Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii.

Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis; however, the importance and homeostasis of R5P in the intracellular parasite Toxoplasma gondii remain enigmatic. Here, we show that the cytoplasmic sedoheptulose-1,7-bisphosphatase (SBPase) is dispensable. Still, its co-deletion with transaldolase (TAL) impairs the double mutant's growth and increases 13C-glucose-derived flux into pentose sugars via the transketolase (TKT) enzyme. Deletion of the latter protein affects the parasite's fitness but is not lethal and is correlated with an increased carbon flux via the oxidative pentose phosphate pathway. Further, loss of TKT leads to a decline in 13C incorporation into glycolysis and the TCA cycle, resulting in a decrease in ATP levels and the inability of phosphoribosyl-pyrophosphate synthetase (PRPS) to convert R5P into 5'-phosphoribosyl-pyrophosphate and thereby contribute to the production of AMP and IMP. Likewise, PRPS is essential for the lytic cycle. Not least, we show that RuPE-mediated metabolic compensation is imperative for the survival of the ΔsbpaseΔtal strain. In conclusion, we demonstrate that multiple routes can flexibly supply R5P to enable parasite growth and identify catalysis by TKT and PRPS as critical enzymatic steps. Our work provides novel biological and therapeutic insights into the network design principles of intracellular parasitism in a clinically-relevant pathogen.

Deep learning or radiomics based on CT for predicting the response of gastric cancer to neoadjuvant chemotherapy: a meta-analysis and systematic review.

Background: Artificial intelligence (AI) models, clinical models (CM), and the integrated model (IM) are utilized to evaluate the response to neoadjuvant chemotherapy (NACT) in patients diagnosed with gastric cancer. Objective: The objective is to identify the diagnostic test of the AI model and to compare the accuracy of AI, CM, and IM through a comprehensive summary of head-to-head comparative studies. Methods: PubMed, Web of Science, Cochrane Library, and Embase were systematically searched until September 5, 2023, to compile English language studies without regional restrictions. The quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) criteria. Forest plots were utilized to illustrate the findings of diagnostic accuracy, while Hierarchical Summary Receiver Operating Characteristic curves were generated to estimate sensitivity (SEN) and specificity (SPE). Meta-regression was applied to analyze heterogeneity across the studies. To assess the presence of publication bias, Deeks' funnel plot and an asymmetry test were employed. Results: A total of 9 studies, comprising 3313 patients, were included for the AI model, with 7 head-to-head comparative studies involving 2699 patients. Across the 9 studies, the pooled SEN for the AI model was 0.75 (95% confidence interval (CI): 0.66, 0.82), and SPE was 0.77 (95% CI: 0.69, 0.84). Meta-regression was conducted, revealing that the cut-off value, approach to predicting response, and gold standard might be sources of heterogeneity. In the head-to-head comparative studies, the pooled SEN for AI was 0.77 (95% CI: 0.69, 0.84) with SPE at 0.79 (95% CI: 0.70, 0.85). For CM, the pooled SEN was 0.67 (95% CI: 0.57, 0.77) with SPE at 0.59 (95% CI: 0.54, 0.64), while for IM, the pooled SEN was 0.83 (95% CI: 0.79, 0.86) with SPE at 0.69 (95% CI: 0.56, 0.79). Notably, there was no statistical difference, except that IM exhibited higher SEN than AI, while maintaining a similar level of SPE in pairwise comparisons. In the Receiver Operating Characteristic analysis subgroup, the CT-based Deep Learning (DL) subgroup, and the National Comprehensive Cancer Network (NCCN) guideline subgroup, the AI model exhibited higher SEN but lower SPE compared to the IM. Conversely, in the training cohort subgroup and the internal validation cohort subgroup, the AI model demonstrated lower SEN but higher SPE than the IM. The subgroup analysis underscored that factors such as the number of cohorts, cohort type, cut-off value, approach to predicting response, and choice of gold standard could impact the reliability and robustness of the results. Conclusion: AI has demonstrated its viability as a tool for predicting the response of GC patients to NACT Furthermore, CT-based DL model in AI was sensitive to extract tumor features and predict the response. The results of subgroup analysis also supported the above conclusions. Large-scale rigorously designed diagnostic accuracy studies and head-to-head comparative studies are anticipated. Systematic review registration: PROSPERO, CRD42022377030.

