Integrated analyses reveal the diagnostic and predictive values of COL5A2 and association with immune environment in Crohn's disease.

The pathogenesis of Crohn's disease (CD) involves abnormal immune cell infiltration and dysregulated immune response. Therefore, thorough research on immune cell abnormalities in CD is crucial for improved treatment of this disease. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data of CD were obtained from the Gene Expression Omnibus (GEO) database. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks evaluated the proportion of immune infiltrating cells, constructed co-expression network and identified key genes, respectively. Based on the dataset (GSE134809), 15 cell clusters were defined and labeled as different cell types. Among the 11 modules, the yellow module had the closest relationship with plasma cells (cluster 5). Confirmed using RNA sequencing and IHC assay, the expression of COL5A2 in CD samples was higher than that in control samples. Furthermore, the COL5A2 protein expression remarkably decreased in the group of patients who responded to anti-tumor necrosis factor (TNF) treatments, compared to the non-response group. The comprehensive analyses described here provided novel insight into the landscape of CD-associated immune environment. In addition, COL5A2 were identified as potential diagnostic indicators for CD, as well as promising predictive markers for CD patients.

Hyperactivation and enhanced cytotoxicity of reduced CD8+ gamma delta T cells in the intestine of patients with Crohn's disease correlates with disease activity.

BACKGROUND AND AIMS: We aimed to investigate the immune characteristics of intestinal CD8+ gamma delta T (CD8+ γδ T) cells in Crohn's disease (CD) and their correlation with disease activity. METHODS: The study cohorts included 21 CD patients and 21 healthy individuals. CD8+ γδ T cells were isolated from human ileal mucosa for detection by flow cytometry. The activation or inhibition status of cells was detected by detecting the expression of activation marker HLA-DR and the immunosuppressive molecule PD-1 on cells. The cytotoxicity of cells was assessed by detecting the expression of cytotoxic molecules (Perforin, Granzyme B, and TRAIL) in cells. Ratios of investigated cells were calculated as prediction factors by receiver operating characteristic curve (ROC) analysis. RESULTS: The study revealed a reduction in intestinal CD8+ γδT cells among active CD patients, with a more pronounced reduction observed in moderately active patients compared to mildly active patients. Moreover, active CD patients exhibited heightened activation levels in their intestinal CD8+ γδT cells, whereas the activation was comparatively weakened in moderately active patients compared with mildly active patients. Additionally, the cytotoxicity of intestinal CD8+ γδT cells was enhanced solely in mildly active patients, while it was impaired in moderately active patients compared with mildly active patients. Furthermore, HLA-DR+ CD8+ γδT cell ratio, CD8+ γδT ratio, and CD8+ γδT count were identified as indicators in the diagnosis of active CD. Meanwhile, the ratios of Granzyme B+ CD8+ γδT cell and Perforin+ CD8+ γδT cell were identified as indicators that distinguish mildly moderately active CD cases. CONCLUSIONS: Intestinal CD8+ γδT was reduced in active CD patients, but their activation and cytotoxicity were enhanced. However, with increased disease activity, intestinal CD8+ γδ T cells became dysfunctional. CD-specific perturbations observed in various phenotypic markers in CD8+ γδ T cells can be used as indicators to assist in diagnosing CD patients.

Patient-derived tumor organoids predict responses to irinotecan-based neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.

