Emerging trends in early-onset gastric cancer.

ABSTRACT: The incidence of early-onset gastric cancer (EOGC) is consistently increasing, and its etiology is notably complex. This increase may be attributed to distinctive factors that differ from those associated with late-onset gastric cancer (LOGC), including genetic predispositions, dietary factors, gastric microbiota dysbiosis, and screening of high-risk cases. These factors collectively contribute to the onset of cancer. EOGC significantly differs from LOGC in terms of clinicopathological and molecular characteristics. Moreover, multiple differences in prognosis and clinical management also exist. This study aimed to systematically review the latest research advancements in the epidemiological characteristics, etiological factors, clinicopathological and molecular features, prognosis, and treatment modalities of EOGC.

Prevalence of Polypharmacy in Elderly Population Worldwide: A Systematic Review and Meta-Analysis.

BACKGROUND: Polypharmacy (PP) is common in elderly population and associated with some adverse clinical outcomes and increases healthcare burdens. We performed this systemic review and meta-analysis to estimate worldwide prevalence of PP and explore associated factors in the elderly. METHODS: The PubMed, Web of Science, Cochrane Library, and Ovid EMBASE databases were searched for studies published until May 30, 2022. We included observational studies representative of general patients aged ≥60 in which PP was defined as multiple drugs ≥5. Studies were excluded if only a particular group of the elderly population (e.g., with diabetes) were included. The primary outcome was the prevalence of PP. Random-effect models were employed to estimate the overall or variable-specific pooled estimates of PP. Secondary outcomes were hyperpolypharmacy (HPP, defined as multiple drugs ≥10) and PP prevalence based on different study years, genders, locations, populations, and so forth. RESULTS: We included 122 original observational studies with an overall population of 57 328 043 individuals in the meta-analysis. The overall prevalence of PP and HPP in the elderly population worldwide was 39.1% (95% confidence interval [CI], 35.5%-42.7%) and 13.3% (95% CI, 10.4%-16.5%), respectively. The prevalence of PP in Europe, Oceania, North America, Asia, and South America was 45.8% (95% CI, 41.5%-50.2%), 45.5% (95% CI, 26.7%-64.3%), 40.8% (95% CI, 29.8%-51.6%), 29.0% (95% CI, 20.0%-38.0%), and 28.4% (95% CI, 24.0%-32.8%), respectively (p < 0.01). Multivariate meta-regressions showed geographical regions of Europe or North America, age ≥70, and residence from nursing homes were independently associated with higher PP prevalence. CONCLUSIONS: Nearly 40% of the elderly population is exposed to PP. The prevalence of PP is significantly higher in elderly individuals aged 70 or older, in developed regions and in nursing homes. It is important to focus on avoiding inappropriate PP in this population to address the growing burden of PP.

Identifying the optimal measurement timing and hemodynamic targets of portal pressure gradient after TIPS in patients with cirrhosis and variceal bleeding: a prospective cohort study.