The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Prognostic role of preoperative lymphocyte/C-reactive protein associated with upper gastrointestinal cancer: a meta-analysis.

Purpose: The lymphocyte/C-reactive protein (LCR) is a novel immunoinflammatory score and prognostic marker, but the relationship between lymphocyte/C-reactive proteins and clinical outcomes in patients with upper gastrointestinal cancers remains controversial. This study aimed to evaluate the relationship between LCR and the prognosis of upper gastrointestinal cancer by systematic evaluation and meta-analysis. Methods: We systematically searched PubMed, EMBASE, Cochrane, and Web of Science databases to obtain related studies on the relationship between LCR and esophageal cancer (EC), gastric cancer (GC), and esophagogastric junction cancers (EGJ), and used hazard ratio (HR), 95% confidence interval (95%CI) to evaluate the prognostic value of LCR. Outcome measures included overall survival (OS) and disease-free survival (DFS). Results: Eight retrospective cohort studies with 2838 patients were included. Meta-analysis showed that patients with low LCR cancers had poor overall survival OS and disease-free survival DFS (HR=2.18, 95%CI=1.87-2.55; HR=1.88, 95%CI=1.56-2.26). Subgroup analysis based on cancer type, treatment modality, gender, T stage, TNM stage, country, and LCR threshold showed that lower LCR levels were all associated with worse OS and DFS (P<0.05). Conclusion: The LCR can be used as a prognostic marker for patients with upper gastrointestinal cancers, and patients with a lower LCR may have a poor prognosis. Due to the limited number of studies included and mostly retrospective studies, the above findings require validation by more high-quality studies. Systematic Review Registration: https://www.crd.york.ac.uk, identifier CRD42023392433.

Diagnostic Efficacy of Plasma-Based Real-Time PCR for Schistosomiasis Japonica in Mice before and after Treatment with Praziquantel.

The prevalence of schistosomiasis japonica in China is now characterized by a low epidemic rate and low-intensity infections. Some diagnostic methods with high sensitivity and specificity are urgently needed to better monitor this disease in the current situation. In this study, the detection efficacy of a real-time fluorescent quantitative PCR (qPCR) assay was assessed for schistosomiasis japonica in mice, and before and after treatment with praziquantel (PZQ). Our results showed that the sensitivity of the qPCR was 99.3% (152/153, 95% CI: 96.41-99.98%) and its specificity was 100% (77/77, 95% CI: 95.32-100%) in mice infected with different numbers of Schistosoma japonicum. After the oral administration of PZQ, mice infected with 10 cercariae or 40 cercariae were all Schistosoma japonicum-negative 6 weeks after treatment. However, the negativity rates on a soluble egg antigen (SEA)-based enzyme-linked immunosorbent assay (ELISA) were only 34.8% (8/23, 10 cercariae group) and 6.7% (1/15, 40 cercariae group) at the sixth week after PZQ treatment. These results demonstrated that the qPCR method had good sensitivity and specificity, and suggested that its sensitivity correlated with the infection intensity in mice. Moreover, this method had better potential utility for evaluating the treatment efficacy of PZQ in schistosome-infected mice than SEA-based ELISA.

Role of 6-phosphogluconate dehydrogenase enzyme 1 in growth and virulence of Toxoplasma gondii and development of attenuated live vaccine.

