Ultrasound-based radiomics nomogram for predicting axillary lymph node metastasis in invasive breast cancer.

OBJECTIVE: To develop a nomogram for predicting axillary lymph node metastasis (ALNM) in patients with invasive breast cancer. METHODS: We included 307 patients with clinicopathologically confirmed invasive breast cancer. The cohort was divided into a training group (n=215) and a validation group (n=92). Ultrasound images were used to extract radiomics features. The least absolute shrinkage and selection operator (LASSO) algorithm helped select pertinent features, from which Radiomics Scores (Radscores) were calculated using the LASSO regression equation. We developed three logistic regression models based on Radscores and 2D image features, and assessed the models' performance in the validation group. A nomogram was created from the best-performing model. RESULTS: In the training set, the area under the curve (AUC) for the Radscore model, 2D feature model, and combined model were 0.76, 0.85, and 0.88, respectively. In the validation set, the AUCs were 0.71, 0.78, and 0.83, respectively. The combined model demonstrated good calibration and promising clinical utility. CONCLUSION: Our ultrasound-based radiomics nomogram can accurately and non-invasively predict ALNM in breast cancer, suggesting potential clinical applications to optimize surgical and medical strategies.

Mitigating sub-synchronous oscillation using intelligent damping control of DFIG based on improved TD3 algorithm with knowledge fusion.

The occurrence of sub-synchronous oscillation (SSO) phenomenon in doubly-fed induction generators (DFIGs)-based wind turbines threatens the secure and stable operation of the power grid. Conventional sub-synchronous damping controllers encounter challenges in adapting to the dynamic operating conditions of power systems. This paper introduces an Intelligent Sub-Synchronous Damping Controller (I-SSDC) for DFIGs that integrates deep reinforcement learning (DRL) and knowledge to address the limitations of conventional methods for SSO mitigation. The initial step involves formulating a framework for I-SSDC using the improved twin delayed deep deterministic policy gradient (TD3) algorithm incorporating Softmax. Following this, a surrogate model is constructed, employing Weighted Linear Regression and regularization. This model is designed to identify the predominant influencing factors of SSO, focusing on the selection of the output signal (installation position) to optimize decision-making in I-SSDC. The objective is to enhance the controller's environmental adaptability and interpretability. Moreover, knowledge and experience related to SSOs are integrated into agent training to improve the exploration efficiency of the agent. Case studies under various operating conditions of the test power system validate the efficacy of the proposed I-SSDC in suppressing SSOs.

Design, fabrication and clinical characterization of additively manufactured tantalum hip joint prosthesis.

The joint prosthesis plays a vital role in the outcome of total hip arthroplasty. The key factors that determine the performance of joint prostheses are the materials used and the structural design of the prosthesis. This study aimed to fabricate a porous tantalum (Ta) hip prosthesis using selective laser melting (SLM) technology. The feasibility of SLM Ta use in hip prosthesis was verified by studying its chemical composition, metallographic structure and mechanical properties. In vitro experiments proved that SLM Ta exhibited better biological activities in promoting osteogenesis and inhibiting inflammation than SLM Ti6Al4V. Then, the topological optimization design of the femoral stem of the SLM Ta hip prosthesis was carried out by finite element simulation, and the fatigue performance of the optimized prosthesis was tested to verify the biomechanical safety of the prosthesis. A porous Ta acetabulum cup was also designed and fabricated using SLM. Its mechanical properties were then studied. Finally, clinical trials were conducted to verify the clinical efficacy of the SLM Ta hip prosthesis. The porous structure could reduce the weight of the prosthesis and stress shielding and avoid bone resorption around the prosthesis. In addition, anti-infection drugs can also be loaded into the pores for infection treatment. The acetabular cup can be custom-designed based on the severity of bone loss on the acetabular side, and the integrated acetabular cup can repair the acetabular bone defect while achieving the function of the acetabular cup.

Gut microbiome-derived hydrolases-an underrated target of natural product metabolism.

In recent years, there has been increasing interest in studying gut microbiome-derived hydrolases in relation to oral drug metabolism, particularly focusing on natural product drugs. Despite the significance of natural product drugs in the field of oral medications, there is a lack of research on the regulatory interplay between gut microbiome-derived hydrolases and these drugs. This review delves into the interaction between intestinal microbiome-derived hydrolases and natural product drugs metabolism from three key perspectives. Firstly, it examines the impact of glycoside hydrolases, amide hydrolases, carboxylesterase, bile salt hydrolases, and epoxide hydrolase on the structure of natural products. Secondly, it explores how natural product drugs influence microbiome-derived hydrolases. Lastly, it analyzes the impact of interactions between hydrolases and natural products on disease development and the challenges in developing microbial-derived enzymes. The overarching goal of this review is to lay a solid theoretical foundation for the advancement of research and development in new natural product drugs and personalized treatment.

