Review of pharmacogenetics of antiseizure medications: focusing on genetic variants of mechanistic targets.

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs.

Slow Mohs Micrographic Surgery and Reconstruction With Artificial Dermis for Atrophic Dermatofibrosarcoma Protuberans: A Case Report.

This case report describes the utility of artificial dermis in reconstruction for atrophic dermatofibrosarcoma protuberans (DFSP) after slow Mohs micrographic surgery (MMS). A 34-year-old man presented as a slowly growing nodule from an atrophic scar on his right chest for over 10 years. The pathology report confirmed the diagnosis of atrophic DFSP. Further magnetic resonance imaging (MRI) revealed a 9.3 cm x 6.5 cm cutaneous-subcutaneous lesion with close contact with the pectoralis major muscle. The patient underwent a slow MMS, and we utilized a rotational flap in combination with synthetic xenogeneic artificial dermis to reconstruct the final 13 cm x 12 cm defect.

The mediation role of allostatic load/chronic stress on the relationship between cancer survivorship and cardiovascular disease mortality.

Background: Cancer survivors face an elevated risk of cardiovascular disease (CVD) and cardiovascular disease mortality (CVDm) compared to the general population. Allostatic load (AL), a composite score reflecting cardiovascular, metabolic, and immune markers, assesses the cumulative impact of chronic stress and life events. Increased AL in cancer patients is linked to up to a 30 % higher CVD risk. We hypothesized that cancer diagnosis and therapy contribute to increased AL, mediating the association between cancer survivorship and CVDm. Methods: This retrospective cohort study analyzed National Health and Nutrition Examination Survey (NHANES) data linked with the National Death Index (NDI) from 1988 to 2019. Cancer survivorship (yes vs. no), AL, and CVDm were the exposure, mediator, and outcome variables, respectively. Mediation analyses adapted to survival outcomes were performed. Results: Among 14,416 participants, cancer survivors <65 years-old exhibited a 41 % higher associated CVDm risk. High AL mediated 5.4 %, 8.9 %, and 3.6 % of the effect for all adults, 18-64 years, and ≥65 years, respectively. Black patients <65 years-old had an 84 % higher associated CVDm risk, with AL mediating 9.2 %, 5.8 %, and 12.6 % for all adults, 18-64 years, and ≥65 years, respectively. White patients showed a 20 % higher associated CVDm risk, with AL mediating 4.4 %, 2.8 %, and 5.7 % for all adults, 18-64 years, and ≥65 years, respectively. Conclusions: Increased CVDm risk among cancer survivors, particularly in Black individuals, is associated with higher AL mediation. These disparities may stem from social determinants of health.

Intersection of Poverty and Rurality for Early-Onset Colorectal Cancer Survival.

This cross-sectional study examines poverty, rurality, and the intersection of persistent poverty and rurality on early-onset colorectal cancer survival among adults aged 18 to 49 years.

Cancer History and Social Support Impact Colorectal Cancer Screening Utilization by Race/Ethnicity.

This study examined the association between cancer history, social support, and up to date colorectal cancer (CRC) screening among four racial/ethnic groups. We conducted a cross-sectional analysis using data on respondents aged 45-75 years from the 2022 Behavioral Risk Factor Surveillance System. Our outcome of interest was CRC screening and exposures of interest were race/ethnicity, cancer history, and social support. Weighted multivariable logistic regression was performed. Among 73,869 adults, the CRC screening rate was 66.8% with the highest rate in non-Hispanic (NH) Whites (72.2%) and the lowest in Hispanics (52.6%). Screening rates were higher in adults with a cancer history (81.9%) and those having social support (69%). Hispanic adults with a cancer history had lower screening use (50.9% vs. 77.4% in no cancer history group; p-value <0.001). Regardless of race/ethnicity, adults without social support had lower screening utilization (p-value<0.05). In effect modification, NH White adults who reported no cancer history and lack of social support were 12% less likely to have CRC screening than those with social support but without cancer history (OR,0.88;95% CI, 0.79-0.98). Similar results were observed among Hispanic adults without a cancer history and social support, with 37% less likely to have CRC screening than those with social support but no cancer history (OR,0.63;95% CI, 0.42-0.93). NH White and Hispanic adults without a cancer history and limited social support were less likely to have CRC screening uptake. By implementing culturally tailored interventions that address social support needs, greater CRC screening compliance may be increased among these populations.

Metformin administration in prevention of colorectal polyps in type 2 diabetes mellitus patients.