Toxoplasma gondii is a ubiquitous pathogen that infects all warm-blooded animals, including humans, causing substantial socioeconomic and healthcare burdens. However, there is no ideal vaccine for toxoplasmosis. As metabolism is important in the growth and virulence of Toxoplasma, some key pathways are promising antiparasitic targets. Here, we identified 6-phosphogluconate dehydrogenase 1 (Tg6PGDH1) in the oxidative pentose phosphate pathway as a cytoplasmic protein that is dispensable for tachyzoite growth of T. gondii in vitro but critical for virulence and cyst formation in vivo. The depletion of Tg6PGDH1 causes decreased gene transcription involved in signal transduction, transcriptional regulation and virulence. Furthermore, we analysed the protective effect of the ME49Δ6pgdh1 mutant as an attenuated vaccine and found that ME49Δ6pgdh1 immunization stimulated strong protective immunity against lethal challenges and blocked cyst formation caused by reinfection. Furthermore, we showed that ME49Δ6pgdh1 immunization stimulated increased levels of interferon-gamma, tumour necrosis factor-alpha and Toxoplasma-specific IgG antibodies. These data highlight the role of Tg6PGDH1 in the growth and virulence of T. gondii and its potential as a target for the development of a live-attenuated vaccine.

Efficacy and Safety of Keverprazan Compared With Lansoprazole in the Treatment of Duodenal Ulcer: A Phase III, Randomized, Double-Blind, Multicenter Trial.

INTRODUCTION: Keverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related disorders requiring potent acid inhibition. This study aimed to establish the noninferiority of keverprazan to lansoprazole in the treatment of patients with duodenal ulcer (DU). METHODS: In this phase III, double-blind, multicenter study, 360 Chinese patients with endoscopically confirmed active DU were randomized 1:1 to take either keverprazan (20 mg) or lansoprazole (30 mg) treatment for up to 6 weeks. The primary end point was DU healing rate at week 6. The secondary end point was DU healing rate at week 4. Symptom improvement and safety were also assessed. RESULTS: Based on the full analysis set, the cumulative healing rates at week 6 were 94.4% (170/180) and 93.3% (166/178) for keverprazan and lansoprazole, respectively (difference: 1.2%; 95% confidence intervel: -4.0%-6.5%). At week 4, the respective healing rates were 83.9% (151/180) and 80.3% (143/178). In the per protocol set, the 6-week healing rates in keverprazan and lansoprazole groups were 98.2% (163/166) and 97.6% (163/167), respectively (difference: 0.6%; 95% confidence intervel: -3.1%-4.4%); the 4-week healing rates were respectively 86.8% (144/166) and 85.6% (143/167). Keverprazan was noninferior to lansoprazole in DU healing after the treatment for 4 and 6 weeks. The incidence of treatment-emergent adverse events was comparable among groups. DISCUSSION: Keverprazan 20 mg had a good safety profile and was noninferior to lansoprazole 30 mg once daily for DU healing.

Two Molecular Plasma-Based Diagnostic Methods to Evaluate Early Infection of Schistosoma japonicum and Schistosomiasis Japonica.

The prevalence and infectious intensity of schistosomiasis japonica has decreased significantly in China in the past few decades. However, more accurate and sensitive diagnostic methods are urgently required for the further control, surveillance, and final elimination of the disease. In this study, we assessed the diagnostic efficacy of a real-time fluorescence quantitative PCR (qPCR) method and recombinase polymerase amplification (RPA) combined with a lateral-flow dipstick (LFD) assay for detecting early infections of Schistosoma japonicum and different infection intensities. The sensitivity of the qPCR at 40 days post-infection (dpi) was 100% (8/8) in mice infected with 40 cercariae, which was higher than in mice infected with 10 cercariae (90%, 9/10) or five cercariae (77.8%, 7/9). The results of the RPA-LFD assays were similar, with sensitivities of 55.6% (5/9), 80% (8/10), and 100% (8/8) in mice infected with 5, 10, and 40 cercariae, respectively. In goats, both the qPCR and RPA-LFD assays showed 100% (8/8) sensitivity at 56 dpi. In the early detection of S. japonicum infection in mice and goats with qPCR, the first peak in positivity appeared at 3-4 dpi, when the positivity rate exceeded 40%, even in the low infection, intensity mice. In the RPA-LFD assays, positive results first peaked at 4-5 dpi in the mice, and the positivity rate was 37.5% in the goats at 1 dpi. In conclusion, neither of the molecular methods produced exceptional results for the early diagnosis of S. japonicum infection. However, they were useful methods for the regular diagnosis of schistosomiasis in mice and goats.

