Pharmacodynamics and pharmacological mechanism of Moluodan concentrated pill in the treatment of atrophic gastritis: A network pharmacological study and in vivo experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Moluodan concentrated pill (MLD) is a traditional herbal formula used in China for the treatment of chronic atrophic gastritis (CAG). However, its pharmacological mechanism of action remains unclear. AIM OF THE STUDY: The aim of this study was to investigate the therapeutic effect and mechanism of action of MLD in the treatment of CAG using network pharmacology and in vivo experiments. MATERIALS AND METHODS: The active compounds of MLD were determined using network pharmacology, utilizing various Chinese medicine databases such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Traditional Chinese Medicine Integrated Database, Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine, and a comprehensive database of Traditional Chinese Medicine on Immuno-Oncology. The compounds found in the root of Anemone altaica Fisch. were extracted from the China National Knowledge Infrastructure literature database. Additionally, the Swiss Target Prediction database and Similarity Ensemble Approach were employed to identify the potential targets of these components. CAG-related targets were gathered from the GeneCards and DisGeNET databases. Protein-protein interactions (PPIs) of the genes associated with the drug-disease crossover were examined, and a core PPI network was constructed using the STRING database (version 11.5) and Cytoscape (version 3.7.2). A gene-pathway network was established to identify significant target genes and pathways through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, based on these findings and existing data, the tumor necrosis factor (TNF) signaling pathway was selected for further validation through in vivo experiments. RESULTS: A total of 724 active molecules in MLD yielded 961 identified target genes, of which 179 were found to be potentially associated with CAG. From the common targets, a PPI network revealed ten core targets. Enrichment analysis suggested that MLD may primarily target TNF and AKT in the treatment of CAG. Essential signaling pathways, such as the PI3K-AKT and TNF pathways, were found to be crucial for the therapeutic effects of MLD on CAG. Furthermore, potential interactions and crosstalk between these pathways were identified. Moreover, we confirmed that MLD effectively improved gastric mucosa atrophy and cellular ultrastructural damage, while increasing pepsinogen secretion and decreasing gastrin, somatostatin, and motilin levels. Subsequent molecular biology studies in rat models of CAG demonstrated that MLD treatment significantly reduced the expression levels of TNF-α, phosphatidylinositol 3'-kinase (PI3K), and phosphorylated Akt (P < 0.05). Notably, the expression of nuclear factor kappa-B (NF-κB) exhibited a contrasting trend (P < 0.05), potentially associated with the crucial tumor suppressor role of NF-κB p105. CONCLUSION: This study provides evidence that MLD effectively alleviates stomach mucosal atrophy through modulation of the TNF/PI3K/AKT signaling pathway. These findings establish a solid theoretical foundation for the practical management of CAG.

In situ immunomodulation of tumors with biosynthetic bacteria promote anti-tumor immunity.

Immune checkpoint blockade (ICB) therapy potently revives T cell's response to cancer. However, patients suffered with tumors that had inadequate infiltrated immune cells only receive limited therapeutic benefits from ICB therapy. Synthetic biology promotes the alternative strategy of harnessing tumor-targeting bacteria to synthesize therapeutics to modulate immunity in situ. Herein, we engineered attenuated Salmonella typhimurium VNP20009 with gene circuits to synthetize granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 7 (IL-7) within tumors, which recruited dendritic cells (DCs) and enhanced T cell priming to elicit anti-tumor response. The bacteria-produced GM-CSF stimulated the maturation of bone marrow-derived dendritic cells (BMDCs), while IL-7 promoted the proliferation of spleen isolated T cells and inhibited cytotoxicity T cell apoptosis in vitro. Virtually, engineered VNP20009 prefer to colonize in tumors, and inhibited tumor growth by enhancing DCs and T cell infiltration. Moreover, the tumor-toxic GZMB+ CD8+ T cell and IFN-γ+ CD8+ T cell populations conspicuously increased with the treatment of engineered bacteria. The combination of GM-CSF-IL-7-VNP20009 with PD-1 antibody synergistically stunted the tumor progress and stasis.