Adding irinotecan to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) increases the pathologic complete response (pCR) rate but brings more toxicities. Robust biomarkers to predict response to irinotecan-based nCRT are extremely necessary for selecting the right patients. Our previous study suggests that patient-derived tumor organoids (PDTOs) sensitivity to chemoradiotherapy matches patient responses. In this study, we investigated whether PDTOs sensitivity to irinotecan can predict complete response (CR) and survival. Eligible patients receiving irinotecan-based nCRT between April 5, 2017 and December 11, 2020 were enrolled in the training cohort (n = 91) for response prediction and survival analysis. Patients receiving nCRT between February 21, 2021 and September 17, 2021 were included in the validation cohort (n = 27). Predictive performances of irinotecan organoid size ratio (OSR) for CR or pCR were evaluated. The irinotecan-sensitive groups had higher response rates compared with the insensitive groups (training cohort: 71.8% vs 24.4%, P < .0001; validation cohort, 81.8% vs 18.8%, P = .002). Moreover, the irinotecan-sensitive group had higher rates of 3-year disease-free survival (DFS: 71.6% vs 55.5%, P = .034) and distant metastasis-free survival (DMFS, 77.9% vs 57.2%, P = .015) than the irinotecan-insensitive group. 5-FU and irradiation sensitivities failed to predict 3-year DFS (5-FU: 65.4% vs 61.9%, P = .643; irradiation: 84.8% vs 57.8%; P = .072). Performances of irinotecan OSR to predict CR or pCR were good in the training cohort (CR: AUC = 0.828; 95% CI = 0.723-0.932; pCR: AUC = 0.864; 95% CI = 0.759-0.961). The validation showed robust predictive ability (CR: AUC = 0.796, 95% CI = 0.5974-0.9952; pCR: AUC = 0.917, 95% CI = 0.7921-1.0000). Irinotecan sensitivity in PDTOs was a predictive and prognostic factor in LARC.

Identifying peripheral arterial disease in the elderly patients using machine-learning algorithms.

BACKGROUND: Peripheral artery disease (PAD) is a common syndrome in elderly people. Recently, artificial intelligence (AI) algorithms, in particular machine-learning algorithms, have been increasingly used in disease diagnosis. AIM: In this study, we designed an effective diagnostic model of PAD in the elderly patients using artificial intelligence. METHODS: The study was performed with 539 participants, all over 80 years in age, who underwent the measurements of Doppler ultrasonography and ankle-brachial pressure index (ABI). Blood samples were collected. ABI and two machine-learning algorithms (MLAs)-logistic regression and a random forest (RF) model-were established to diagnose PAD. The sensitivity and specificity of the models were analyzed. An additional RF model was designed based on the most significant features of the original RF model and a prospective study was conducted to demonstrate its external validity. RESULTS: Thirteen of the 28 features introduced to the MLAs differed significantly between PAD and non-PAD participants. The respective sensitivities and specificities of logistic regression, RF, and ABI were as follows: logistic regression (81.5%, 83.8%), RF (89.3%, 91.6%) and ABI (85.1%, 84.5%). In the prospective study, the newly designed RF model based on the most significant seven features exhibited an acceptable performance rate for the diagnosis of PAD with 100.0% sensitivity and 90.3% specificity. CONCLUSIONS: An RF model was a more effective method than the logistic regression and ABI for the diagnosis of PAD in an elderly cohort.

Gene expression profiling for the diagnosis of multiple primary malignant tumors.

BACKGROUND: The incidence of multiple primary malignant tumors (MPMTs) is rising due to the development of screening technologies, significant treatment advances and increased aging of the population. For patients with a prior cancer history, identifying the tumor origin of the second malignant lesion has important prognostic and therapeutic implications and still represents a difficult problem in clinical practice. METHODS: In this study, we evaluated the performance of a 90-gene expression assay and explored its potential diagnostic utility for MPMTs across a broad spectrum of tumor types. Thirty-five MPMT patients from Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University and Fudan University Shanghai Cancer Center were enrolled; 73 MPMT specimens met all quality control criteria and were analyzed by the 90-gene expression assay. RESULTS: For each clinical specimen, the tumor type predicted by the 90-gene expression assay was compared with its pathological diagnosis, with an overall accuracy of 93.2% (68 of 73, 95% confidence interval 0.84-0.97). For histopathological subgroup analysis, the 90-gene expression assay achieved an overall accuracy of 95.0% (38 of 40; 95% CI 0.82-0.99) for well-moderately differentiated tumors and 92.0% (23 of 25; 95% CI 0.82-0.99) for poorly or undifferentiated tumors, with no statistically significant difference (p-value > 0.5). For squamous cell carcinoma specimens, the overall accuracy of gene expression assay also reached 87.5% (7 of 8; 95% CI 0.47-0.99) for identifying the tumor origins. CONCLUSIONS: The 90-gene expression assay provides flexibility and accuracy in identifying the tumor origin of MPMTs. Future incorporation of the 90-gene expression assay in pathological diagnosis will assist oncologists in applying precise treatments, leading to improved care and outcomes for MPMT patients.