A novel circRNA, hsa_circ_0069382, regulates gastric cancer progression.

Aberrant expression of circRNAs is closely associated with the progression of gastric cancer; however, the specific mechanisms involved remain unclear. Our aim was to identify new gastric cancer biomarkers and explore the molecular mechanisms of gastric cancer progression. Therefore, we analyzed miRNA and circRNA microarrays of paired early-stage gastric cancer samples. Our study identified a new circRNA called hsa_circ_0069382, that had not been reported before and was expressed at low levels in gastric cancer tissues. Our study also included bioinformatics analyses which determined that the high expression of hsa_circ_0069382 regulated the BTG anti-proliferation factor 2 (BTG2)/ focal adhesion kinase (FAK) axis in gastric cancer lines by sponging for miR-15a-5p. Therefore, proliferation, invasion, and migration of gastric cancer is impacted. miR-15a-5p overexpression partially restored the effects of hsa_circ_0069382. This study provides potential new therapeutic options and a future direction to explore for gastric cancer treatment, and biomarkers.

Small intestinal angiosarcoma on clinical presentation, diagnosis, management and prognosis: A case report and review of the literature.

BACKGROUND: Angiosarcoma is a highly malignant soft-tissue sarcoma derived from vascular endothelial cells that mainly occurs in the skin and subcutaneous tissues. Small-intestinal angiosarcomas are rare, and the prognosis is poor. CASE SUMMARY: We reported a case of primary multifocal ileal angiosarcoma and analyze previously reported cases to improve our understanding of small intestinal angiosarcoma. Small intestinal angiosarcoma is more common in elderly and male patients. Gastrointestinal bleeding, anemia, abdominal pain, weakness, and weight loss were the common symptoms. CD31, CD34, factor VIII-related antigen, ETS-related gene, friend leukemia integration 1, and von Willebrand factor are valuable immunohistochemical markers for the diagnosis of small-intestinal angiosarcoma. Small-intestinal angiosarcoma most commonly occurs in the jejunum, followed by the ileum and duodenum. Radiation and toxicant exposure are risk factors for angiosarcoma. After a definite diagnosis, the mean and median survival time was 8 mo and 3 mo, respectively. Kaplan-Meier survival analysis showed that age, infiltration depth, chemotherapy, and the number of small intestinal segments invaded by tumor lesions were prognostic factors for small intestinal angiosarcoma. Multivariate Cox regression analysis showed that chemotherapy and surgery significantly improved patient prognosis. CONCLUSION: Angiosarcoma should be considered for unexplained melena and abdominal pain, especially in older men and patients with a history of radiation exposure. Prompt treatment, including surgery and adjuvant chemotherapy, is essential to prolonging patient survival.

Severe influenza A virus pneumonia complicated with Curvularia lunata infection: Case Report.

Human infection with Curvularia lunata (C. lunata) is exceptionally rare. A 23-year-old female patient contracted both bacterial and Curvularia lunata infections during influenza A virus infection. Multiple etiological tests were performed repeatedly during hospitalization due to fluctuations in condition. On the 17th day after hospital admission, mold hyphae were discovered in the pathogen culture of the patient's bronchoalveolar lavage fluid during one of these examinations. The patient was suspected to have a filamentous fungal infection. Consequently, we further obtained sputum samples for fungal culture, which confirmed the diagnosis of Curvularia infection. The patient, in this case, was in a critical condition, experiencing complications of lung abscess, pneumothorax, sepsis, and multiorgan failure. Despite prompt initiation of antifungal therapy including amphotericin B cholesteryl sulfate complex and isavuconazole upon detection of the fungal infection and concurrent administration of active organ function support treatment, the patient's condition rapidly deteriorated due to compromised immune function. Ultimately, on the 27th day of treatment, the patient succumbed to septic shock and multiple organ dysfunction syndrome. This is the first case of Curvularia lunata infection in our hospital. In this paper, we aim to raise awareness of Curvularia lunata infection and to emphasize that the possibility of this fungal infection should be considered in patients with severe pneumonia caused by influenza A virus and that empirical antifungal therapy should be given promptly when the patient has invasive lung damage.