Spatial distribution of groundwater fluoride and arsenic and its related disease in typical drinking endemic regions.

c exposure to geogenic fluoride and arsenic iChronic exposure to geogenic fluoride and arsenic in groundwater has a deleterious influence on the health of billions of people globally. The health status of residents impacted by connected diseases is urgently needed. A twelve-year study was carried out to identify the spatial distribution pattern of high fluoride/arsenic groundwater in an arid/semi-arid area and to estimate the population exposed to related disease. A geostatistical interpolation method and a disease inversion model were used. The results indicated that fluoride/arsenic-rich groundwater primarily accumulated in basins of Shanxi Province. Groundwater fluoride exposure provided a health concern to 3.16 million persons (9.08 % of the population), including 2.50 million children at risk of dental caries. Exposure to groundwater arsenic caused a health risk to 4.38 million inhabitants (12.58 % of total), with 1.92 million at risk of lung cancer, 1.87 million at risk of bladder cancer, and 0.29 million at risk of skin cancer, respectively. The pollution and impact of groundwater fluoride and arsenic vary greatly among residents in different environments, and accurate assessment of the affected population is of great significance for residents' health and water quality management. Our research study complements the critical data on the disease risks associated with geogenic-contaminated groundwater and provides scientific basis of water quality management for policy makers.

Fluorochloridone induces mitochondrial dysfunction and apoptosis in primary goat Sertoli cells.

Fluorochloridone (FLC), a pyrrolidone herbicide, has been recognized as a hazardous chemical. The in vitro adverse effects of FLC on the reproduction of livestock have not been assessed. This study was conducted to explore the cytotoxicity and toxicological mechanisms of FLC on cultured goat Sertoli cells. The results showed that FLC exposure significantly decreased goat Sertoli cell viability (p < 0.05) and induced oxidative stress. And FLC treatment promoted apoptosis and initiation of autophagy. Interestingly, FLC inhibited lysosomal biogenesis and blocked autophagic flux in goat Sertoli cells. The expression levels of autophagy-related proteins Atg5, LC3II, and p62 were significantly increased (p < 0.05) in FLC-treated goat Sertoli cells compared with the control. Importantly, FLC-induced ROS accumulation further causes mitochondrial dysfunction and disturbs mitophagy. FLC significantly decreased (p < 0.05) the expression levels of OPA1, MFN2, p-Drp1, FIS1, PINK1, and Parkin in goat Sertoli cells. Moreover, pretreatment with N-acetyl-l-cysteine (NAC, an antioxidant) significantly reduced (p < 0.01) FLC-induced ROS accumulation and reversed the disorder of autophagy levels. Our results indicated that FLC-induced toxicity in primary goat Sertoli cells was characterized by ROS accumulation, inducing oxidative stress, inhibiting lysosomal biogenesis, blocking autophagic flux, and promoting mitochondrial dysfunction, resulting in apoptosis via the mitochondrial pathway.

Soil amendments promoting nitrifying bacteria recovery faster than the denitrifying bacteria at post soil fumigation.

Chloropicrin (CP) is a soil fumigant that not only reduces disease-causing pathogenic microbes but regrettably also those that benefit soil quality and crop health. However, we have few knowledge on rapidly restoring populations of beneficial microbes suppressed by CP fumigation. Here we used genetic sequencing technology to monitor changes in the recovery of soil bacteria in response to ammonium sulfate added to the soil following CP fumigation. The results showed that regardless of the N fertilizer addition rate, the accumulated NH4+-N in CP fumigated soil was rapidly consumed within 42 d. The rapid reduction in NH4+-N coincided with the observed recovery nitrogen-cycling microorganisms, especially the nitrification bacteria AOA and AOB that contributed to the formation of NH4+-N. Additionally, we further observed that the resilience index of nitrifying bacteria (AOB and AOA) was greater than the resilience index of denitrifying bacteria that contain the denitrification genes nirS, nirK and nosZ (0.12 to 0.55 vs. -0.27 to 0.073). These results revealed that N fertilizer stimulated the recovery of nitrifying bacteria more than denitrifying bacteria. Our research suggests that ammonium sulfate applied to CP fumigated soil could be used commercially to improve soil health as a result of an increase in beneficial microbes.