A low follicle-stimulating hormone level is a protective factor for non-alcoholic fatty liver disease in older men aged over 80.

PURPOSE: Recent studies have suggested the significant relationship between follicle-stimulating hormone (FSH) and non-alcoholic fatty liver disease (NAFLD) in postmenopausal women. However, it is unknown whether FSH impacts the risk of NAFLD in men. This study aimed to investigate the association between serum FSH levels and NAFLD in elderly Chinese men aged 80-98, a particular group with worse outcomes of NAFLD. PATIENTS AND METHODS: A cross-sectional analysis was performed in 444 subjects in a geriatric health center. The highest quartile of serum FSH was used as reference. Hepatic steatosis was defined according to the results of liver ultrasound. Fibrosis-4 (FIB-4) Index > 2.67 was defined as advanced fibrosis. RESULTS: Based on liver ultrasound, 108 (24.3%) subjects had NAFLD. FSH level were negatively correlated with total testosterone, estradiol, nutritional risk, and the prevalence of high education level (all P < 0.01), and positively correlated with age, luteinizing hormone, alanine aminotransferase and aspartate aminotransferase (all P < 0.05). The correlation between FSH and body mass index or antihypertensive drug usage was marginally significant (P = 0.057; P = 0.066, respectively). The percentage of subjects with NAFLD had a trend to increase following the quartiles of serum FSH (20.0% in quartile 1, 18.2% in quartile 2, 27.3% in quartile 3, and 31.6% in quartile 4). After adjustment for common pathogenic risk factors, nutritional risk, and other sex hormones, serum FSH were progressively associated with odds ratios for NAFLD. The adjusted odds ratios and 95% CIs for quartile 1, quartile 2, and quartile 3, compared with quartile 4 were 0.132 (0.034-0.516), 0.190 (0.052-0.702), and 0.404 (0.139-1.173), respectively. Obesity was not involved in the potential negative role of circulating FSH on the risk of NAFLD in our population. Furthermore, our results revealed no significant association between FSH and advance fibrosis, the OR (95% CI) for advanced fibrosis was 1.018 (0.983-1.054) (P = 0.316) after adjusting for the potential covariates, although a positive correlation of FSH and FIB-4 score was observed (r = 0.325, P = 0.001). CONCLUSION: Low FSH level may decrease the risk of NAFLD in elderly Chinese men. These findings warrant replication in more extensive studies.

A novel human colon signet-ring cell carcinoma organoid line: establishment, characterization and application.

Colon signet-ring cell carcinoma (SRCC) is a rare type of malignant dedifferentiated adenocarcinomas, and is associated with poor survival. However, an in-depth study of the biological features of SRCC is hindered by the lack of a reliable in vitro model of colon SRCC. Thus, the establishment of cell cultures from SRCC has become the most challenging task. Here, by harnessing the power of the organoid culture system, we describe the establishment of a human colon SRCC organoid line from a surgical sample from one patient with colon SRCC. The colon SRCC organoid line, YQ-173, was characterized for morphology, histology, ultrastructure and chromosome stability levels, showing that it resembles the histological and growth characteristics of the original tumor cells; xenografts were used to show that it also has a high tumor formation rate. RNA sequencing of YQ-173 compared with the normal tissue verified its mucinous nature. Capture-based targeted DNA sequencing combined with drug screening based on a bespoke 88 compound library identified that JAK2 might be a treatment target. An in vitro drug screening found that AT9283 and Pacritinib could be effective JAK2 inhibitors, which was consistent with the in vivo xenograft response. We report, for the first time, the establishment of an SRCC organoid line allowing in-depth study of SRCC biology, as well as a strategy to assess in vitro drug testing in a personalized fashion.

