We investigated the incidence rates of hepatocellular carcinoma (HCC) in metabolic dysfunction-associated steatotic liver disease (MASLD) categories, focusing on its association with alcohol consumption in patients with type 2 diabetes mellitus (T2DM).

This study included 2,418,858 patients with T2DM aged 20 years and older who underwent a health examination between 2009 and 2012. Participants were categorized into five groups according to hepatic steatosis, cardiometabolic risk factors, other liver diseases, and alcohol consumption. Hepatic steatosis was defined as the fatty liver index ≥30. Cox regression analysis was used to analyze the association between steatotic liver disease and development of HCC.

The MASLD group showed a higher risk of HCC development regardless of alcohol consumption or presence of other liver diseases (adjusted hazard ratio [aHR], 1.38; 95% confidence interval [CI], 1.33 to 1.44). The MASLD with other combined group expressed the highest risk (aHR, 5.02; 95% CI, 4.79 to 5.27). In the metabolic dysfunction and alcohol-related steatotic liver disease and alcohol-related liver disease groups, heavy to excessive alcohol consumption increased the risk of HCC development, with a higher risk associated with greater alcohol intake (aHR, 2.40; 95% CI, 2.27 to 2.53 and aHR, 3.16; 95% CI, 2.93 to 3.41). Fine and Gray analysis also exhibited a consistent trend.

MASLD in patients with T2DM was associated with an increased risk of developing HCC, particularly when accompanied by other liver diseases. Moreover, alcohol consumption proportionally increased the risk of HCC with the amount of alcohol consumed.

Preclinical studies have reported anticancer properties of sodium-glucose cotransporter 2 inhibitors (SGLT2is). We aimed to elucidate the association between the use of SGLT2is and the risk of prostate cancer among male patients with type 2 diabetes mellitus (T2DM).

An active-comparator, new-user cohort design using a nationwide database between September 2014 and June 2020 was conducted on 45,601 new SGLT2i users and 205,395 new users of other glucose-lowering medications (oGLMs). In the following 1:1 propensity score matched (PSM) analysis, 35,371 SGLT2i users matched with an equivalent number of oGLM users were assessed. The hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer were calculated.

Among the cohort, prostate cancer was diagnosed in 210 out of 45,601 SGLT2i users, corresponding to a cumulative incidence of 1.0%, in contrast to 1,880 cases among 205,395 users of oGLMs, with a cumulative incidence of 1.5%. The use of SGLT2is was significantly correlated with a reduced risk of prostate cancer based on a multivariable-adjusted HR of 0.83 (95% CI, 0.71 to 0.98). PSM analysis affirmed 18% reduction in prostate cancer risk associated with SGLT2i use (HR, 0.82; 95% CI, 0.67 to 0.99). Subgroup analyses revealed that body mass index (BMI) significantly influenced the effect of SGLT2i on prostate cancer risk, with a more pronounced reduction in the subgroup with a BMI <25 kg/m2 (P=0.037).

The use of SGLT2is in Korean male patients with T2DM is associated with a lower risk of prostate cancer.

There is a lack of reliable in vivo models that replicate limb-threatening ischemia in humans. To fill this gap, we developed and validated two novel porcine ischemic models: ischemic limb and dorsal flap models, both with and without streptozotocin-induced hyperglycemia (N = 3 per group, 12 in total). Hind limb ischemia model was induced via different arterial ligations, with two ischemic and three control wounds per animal. In the flap model, four full-thickness flaps were created on the dorsum with silicone sheets to block reperfusion, and excisional wounds were made on the top. One non-ischemic wound served as control. Transcutaneous oxygen pressure (TcPO₂), wound area, and microvascular density were measured, with TcPO₂ and wound area assessed longitudinally. Data analysis focused on detailed visualization and Bayesian hierarchical modelling to account for the small sample size. Developed models exhibited stable ischemia and prolonged wound healing, with TcPO₂ remaining under 30 mmHg over 28 days, and wound healing extending beyond two weeks. The flap model showed slower TcPO₂ recovery and greater chronicity compared to the limb model, without reliable effect of hyperglycemia. Thus, the porcine flap model shows the highest potential as a relevant model for chronic limb-threatening ischemia.