Neural mechanisms for integrating time and visual velocity cues in a prediction motion task: An fNIRS study.

Human beings use accurate estimates of the time-to-collision of moving objects effortlessly in everyday life. In the laboratory, researchers typically apply prediction motion (PM) tasks to investigate motion processing. In the PM tasks, time structure refers to the ratio of travel time between the visible segment (first segment) and occluded segment (second segment). The condition of T = 1.0, which indicates that the time spent moving is the same across the two segments, is called equal time structure. The present study investigated the neural mechanisms of time and visual velocity information in prediction motion using functional near-infrared spectroscopy (fNIRS). Experiment 1 showed that when visual velocity was not available, participants performed better in equal time structure conditions than in unequal time structure conditions. Moreover, the left inferior parietal lobe (IPL) showed higher activation under equal time structure conditions. Experiment 2 showed that participants also performed better in equal time structure conditions when visual velocity was available. Both the left IPL and superior parietal lobe (SPL) exhibited stronger activation under equal time structure conditions in Experiment 2. A comparison between the two experiments showed that participants integrated time structure and visual velocity to estimate arrival time of the moving object. The fNIRS data indicated that the left SPL could be involved in information integration when judging arrival time.

The development of a method for the global health community to assess the proportion of food and beverage companies' sales that are derived from unhealthy foods.

CONTEXT: Corporate engagement with food and beverage companies who produce food associated with health harms is a divisive topic in the global nutrition community, with high-profile cases of conflict of interest increasingly coming under scrutiny. There is a need for an agreed method to support health organizations in deciding whether and how to engage with large food and beverage manufacturers. AIM: The aim of this study was to develop a method to quantify the proportion of sales from food and beverage companies that are derived from unhealthy foods to support organizations in determining which companies might be considered high-risk for engagement. METHODS: The 2015 WHO Euro nutrient profile model was applied to 35,550 products from 1294 brands manufactured by the top 20 global food and beverage companies from seven countries (Australia, Brazil, China, India, South Africa, UK and USA). For the purpose of this study, products that met the WHO Euro criteria were classified as "healthier" and those that failed were classified as "unhealthy". Products were grouped by brand and weighted by the brand's value sales for 2020. The primary outcome was the proportion of each company's sales that were classified as unhealthy and healthier by company and category. RESULTS: Overall, 89% of the top 20 companies' brand sales were classified as unhealthy. For every USD$10 spent on the top 20 companies' brands, only $1.10 was spent on products considered healthier. All companies saw the majority of their sales come from unhealthy foods, including soft drinks, confectionery and snacks. None of Red Bull or Ferrero's sales were classified as healthier and less than 5% of total sales were healthier for Mondelez, Mars, and PepsiCo. Some companies had higher proportions of sales deriving from healthier products, including Grupo Bimbo (48%), Danone (34%) and Conagra (32%), although the majority of their sales were still derived from unhealthy foods. DISCUSSION: The results presented in this study highlight the reliance the leading food and beverage companies have on sales of unhealthy products that are contributing to diet-related disease globally. The method and steps we have laid out here could be used by organizations in the global health community to identify companies that have conflicts of interest when it comes to engaging with governments, international organizations and public health bodies on issues of policy and regulation.

Unveiling the Research Landscape and Emerging Trends in Cell Cycle for Cancer Immunotherapy: A Bibliometric Analysis (1990-2022).