eIF4EBP3 was downregulated by methylation and acted as a tumor suppressor by targeting eIF4E/ß-catenin in gastric cancer.

BACKGROUND: Epigenetic aberrations of tumor suppressor genes (TSGs), particularly DNA methylation, are frequently involved in the pathogenesis of gastric cancer (GC). Through a methylome study, we identified eIF4EBP3 as a methylated gene in GC. However, the role of eIF4EBP3 in GC progression has not been explored. METHODS: The expression and promoter region methylation of eIF4EBP3 in GC and healthy tissues were analyzed in public datasets. eIF4EBP3 expression in GC was detected by semi-quantitative RT-PCR, western blot and immunohistochemistry. We also studied epigenetic alterations and functions in GC. The effects of eIF4EBP3 on cell proliferation, migration and invasion were conducted by functional experiments in vitro and in vivo. Label-free proteomic analysis was applied to identify targets of eIF4EBP3. RESULTS: The expression level of eIF4EBP3 was downregulated in gastric cancer due to promoter region methylation, and was associated with poor survival and tumor progression. Ectopic expression of eIF4EBP3 significantly inhibited tumor cell growth, migration and invasion both in vitro and in vivo. Label-free proteomic analysis indicated eIF4EBP3 downregulated the protein level of ß-catenin, which was confirmed by western blot. Overexpression of ß-catenin reversed the inhibitory effects of eIF4EBP3 on cell growth and migration, indicating that eIF4EBP3 acts on GC cells by targeting the eIF4E/ß-catenin axis. CONCLUSION: These results suggest that eIF4EBP3 is a novel TSG methylated in gastric cancer that may play important roles in GC development and liver metastasis and indicate eIF4EBP3 as a potential metastasis and survival biomarker for GC.

Carotid plague formation is associated with ankle-brachial index in elderly people.

AIMS: This study aimed at examining whether ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) were independently associated with carotid Intima-media thickness (CIMT) or carotid artery plaque (CAP) in elderly people. METHODS: A cross-sectional analysis was performed in 155 individuals aged over 75 years who underwent the measurements of ABI and baPWV. Low ABI was defined as ABI ≤ 1.0. High baPWV was defined as baPWV > 2000 cm/s. The CIMT and CAP were measured with a B-mode tomographic ultrasound system. RESULTS: Neither ABI nor baPWV was associated with CIMT in this elderly population. The group with low ABI (≤ 1.0) was significantly associated with a higher prevalence of carotid plaque (P = 0.001), while the relationship between baPWV and prevalence of carotid plaque was not found. Linear regression analysis showed that the value of ABI was significantly associated with the thickness of carotid plaque. Even in the full adjusted model, each 0.01unit ABI decreasing still increased 0.1663 mm of carotid plaque thickness (P = 0.004). Logistic Regression Analysis demonstrated that ABI lower than 1.0 had predictive value in the formation of carotid plaque with top quartile thickness (OR 2.834, 95% CI 1.131-7.099, P = 0.026). Furthermore, individuals with low ABI (≤ 1.0) were more likely to form hypoechoic carotid plaques according to ultrasonography. CONCLUSION: Low ABI but not high baPWV was associated with the formation of carotid plaque. Furthermore, ABI was significantly associated with the thickness and morphology of carotid plaque in elderly people.

Erythrocyte rheological properties but not whole blood and plasma viscosity are associated with severity of hypertension in older people.