Development and validation of an ECM-related prognostic signature to predict the immune landscape of human hepatocellular carcinoma.

BACKGROUND: The global burden of hepatocellular carcinoma (HCC) is increasing, negatively impacting social health and economies. The discovery of novel and valuable biomarkers for the early diagnosis and therapeutic guidance of HCC is urgently needed. METHODS: Extracellular matrix (ECM)-related gene sets, transcriptome data and mutation profiles were downloaded from the Matrisome Project and The Cancer Genome Atlas (TCGA)-LIHC datasets. Coexpression analysis was initially performed with the aim of identifying ECM-related lncRNAs (r > 0.4, p < 0.001). The screened lncRNAs were subjected to univariate analysis to obtain a series of prognosis-related lncRNA sets, which were incorporated into least absolute selection and shrinkage operator (LASSO) regression for signature establishment. Following the grouping of LIHC samples according to risk score, the correlations between the signature and clinicopathological, tumour immune infiltration, and mutational characteristics as well as therapeutic response were also analysed. lncRNA expression levels used for modelling were finally examined at the cellular and tissue levels by real-time PCR. All analyses were based on R software. RESULTS: AL031985.3 and MKLN1-AS were ultimately identified as signature-related lncRNAs, and both were significantly upregulated in HCC tissue samples and cell lines. The prognostic value of the signature reflected by the AUC value was superior to that of age, sex, grade and stage. Correlation analysis results demonstrated that high-risk groups exhibited significant enrichment of immune cells (DCs, macrophages and Tregs) and increased expression levels of all immune checkpoint genes. Prominent differences in clinicopathological profiles, immune functions, tumour mutation burden (TMB) and drug sensitivity were noted between the two risk groups. CONCLUSIONS: Our signature represents a valuable predictive tool in the prognostic management of HCC patients. Further validation of the mechanisms involved is needed.

Metabolic flexibilities and vulnerabilities in the pentose phosphate pathway of the zoonotic pathogen Toxoplasma gondii.

Metabolic pathways underpin the growth and virulence of intracellular parasites and are therefore promising antiparasitic targets. The pentose phosphate pathway (PPP) is vital in most organisms, providing a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose sugar for nucleotide synthesis; however, it has not yet been studied in Toxoplasma gondii, a widespread intracellular pathogen and a model protozoan organism. Herein, we show that T. gondii has a functional PPP distributed in the cytoplasm and nucleus of its acutely-infectious tachyzoite stage. We produced eight parasite mutants disrupting seven enzymes of the PPP in T. gondii. Our data show that of the seven PPP proteins, the two glucose-6-phosphate dehydrogenases (TgG6PDH1, TgG6PDH2), one of the two 6-phosphogluconate dehydrogenases (Tg6PGDH1), ribulose-5-phosphate epimerase (TgRuPE) and transaldolase (TgTAL) are dispensable in vitro as well as in vivo, disclosing substantial metabolic plasticity in T. gondii. Among these, TgG6PDH2 plays a vital role in defense against oxidative stress by the pathogen. Further, we show that Tg6PGDH2 and ribulose-5-phosphate isomerase (TgRPI) are critical for tachyzoite growth. The depletion of TgRPI impairs the flux of glucose in central carbon pathways, and causes decreased expression of ribosomal, microneme and rhoptry proteins. In summary, our results demonstrate the physiological need of the PPP in T. gondii while unraveling metabolic flexibility and antiparasitic targets.