BACKGROUND The direct and indirect roles of the cell cycle in immunology of the tumor microenvironment (TME) are topics of intense scientific interest. Therefore, this study aimed to investigate the knowledge domain and hotspots related to the cell cycle for cancer immunology applications. MATERIAL AND METHODS The Web of Science Core Collection (WoSCC) was used as a powerful tool for identifying articles related to cell cycle for cancer immunology applications. Co-occurrence relationships were examined with R, VOSviewer, and CiteSpace software. Related research hotspots and possible future trends were also examined. RESULTS A total of 1844 qualified English-language documents were obtained in WoSCC between 1999 and 2022, with a 7.66% annual growth rate. These eligible studies were co-authored by 2246 institutions in 51 countries/regions, with the greatest article number being published in the United States (36%, 664/1844), followed by China (19%, 351/1844) and Germany (4.5%, 83/1844). The top 3 institutions with the most publications and the top 3 academic journals (n=390 in total) on this topic that published the most articles were identified. Key nodes from the co-cited network were aggregated and identified to reveal the shift in cell cycle for cancer immunology applications. Notably, the current research hotspots in this field include "tumor progression", "chemotherapy", "resistance", "clinical trial", and "target population". CONCLUSIONS This study revealed field profiles, research hotspots, and future directions of cell cycle dysregulation-related immunology, and the findings will offer a vigorous roadmap for further studies in the combination therapy of cell cycle inhibitors and immune checkpoint inhibitors for treating various cancers. Our results can shed more light on relevant research in this field.

Interaction of narcissoside with α-amylase from Bacillus subtilis and Porcine pancreatic by multi-spectral analysis and molecular dynamics simulation.

In this work, interaction mechanism of narcissoside with two α-amylase from Bacillus subtilis (BSA) and Porcine pancreatic (PPA) are comparatively studied by multi-spectral analysis, molecular docking and molecular dynamics simulation. The results prove that narcissoside can statically quench fluorescence of BSA/PPA. Two complexes are mainly formed by hydrogen bond and van der Waals force. With the increase of temperature, the two complexes formed by narcissoside and two enzymes become unstable. At the same experimental temperature, the binding force of narcissoside to PPA is higher than that of BSA. The binding of narcissoside to PPA/BSA increases the hydrophobicity of microenvironment. Moreover, the secondary structure of PPA/BSA is mainly changed by decreasing the α-helix. The optimal binding modes of narcissoside with BSA/PPA are predicted by molecular docking, and the stability of the two complexes is evaluated by molecular dynamics simulations.

The efficacy and safety of hydrotherapy in patients with knee osteoarthritis: a meta-analysis of randomized controlled trials.

BACKGROUND: Currently, there is poor evidence of the effect of hydrotherapy on patients with knee osteoarthritis. We performed a meta-analysis from randomized controlled trials to determine the efficacy and safety of a hydrotherapy program on measures of pain and knee function in individuals living with knee osteoarthritis. METHODS: A literature review included PubMed, EMBASE, Cochrane Library, Science Citation Index, ScienceDirect and Ovid. Studies evaluating the efficacy of hydrotherapy for knee osteoarthritis up to August 2023 were included. The research was reported based on the preferred reporting items for systematic reviews and meta-analysis guidelines to ensure the reliability and verity of results. Statistical analysis was performed using Stata/SE version 15.0. RESULTS: A total of six randomized controlled trials were included for data extraction and meta-analysis. The present study revealed that there were significant differences between the two groups regarding the pain intensity at 1 week (WMD= -0.429; 95% CI: -0.679 to -0.179; P=0.001), 4 week (WMD= -0.308; 95% CI: -0.587 to -0.030; P=0.030) and 8 week(WMD= -0.724; 95% CI: -1.099 to -0.348, P<0.001). Furthermore, hydrotherapy was associated with improved outcome of the Western Ontario and McMaster Universities Arthritis index at 1 week (WMD= -3.314; 95% CI: -6.484 to -0.145, P=0.040), 4 week (WMD= -3.630; 95% CI:-6.893 to -0.366, P=0.029) and 8 week (WMD= -3.775; 95% CI: -7.315 to -0.235; P=0.037). No serious adverse events were observed in all patients who received hydrotherapy. CONCLUSION: Hydrotherapy is efficacious and safe for reducing pain and improving functional status in individuals with knee osteoarthritis, without increasing the risk of adverse effects.