OBJECTIVE: This study was carried out to determine whether changes in hemorheological parameters parallel the severity of essential hypertension. METHODS: A total of 198 older hypertensive patients were recruited and classified into 3 stages of hypertension according to the grading standard of hypertension. The whole blood viscosity (WBV) at various shear rates, plasma viscosity and erythrocyte rheology (including erythrocyte rigidity index, erythrocyte aggregation index and erythrocyte deformation index) were examined. RESULTS: Erythrocyte rheology paralleled the severity of essential hypertension and was significantly correlated to the average 24 h systolic blood pressure and diastolic blood pressure. Logistic analysis revealed that erythrocyte rigidity and the erythrocyte aggregation index were positively correlated with the severity of hypertension, while the erythrocyte deformation index was negatively correlated. No association was found between WBV, plasma viscosity and the severity of hypertension. CONCLUSION: The rheological properties of erythrocyte viscosity were correlated with the severity of hypertension in older people but the WBV and plasma viscosity were not.

Serum levels of cathepsin D, sirtuin1, and endothelial nitric oxide synthase are correlatively reduced in elderly healthy people.

AIM: Nowadays, cathepsins have been reported to be related to aging. The aim of this study is to evaluate the association between serum levels of cathepsin D (CTSD) and human aging. METHODS: In the present study, we analyzed the serum levels of CTSD and its relation with levels of sirtuin1 (SIRT1) and endothelial nitric oxide synthase (eNOS) activity, which were known having an important role in aging. This study recruited 90 healthy subjects (62 men and 28 women), which were subdivided into three groups with respect to age: young (about 19 years old, n = 30), middle-age (about 40 years old, n = 30), and aged (above 65 years old, n = 30). Altered serum levels of CTSD and SIRT1 were measured by enzyme-linked immunosorbent assay, and eNOS activity was assessed by the conversion of 14(C)-L-arginine to 14(C)-L-citrulline. RESULTS: Elderly subjects had significantly lower CTSD, SIRT1, and eNOS than younger ones. Serum levels of CTSD were negatively correlated with age. There was a statistically significant positive correlation between serum levels of CTSD, eNOS, and SIRT1. CONCLUSIONS: This study shows lower serum CTSD values in elderly subjects than in younger subjects. This is the first to demonstrate age-related changes in cathepsin D levels in humans and the association between SIRT1 and eNOS.

Decreased serum level of HMGB1 and MyD88 during human aging progress in healthy individuals.

AIMS: Previous studies have suggested that high mobility group box-1 protein (HMGB1) binds to the toll-like receptor 4 (TLR4) signaling mediates the progression of various inflammatory diseases. But the roles of HMGB1 and TLR4 in aging remain poorly unknown. In this study, we aimed to investigate the serum levels of HMGB1 and myeloid differentiation factor 88 (MyD88), which is one of TLR4's intracellular adaptor proteins during human aging process and their relevance with cathepsin B (CTSB). METHODS: This research was conducted using the blood samples provided by healthy people (n = 90, 63 men and 27 women). Subjects were subdivided into groups with respect to age: young (about 25 years old, n = 30), middle age (about 40 years old, n = 30), and aged (above 65 years old, n = 30). Altered serum levels of HMGB1, MyD88 and CTSB were measured using an enzyme-linked immunosorbent assay. RESULTS: The serum levels of HMGB1 and MyD88 were significantly decreased in the aged group compared with those in the young group. Linear regression analysis showed that HMGB1 and MyD88 positively correlated with CTSB among the whole healthy people. A negative correlation was determined between MyD88 and age. CONCLUSIONS: The serum levels of HMGB1 and MyD88 significantly decreased with age. MyD88, but not HMGB1, was negatively correlated with age.

Association of urinary calcium excretion with chronic kidney disease in patients with type 2 diabetes.