Chronic neuroinflammation is a pivotal pathogenesis in neurodegenerative diseases (NDDs). Transient receptor potential canonical protein 6 (TRPC6) has an essential role in the maintenance of calcium homeostasis in cells. Our previous study indicated that TRPC6 signaling is involved in Aβ deposition and NLRP1 inflammasome activation in type 2 diabetes mellitus-associated cognitive dysfunction. However, whether TRPC6 signaling contributes to chronic lipopolysaccharide (LPS)-induced neuroinflammatory injury and the mechanism remain unclear.

In this study, male mice received intraperitoneal injections of LPS (200 µg/kg) for 21 days to induce a chronic neuroinflammation model. The open field test, hole-board test, and Morris water maze were conducted to evaluate cognitive function. The H&E and Nissl staining was employed to examine neuronal injury. The immunofluorescence, western blotting, or q-PCR were used to analyze TRPC6, AIM2 inflammasome expression, and Nrf2 activation. The fluorescent probes and calcium imaging were performed to assess ROS accumulation and calcium dysregulation in LPS-induced HT22 neuron cells.

Chronic LPS exposure induced behavioral deficits in locomotion, exploratory behavior, and learning and memory, and neuronal damages with less expressions of PSD95 and Synaptophysin in mice. Mechanistically, LPS exposure significantly increased ROS production, TRPC6 expression and calcium overload, and induced AIM2 inflammasome activation in vivo or in vitro. While Trpc6 knockout could significantly improve LPS-induced cognitive dysfunction and neuronal injuries, inhibit TRPC6-mediated calcium overload, and downregulate the expressions of AIM2, caspase-1, IL-1β, IL-6, caspase-3 and Bax in vivo or in vitro. Additionally, Rg1 treatment significantly inhibited calcium overload and AIM2 inflammasome activation in LPS-induced HT22 cells. More importantly, Rg1 significantly activated Nrf2 signaling and reduced ROS production in LPS-induced mice or HT22 cells.

Trpc6 knockout can improve chronic LPS-induced neuroinflammation and injury by inhibiting TRPC6-AIM2 inflammasomes. While Rg1 treatment can alleviate LPS-induced neuroinflammation and injury not only by inhibiting TRPC6-AIM2 inflammasomes activation but also activating Nrf2 signaling.

This study aimed to evaluate the potential associations between asprosin, Macrophage inhibitory cytokine-1 (MIC-1), and metabolic parameters related to appetite regulation in elderly individuals with and without type 2 diabetes mellitus (T2DM).

Eighty-six elderly patients (44 with T2DM, 42 non-diabetics) were evaluated. Appetite was assessed using the Three-Factor Eating Questionnaire (TFEQ), and serum levels of asprosin and (MIC-1) were measured using ELISA.

Asprosin and MIC-1 levels were significantly lower in T2DM patients (p = 0.032 and p < 0.001, respectively; compared to non-diabetics. In the diabetic group, uncontrolled eating was positively associated with waist circumference and ferritin levels, while emotional eating showed a positive correlation with systolic blood pressure and an inverse correlation with vitamin D levels, based on multivariate regression analysis. Among non-diabetics, triglyceride levels were negatively associated with emotional eating (p = 0.019). No statistically significant associations were found between appetite scores and serum levels of asprosin or MIC-1.

Metabolic and circulatory factors, including waist circumference, serum ferritin, vitamin D [25(OH)D], triglycerides, and systolic blood pressure, appear to influence appetite regulation in elderly individuals. Despite reduced levels of asprosin and MIC-1 in T2DM patients, their independent roles in appetite regulation were not evident. Further studies to clarify these relationships.

The causal relationships between attention-deficit/hyperactive disorder (ADHD) and vascular risk factors remain insufficiently understood. This study aimed to comprehensively investigate the causal effects of ADHD on vascular risk factors and identify crucial mediators in these relationships. Utilizing instrumental variables from genome-wide association study (GWAS) datasets, we applied two-sample Mendelian randomization (MR) to explore the causal influences of ADHD on adiposity-related traits, blood pressure regulation, glucose metabolism, lipid profiles, lifestyle habits, chronic kidney disease, and systemic inflammation. Additionally, two-step MR was employed to evaluate the mediating effect of educational attainment (EA) in each newly established causal pair. Genetically determined ADHD was causally linked to increased body mass index (BMI, β = 0.054, p = 1.01E-08), waist-to-hip ratio (WHR, β = 0.041, p = 1.65E-07), waist circumference (WC, β = 0.048, p = 5.78E-15), body fat percentage (BF%, β = 0.024, p = 7.19E-05), risk of type-2 diabetes mellitus (T2DM, OR = 1.104, p = 6.07E-07), and number of cigarettes smoked per day (β = 0.094, p = 3.99E-06), earlier smoking initiation (β = 0.115, p = 2.71E-12), and higher levels of C-reactive protein (CRP, β = 0.054, p = 6.35E-14). Furthermore, EA was demonstrated to play a key mediating role in these causal relationships, with mediation proportions ranging from 41.67% to 11.30%. Our MR analyses supported the causal impacts of ADHD on several vascular risk factors, including BMI, WHR, WC, BF%, T2DM, early smoking initiation, cigarettes consumed per day, and CRP. Moreover, we recognized EA as a critical mediator underlying the established causal pathways. Overall, this study highlighted that individuals with ADHD were more likely to suffer from obesity, T2DM, poor lifestyle habits, and intense inflammation.