A comparative study on the features of breast sclerosing adenosis and invasive ductal carcinoma via ultrasound and establishment of a predictive nomogram.

Objective: To analyze the clinical and ultrasonic characteristics of breast sclerosing adenosis (SA) and invasive ductal carcinoma (IDC), and construct a predictive nomogram for SA. Materials and methods: A total of 865 patients were recruited at the Second Hospital of Shandong University from January 2016 to November 2022. All patients underwent routine breast ultrasound examinations before surgery, and the diagnosis was confirmed by histopathological examination following the operation. Ultrasonic features were recorded using the Breast Imaging Data and Reporting System (BI-RADS). Of the 865 patients, 203 (252 nodules) were diagnosed as SA and 662 (731 nodules) as IDC. They were randomly divided into a training set and a validation set at a ratio of 6:4. Lastly, the difference in clinical characteristics and ultrasonic features were comparatively analyzed. Result: There was a statistically significant difference in multiple clinical and ultrasonic features between SA and IDC (P<0.05). As age and lesion size increased, the probability of SA significantly decreased, with a cut-off value of 36 years old and 10 mm, respectively. In the logistic regression analysis of the training set, age, nodule size, menopausal status, clinical symptoms, palpability of lesions, margins, internal echo, color Doppler flow imaging (CDFI) grading, and resistance index (RI) were statistically significant (P<0.05). These indicators were included in the static and dynamic nomogram model, which showed high predictive performance, calibration and clinical value in both the training and validation sets. Conclusion: SA should be suspected in asymptomatic young women, especially those younger than 36 years of age, who present with small-size lesions (especially less than 10 mm) with distinct margins, homogeneous internal echo, and lack of blood supply. The nomogram model can provide a more convenient tool for clinicians.

Quality of Life Bronchiectasis Respiratory Symptom Predicts the Risk of Exacerbations in Adults with Bronchiectasis: A Prospective Observational Study.

RATIONALE: The relationship between symptoms, measured using a validated disease-specific questionnaire, and longitudinal exacerbation risk has not been demonstrated in bronchiectasis. OBJECTIVES: The aim of this study is to investigate whether baseline symptoms, assessed using the Quality of Life-Bronchiectasis-Respiratory Symptom Scale (QoL-B-RSS) and its individual component scores, could predict future exacerbation risk in patients with bronchiectasis. METHODS: The study included 436 adults with bronchiectasis from three tertiary hospitals. Symptoms were measured using the QoL-B-RSS, with scores ranging from 0 to 100, where lower scores indicated more severe symptoms. We examined whether symptoms as continuous measures were associated with the risk of exacerbation over 12 months. The analysis was also repeated for individual components of the QoL-B-RSS score. RESULTS: The baseline QoL-B-RSS score was associated with an increased risk of exacerbations (rate ratio [RR] 1.25 for each 10-point decrease, 95% CI 1.15-1.35, P<0.001), hospitalizations (RR 1.24, 95% CI 1.05-1.43, P=0.02), and reduced time to the first exacerbation (hazard ratio [HR] 1.12, 95% CI 1.03-1.21, P=0.01) over 12 months, even after adjusting for relevant confounders, including exacerbation history. The QoL-B-RSS score was comparable to exacerbation history in its association with future frequent exacerbation (defined as three or more exacerbations per year) and hospitalization (area under the curve [AUC] 0.86 vs 0.84, p=0.46; AUC 0.81 vs 0.83, p=0.41, respectively). Moreover, patients with more severe symptoms in the majority of individual components of the QoL-B-RSS were more likely to experience exacerbations. CONCLUSIONS: Symptoms can serve as useful indicators for identifying patients at increased risk of exacerbation in bronchiectasis. Beyond relying solely on exacerbation history, a comprehensive assessment of symptoms could facilitate timely and cost-effective implementation of interventions for exacerbation prevention.

Induction Toripalimab And Chemotherapy For Organ Preservation In Locally Advanced Laryngeal And Hypopharyngeal Cancer: A Single-Arm Phase 2 Clinical Trial.

PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with PD-1 inhibitor in locally advanced laryngeal and hypopharyngeal cancer. METHODS: This is a single-arm phase II study. Patients with histopathologic confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and ECOG PS 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175mg/m2 d1, cisplatin 25mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1·1 criteria. Patients with complete/partial response of primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo)radiation, and maintenance therapy of toripalimab. The primary endpoint is larynx-preservation rate at three months post-radiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81·5%), with T4 representing 37·0%. Five patients underwent pretreatment tracheostomy due to impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85·2%. At three months post-radiation, the larynx preservation rate was 88·9%. With a median follow-up of 18·7 months, 1-year OS rate, PFS rate, larynx preservation rate was 84·7%, 77·6% and 88·7%, respectively. When excluding those with pretreatment tracheostomy, 1-year larynx preservation rate was 95·5%. Exploratory analysis revealed relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophages associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.

Splitting phenomenon of ferromagnetic resonance spectra in NiFe films deposited on periodically rippled sapphire substrates.

The splitting phenomenon of ferromagnetic resonance (FMR) spectra of Ni80Fe20 (NiFe) films deposited on periodically rippled sapphire substrates is studied experimentally and with the help of micromagnetic simulation. The analyses show that the splitting of FMR spectra is related to the periodic ripple topography of films. When the applied magnetic field is perpendicular to the ripple direction, the effective field of periodically rippled films becomes inhomogeneous. The splitting of ferromagnetic resonance spectra originates from localized FMR peaks corresponding to different regions with different effective field intensities in the rippled structure. Furthermore, the relative intensity and position between the split mode and the main FMR mode can be changed by designing ripple topography. This work would help understand the splitting phenomenon of FMR spectra for these NiFe films deposited on the periodically rippled sapphire substrates.

Identification of potential ferroptosis key genes and immune infiltration in rheumatoid arthritis by integrated bioinformatics analysis.

Objective: Ferroptosis is of vital importance in the development of Rheumatoid arthritis (RA). The purpose of this project is to clarify the potential ferroptosis-related genes, pathways, and immune infiltration in RA by bioinformatics analysis. Methods: We acquired ferroptosis-related genes (FRGs) from Ferroptosis database (FerrDb). We obtained the Gene dataset of RA (GSE55235) from the Gene Expression Omnibus (GEO) Database, screened the differentially expressed genes (DEGs) in RA and control samples, and then took the intersection of it and FRGs. Aiming to construct the protein-protein interaction (PPI) networks of the FRGs-DEGs, STRING database and Cytoscape software 3.7.0 would be used. Furthermore, hub genes were identified by CytoNCA, a Cytoscape plug-in. The gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of FRGs-DEGs were performed. Results: We identified 34 FRGs-DEGs, including 7 upregulated and 27 downregulated genes by taking the intersection of the FRGs and DEGs. PPI analysis identified a total of 3 hub genes(VEGFA, PTGS2, and JUN). GO enrichment analyses and KEGG Pathway enrichment displayed that the FRGs-DEGs are involved in the response to oxidative stress and corticosteroid, heme binding, FoxO-signal pathway. Results of immune infiltration displayed that increased infiltration of T cells, while Macrophages M2 less may be related to the occurrence of RA. Conclusion: The hub genes involved in ferroptosis in RA may be VEGFA, PTGS2, and JUN, which are mainly involved in FoxO-signal pathway. T cell, Mac, and plasma cells may be involved in the regulation of RA-joints-synovial-inflammation.