PURPOSE: Herein, we investigated the correlation between urinary calcium excretion (UCaE) and chronic kidney disease (CKD) in patients with type 2 diabetes mellitus (T2DM). METHODS: From August 2018 to January 2023, a total of 2031 T2DM patients providing 24-h urine samples were included in the final analyses. Patients were separated into four cohorts, based on the UCaE quartiles. We then analyzed renal functional indicators like estimated glomerular filtration rate (eGFR) and urinary albumin excretion (UAE) among the four groups. Lastly, we utilized multivariable logistic regression models to investigate the correlation between UCaE and CKD. RESULTS: After adjusting for confounding factors, we observed a decreasing trend in CKD prevalence (36.3%, 13.0%, 7.5%, and 6.6%, respectively, P < 0.001) across the UCaE quartiles. Albuminuria (55.5% vs. 40.0%, 36.5%, 37.4%) and macroalbuminuria prevalence (20.0% vs. 9.3%, 5.2%, 5.7%) in the lowest quartile were markedly elevated, compared to the remaining three quartiles (P < 0.001). Meanwhile, the eGFR level (P < 0.001) showed a clearly increasing trend across the UCaE quartiles, and patients with moderate-to-severe decreases in eGFR levels (with cutoff limits at 30-59, 15-30, and < 15 mL/min/1.73m2) were mostly found in the lowest quartile (P < 0.001). Logistic regression analysis revealed that patients in the lowest quartile experienced an enhanced prevalence of CKD, relative to those in the highest quartile (odds ratio: 5.90, 95% confidence interval: 3.60-9.67, P < 0.001). CONCLUSION: Decreased UCaE was independently associated with the CKD prevalence in T2DM patients.

A study of machine learning models for rapid intraoperative diagnosis of thyroid nodules for clinical practice in China.

BACKGROUND: In China, rapid intraoperative diagnosis of frozen sections of thyroid nodules is used to guide surgery. However, the lack of subspecialty pathologists and delayed diagnoses are challenges in clinical treatment. This study aimed to develop novel diagnostic approaches to increase diagnostic effectiveness. METHODS: Artificial intelligence and machine learning techniques were used to automatically diagnose histopathological slides. AI-based models were trained with annotations and selected as efficientnetV2-b0 from multi-set experiments. RESULTS: On 191 test slides, the proposed method predicted benign and malignant categories with a sensitivity of 72.65%, specificity of 100.0%, and AUC of 86.32%. For the subtype diagnosis, the best AUC was 99.46% for medullary thyroid cancer with an average of 237.6 s per slide. CONCLUSIONS: Within our testing dataset, the proposed method accurately diagnosed the thyroid nodules during surgery.

Cathepsin L was involved in vascular aging by mediating phenotypic transformation of vascular cells.

Vascular media and adventitia-induced remodeling plays an important role in vascular aging. However, the mechanism remains unclear. This study aims to investigate the mechanisms underlying vascular aging. Transcriptome analysis revealed that the expression of cathepsin L (CTSL) significantly decreased in arteries of old mice (24 months old) compared with that in arteries of young mice (4 months old), which was confirmed by immunohistochemistry and Western blot. The expression of CTSL in adventitia fibroblasts (AFs) and vascular smooth muscle cells (VSMCs) of aged mice was lower than that of young mice. Compared with wild-type control mice, CTSL knockout (CTSL - /-) mice had increased collagen deposition (fibrosis) and decreased telomerase activity and LC3Ⅱ/ LC3Ⅰratio. The expression of mammalian target of rapamycin (mTOR) and osteopontin (OPN) increased in aortas of CTSL-/-mice compared with that in aortas of wild-type control mice. In vitro, lentivirus-mediated CTSL knockdown induced VSMCs senescence and AFs transformed into myofibroblasts (MFs). Rapamycin, a mTOR inhibitor, inhibited CTSL deficiency induced VSMCs senescence, osteopontin (OPN) secretion and AFs migration. In conclusion, the decreased level of CTSL with age may participate in vascular aging by promoting the phenotypic transformation of vascular cells.

