The role of microbiota in gastric cancer: A comprehensive review.

BACKGROUND: Gastric cancer (GC) continues to pose a significant global threat in terms of cancer-related fatalities. Despite notable advancements in medical research and therapies, further investigation is warranted to elucidate its underlying etiology and risk factors. Recent times have witnessed an escalated emphasis on comprehending the role of the microbiota in cancer development. METHODS: This review briefly delves into recent developments in microbiome-related research pertaining to gastric cancer. RESULTS: According to studies, the microbiota can influence GC growth by inciting inflammation, disrupting immunological processes, and generating harmful microbial metabolites. Furthermore, there is ongoing research into how the microbiome can impact a patient's response to chemotherapy and immunotherapy. CONCLUSION: The utilization of the microbiome for detecting, preventing, and managing stomach cancer remains an active area of exploration.

A predictive nomogram developed and validated for gastric cancer patients with triple-negative tumor markers.

Aim: To predict the prognosis of gastric cancer patients with triple-negative tumor markers. Materials & methods: Prognostic factors of the nomogram were identified through univariate and multivariate Cox regression analyses. Calibration and receiver operating characteristic curves were used to assess accuracy. Decision curve analysis and concordance indexes were utilized to compare the nomogram with the pathological tumor, node, metastasis stage. Results: A nomogram incorporating log odds of positive lymph nodes, tumor size and lymphocyte-to-monocyte ratio was constructed. The calibration and receiver operating characteristic curves (area under the curve >0.85) showed high accuracy in predicting overall survival. The concordance indexes (0.832 vs 0.760; p < 0.001) and decision curve analysis demonstrated that the nomogram was superior to the pathological tumor, node, metastasis stage. Conclusion: A prediction and risk stratification nomogram has been developed and validated for gastric cancer patients with triple-negative tumor markers.

Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.

Molecular architecture of proliferative lupus nephritis as elucidated using 50-plex imaging mass cytometry proteomics.

Due to unique advantages that allow high-dimensional tissue profiling, we postulated imaging mass cytometry (IMC) may shed novel insights on the molecular makeup of proliferative lupus nephritis (LN). This study interrogates the spatial expression profiles of 50 target proteins in LN and control kidneys. Proliferative LN glomeruli are marked by podocyte loss with immune infiltration dominated by CD45RO+, HLA-DR+ memory CD4 and CD8 T-cells, and CD163+ macrophages, with similar changes in tubulointerstitial regions. Macrophages are the predominant HLA-DR expressing antigen presenting cells with little expression elsewhere, while macrophages and T-cells predominate cellular crescents. End-stage sclerotic glomeruli are encircled by an acellular fibro-epithelial Bowman's space surrounded by immune infiltrates, all enmeshed in fibronectin. Proliferative LN also shows signs indicative of epithelial to mesenchymal plasticity of tubular cells and parietal epithelial cells. IMC enabled proteomics is a powerful tool to delineate the spatial architecture of LN at the protein level.

The Sympathetic Nervous System Modulates Cancer Vaccine Activity through Monocyte-Derived Cells.

The sympathetic nervous system (SNS) is an important regulator of immune cell function during homeostasis and states of inflammation. Recently, the SNS has been found to bolster tumor growth and impair the development of antitumor immunity. However, it is unclear whether the SNS can modulate APC function. Here, we investigated the effects of SNS signaling in murine monocyte-derived macrophages (moMФ) and dendritic cells (DCs) and further combined the nonspecific ß-blocker propranolol with a peptide cancer vaccine for the treatment of melanoma in mice. We report that norepinephrine treatment dramatically altered moMФ cytokine production, whereas DCs were unresponsive to norepinephrine and critically lack ß2-adrenergic receptor expression. In addition, we show that propranolol plus cancer vaccine enhanced peripheral DC maturation, increased the intratumor proportion of effector CD8+ T cells, and decreased the presence of intratumor PD-L1+ myeloid-derived suppressor cells. Furthermore, this combination dramatically reduced tumor growth compared with vaccination alone. Taken together, these results offer insights into the cell-specific manner by which the SNS regulates the APC immune compartment and provide strong support for the use of propranolol in combination with cancer vaccines to improve patient response rates and survival.