BACKGROUND: Colorectal polyps are frequently observed in patients with type 2 diabetes mellitus (DM), posing a significant risk for colorectal cancer. Metformin, a widely prescribed biguanidine drug for type 2 DM, has been suggested to have potential chemoprophylactic effects against various cancers. AIM: To explore the correlation between colorectal polyps and metformin use in type 2 DM patients. METHODS: Type 2 DM patients were categorized into polyp and non-polyp groups. Following this, all patients were categorized into the type 2 DM-metformin, type 2 DM-non-metformin, and non-type 2 DM groups. Based on the baseline colonoscopy results, we performed pairwise comparisons of the incidence of colorectal polyps among the three groups. Additionally, we analyzed the relationship between colorectal polyps and the duration of metformin use and between the size and number of polyps and metformin use. Simultaneously, we focused on the specific pathological types of polyps and analyzed their relationship with metformin use. Finally, we compared the incidence of polyps between metformin and non-metformin groups according to the interval colonoscopy results. RESULTS: The rate of metformin use in patients with colorectal polyps was 0.502 times that of patients without colorectal polyps [odds ratio (OR) = 0.502, 95% confidence interval (CI): 0.365-0.689; P < 0.001]. The incidence of colorectal polyps did not differ significantly between the type 2 DM-metformin and non-type 2 DM groups (P > 0.05). Furthermore, the correlations between the duration of metformin use and the incidence of colorectal polyps and between the size and number of polyps and metformin use were not statistically significant (P > 0.05). Metformin use did not affect the incidence of colorectal polyps during interval colonoscopy (P > 0.05). CONCLUSION: Metformin use and colorectal polyp incidence in type 2 DM patients showed a negative correlation, independent of the hypoglycemic effect of metformin.

The role of a social determinants of health summary measure on the association between cancer history status and colorectal cancer screening utilization among screening eligible adults.

Objective: We sought to examine the influence of social needs on the relationship between cancer history and colorectal cancer (CRC) screening utilization among adults in the United States. Methods: We conducted a cross-sectional analysis using data from the 2022 Behavioral Risk Factor Surveillance System. Our outcome of interest was utilization of guideline-concordant CRC screening and exposures of interest were cancer history/levels of social needs. Multivariable logistic regression was performed to examine the association. Results: Among 74,743 eligible adults, a majority did not have a personal history of cancer (87.9 %), had at least one social need (58.4 %), and had undergone CRC screening (72.2 %). In multivariable analysis, a history of cancer was positively associated with use of CRC screening (OR = 1.59, 95 %CI, 1.35 - 1.87). Having at least one social need was associated with lower likelihood of being screened (one social need: OR = 0.85 95 %CI, 0.76 - 0.95; two + social needs: OR = 0.77, 95 % CI, 0.69 - 0.87). When exploring the effects of social needs, adults without a history of cancer who reported at least one need were 12-20 % less likely to be screened for CRC. Conclusions: A personal history of cancer was associated with greater utilization of CRC screening, whilst having at least one social need had lower screening use. Having social needs plays an important role in reducing screening uptake among adults without a history of cancer. Integrated care that considers both cancer history and social needs may have implications for improved adherence of CRC screening recommendations.

Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.

BACKGROUND: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown. METHODS AND RESULTS: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis. CONCLUSIONS: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.

Raddeanin A Protects the BRB Through Inhibiting Inflammation and Apoptosis in the Retina of Alzheimer's Disease.

Neuroinflammation and endothelial cell apoptosis are prominent features of blood-brain barrier (BBB) disruption, which have been described in Alzheimer's disease (AD) and can predict cognitive decline. Recent reports revealed vascular ß-amyloid (Aß) deposits, Muller cell degeneration and microglial dysfunction in the retina of AD patients. However, there has been no in-depth research on the roles of inflammation, retinal endothelial cell apoptosis, and blood-retinal barrier (BRB) damage in AD retinopathy. We found that Raddeanin A (RDA) could improve pathological and cognitive deficits in a mouse model of Alzheimer's disease by targeting ß-amyloidosis, However, the effects of RDA on AD retinal function require further study. To clarify whether RDA inhibits inflammation and apoptosis and thus improves BRB function in AD-related retinopathy. In vitro we used Aß-treated HRECs and MIO-M1 cells, and in vivo we used 3×Tg-AD mice to investigate the effect of RDA on BRB in AD-related retinopathy. We found that RDA could improve BRB function in AD-related retinopathy by inhibiting NLRP3-mediated inflammation and suppressing Wnt/ß-catenin pathway-mediated apoptosis, which is expected to improve the pathological changes in AD-related retinopathy and the quality of life of AD patients.

Comparison of Prompt Engineering and Fine-Tuning Strategies in Large Language Models in the Classification of Clinical Notes.