Comprehensive analysis of microbiota signature across 32 cancer types.

Microbial communities significantly inhabit the human body. Evidence shows the interaction between the human microbiome and host cells plays a central role in multiple physiological processes and organ microenvironments. However, the majority of related studies focus on gut microbiota or specific tissues/organs, and the component signature of intratumor microbiota across various cancer types remains unclear. Here, we systematically analyzed the correlation between intratumor microbial signature with survival outcomes, genomic features, and immune profiles across 32 cancer types based on the public databases of Bacteria in Cancer (BIC) and The Cancer Genome Atlas (TCGA). Results showed the relative abundance of microbial taxa in tumors compared to normal tissues was observed as particularly noticeable. Survival analysis found that specific candidate microbial taxa were correlated with prognosis across various cancers. Then, a microbial-based scoring system (MS), which was composed of 64 candidate prognostic microbes, was established. Further analyses showed significant differences in survival status, genomic function, and immune profiles among the distinct MS subgroups. Taken together, this study reveals the diversity and complexity of microbiomes in tumors. Classifying cancer into different subtypes based on intratumor microbial signatures might reasonably reflect genomic characteristics, immune features, and survival status.

Identification of immune-related hub genes contributing to the pathogenesis, diagnosis, and remission of ulcerative colitis by integrated bioinformatic analyses.

The inflammatory disease ulcerative colitis (UC) is multifaceted, immune-mediated, chronic, and relapsing, which is considered to be mainly driven by dysregulated mucosal immune response. The remission of the inflammatory response is a marker of mucosal healing, relating to the low risk of hospitalizations, colorectal cancer, and colectomy. In spite of this, it is still unclear what the key immunological mechanism is which contributes to UC. Here, we explored the immune mechanism and related key genes underlying the state of inflammation in UC. Co-expression networks were constructed based on the expression profiles of immune-related genes in GSE179285. Using Weighted Gene Co-expression Network Analysis and Protein-protein interactions analysis, common hub genes were identified in the module of interest. Then, screening of real hub genes, significantly differentially expressing in inflamed UC, was carried out by Differential Expression Genes Analysis of GSE75214, GSE53306, and GSE6731datasets and immunohistochemistry of clinical samples. The diagnosis Capacity of the hub gene was identified by "glm" function in R. The potential key immune-related mechanisms were investigated using functional enrichment analysis and gene set enrichment analysis (GSEA). Bioinformatics tools were used to predict potential upstream transcription factors (TF), including the UCSC genome browser, correlation analyses, and JASPAR browser. The analysis revealed the blue module, consisting of 227 immune-related genes, showed the highest correlation with inflamed UC. And then, forty-three common candidates were distinguished. S100A9 was identified within the key module as a real hub gene with good diagnostic performance. The immune genes in the blue module were markedly enriched in the Cytokine-Cytokine receptor interaction. S100A9 most likely gets involved NOD-like receptor (NLR) signaling pathway. SPI1 showed the strongest likelihood to be the regulator. S100A9 was identified as the real immune-related hub gene for inflamed UC. Both diagnosis and remission may be aided by its high expression in the inflamed UC.

The diagnosis and treatment for a patient with cancer of unknown primary: A case report.

