEITEM intervention resulted in a moderate but clinically relevant shorter DNT and better functional outcome in AIS patients receiving IVT. TRIAL REGISTRATION: Clinicaltrials.gov NCT03317639.

Type I Interferon Promotes Humoral Immunity in Viral Vector Vaccination.

Recombinant viral vectors represent an important platform for vaccine delivery. Our recent studies have demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus versus poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type I interferon (IFN) and inflammasome activation. However, the impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we show that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated a type I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo. Following vaccination, type I IFN receptor-knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to wild-type (WT) mice. Consistent with the antibody response, a type I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type I IFN signaling also promoted the generation of a vaccine-specific CD4 T-cell response and a T follicular helper (Tfh) response in mice. Together, our data indicate a role for type I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and their impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1-/- mice as a model, we report that type I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Our findings provide insights that not only add to our basic understanding of host-viral vector interactions but also will aid in improving vaccine design by potentially modulating type I IFN and its associated innate immune pathways in viral vector vaccination.