Identification of N7-methylguanosine-related IncRNA signature as a potential predictive biomarker for colon adenocarcinoma.

N7-Methylguanosine (m7G) is an RNA modification serving as a key part of colon cancer development. Thus, a comprehensive analysis was executed to explore prognostic roles and associations with the immune status of the m7G-related lncRNA (m7G-RNAs) in colon adenocarcinoma (COAD). Identification of m7G-RNAs was achieved via Pearson's correlation analysis of lncRNAs in the TCGA-COAD dataset and m7G regulators. A prognostic signature was developed via LASSO analyses. ESTIMATE, CIBERSORT, and ssGSEA algorithms were utilized to assess immune infiltration between different risk groups. Survival analysis suggested the high-risk group possesses poor outcomes compared with the low-risk group. According to the ROC curves, the m7G-RNAs signature exhibited a reliable capability of prediction (AUCs at 1, 3, and 5 years were 0.770, 0.766, and 0.849, respectively). Multivariate hazard analysis proved that the signature was an independent predictive indicator for OS. Moreover, the risk score was related to infiltration levels of naïve B cells, CD4+ memory T cells, and resting NK cells. The result revealed the prognostic value of m7G modification in COAD and provided a novel perspective on personalized immunotherapy strategies.

Seroprevalence and risk factors of Toxoplasma gondii in urban cats from China.

BACKGROUND: Toxoplasma gondii infects almost all warm-blooded animals, and cats play a crucial role in the epidemiology of T. gondii as the definitive host. Despite sporadic reports on the seroprevalence of T. gondii in domestic cats, systematic surveys are lacking and some regions remain in China uninvestigated. METHODS: A total of 1,521 serum samples were collected from 10 regions of China and analyzed by antibodies against T. gondii by ELISA with the purpose of identifying risk factors of T. gondii infection in cats across China and obtaining seroprevalence data from some previously uninvestigated areas. RESULTS: Antibodies to T. gondii were detected in 62 of 1,478 (4.2%) urban pet cats and in 9 of 43 (20.9%) stray cats. Among the regions examined, the prevalence was 13% in Sichuan, 12.8% in Chongqing, 6.4% in Hunan, 2.5% in Hubei and 0.9% in Guangdong. Additionally, this is the first report on the seroprevalence of T. gondii in urban pet cats from Qinghai (6.2%), Anhui (3.1%), Jiangxi (2.5%), Shaanxi (2.4%) and Ningxia (1.6%). The age and lifestyle (stray or pet) of cats were identified as the risk factors for seropositivity by multivariate analysis of the data. CONCLUSIONS: Our findings improve our understanding of seroprevalence and risk factors of T. gondii infection in cats across China, and provide useful information for the formulating of preventive and control measures against this widespread zoonotic parasite.

Association between bilirubin and nonalcoholic fatty liver disease in the non-obese Chinese population: a cross-sectional study.