Background: Cancer of unknown primary (CUP) is a class of metastatic malignant tumors whose primary location cannot be determined. The diagnosis and treatment of CUP are a considerable challenge for clinicians. Herein, we report a CUP case whose corresponding primary tumor sites were successfully identified, and the patient received proper treatment. Case report: In February 2022, a 74-year-old woman was admitted to the Medical Oncology Department at Sir Run Run Shaw Hospital for new lung and intestinal tumors after more than 9 years of breast cancer surgery. After laparoscopically assisted right hemicolectomy, pathology revealed mucinous adenocarcinoma; the pathological stage was pT2N0M0. Results from needle biopsies of lung masses suggested poorly differentiated cancer, ER (-), PR (-), and HER2 (-), which combined with the clinical history, did not rule out metastatic breast cancer. A surgical pathology sample was needed to determine the origin of the tumor tissue, but the patient's chest structure showed no indications for surgery. Analysis of the tumor's traceable gene expression profile prompted breast cancer, and analysis of next-generation amplification sequencing (NGS) did not obtain a potential drug target. We developed a treatment plan based on comprehensive immunohistochemistry, a gene expression profile, and NGS analysis. The treatment plan was formulated using paclitaxel albumin and capecitabine in combination with radiotherapy. The efficacy evaluation was the partial response (PR) after four cycles of chemotherapy and two cycles combined with radiotherapy. Conclusion: This case highlighted the importance of identifying accurate primary tumor location for patients to benefit from treatment, which will provide a reference for the treatment decisions of CUP tumors in the future.

Correlation between ankle-brachial index and subtle cognitive decline.

BACKGROUND: Subtle cognitive decline (SCD) is considered the early stage of Alzheimer's disease (AD) and is of great clinical significance for the prevention and treatment of AD. The ankle-brachial index (ABI) has been reported to be associated with cognitive impairment; however, there are few studies on the relationship between ABI and SCD. METHODS: From August 2019 to April 2021, subjects were recruited to participate in a cognitive function test at the Shanghai Sixth People's Hospital. Based on the test results, 217 patients with SCD were selected as the experimental group and 259 patients with normal cognitive function were selected as the control group. The data of the two groups were compared, and the correlation between the ABI and cognitive decline was analyzed. RESULTS: There were significant differences in age, sex, smoking status, hypertension, diabetes, triglycerides, serum creatinine, and ABI (p < .05)between the two groups. Logistic regression analysis showed that age, hypertension, diabetes, and ABI influenced cognitive decline(p < .05). After correcting for other factors, ABI was independently related to cognitive decline. Pearson's correlation analysis showed that a low ABI (<0.9) had a significant effect on memory and visual space of the cognitive domain (p < . 05). CONCLUSIONS: ABI is significantly associated with SCD and may be a critical tool to predict early cognitive decline.

The developmental regulator HAND1 inhibits gastric carcinogenesis through enhancing ER stress apoptosis via targeting CHOP and BAK which is augmented by cisplatin.

Epigenetic disruption of tumor suppressor genes, particularly aberrant CpG methylation, plays a crucial role in gastric cancer (GC) pathogenesis. Through CpG methylome and expression profiling, a developmental transcription factor - Hand-And-Neural-crest-Derivative-expressed 1 (HAND1), was identified methylated and downregulated in GC. However, its role and underlying mechanisms in GC progression are poorly understood. Here, we show that HAND1 was frequently downregulated in GC by promoter methylation, and significantly correlated with tumor progression and poor prognosis of GC patients. High expression of HAND1 in GC patients was associated with significantly higher 5-year overall survival rates. Ectopic expression of HAND1 inhibited GC cell growth and migration in vitro and in vivo. HAND1 expression increased ROS levels and cytosolic Ca2+ concentration, enhanced cisplatin-induced apoptosis through endoplasmic reticulum (ER) stress/mitochondria-mediated apoptosis. Knockdown of CHOP and BAK attenuated HAND1-induced cell apoptosis. Overexpression of CHOP increased BAK expression. HAND1 interacts with CHOP, also directly binds to CHOP and BAK promoters and positively regulates BAK transcription. Thus, the present study demonstrates that HAND1 is a tumor suppressor gene methylated in GC, induces ER stress and apoptosis via CHOP and BAK, which is augmented by cisplatin. Low HAND1 expression is an independent poor prognostic factor for GC. The tumor-specific methylation of HAND1 promoter could be a candidate biomarker for GC.