Cyanobacterial blooms in Lake Taihu: Temporal trends and potential drivers.

Lake Taihu, an inland lake, frequently experiences Cyanobacterial blooms that have historically posed severe threats to its aquatic ecosystem. Combining field observations and satellite remote-sensed data, factors that influence algal bloom intensity in Lake Taihu over an eight-year period, from 2016 to 2023, are examined, and changes in phytoplankton community composition, climate, water quality, economic activities, and food web dynamics are reported. Sentinel-2 MSI data analysis reveals a dramatic decrease in Cyanobacterial blooms in 2023, with a reduction in the annual maximum bloom area of 76.90 % from 2016 values. From 2016 to 2022, the ratio of Cyanobacteria to other phytoplankton ranged 82.09 %-98.29 %, but in 2023, this dropped to 60.98 %. Concurrently, Cyanobacteria density dropped to an historic low of 2.29 × 107 cells/L (16.4 % of 2021 peak values). Redundancy and random forest analyses indicated that nitrogen has a greater influence on phytoplankton than phosphorus, with temperature and permanganate index being the important parameters to affect phytoplankton community structure. We attribute the decrease in Cyanobacterial blooms in Lake Taihu in 2023 to be largely caused by shifts in phytoplankton community structure, particularly the sharp decline in Microcystis sp. density, a genus often linked to bloom formation. Meteorological conditions such as reduced rainfall and wind speed during the winter and spring of 2023 also contributed to diminishing Cyanobacterial blooms. Ongoing improvements in water quality, reduced economic activities because of pandemic restrictions, and implementation of a fishing ban since 2020 have likely further contributed to reductions in bloom frequency. These results improve our understanding of the processes that affect algal blooms in Lake Taihu, and potentially other eutrophic inland lakes.

Diagnosis of membranous nephropathy with Anti-GBM glomerulonephritis: a case series report.

BACKGROUND: The concomitant occurrence of membranous nephropathy and anti-glomerular basement (anti-GBM) disease has been previously described but is extremely rare. However, delayed recognition or misdiagnosis leads to delayed treatment, resulting in worse renal and patient outcomes. CASE PRESENTATION: We present 3 patients with rapidly progressive glomerulonephritis (RPGN), anti-GBM and serum-positive M-type phospholipase A2 receptor (anti-PLA2R) antibody. Renal biopsies revealed PLA2R-associated membranous nephropathy with anti-GBM glomerulonephritis. We analyzed the clinical and pathological characteristics and discussed that the correct diagnosis of membranous nephropathy with anti-GBM should rely on a combination of renal biopsy findings and serological testing. Despite aggressive treatment, one patient received maintenance hemodialysis, one patient progressed to CKD 3 stage, and the other patient died of cerebral infarction. CONCLUSION: The simultaneous occurrence of membranous nephropathy and anti-GBM disease is extremely rare. The correct diagnosis of membranous nephropathy with anti-GBM relies on a combination of renal biopsy findings and serological testing. Early diagnosis is needed to improve the renal dysfunction.

Ammonium sulfate denatures transport medium less dependent on guanidinium isothiocyanate and enables SARS-CoV-2 RNA and antigen detection compatibility.

Introduction: Rapid identification of infected individuals through viral RNA or antigen detection followed by effective personal isolation is usually the most effective way to prevent the spread of a newly emerging virus. Large-scale detection involves mass specimen collection and transportation. For biosafety reasons, denaturing viral transport medium has been extensively used during the SARS-CoV-2 pandemic. However, the high concentrations of guanidinium isothiocyanate (GITC) in such media have raised issues around sufficient GITC supply and laboratory safety. Moreover, there is a lack of denaturing transport media compatible with SARS-CoV-2 RNA and antigen detection. Methods: Here, we tested whether supplementing media containing low concentrations of GITC with ammonium sulfate (AS) would affect the throat-swab detection of SARS-CoV-2 or a viral inactivation assay targeting coronavirus and other enveloped and non-enveloped viruses. The effect of adding AS to the media on RNA stability and its compatibility with SARS-CoV-2 antigen detection were also tested. Results and discussion: We found that adding AS to the denaturing transport media reduced the need for high levels of GITC, improved SARS-COV-2 RNA detection without compromising virus inactivation, and enabled the denaturing transport media compatible with SARS-CoV-2 antigen detection.