Background: Serum bilirubin may play a role in preventing antioxidant and cytoprotective effects in physiological conditions. Serum bilirubin levels are inversely correlated with insulin resistance and the prevalence of cardiovascular diseases and diabetes mellitus. However, the correlation between serum bilirubin and nonalcoholic fatty liver disease (NAFLD) is unclear. NAFLD in non-obese participants may lead to serious health problems, calling for prompt recognition and early management. This study aimed at investigating the relationship between the serum bilirubin levels and NAFLD in non-obese Chinese adults. Methods: We evaluated 4,900 non-obese subjects (body mass index <25 kg/m2) residing in Wuwei, China. The subjects received a baseline questionnaire, physical examination, abdominal ultrasonography, and laboratory check-ups. Fasting serum bilirubin was measured with an automated biochemical analyzer. NAFLD was diagnosed based on imaging findings of fatty liver disease on ultrasonography, without excessive alcohol intake and other known causes for chronic liver disease. A logistic regression model was applied to calculate the association between serum bilirubin level and NAFLD in non-obese subjects. Results: NAFLD was diagnosed in 408 (203 men) of the subjects, and they had a mean age of 51-year-old. Non-obese NAFLD patients had lower serum direct bilirubin (DBIL) levels than control group did [2.50 (1.80-3.25) vs. 2.60 (1.90-3.50), P=0.004], but no significant differences in indirect bilirubin (IBIL) and total bilirubin (TBIL) levels of the two groups was seen (both P>0.05). After adjusting confounding factors such as age, gender, body mass index, blood glucose, and blood lipids, multivariate analysis showed serum DBIL (OR: 0.96, 95% CI: 0.83-1.11, P trend =0.6022), IBIL (OR: 1.02, 95% CI: 0.89-1.17, P trend =0.7756), and TBIL (OR: 1.00, 95% CI: 0.87-1.15, P trend =0.991) levels were not associated with NAFLD in the non-obese population. In addition, subgroup analyses (stratified according to age, gender, and medical histories of hypertension, and diabetes mellitus) suggested no independent association between NAFLD and DBIL, IBIL, or TBIL. Conclusions: Our data suggest that serum bilirubin levels are unlikely to be associated with NAFLD in non-obese subjects.

In silico development and validation of a novel glucose and lipid metabolism-related gene signature in gastric cancer.

Background: Abnormal glucose and lipid metabolism plays a critical role in gastric carcinogenesis and development. Hence, we presented a systematic analysis of glucose and lipid metabolism-related genes to explore their function and prognostic value in gastric cancer (GC). Methods: The consensus clustering algorithm was used to identify the molecular subtypes based on glucose and lipid metabolism-related genes. Subsequently, cox regression analysis and lasso regression analysis were utilized to establish a risk prediction model. A clinical nomogram was constructed to assist prognosis assessment. In addition, ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) algorithms were performed to evaluate the immune infiltration of the metabolic model, and GSEA was used for enrichment analysis of the metabolic signature. Finally, we explored the association between the risk model and anti-cancer therapy for the purpose of clinical application for GC treatment. Results: GC samples were divided into 2 subtypes based on glucose and lipid metabolism-related genes, patients in cluster 2 had a better overall survival (OS) than those in cluster 1. Fifty-two genes were identified by univariable regression analysis. Finally, a 13-gene metabolic signature (CACNA1H, CHST1, IGFBP3, NASP, STC1, VCAN, NUP205, NUP43, PGM2L1, CAV1, ELOVL4, PRKAA2, TNFAIP8L3) was successfully constructed that demonstrated good performance in different datasets, as well as an independent hazardous factor for prognosis. In addition, the nomogram constructed with the clinical variables showed higher predictive efficacy for predicting the 1-, 3-, and 5-year OS. The 13-gene metabolic signature was significantly associated with immune scores and immune cell infiltration in high-risk group. Moreover, GSEA analysis revealed that cancer- and immune-related pathways were enriched in the high-risk group. Finally, our results indicated that there might exist an immunosuppressive status in the high-risk groups. Conclusions: This study demonstrated that glucose and lipid metabolism-related genes were significantly associated with prognosis. Meanwhile, it will provide novel insights into exploring the immunoregulation roles of these genes.

A Novel Matrisomal-Related LncRNA Signature Associated With Survival Outcome and Immune Evasion in Patients With Gastric Cancer.

Background: Different matrisomal patterns are shared across carcinomas. However, little is known about whether there exists a unique tumor matrisome that modulates GC progression and immune regulation. Methods: We conducted a genome-wide analysis based on matrisomal-related lncRNAs (MRLs) in 375 patients with GC from the Cancer Genome Atlas (TCGA) database. Patients were split into the training set and validation set at a ratio of 1:1 using the R package cart. Pearson correlation analysis (PCA) was performed to identify lncRNAs that correlated with matrisome based on differential expression genes. Subsequently, we performed univariate Cox regression analyses and lasso Cox analysis on these lncRNAs to construct a risk model. Considering the primary effect of GRASLND on the GC prognosis, we chose it for further validation in an experimental setting. Results: We identified a 15-MRL signature to predict overall survival and immune cell infiltration of patients with GC. The AUC values to predict 5-year outcome in three sets were 0.89, 0.65, and 0.78, respectively. Further analyses suggested that the high-risk group showed more obvious immune cell infiltration, and demonstrated an immunologically "cold" profile. In vitro, knockdown of GRASLND could inhibit the invasion capability of GC cells, and downregulate the protein expression of crucial matrisomal-related gene MMP9. Conclusions: The 15-MRL gene signature might serve as a relatively good predictive tool to manage patients with GC.