Progress and application of epitranscriptomic m6A modification in gastric cancer.

The relationship between epitranscriptomics and malignant tumours has become a popular research topic in recent years. N6-methyladenosine (m6A), the most common post-transcriptional modification in mammals, is involved in various physiological processes in different cancer types, including gastric cancer (GC). The incidence and mortality of GC have been increasing annually, especially in developing countries. Insights into the epitranscriptomic mechanisms of gastric carcinogenesis could provide potential strategies for the prevention, diagnosis, and treatment of GC. In this review, we describe the mechanisms of RNA m6A modification; the functions of m6A regulators in GC; the functional crosstalk among m6A, messenger RNA, and noncoding RNA; and the promising application of m6A in the diagnosis and treatment of GC.

Integrated assessment of endocrine disrupting potential of four novel brominated flame retardants.

Novel brominated flame retardants (NBFRs) have emerged as alternatives to the legacy BFRs due to BFRs' persistence, bioaccumulation and evidence of adverse health effects. The increasing production of NBFRs has led to the frequent detection in environmental media and even in organisms. Thus the potential health risks of these novel NBFRs need to be taken into account. Herein, the endocrine disrupting effects of the four NBFRs (α/ß-TBCO, PBEB, EHTBB and BEHTBP) were evaluated by constructing an estrogen receptor (ERα), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) mediated dual-luciferase reporter gene assays on the CHO cells, in combination with steroid experiments on the H295R cells and molecular docking. The results revealed that α/ß-TBCO, PBEB and EHTBB induced anti-estrogenic activity at certain concentrations while none of the four NBFRs was agonistic to ERα. For reporter gene assay, only PBEB exhibited GR antagonistic effects. Notably, none of the four NBFRs possess neither agonistic nor antagonistic activity of MR. The molecular docking results were generally consistent with the reporter gene assay, which showed the different binding affinities between NBFRs and the receptors. For steroidogenesis, α/ß-TBCO, PBEB, and EHTBB all upregulated genes encoding for steroid synthesis enzymes, including 17ßHSD, CYP11B1 and CYP17. Altogether, the data clarified that NBFRs may pose risks of endocrine disruption.

Exploitation of Synthetic mRNA To Drive Immune Effector Cell Recruitment and Functional Reprogramming In Vivo.

Therapeutic strategies based on in vitro-transcribed mRNA (IVT) are attractive because they avoid the permanent signature of genomic integration that is associated with DNA-based therapy and result in the transient production of proteins of interest. To date, IVT has mainly been used in vaccination protocols to generate immune responses to foreign Ags. In this "proof-of-principle" study, we explore a strategy of combinatorial IVT to recruit and reprogram immune effector cells to acquire divergent biological functions in mice in vivo. First, we demonstrate that synthetic mRNA encoding CCL3 is able to recruit murine monocytes in a nonprogrammed state, exhibiting neither bactericidal nor tissue-repairing properties. However, upon addition of either Ifn-γ mRNA or Il-4 mRNA, we successfully polarized these cells to adopt either M1 or M2 macrophage activation phenotypes. This cellular reprogramming was demonstrated through increased expression of known surface markers and through the differential modulation of NADPH oxidase activity, or the superoxide burst. Our study demonstrates how IVT strategies can be combined to recruit and reprogram immune effector cells that have the capacity to fulfill complex biological tasks in vivo.

Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.

Overexpression of Hsc70 promotes proliferation, migration, and invasion of human glioma cells.