BACKGROUND & AIMS: The optimal timing of measurement and hemodynamic targets of portacaval pressure gradient (PPG) after TIPS remains inconclusive. This study aimed to identify the ideal moment of hemodynamic measurements and the optimal target of PPG in patients undergoing covered TIPS for variceal bleeding. METHODS: Between May 2018 and December 2021, 466 consecutive patients with recurrent variceal bleeding treated with covered TIPS were prospectively included. Post-TIPS PPG were measured immediately (immediate PPG), 24-72 hours (early PPG), and again 1 month (late PPG) after TIPS placement. The agreement among PPGs measured at different time points was assessed by intra-class correlation coefficient (ICC) and Bland-Altman method. The unadjusted and confounder-adjusted effects of PPGs on the clinical outcomes (portal hypertension complications [PHC], overt hepatic encephalopathy [OHE], further decompensation, and death) were assessed using Fine and Gray competing risk regression models. RESULTS: The agreement between early PPG and late PPG (ICC: 0.34) was better than that between immediate PPG and late PPG (ICC: 0.23, p<0.001). Early PPG revealed an excellent predictive value for PHC risk (early PPG ≥ vs <12 mmHg: adjusted HR [95%CI]: 2.17 [1.33-3.55], p=0.002) as well as OHE (0.40 [0.17-0.91], p=0.030) while immediate PPG did not. Late PPG showed a predictive value for PHC risk but not OHE. By targeting the lowest risk of further decompensation, we identified an optimal hemodynamic target with early PPG ranging 11 to 14 mmHg that was associated with a decreased risk of OHE while effectively preventing PHC. CONCLUSIONS: PPG measured 24 to 72 hours after TIPS correlates with long term PPG and clinical outcomes, and hemodynamic target with a PPG 11-14 mmHg reduced encephalopathy but not compromised clinical efficacy. IMPACT AND IMPLICATIONS: The optimal timing of measurement and hemodynamic targets of portacaval pressure gradient (PPG) after transjugular intrahepatic portosystemic shunt (TIPS) remains inconclusive. Here we show that post-TIPS PPG measured at least 24 hours but not immediately after the procedure correlated with long-term PPG and clinical events, therefore should be used for decision making in order to improve clinical outcomes. Targeting post-TIPS PPG at 11-14 mmHg or 20%-50% relative reduction from pre-TIPS baseline that measured 24-72 hours after procedure reduced encephalopathy but not compromised clinical efficacy, therefore could be used to guide TIPS creation and revision in patients with cirrhosis and variceal bleeding undergoing covered TIPS. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, ID: NCT03590288.

SOX12 Facilitates Hepatocellular Carcinoma Progression and Metastasis through Promoting Regulatory T-Cells Infiltration and Immunosuppression.

Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T-cell (Treg) infiltration, decreases CD8+T-cell infiltration, and hastens HCC metastasis. Hepatocyte-specific SOX12 knockout attenuates DEN/CCl4-induced HCC progression and metastasis, whereas hepatocyte-specific SOX12 knock-in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C-C motif chemokine ligand 22 (CCL22) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8+T-cell infiltration. Either knockdown of CCL22 or PD-L1 dampens SOX12-mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C-021 or Treg-specific knockout of CCR4 inhibits SOX12-mediated HCC metastasis. Transforming growth factor-ß1 (TGF-ß1)/TGFßR1-Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C-021 or TGFßR1 inhibitor galunisertib with anti-PD-L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4-Treg and PD-L1-CD8+T axes. Blocking of CCR4 or TGFßR1 improves the efficacy of anti-PD-L1 in SOX12-mediated HCC.

O-GlcNAc signaling: Implications for stress-induced adaptive response pathway in the tumor microenvironment.

The tumor microenvironment (TME) consists of tumor cells, non-tumor cells, extracellular matrix, and signaling molecules, which can contribute to tumor initiation, progression, and therapy resistance. In response to starvation, hypoxia, and drug treatments, tumor cells undergo a variety of deleterious endogenous stresses, such as hypoxia, DNA damage, and oxidative stress. In this context, to survive the difficult situation, tumor cells evolve multiple conserved adaptive responses, including metabolic reprogramming, DNA damage checkpoints, homologous recombination, up-regulated antioxidant pathways, and activated unfolded protein responses. In the last decades, the protein O-GlcNAcylation has emerged as a crucial causative link between glucose metabolism and tumor progression. Here, we discuss the relevant pathways that regulate the above responses. These pathways are adaptive adjustments induced by endogenous stresses in cells. In addition, we systematically discuss the role of O-GlcNAcylation-regulated stress-induced adaptive response pathways (SARPs) in TME remodeling, tumor progression, and treatment resistance. We also emphasize targeting O-GlcNAcylation through compounds that modulate OGT or OGA activity to inhibit tumor progression. It seems that targeting O-GlcNAcylated proteins to intervene in TME may be a novel approach to improve tumor prognosis.