Volatile Organic Compounds Produced by a Deep-Sea Bacterium Efficiently Inhibit the Growth of Pseudomonas aeruginosa PAO1.

The deep-sea bacterium Spongiibacter nanhainus CSC3.9 has significant inhibitory effects on agricultural pathogenic fungi and human pathogenic bacteria, especially Pseudomonas aeruginosa, the notorious multidrug-resistant pathogen affecting human public health. We demonstrate that the corresponding antibacterial agents against P. aeruginosa PAO1 are volatile organic compounds (VOCs, namely VOC-3.9). Our findings show that VOC-3.9 leads to the abnormal cell division of P. aeruginosa PAO1 by disordering the expression of several essential division proteins associated with septal peptidoglycan synthesis. VOC-3.9 hinders the biofilm formation process and promotes the biofilm dispersion process of P. aeruginosa PAO1 by affecting its quorum sensing systems. VOC-3.9 also weakens the iron uptake capability of P. aeruginosa PAO1, leading to reduced enzymatic activity associated with key metabolic processes, such as reactive oxygen species (ROS) scavenging. Overall, our study paves the way to developing antimicrobial compounds against drug-resistant bacteria by using volatile organic compounds.

RAD51 Expression as a Biomarker to Predict Efficacy of Platinum-Based Chemotherapy and PD-L1 Blockade for Muscle-Invasive Bladder Cancer.

RAD51, a key recombinase that catalyzes homologous recombination (HR), is commonly overexpressed in multiple cancers. It is curial for DNA damage repair (DDR) to maintain genomic integrity which could further determine the therapeutic response. Herein, we attempt to explore the clinical value of RAD51 in therapeutic guidance in muscle-invasive bladder cancer (MIBC). In this retrospective study, a total of 823 patients with MIBC were included. Zhongshan hospital (ZSHS) cohort (n=134) and The Cancer Genome Atlas-Bladder Cancer (TCGA-BLCA) cohort (n=391) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n=298) was utilized to interrogate the predictive efficacy of RAD51 status to programmed cell death ligand-1 (PD-L1) blockade. In addition, the association of RAD51 with genomic instability and tumor immune contexture was investigated. Patients with RAD51 overexpression were more likely to benefit from both platinum-based chemotherapy and immunotherapy rather than RAD51-low patients. The TMB high PD-L1 high RAD51 high subgroup possessed the best clinical benefits from PD-L1 blockade. RAD51-high tumors featured by genomic instability were correlated to highly inflamed and immunogenic contexture with activated immunotherapeutic pathway in MIBC. RAD51 could serve as a prognosticator for treatment response to platinum-based chemotherapy and PD-L1 inhibitor in MIBC patients. Besides, it could also improve the predictive efficacy of TMB and PD-L1.

Individualized Dose-Response to Statins Associated with Cardiovascular Disease Outcomes.

Background: Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E0 (baseline LDL-C), (2) ED50 (potency: median dose achieving 50% reduction in LDL-C); and (3) Emax (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown. Objective: We analyze the relationship between ED50 and Emax with real-world cardiovascular disease outcomes. Method: We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED50 and Emax to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality. Results: We estimated ED50 and Emax for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED50 and Emax are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED50 and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for Emax in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively. Conclusion: The class-wide association of ED50 and Emax with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.

Performance of Phenotype Algorithms for the Identification of Opioid-Exposed Infants.