Migration and invasion are often recognized as the main reasons for the high recurrence and death rates of glioma and limit the efficacy of surgery and other antitumor therapies. In this study, we found over activation of heat shock cognate protein 70 (Hsc70) in human glioma specimens, which was closely related to glioma grade. We investigated whether Hsc70 induced the migration and invasion of glioma cells. Wound healing and transwell migration assay were used to determine the migration and invasion ability of human glioma U251 and U87 cells, in which the expression of Hsc70 was knocked down by small interfering RNA. Western blot analysis was performed to determine the expression of FAK-Src signaling in malignant glioma cells. The results showed that Hsc70 deficiency significantly retarded migration and invasion and reduced the phosphorylation of FAK, Src, and Pyk2 in U251 and U87 cells. Overall, our results indicate that the migration and invasion capacity of human brain glioma cells is at least partly induced by Hsc70-dependent activation of FAK-Src signaling.

MTKSVCR: A novel multi-task multi-class support vector machine with safe acceleration rule.

Regularized multi-task learning (RMTL) has shown good performance in tackling multi-task binary problems. Although RMTL can be used to handle multi-class problems based on "one-versus-one" and "one-versus-rest" techniques, the information of the samples is not fully utilized and the class imbalance problem occurs. Motivated by the regularization technique in RMTL, we propose an original multi-task multi-class model termed MTKSVCR based on "one-versus-one-versus-rest" strategy to achieve better testing accuracy. Due to the utilization of the idea of RMTL, the related information included in multiple tasks is mined by setting different penalty parameters before task-common and task-specific regularization terms. However, the proposed MTKSVCR is time-consuming since it employs all samples in each optimization problem. Therefore, a multi-parameter safe acceleration rule termed SA is further presented to reduce the time consumption. It identifies and deletes most of the superfluous samples corresponding to 0 elements in the dual optimal solution before solving. Then, only a reduced dual problem is to be solved and the computational efficiency is improved accordingly. The biggest advantage of the proposed SA lies in safety. Namely, it derives an identical optimal solution to the primal problem without SA. In addition, our method remains effective when multiple parameters change simultaneously. Experiments on different artificial datasets and benchmark datasets verify the validity of the proposed methods.

Sequential safe static and dynamic screening rule for accelerating support tensor machine.

Support tensor machine (STM), as a higher-order extension of support vector machine, is adept at effectively addressing tensorial data classification problems, which maintains the inherent structure in tensors and mitigates the curse of dimensionality. However, it needs to resort to the alternating projection iterative technique, which is very time-consuming. To overcome this shortcoming, we propose an efficient sequential safe static and dynamic screening rule (SS-SDSR) for accelerating STM in this paper. Its main idea is to reduce every projection iterative sub-model by identifying and deleting the redundant variables before and during the training process without sacrificing accuracy. Its construction mainly consists of two parts: (1) The static screening rule and dynamic screening rule are first built based on the variational inequality and duality gap, respectively. (2) The sequential screening process is achieved by using the static screening rule with the different adjacent parameters and applying the dynamic screening rule under the same parameter. In the experiment, on the one hand, to verify the influence of different parameter intervals, screening frequencies, and forms of data on the effectiveness of our method, three experiments on artificial datasets are conducted, which indicate that our method is effective for any forms of data when the parameter interval is small and the screening frequency is appropriate. On the other hand, to demonstrate the feasibility and validity of our SS-SDSR, numerical experiments on eleven vector-based datasets, and six tensor-based datasets are conducted and compared with the other five algorithms. Experimental results illustrate the effectiveness and safety of our SS-SDSR.

5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer.