Causal relationships between psychological disorders and functional gastrointestinal disorders: a bidirectional two-sample Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have shown bidirectional associations between psychological disorders (e.g. depression and anxiety) and functional gastrointestinal disorders. However, whether the relationships are causal is uncertain. Here, we used a bidirectional two-sample Mendelian randomization method to investigate the association between psychological disorders and functional gastrointestinal disorders (FGIDs). METHODS: We obtained genome-wide association study summary statistics for two common psychological disorders: depression (170 756 cases) and anxiety (31 977 cases), as well as for three common FGIDs: functional dyspepsia with 6666 cases, constipation with 26 919 cases, and irritable bowel syndrome (IBS) with 7053 cases. These summary statistics were retrieved from several publicly available genome-wide association study databases. The inverse variance weighted method was used as the main Mendelian randomization method. RESULTS: Inverse variance weighted Mendelian randomization analyses showed statistically significant associations between genetically predicted depression and risk of functional dyspepsia [odds ratio (OR): 1.40, 95% confidence interval (CI): 1.08-1.82], constipation (OR: 1.28, 95% CI: 1.13-1.44), and IBS (OR: 1.51, 95% CI: 1.37-1.67). Genetically predicted anxiety was associated with a higher risk of IBS (OR: 1.13, 95% CI: 1.10-1.17) instead of functional dyspepsia and constipation. In addition, genetically predicted IBS instead of functional dyspepsia and constipation was associated with a higher risk of depression (OR: 1.33, 95% CI: 1.12-1.57) and anxiety (OR: 2.05, 95% CI: 1.05-4.03). CONCLUSION: Depression is a causal risk factor for three common FGIDs. A bidirectional causal relationship between IBS and anxiety or depression was also identified.

Postoperative Spindle Cell Nodule Mimicking Metastatic Lesion With Persistently Increasing 68Ga-FAPI-04 Uptake After Receiving Personalized Antigen Peptide Tumor Vaccine.

ABSTRACT: A 59-year-old woman underwent radical surgery and chemotherapy for gastric adenocarcinoma. After the personalized antigen peptide tumor vaccine, a new nodular lesion, in the upper abdomen, was discovered during 68Ga-FAPI-04 PET/MRI follow-up. To determine possible pseudoprogression, 68Ga-FAPI-04 PET/MRI was repeated 39 days later, referring to immune PET response criteria in solid tumors. The lesion showed increased 68Ga-FAPI-04 uptake, whereas uptake in vaccine injection sites decreased, and was ultimately diagnosed as a postoperative spindle cell nodule.

Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.

miR-107 reverses the multidrug resistance of gastric cancer by targeting the CGA/EGFR/GATA2 positive feedback circuit.

Chemotherapy is still the main therapeutic strategy for gastric cancer (GC). However, most patients eventually acquire multidrug resistance (MDR). Hyperactivation of the EGFR signaling pathway contributes to MDR by promoting cancer cell proliferation and inhibiting apoptosis. We previously identified the secreted protein CGA as a novel ligand of EGFR and revealed a CGA/EGFR/GATA2 positive feedback circuit that confers MDR in GC. Herein, we outline a microRNA-based treatment approach for MDR reversal that targets both CGA and GATA2. We observed increased expression of CGA and GATA2 and increased activation of EGFR in GC samples. Bioinformatic analysis revealed that miR-107 could simultaneously target CGA and GATA2, and the low expression of miR-107 was correlated with poor prognosis in GC patients. The direct interactions between miR-107 and CGA or GATA2 were validated by luciferase reporter assays and Western blot analysis. Overexpression of miR-107 in MDR GC cells increased their susceptibility to chemotherapeutic agents, including fluorouracil, adriamycin, and vincristine, in vitro. Notably, intratumor injection of the miR-107 prodrug enhanced MDR xenograft sensitivity to chemotherapies in vivo. Molecularly, targeting CGA and GATA2 with miR-107 inhibited EGFR downstream signaling, as evidenced by the reduced phosphorylation of ERK and AKT. These results suggest that miR-107 may contribute to the development of a promising therapeutic approach for the treatment of MDR in GC.