This study aims to assess the predictive capability of PSMA-PET imaging for disease outcomes in primary prostate cancer post-radical prostatectomy. In addition to conventional lesion uptake measures, the evaluation includes the distance of lesion to the prostate to enhance risk stratification and outcome prediction.

A cohort of 190 men diagnosed with primary prostate cancer and undergoing prostatectomy were initially screened, resulting in 103 patients meeting the selection criteria. Imaging parameters, including lesion SUVmax, primary metabolic tumor volume (PMTV), maximum distance from the lesion to the prostate (Dmax), and total distances from the lesion to the prostate (Dtotal), were extracted from 68Ga-PSMA-11 PET images. Findings were dichotomized based on primary lesion uptake, the tumor volume size, Dmax distance, and the presence of metastatic disease. Postoperative biochemical recurrence-free survival (BCRFS) was analyzed using Kaplan-Meier survival plots and Log-rank tests. Furthermore, univariate and multivariate Cox regression analyses were performed to evaluate the association of PET parameters with survival outcomes.

Clinical and histopathological characteristics were summarized, including age, weight, height, metastasis status, baseline PSA, biopsy Gleason score, pt stage, margin status, and lymph node status. After a median follow-up of 20 months, 66 events occurred, with the estimated 3-year BCRFS being 46%. Increased PSMA intensity (SUVmax > 17.06) was associated with less favorable BCRFS (log-rank p = 0.017). Increased primary metabolic tumor volume (PMTV > 41.59 cm³) was also linked to less favorable BCRFS (log-rank p = 0.003). Dmax and Dtotal greater than 9.69 cm and 11.95 cm were identified as negative prognostic factors for BCRFS (log-rank p < 0.001 and p = 0.002, respectively). Based on PMTV and Dmax, patients were stratified into low-, intermediate-, and high-risk groups, with 3-year BCRFS rates of 57%, 31%, and 8%, respectively. Univariate Cox regression analysis revealed significant associations between BCRFS and factors such as baseline PSA (HR: 1.69, 95% CI 1.02-2.79, p = 0.042), SUVmax (HR: 1.56, 95% CI 1.04-1.91, p = 0.018), PMTV (HR: 2.05, 95% CI 1.26-3.34, p = 0.004), Dmax (HR: 2.24, 95% CI 1.37-3.65, p = 0.001), and Dtotal (HR: 2.11, 95% CI 1.29-3.45, p = 0.003). Multivariable Cox regression analysis identified the best model with PMTV (HR: 2.57, p = 0.004) and Dmax (HR: 1.98, p = 0.009) as independent predictors for biochemical recurrence (C-index = 0.68).

The lesion distance to prostate was defined and assessed in conjunction with conventional PET parameters to facilitate preoperative risk stratification in primary prostate cancer following radical prostatectomy. The findings contribute to improved outcome prediction and emphasize the potential of PSMA-PET imaging in enhancing management strategies for prostate cancer patients.

There is a critical need for non-invasive biomarkers that can predict treatment outcomes for patients with primary prostate cancer. Our study introduces the concept of using distance metrics, specifically the lesion distance to prostate in baseline PSMA-PET scans, to improve the prediction of biochemical recurrence following prostatectomy. These distance metrics consider the spatial distribution of lesions, offering a novel approach to assessing tumor spread and its implications for patient outcomes.

This study examines the dynamic changes between cultural worldview and self-esteem as distal defense mechanisms in cancer patients and explores the role of these mechanisms in the different psychological stages of cancer patients' resistance to death, thereby elucidating the unique responses of cancer patients to the salience of death.