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurately predicting individual patient responses to ICIs remains a challenge. We performed the genome-wide profiling of 5-hydroxymethylcytosine (5hmC) in 85 plasma cell-free DNA (cfDNA) samples from lung cancer patients and developed a 5hmC signature that was significantly associated with progression-free survival (PFS). We built a 5hmC predictive model to quantify the 5hmC level and validated the model in the validation, test, and control sets. Low weighted predictive scores (wp-scores) were significantly associated with a longer PFS compared to high wp-scores in the validation [median 7.6 versus 1.8 months; p = 0.0012; hazard ratio (HR) 0.12; 95% confidence interval (CI), 0.03-0.54] and test (median 14.9 versus 3.3 months; p = 0.00074; HR 0.10; 95% CI, 0.02-0.50) sets. Objective response rates in patients with a low or high wp-score were 75.0% (95% CI, 42.8-94.5%) versus 0.0% (95% CI, 0.0-60.2%) in the validation set (p = 0.019) and 80.0% (95% CI, 44.4-97.5%) versus 0.0% (95% CI, 0.0-36.9%) in the test set (p = 0.0011). The wp-scores were also significantly associated with PFS in patients receiving single-agent ICI treatment (p < 0.05). In addition, the 5hmC predictive signature demonstrated superior predictive capability to tumor programmed death-ligand 1 and specificity to ICI treatment response prediction. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. This study provides proof-of-concept evidence that the cfDNA 5hmC signature is a robust biomarker for predicting ICI treatment response in lung cancer.

A Phase 2 Study of In Situ Oncolytic Virus Therapy and Stereotactic Body Radiation Therapy Followed by Pembrolizumab in Metastatic Non-Small Cell Lung Cancer.

PURPOSE: A phase 2 study of stereotactic body radiation therapy (SBRT) and in situ oncolytic virus therapy in metastatic non-small cell lung cancer (mNSCLC) followed by pembrolizumab (STOMP) was designed to explore the dual approach in enhancing single pembrolizumab with ADV/HSV-tk plus valacyclovir gene therapy and SBRT in mNSCLC. METHODS AND MATERIALS: STOMP is a single-arm, open-label phase 2 study. Patients with mNSCLC received intratumoral injections of ADV/HSV-tk (5 × 1011 vp) and SBRT (30 Gy in 5 fractions) followed by pembrolizumab 200 mg IV every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) (complete response [CR] and partial response [PR]). Secondary endpoints included clinical benefit rate (CBR) (CR, PR and stable disease [SD]), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 28 patients were enrolled, of whom 27 were evaluated for response. The ORR was 33.3%, including 2 CR (7.4%) and 7 PR (25.9%). CBR was 70.4%. Six of eight (75.0%) patients who were immune checkpoint inhibitor (ICI) refractory derived clinical benefits. Responders had durable responses with median PFS, and OS not reached. The entire cohort had a median PFS of 7.4 months (95% CI, 5.1-9.6 months), and median OS of 18.1 months (95% CI, 15.4-20.9 months). The combination was well tolerated, with grade 3 or higher toxicity in 6 (21.4%) patients. CONCLUSIONS: The dual approach of in situ ADV/HSV-tk plus valacyclovir gene therapy and SBRT as a chemotherapy-sparing strategy to enhance the antitumor effect of pembrolizumab is a well-tolerated encouraging treatment in patients with mNSCLC.

Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

Multiview Structural Large Margin Classifier and Its Safe Acceleration Strategy.

Multiview learning (MVL) concentrates on the problem where each instance is represented by multiple different feature sets. Efficiently exploring and exploiting the common and complementary information among different views remains challenging in MVL. Nevertheless, many existing algorithms deal with multiview problems via pairwise strategies, which limit the exploration of relationships among different views and dramatically increase the computational cost. In this article, we propose a multiview structural large margin classifier (MvSLMC) that simultaneously satisfies the consensus and complementarity principles in all views. Specifically, on the one hand, MvSLMC employs a structural regularization term to promote cohesion within-class and separability between-class in each view. On the other hand, different views provide extra structural information to each other, which favors the diversity of the classifier. Moreover, the introduction of hinge loss in MvSLMC results in sample sparsity, which we leverage to construct a safe screening rule (SSR) for accelerating MvSLMC. To the best of our knowledge, this is the first attempt at safe screening in MVL. Numerical experimental results demonstrate the effectiveness of MvSLMC and its safe acceleration method.

CovidViT: a novel neural network with self-attention mechanism to detect Covid-19 through X-ray images.