Obesity, peptic ulcer disease and metabolic status in the Wuwei Cohort of northwest China: A cross-sectional study.

BACKGROUND AND OBJECTIVES: Peptic ulcer disease is a common digestive system disease. However, whether peptic ulcer disease and obesity are related is unclear. We assessed the associations of obesity and metabolic status with peptic ulcer disease. METHODS AND STUDY DESIGN: We conducted a cross-sectional study of 3561 individuals from the Wuwei cohort. We evaluated the associations of general and abdominal adiposity, as defined by different anthropometric indices, with peptic ulcer disease. Odds ratios and 95% confidence intervals were determined through binary logistic regression. RESULTS: The odds ratio for peptic ulcer disease was 2.37 (1.46-3.84) for women with obesity, compared with the normal group. The association remained significant in Models 2 and 3, with odds ratios of 2.23 (1.35-3.69) and 2.03 (1.19-3.49), respectively. In Model 1, women with obesity had an odds ratio for duodenal ulcer of 2.76 (1.41-5.42) compared with the control group; this result remained significant in Models 2 and 3, with odds ratios of 2.52 (1.24-5.13) and 2.44 (1.13-5.28), respectively. In Model 1, women with metabolically healthy and unhealthy obesity had odds ratios for peptic ulcer disease of 2.26 (1.19-4.28) and 2.15 (1.12-4.15), respectively, compared with the control group. After adjustments for major covariates and H. pylori status, these respective odds ratios became 2.27 (1.20-4.30) and 2.17 (1.12-4.20) in Model 2 and 2.2 (1.15-4.20) and 2.16 (1.11-4.19) in Model 3. CONCLUSIONS: General adiposity defined by body mass index is associated with peptic ulcer disease in women.

Identification of immunophenotypes in esophageal squamous cell carcinoma based on immune gene sets

PurposeEsophageal squamous cell carcinoma (ESCC) is a malignant tumor with high heterogeneity. Research on molecular mechanisms involved in the process of tumor origination and progression is extremely limited to investigating mechanisms of molecular typing for ESCC.MethodsAfter comprehensively analyzing the gene expression profiles in The Cancer Genome Atlas and Gene Expression Omnibus databases, we identified four immunotypes of ESCC (referred to as C1–C4) based on the gene sets of 28 immune cell subpopulations. The discrepancies in prognostic value, clinical features, drug sensitivity, and tumor components between the immunotypes were individually analyzed.ResultsThe ranking of immune infiltration is C1 > C4 > C3 > C2. These subtypes are characterized by high and low expression of immune checkpoint proteins, enrichment and insufficiency of immune-related pathways, and differential distribution of immune cell subgroups. Poorer survival was observed in the C1 subtype, which we hypothesized could be caused by an immunosuppressive cell population. Fortunately, C1’s susceptibility to anti-PD-1 therapy offers hope for patients with poor prognosis in advanced stages. On the other hand, C4 is sensitive to docetaxel, which may offer novel treatment strategies for ESCC in the future. It is worth noting that immunophenotyping is tightly bound to the abundance of stromal components and stem cells, which could explain the tumor immune escape to some extent. Ultimately, determination of hub genes based on the C1 subtypes provides a reference for the discovery of immunotarget drugs against ESCC.ConclusionThe identification of immunophenotypes in our study provides new therapeutic strategies for patients with ESCC.