Our sample comprises 113 cancer patients and 92 dental pain patients. We measured participants' levels of cultural worldview defenses, death thought accessibility (DTA), self-esteem, depression, and suicidal ideation in two studies.

In Study 1, increased levels of cultural worldview defenses coincided with increased levels of DTA. Initial avoidance and denial inhibited cultural worldview defenses in cancer patients, which were progressively strengthened in subsequent psychological stages of death. In Study 2, there were no significant differences in explicit self-esteem among cancer patients in different psychological stages of death; however, there were differences in tests of implicit self-esteem, with the lowest scores on the depression and suicidal ideation scales in the Acceptance of Death stage, the most pronounced suicidal ideation in the Bargaining stage, and the highest scores on depression in the Avoidance of Death stage.

The findings of the study indicate that cancer patients exhibited dynamic shifts in their cultural worldviews and self-esteem during the psychological phases of death. Interestingly, self-esteem may be a more effective defense mechanism than cultural worldview in this context.

Prognosis in advanced pancreatic ductal adenocarcinoma (aPDAC) is particularly poor, only few patients benefit from treatment, and there are few biomarkers. The PREDICT trial examined whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) in aPDAC patients but found no association. We hypothesized that the tumor immune microenvironment (TiME) could correlate with the outcome in this trial and assessed whether tissue features were reflected in peripheral blood.

PREDICT patients received 5-FU/LV plus nanoliposomal irinotecan as second-line treatment. We stratified patients by shortest vs. longest TTF2 and analyzed 20 treatment-naïve tumor tissues samples via transcriptomics and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from 82 patients collected prior to second-line therapy underwent flow cytometry and gene expression profiling. A machine learning pipeline integrated PBMC and clinical data to predict second-line outcome including external validation in 30 patients.

Long-TTF2 tumors exhibited an immune-active ("hot") TiME with cytotoxic CXCR3⁺CD8⁺-T-cell infiltration. PBMC analysis showed that these immune features were reflected in peripheral blood after one line of treatment. A novel 7-feature PBMC-based model ("TTF2Pred") accurately predicted TTF2 and overall survival, outperforming clinical or CA19-9 models and was confirmed in an external validation cohort. Long-TTF2 patients exhibited more circulating CXCR3⁺-T-cells and plasmacytoid dendritic cells. Short-TTF2 patients had more platelet-leukocyte aggregates.

An immune-active, treatment-naïve TiME predicts a better second-line outcome, and these characteristics imprinted into PBMCs obtained after one line of chemotherapy. We here first describe a minimally invasive, PBMC-based predictor of second-line outcome as a powerful prognostic tool for triaging patients.

ClinicalTrials.gov NCT03468335 (registered March 15, 2018).

The limited response rates of immune checkpoint inhibitors in biliary tract cancers (BTC) highlight the need for effective biomarkers to optimize patient selection.

Baseline tumor tissues from 125 patients with advanced BTC treated with first-line chemoimmunotherapy (chemoIO) were analyzed using targeted DNA sequencing and bulk RNA sequencing. In vitro and in vivo experiments were conducted to investigate the role of identified biomarkers in BTC.

Mutations in TP53, BRCA2, cytokine genes, and high tumor mutation burden were significantly associated with treatment response. In contrast, KRAS G12D and ARID1A mutations were linked to poorer survival outcomes. High expression levels of CXCL9 and CTLA4 expression were associated with improved treatment response, prolonged progression-free survival, and overall survival. Using these biomarkers, patients were categorized into three molecular subtypes, with Type I patients demonstrating the most favorable outcomes under chemoIO. Subsequent RNA analysis revealed that elevated CXCL9 expression was associated with increased immune checkpoint expression within the tumor and heightened immune activity in the tumor microenvironment. In the mouse orthotopic cholangiocarcinoma model, CXCL9 overexpression enhanced chemoIO efficacy. Immunohistochemistry and flow cytometry showed that CXCL9 promoted T-cell infiltration and activation. In vitro experiments using multiple BTC cell lines further demonstrated that CXCL9 was essential for maintaining T cell cytotoxicity. The immune-modulatory effects of CXCL9/CTLA4 and their predictive value for treatment efficacy were further validated in a multicenter BTC cohort.

This study identified several predictive biomarkers associated with the response and efficacy of chemoIO in advanced BTC, offering valuable insights into patient stratification and refining therapeutic strategies.