Since the emergence of the novel coronavirus in December 2019, it has rapidly swept across the globe, with a huge impact on daily life, public health and the economy around the world. There is an urgent necessary for a rapid and economical detection method for the Covid-19. In this study, we used the transformers-based deep learning method to analyze the chest X-rays of normal, Covid-19 and viral pneumonia patients. Covid-Vision-Transformers (CovidViT) is proposed to detect Covid-19 cases through X-ray images. CovidViT is based on transformers block with the self-attention mechanism. In order to demonstrate its superiority, this research is also compared with other popular deep learning models, and the experimental result shows CovidViT outperforms other deep learning models and achieves 98.0% accuracy on test set, which means that the proposed model is excellent in Covid-19 detection. Besides, an online system for quick Covid-19 diagnosis is built on http://yanghang.site/covid19.

Integrated exposure assessment and potential risks of neonicotinoids in vegetables from three different sources in Zhejiang, China (2018-2020).

Dietary exposure is the primary route of human exposure to neonicotinoids (neonics), and vegetables are essential foods in people's daily diet. However, the residues and potential health risks of neonics in vegetables from different sources have not been well examined. In this study, we collected 1588 samples of vegetables from organic vegetable bases, farmer's markets, and supermarkets in Zhejiang, China. Three frequently used neonics, acetamiprid, imidacloprid, and thiamethoxam, were selected and analyzed. We investigated the residue, temporal and spatial distribution, and potential health risks. Cowpea was detected with the highest mean imidacloprid-equivalent total neonics (IMIRPF) by value of 655 µg/kg. Vegetable samples from farmer's markets were detected with the highest mean IMIRPF by value of 168 µg/kg, followed by supermarkets (134 µg/kg) and the lowest in organic vegetable bases (76.9 µg/kg). The outcomes of integrated risk assessment for dietary intake of those three neonics in vegetables were all within the safety.

Pharmacological properties and underlying mechanisms of aurantio­obtusin (Review).

Herbal medicine has been widely applied for a range of diseases in China since antiquity. Cassia obtusifolia L. and Cassia tora L. are plants whose seeds have high reported medicinal values and have been documented to function as a laxative, to lower lipid level and to lower blood pressure. The main active ingredient in Cassia seeds is aurantio-obtusin (AO), which is an anthraquinone monomer compound. Currently, AO is listed in China as a quality control index component of Cassia seeds. In clinical practice in China, AO is typically used to treat obesity, diabetes and its complications, non-alcoholic fatty liver disease and allergic reactions. In addition, AO has been reported to confer insecticidal activities and antimalarial effects. Previous studies have even suggested that AO is a potential therapeutic candidate for a variety of diseases with research value. Therefore, the present review summarizes and discuss the existing literature on AO to provide a review of its pharmacological activity and mechanism of action, with the aim of providing a basis for its development and utilization in a clinical setting.

The integrated exposure assessment and potential risks of five organophosphorus pesticides in vegetables in Zhejiang, China (2018-2020).

This research surveyed the concentrations of five organophosphorus pesticides (OPs) in vegetables with the purpose of assessing the potential integrated health risks of residents. From 2018 to 2020, 870 samples of eight kinds of vegetables from Zhejiang Province were collected. Gas chromatography coupled with a flame photometric detector (GC-FPD) analyzed the five OPs. OPs were most frequently detected in celery (18.9% of samples), cowpeas (18.3% of samples), and leeks (16.9% of samples) compared to other vegetables. Among the 11 cities in Zhejiang, the cities with high detection rates of OPs were Ningbo and Hangzhou. The integrated concentrations of OPs in different cities ranged from 71.9 to 376 µg/kg. The cumulative risk assessment revealed that the estimated daily intake (EDI) of leek in Wenzhou was the highest, which was 0.0077 (mg/kg bw) and 0.0059 (mg/kg bw) in adults and children respectively. The health risks of residents who consume these vegetables were within a safe range. The data provided demonstrate the distribution and potential health hazards of OPs in commonly consumed vegetables.