Harnessing the benefits of glycine supplementation for improved pancreatic microcirculation in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is predominantly managed using insulin replacement therapy, however, pancreatic microcirculatory disturbances play a critical role in T1DM pathogenesis, necessitating alternative therapies. This study aimed to investigate the protective effects of glycine supplementation on pancreatic microcirculation in T1DM. Streptozotocin-induced T1DM and glycine-supplemented mice (n = 6 per group) were used alongside control mice. Pancreatic microcirculatory profiles were determined using a laser Doppler blood perfusion monitoring system and wavelet transform spectral analysis. The T1DM group exhibited disorganized pancreatic microcirculatory oscillation. Glycine supplementation significantly restored regular biorhythmic contraction and relaxation, improving blood distribution patterns. Further-more, glycine reversed the lower amplitudes of endothelial oscillators in T1DM mice. Ultrastructural deterioration of islet microvascular endothelial cells (IMECs) and islet microvascular pericytes, including membrane and organelle damage, collagenous fiber proliferation, and reduced edema, was substantially reversed by glycine supplementation. Additionally, glycine supplementation inhibited the production of IL-6, TNF-α, IFN-γ, pro-MMP-9, and VEGF-A in T1DM, with no significant changes in energetic metabolism observed in glycine-supplemented IMECs. A statistically significant decrease in MDA levels accompanied by an increase in SOD levels was also observed with glycine supplementation. Notably, negative correlations emerged between inflammatory cytokines and microhemodynamic profiles. These findings suggest that glycine supplementation may offer a promising therapeutic approach for protecting against pancreatic microcirculatory dysfunction in T1DM.

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis.

BACKGROUND: Venetoclax is clinically active in treating relapsed/refractory multiple myeloma (RRMM). This study evaluated the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. METHODS: PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched. We included studies investigating the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. Overall response rates (ORR), stringent complete response rates (sCR), complete response rates (CR), very good partial response rates (VGPR), partial response rates (PR), stable disease (SD), progressive disease (PD) and adverse events were synthesized using either a random-effects model or a fixed-effects model. RESULTS: A total of 7 clinical trials with 482 patients with RRMM were included. Concerning venetoclax with other agents, the pooled ORR, sCR, CR, VGPR, PR, SD, and PD were 0.76 (95% CIs: 0.62, 0.87), 0.11 (95% CIs: 0.04, 0.21), 0.18 (95% CIs: 0.11, 0.26), 0.16 (95% CIs: 0.12, 0.25), 0.29 (95% CIs: 0.25, 0.34), 0.07 (95% CIs: 0.05, 0.10), and 0.11 (95% CIs: 0.04, 0.23). The overall rate of adverse events ≥ Grade 3 was 0.84 (95% CIs: 0.77, 0.91). The most common non-hematologic adverse events were nausea, diarrhea, fatigue, back pain, and vomiting; hematologic adverse events included thrombocytopenia, neutropenia, anemia, leukopenia, and lymphopenia. CONCLUSIONS: This study indicates that venetoclax alone or in combination with other agents reveals favorable treatment responses and acceptable adverse events in treating RRMM.

A neutrophil extracellular traps-related classification predicts prognosis and response to immunotherapy in colon cancer.

Neutrophil extracellular traps (NETs) have been categorized as a form of inflammatory cell death mode of neutrophils (NETosis) involved in natural immunity and the regulation of adaptive immunity. More and more studies revealed the ability of NETs to reshape the tumor immune microenvironment (TIME) by limiting antitumor effector cells, which may impair the efficacy of immunotherapy. To explore whether NETs-related genes make vital impacts on Colon carcinoma (COAD), we have carried out a systematic analysis and showed several findings in the present work. First, we obtained the patient's data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset, aiming to detect two NETs-associated subtypes by consensus clustering. For the purpose of annotating the roles of NETs-related pathways, gene ontology enrichment analyses were adopted. Next, we constructed a 6 novel NETs-related genes score using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model. We found that the NETs risk score was notably upregulated in COAD patient samples, and its levels were notably correlated with tumor clinicopathological and immune traits. Then, according to NETs-associated molecular subtypes and the risk signature, this study compared immune cell infiltration calculated through the estimate, CIBERSORT, TIMER, ssGSEA algorithms, tumor immune dysfunction, as well as exclusion (TIDE). Furthermore, we confirm that MPO(myeloperoxidase) was significantly upregulated in COAD patient samples, and its levels were significantly linked to tumor malignancy and clinic outcome. Moreover, multiplex immunohistochemistry (mIHC) spatial analysis confirmed that MPO was closely related to Treg and PD-1 + Treg in spatial location which suggested MPO may paly an important role in TIME formation. Altogether, the obtained results indicated that a six NETs-related genes prognostic signature was conducive to estimating the prognosis and response of chemo-/immuno-therapy of COAD patients.