OBJECTIVE: Observational studies examining outcomes among opioid-exposed infants are limited by phenotype algorithms that may under identify opioid-exposed infants without neonatal opioid withdrawal syndrome (NOWS). We developed and validated the performance of different phenotype algorithms to identify opioid-exposed infants using electronic health record data. METHODS: We developed phenotype algorithms for the identification of opioid-exposed infants among a population of birthing person-infant dyads from an academic health care system (2010-2022). We derived phenotype algorithms from combinations of 6 unique indicators of in utero opioid exposure, including those from the infant record (NOWS or opioid-exposure diagnosis, positive toxicology) and birthing person record (opioid use disorder diagnosis, opioid drug exposure record, opioid listed on medication reconciliation, positive toxicology). We determined the positive predictive value (PPV) and 95% confidence interval for each phenotype algorithm using medical record review as the gold standard. RESULTS: Among 41 047 dyads meeting exclusion criteria, we identified 1558 infants (3.80%) with evidence of at least 1 indicator for opioid exposure and 32 (0.08%) meeting all 6 indicators of the phenotype algorithm. Among the sample of dyads randomly selected for review (n = 600), the PPV for the phenotype requiring only a single indicator was 95.4% (confidence interval: 93.3-96.8) with varying PPVs for the other phenotype algorithms derived from a combination of infant and birthing person indicators (PPV range: 95.4-100.0). CONCLUSIONS: Opioid-exposed infants can be accurately identified using electronic health record data. Our publicly available phenotype algorithms can be used to conduct research examining outcomes among opioid-exposed infants with and without NOWS.

Variations in surface area and biogeochemistry of subarctic-arctic lakes established through satellite and in-situ observations: An overview of published research from the past 30 years.

Human activities have strongly impacted the global climate, and during the last few decades the global average temperature has risen at a rate faster than at any time on record. High latitude lakes in the subarctic and arctic permafrost regions have particularly been vulnerable given the "Arctic amplification" phenomenon and acceleration in warming rate in the northern hemisphere (0.2-0.8 °C/decade). This paper presents a comprehensive overview of the last 30 years of research investigating how subarctic and Arctic lakes respond to climate warming. The review focused on studies where remote sensing technology was used to quantify these responses. The difference between summer lake water temperature and air temperature varied between 1.7 and 5.4 °C in subarctic lakes and 2.4-3.2 °C in Arctic lakes. Overall, the freezing date of lake ice is generally delayed and the date of lake thawing occurs earlier. Lake surface area (4-48.5 %), and abundance in the subarctic and Arctic region have increased significantly due to rising temperature, permafrost thawing, increased precipitation and other localized surface disturbances. However, in recent years, instances of lake shrinkage (between -0.4 % and -40 %) have also been reported, likely due to riparian overflow, groundwater infiltration and lateral drainage. Furthermore, in subarctic and Arctic lakes, climate change and permafrost thawing would release CO2 and CH4, and alter carbon dynamics in impacted lakes through various interconnected processes which could potentially affect the quality of carbon (terrestrial, algae) entering a lake system. The review also highlighted a potential intersection between permafrost melting and public health through human exposure to long-buried viruses. Subarctic and arctic ecosystems' responses to climate change will continue to be an area of intense research interest, and this review has highlighted priority areas for research and how remote sensing technologies can facilitate the pursuit of such a research agenda.

Neuroprotective effect of acetoxypachydiol against oxidative stress through activation of the Keap1-Nrf2/HO-1 pathway.

BACKGROUND: Excessive oxidative stress in the brain is an important pathological factor in neurological diseases. Acetoxypachydiol (APHD) is a lipophilic germacrane-type diterpene extracted as a major component from different species of brown algae within the genus Dictyota. There have been no previous reports on the pharmacological activity of APHD. The present research aims to explore the potential neuroprotective properties of APHD and its underlying mechanisms. METHODS: The possible mechanism of APHD was predicted using a combination of molecular docking and network pharmacological analysis. PC12 cells were induced by H2O2 and oxygen-glucose deprivation/reoxygenation (OGD/R), respectively. Western blot, flow cytometry, immunofluorescence staining, and qRT-PCR were used to investigate the antioxidant activity of APHD. The HO-1 inhibitor ZnPP and Nrf2 gene silencing were employed to confirm the influence of APHD on the signaling cascade involving HO-1, Nrf2, and Keap1 in vitro. RESULTS: APHD exhibited antioxidant activity in both PC12 cells subjected to H2O2 and OGD/R conditions by downregulating the release of LDH, the concentrations of MDA, and ROS, and upregulating SOD, GSH-Px, and GSH concentrations. APHD could potentially initiate the Keap1-Nrf2/HO-1 signaling cascade, according to the findings from network pharmacology evaluation and molecular docking. Furthermore, APHD was observed to increase Nrf2 and HO-1 expression at both mRNA and protein levels, while downregulating the protein concentrations of Keap1. Both Nrf2 silencing and treatment with ZnPP reversed the neuroprotective effects of APHD. CONCLUSIONS: APHD activated antioxidant enzymes and downregulated the levels of LDH, MDA, and ROS in two cell models. The neuroprotective effect is presumably reliant on upregulation of the Keap1-Nrf2/HO-1 pathway. Taken together, APHD from brown algae of the genus Dictyota shows potential as a candidate for novel neuroprotective agents.