Rapid, Efficient, and Universally Applicable Genetic Engineering of Intestinal Organoid with a Sequential Monolayer to Three-Dimensional Strategy.

Genetically modified intestinal organoids are being explored as potential surrogates of immortalized cell lines and gene-engineered animals. However, genetic manipulation of intestinal organoids is time-consuming, and the efficiency is far beyond satisfactory. To ensure the yield of the genetically modified organoids, large quantity of starting materials is required, and the procedure usually takes more than 10 days. Two major obstacles that restrict the genetic delivery efficiency are the three-dimensional culture condition and that the genetic delivery is carried out in cell suspensions. In the present study, we introduce a novel highly efficient strategy for building genetically modified intestinal organoids in which genetic delivery was performed in freshly established monolayer primary intestinal epithelial cells under two-dimensional conditions and subsequentially transformed into three-dimensional organoids. The total procedure can be finished within 10 hr while displaying much higher efficiency than the traditional methods. Furthermore, this strategy allowed for the selection of transgenic cells in monolayer conditions before establishing high-purity genetically modified intestinal organoids.

Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

Development and validation of serological dynamic risk score to predict outcome in gastric cancer with adjuvant chemotherapy: a multicentre, longitudinal, cohort study.

Background: Baseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests. Materials and methods: This was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters. Results: The Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63). Conclusion: The dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy.

TGF-ß1-Induced SOX18 Elevation Promotes Hepatocellular Carcinoma Progression and Metastasis Through Transcriptionally Upregulating PD-L1 and CXCL12.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is characterized by an immune-suppressive microenvironment, which contributes to tumor progression, metastasis, and immunotherapy resistance. Identification of HCC-intrinsic factors regulating the immunosuppressive microenvironment is urgently needed. Here, we aimed to elucidate the role of SYR-Related High-Mobility Group Box 18 (SOX18) in inducing immunosuppression and to validate novel combination strategies for SOX18-mediated HCC progression and metastasis. METHODS: The role of SOX18 in HCC was investigated in orthotopic allografts and diethylinitrosamine/carbon tetrachloride-induced spontaneous models by using murine cell lines, adeno-associated virus 8, and hepatocyte-specific knockin and knockout mice. The immune cellular composition in the HCC microenvironment was evaluated by flow cytometry and immunofluorescence. RESULTS: SOX18 overexpression promoted the infiltration of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) while diminishing cytotoxic T cells to facilitate HCC progression and metastasis in cell-derived allografts and chemically induced HCC models. Mechanistically, transforming growth factor-beta 1 (TGF-ß1) upregulated SOX18 expression by activating the Smad2/3 complex. SOX18 transactivated chemokine (C-X-C motif) ligand 12 (CXCL12) and programmed death ligand 1 (PD-L1) to induce the immunosuppressive microenvironment. CXCL12 knockdown significantly attenuated SOX18-induced TAMs and Tregs accumulation and HCC dissemination. Antagonism of chemokine receptor 4 (CXCR4), the cognate receptor of CXCL12, or selective knockout of CXCR4 in TAMs or Tregs likewise abolished SOX18-mediated effects. TGFßR1 inhibitor Vactosertib or CXCR4 inhibitor AMD3100 in combination with anti-PD-L1 dramatically inhibited SOX18-mediated HCC progression and metastasis. CONCLUSIONS: SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in the microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFßR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis.

Association of survival with adjuvant chemotherapy in patients with stage IB gastric cancer: a multicentre, observational, cohort study.