Serum sphingolipids aid in diagnosing adult HIV-negative patients with pulmonary cryptococcosis: a clinical cohort study.

Background: Pulmonary cryptococcosis (PC) contributes to the ongoing global disease burden in human immunodeficiency virus (HIV)-negative populations. Since some PC patients are misdiagnosed under existing diagnostic guidelines, new diagnostic markers are needed to improve diagnostic accuracy and therapeutic efficacy and reduce disease risk. Methods: Our previously established sphingolipidomic approach was employed to explore the use of serum sphingolipids (SPLs) in diagnosing HIV-negative patients with PC. A clinical cohort of PC, pulmonary aspergillosis (PA), and tuberculosis (TB) patients and healthy controls was assessed to identify SPL biomarkers. Results: A total of 47 PC, 27 PA, and 18 TB patients and 40 controls were enrolled. PC and TB patients had similar clinical features, laboratory test results and radiological features, excluding plural effusion. The serum ceramide [Cer (d18:1/18:0)] level showed a significant increase in PC patients compared to controls and PA and TB patients (P<0.05). Cer (d18:1/18:0) was identified as a specific diagnostic biomarker for PC. The optimal cut-off value of greater than 18.00 nM showed a diagnostic sensitivity of 76.60% and a specificity of 95.00% and better distinguished PC patients from PA and TB patients. Furthermore, the serum Cer (d18:1/18:0) level gradually decreased after 3 and 6 months of treatment, suggesting the prediction potential for therapeutic efficacy of this biomarker. In addition, Cer (d18:1/18:0) analysis presented a higher sensitivity than the cryptococcal antigen (CrAg) assay. Conclusions: This is the first study to report the use of the SPL Cer (d18:1/18:0) as a serum biomarker for diagnosing Cryptococcus spp. infection in HIV-negative patients.

Pattern of tumor regression after neoadjuvant chemoimmunotherapy for esophageal squamous cell carcinoma.

Background: Immune checkpoint inhibitors have been increasingly applied for esophageal cancer. The aims of this study were to evaluate the pattern of tumor regression after neoadjuvant chemoimmunotherapy. Methods: From January 2020 to December 2021, 138 patients with esophageal squamous cell carcinoma who had esophagectomy after neoadjuvant chemoimmunotherapy were reviewed. Surgical and pathological results were analyzed, and tumor regression pattern was evaluated. Results: Of the 138 patients, 65 (47.1%) patients had chemotherapy combined with camrelizumab, 48 (34.8%) with pembrolizumab, 13 (9.4%) with tislelizumab, and 12 (8.7%) with sintilimab. Sixty-four patients (46.4%) underwent McKewon procedure, and 74 (53.6%) Ivor-Lewis procedure, respectively. There were 131/138 patients (94.9%) who had R0 resections, and the median number of resected lymph nodes was 28. Pneumonia was the most common complication after surgery (14.5%). Pathological complete regression occurred in 28 patients (20.3%). Regarding to residual tumor, there were 50 patients (36.2%) with residual tumor in the mucosa, 81 (58.7%) in the submucosa, 85 (61.6%) in the muscularis propria, 47 (34.1%) in the adventitia and 71 (51.4%) in the lymph nodes. There were 88 patients with no residual tumor in the mucosa, of whom 60 (68.2%) had residual tumors in other layers or in the lymph nodes. Conclusions: In this retrospective study, esophagectomy after neoadjuvant chemoimmunotherapy is safe with acceptable surgical risk. Preferential clearing of tumor cells in mucosa layer is common after immunotherapy, while the rate of complete pathological response is relatively low, indicating surgery is still necessary.