Whole-transcriptome profiling and identification of cold tolerance-related ceRNA networks in japonica rice varieties.

Introduction: Low-temperature stress negatively impacts rice yield, posing a significant risk to food security. While previous studies have explored the physiological and linear gene expression alterations in rice under low-temperature conditions, the changes in competing endogenous RNA (ceRNA) networks remain largely unexamined. Methods: We conducted RNA sequencing on two japonica rice varieties with differing cold-tolerance capabilities to establish ceRNA networks. This enabled us to investigate the transcriptional regulatory network and molecular mechanisms that rice employs in response to low-temperature stress. Results: We identified 364 differentially expressed circular RNAs (circRNAs), 224 differentially expressed microRNAs (miRNAs), and 12,183 differentially expressed messenger RNAs (mRNAs). WRKY family was the most prominent transcription factor family involved in cold tolerance. Based on the expression patterns and targeted relationships of these differentially expressed RNAs, we discerned five potential ceRNA networks related to low-temperature stress in rice: osa-miR166j-5p from the miR166 family was associated with cold tolerance; osa-miR528-3p and osa-miR156j-3p were linked to stress response; and osa-miR156j-3p was involved in the antioxidant system. In addition, Os03g0152000 in the antioxidant system, as well as Os12g0491800 and Os05g0381400, correlated with the corresponding stress response and circRNAs in the network. A gene sequence difference analysis and phenotypic validation of Os11g0685700 (OsWRKY61) within the WRKY family suggested its potential role in regulating cold tolerance in rice. Discussion and conclusion: We identified Os11g0685700 (OsWRKY61) as a promising candidate gene for enhancing cold tolerance in japonica rice. The candidate miRNAs, mRNAs, and circRNAs uncovered in this study are valuable targets for researchers and breeders. Our findings will facilitate the development of cold-tolerant rice varieties from multiple angles and provide critical directions for future research into the functions of cold-tolerance-related miRNAs, mRNAs, and circRNAs in rice.

3D printed osteochondral scaffolds: design strategies, present applications and future perspectives.

Articular osteochondral (OC) defects are a global clinical problem characterized by loss of full-thickness articular cartilage with underlying calcified cartilage through to the subchondral bone. While current surgical treatments can relieve pain, none of them can completely repair all components of the OC unit and restore its original function. With the rapid development of three-dimensional (3D) printing technology, admirable progress has been made in bone and cartilage reconstruction, providing new strategies for restoring joint function. 3D printing has the advantages of fast speed, high precision, and personalized customization to meet the requirements of irregular geometry, differentiated composition, and multi-layered boundary layer structures of joint OC scaffolds. This review captures the original published researches on the application of 3D printing technology to the repair of entire OC units and provides a comprehensive summary of the recent advances in 3D printed OC scaffolds. We first introduce the gradient structure and biological properties of articular OC tissue. The considerations for the development of 3D printed OC scaffolds are emphatically summarized, including material types, fabrication techniques, structural design and seed cells. Especially from the perspective of material composition and structural design, the classification, characteristics and latest research progress of discrete gradient scaffolds (biphasic, triphasic and multiphasic scaffolds) and continuous gradient scaffolds (gradient material and/or structure, and gradient interface) are summarized. Finally, we also describe the important progress and application prospect of 3D printing technology in OC interface regeneration. 3D printing technology for OC reconstruction should simulate the gradient structure of subchondral bone and cartilage. Therefore, we must not only strengthen the basic research on OC structure, but also continue to explore the role of 3D printing technology in OC tissue engineering. This will enable better structural and functional bionics of OC scaffolds, ultimately improving the repair of OC defects.

POLQ identifies a better response subset to immunotherapy in muscle-invasive bladder cancer with high PD-L1.