Background: Recurrence following radical resection in patients with stage IB gastric cancer (GC) is not uncommon. However, whether postoperative adjuvant chemotherapy could reduce the risk of recurrence in stage IB GC remains contentious. Methods: We collected data on 2110 consecutive patients with pathologic stage IB (T1N1M0 or T2N0M0) GC who were admitted to 8 hospitals in China from 2009 to 2018. The survival of patients who received adjuvant chemotherapy was compared with that of postoperative observation patients using propensity score matching (PSM). Two survival prediction models were constructed to estimate the predicted net survival gain attributable to adjuvant chemotherapy. Findings: Of the 2110 patients, 1344 received adjuvant chemotherapy and 766 received postoperative observation. Following the 1-to-1 matching, PSM yielded 637 matched pairs. Among matched pairs, adjuvant chemotherapy was not associated with improved survival compared with postoperative observation (OS: hazard ratio [HR], 0.72; 95% CI, 0.52-1.00; DFS: HR, 0.91; 95% CI, 0.64-1.29). Interestingly, in the subgroup analysis, reduced mortality after adjuvant chemotherapy was observed in the subgroups with elevated serum CA19-9 (HR, 0.22; 95% CI, 0.08-0.57; P = 0.001 for multiplicative interaction), positive lymphovascular invasion (HR, 0.32; 95% CI, 0.17-0.62; P < 0.001 for multiplicative interaction), or positive lymph nodes (HR, 0.17; 95% CI, 0.07-0.38; P < 0.001 for multiplicative interaction). The survival prediction models mainly based on variables associated with chemotherapy benefits in the subgroup analysis demonstrated good calibration and discrimination, with relatively high C-indexes. The C-indexes for OS were 0.74 for patients treated with adjuvant chemotherapy and 0.70 for patients treated with postoperative observation. Two nomograms were built from the models that can calculate individualized estimates of expected net survival gain attributable to adjuvant chemotherapy. Interpretation: In this cohort study, pathologic stage IB alone was not associated with survival benefits from adjuvant chemotherapy compared with postoperative observation in patients with early-stage GC. High-risk clinicopathologic features should be considered simultaneously when evaluating patients with stage IB GC for adjuvant chemotherapy. Funding: National Natural Science Foundation of China; the National Key R&D Program of China.

EGLN3 attenuates gastric cancer cell malignant characteristics by inhibiting JMJD8/NF-κB signalling activation independent of hydroxylase activity.

BACKGROUND: The expression of Egl-9 family hypoxia-inducible factor 3 (EGLN3) is notably decreased in various malignancies, including gastric cancer (GC). While the predominant focus has been on the hydroxylase activity of EGLN3 for its antitumour effects, recent findings have suggested nonenzymatic roles for EGLN3. METHODS: This study assessed the clinical significance of EGLN3 expression in GC and explored the connection between EGLN3 DNA promoter methylation and transcriptional silencing. To investigate the effect of EGLN3 on GC cells, a gain-of-function strategy was adopted. RNA sequencing was conducted to identify the key effector molecules and signalling pathways associated with EGLN3. RESULTS: EGLN3 expression was significantly reduced in GC tissues, correlating with poorer patient prognosis. EGLN3 hypermethylation disrupts transcriptional equilibrium, contributing to deeper tumour invasion and lymph node metastasis, thus exacerbating GC progression. Conversely, restoration of EGLN3 expression in GC cells substantially inhibited cell proliferation and metastasis. EGLN3 was also found to impede the malignant progression of GC cells by downregulating Jumonji C domain-containing protein 8-mediated activation of the NF-κB pathway, independent of its hydroxylase activity. CONCLUSIONS: EGLN3 has the potential to hinder the spread of GC cells through a nonenzymatic mechanism, thereby shedding light on the complex nature of GC progression.

Radiation injury and gut microbiota-based treatment.

The exposure to either medical sources or accidental radiation can cause varying degrees of radiation injury (RI). RI is a common disease involving multiple human body parts and organs, yet effective treatments are currently limited. Accumulating evidence suggests gut microbiota are closely associated with the development and prevention of various RI. This article summarizes 10 common types of RI and their possible mechanisms. It also highlights the changes and potential microbiota-based treatments for RI, including probiotics, metabolites, and microbiota transplantation. Additionally, a 5P-Framework is proposed to provide a comprehensive strategy for managing RI.