BACKGROUND: Though programmed cell death-ligand 1 (PD-L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology-mediated end joining (MMEJ) pathway, DNA polymerase theta (POLQ) was overexpressed in various malignancies, whose expression might have an influence on genomic stability, therefore altering the sensitivity to chemotherapy and immunotherapy. METHODS: A total of 1304 patients with muscle-invasive bladder cancer (MIBC) from six independent cohorts were included in this study. The Zhongshan Hospital (ZSHS) cohort (n = 134), The Cancer Genome Atlas (TCGA) cohort (n = 391), and the Neo-cohort (n = 148) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n = 234) and the UNC-108 cohort (n = 89) were used for the assessment of immunotherapeutic response. In addition, the relationship between POLQ and the immune microenvironment was assessed, and GSE32894 (n = 308) was used only for the evaluation of the immune microenvironment. RESULTS: We identified POLQhigh PD-L1high patients could benefit more from immunotherapy and platinum-based chemotherapy. Further analysis revealed that high POLQ expression was linked to chromosome instability and higher tumor mutational burden (TMB), which might elicit the production of neoantigens. Further, high POLQ expression was associated with an active tumor immune microenvironment with abundant infiltration of immune effector cells and molecules. CONCLUSIONS: The study demonstrated that high POLQ expression was correlated with chromosome instability and antitumor immune microenvironment in MIBC, and the combination of POLQ and PD-L1 could be used as a superior companion biomarker for predicting the efficacy of immunotherapy.

Effect of different exercise modalities on nonalcoholic fatty liver disease: a systematic review and network meta-analysis.

Physical exercise intervention can significantly improve the liver of patients with Non-alcoholic fatty liver disease (NAFLD), but it is unknown which exercise mode has the best effect on liver improvement in NAFLD patients. Therefore, we systematically evaluated the effect of exercise therapy on liver and blood index function of NAFLD patients through network meta-analysis (NMA). Through systematic retrieval of PubMed, Cochrane Library, Web of Science, EBSCO, and CNKI (National Knowledge Infrastructure), two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies by means of databases from inception to January 2023. The NMA was performed using the inconsistency model. A total of 43 studies, 2070 NAFLD patients were included: aerobic training (n = 779), resistance training (n = 159), high-intensity interval training (n = 160), aerobic training + resistance training (n = 96). The results indicate that aerobic training + resistance training could significantly improve serum total cholesterol (TC) (Surface under the cumulative ranking curve (SUCRA) = 71.7), triglyceride (TG) (SUCRA = 96.8), low-density lipoprotein cholesterol (LDL-C) (SUCRA = 86.1) in patients with NAFLD including triglycerides. Aerobic training is the best mode to improve ALT (SUCRA = 83.9) and high-density lipoprotein cholesterol (HDL-C) (SUCRA = 72.3). Resistance training is the best mode to improve aspartate transaminase (AST) (SUCRA = 81.7). Taking various benefits into account, we believe that the best modality of exercise for NAFLD patients is aerobic training + resistance training. In our current network meta-analysis, these exercise methods have different effects on the six indicators of NAFLD, which provides some reference for further formulating exercise prescription for NAFLD patients.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Serine protease inhibitor from the muscle larval Trichinella spiralis ameliorates non-alcoholic fatty liver disease in mice via anti-inflammatory properties and gut-liver crosstalk.

Trichinella spiralis is recognized for its ability to regulate host immune responses. The serine protease inhibitor of T. spiralis (Ts-SPI) participates in T. spiralis-mediated immunoregulatory effects. Studies have shown that helminth therapy exhibits therapeutic effects on metabolic diseases. In addition, we previously found that T. spiralis-derived crude antigens could alleviate diet-induced obesity. Thus, Ts-SPI was hypothesized to alleviate non-alcoholic fatty liver disease (NAFLD). Herein, recombinant Ts-SPI (rTs-SPI) was prepared from the muscle larvae T. spiralis. The relative molecular mass of rTs-SPI was approximately 35,000 Da, and western blot analysis indicated good immunoreactivity. rTs-SPI ameliorated hepatic steatosis, inflammation, and pyroptosis in NAFLD mice, which validated the hypothesis. rTs-SPI also reduced macrophage infiltration, significantly expanded Foxp3+ Treg population, and inactivated TLR4/NF-κB/NLRP3 signaling in the liver. Furthermore, rTs-SPI treatment significantly shifted the gut microbiome structure, with a remarkable increase in beneficial bacteria and reduction in harmful bacteria to improve gut barrier integrity. Finally, Abx-treated mice and FMT confirmed that gut-liver crosstalk contributed to NAFLD improvement after rTs-SPI treatment. Taken together, Taken together, these findings suggest that rTs-SPI exerts therapeutic effects in NAFLD via anti-inflammatory activity and gut-liver crosstalk.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.