The emerging large language models (LLMs) are actively evaluated in various fields including healthcare. Most studies have focused on established benchmarks and standard parameters; however, the variation and impact of prompt engineering and fine-tuning strategies have not been fully explored. This study benchmarks GPT-3.5 Turbo, GPT-4, and Llama-7B against BERT models and medical fellows' annotations in identifying patients with metastatic cancer from discharge summaries. Results revealed that clear, concise prompts incorporating reasoning steps significantly enhanced performance. GPT-4 exhibited superior performance among all models. Notably, one-shot learning and fine-tuning provided no incremental benefit. The model's accuracy sustained even when keywords for metastatic cancer were removed or when half of the input tokens were randomly discarded. These findings underscore GPT-4's potential to substitute specialized models, such as PubMedBERT, through strategic prompt engineering, and suggest opportunities to improve open-source models, which are better suited to use in clinical settings.

Regulation of YAP and Wnt signaling by the endosomal protein MAMDC4.

Maintenance of the intestinal epithelium requires constant self-renewal and regeneration. Tight regulation of proliferation and differentiation of intestinal stem cells within the crypt region is critical to maintaining homeostasis. The transcriptional co-factors ß-catenin and YAP are required for proliferation during normal homeostasis as well as intestinal regeneration after injury: aberrant signaling activity results in over proliferation and tumorigenesis. Although both YAP and ß-catenin activity are controlled along canonical pathways, it is becoming increasingly clear that non-canonical regulation of these transcriptional regulators plays a role in fine tuning their activity. We have shown previously that MAMDC4 (Endotubin, AEGP), an integral membrane protein present in endosomes, regulates both YAP and ß-catenin activity in kidney epithelial cells and in the developing intestinal epithelium. Here we show that MAMDC4 interacts with members of the signalosome and mediates cross-talk between YAP and ß-catenin. Interestingly, this cross-talk occurs through a non-canonical pathway involving interactions between AMOT:YAP and AMOT:ß-catenin.

Establishment of acquired tracheoesophageal fistula using a modified magnetic compression technique in rabbits and its postmodeling evaluation.

BACKGROUND: Previous studies have validated the efficacy of both magnetic compression and surgical techniques in creating rabbit tracheoesophageal fistula (TEF) models. Magnetic compression achieves a 100% success rate but requires more time, while surgery, though less frequently successful, offers rapid model establishment and technical maturity in larger animal models. AIM: To determine the optimal approach for rabbit disease modeling and refine the process. METHODS: TEF models were created in 12 rabbits using both the modified magnetic compression technique and surgery. Comparisons of the time to model establishment, success rate, food and water intake, weight changes, activity levels, bronchoscopy findings, white blood cell counts, and biopsies were performed. In response to the failures encountered during modified magnetic compression modeling, we increased the sample size to 15 rabbit models and assessed the repeatability and stability of the models, comparing them with the original magnetic compression technique. RESULTS: The modified magnetic compression technique achieved a 66.7% success rate, whereas the success rate of the surgery technique was 33.3%. Surviving surgical rabbits might not meet subsequent experimental requirements due to TEF-related inflammation. In the modified magnetic compression group, one rabbit died, possibly due to magnet corrosion, and another died from tracheal magnet obstruction. Similar events occurred during the second round of modified magnetic compression modeling, with one rabbit possibly succumbing to aggravated lung infection. The operation time of the first round of modified magnetic compression was 3.2 ± 0.6 min, which was significantly reduced to 2.1 ± 0.4 min in the second round, compared to both the first round and that of the original technique. CONCLUSION: The modified magnetic compression technique exhibits lower stress responses, a simple procedure, a high success rate, and lower modeling costs, making it a more appropriate choice for constructing TEF models in rabbits.

Brain Network Characterization of Preterm Infants With Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) affects the microstructure of white matter in preterm infants, but its influence on the changes of the brain structural network has not been elaborated. This study aims to investigate the connectivity characteristics of the brain structural network of BPD by using diffusion tensor imaging. METHODS: Thirty-three infants with BPD and 26 infants without BPD were enrolled in this study. Brain structural networks were constructed utilizing automated anatomic labeling mapping by tracing the fibers between each pair of regions in individual space. We calculated network metrics such as global efficiency, local efficiency, clustering coefficients, characteristic path length, and small-worldness. Then we compared the network metrics of these infants with those of 57 healthy term infants of comparable postmenstrual age at magnetic resonance imaging scan. Finally, network-based statistics was used to analyze the differences in brain network connectivity between the groups with and without BPD. RESULTS: Preterm infants with BPD had higher local efficiency and clustering coefficient, lower global efficiency, and longer characteristic path length. Also, preterm infants with BPD had decreased strength of limbic connections mainly in four brain regions: the left lingual gyrus, the left calcarine fissure and surrounding cortex, the right parahippocampal gyrus, and the left precuneus. CONCLUSIONS: Our findings suggest that preterm infants with BPD have lower network integration and higher segregation at term-equivalent age, which may reflect a compensatory mechanism. In addition, BPD affects brain regions involved in visual as well as cognitive functions; these findings provide a new approach to diagnose potential brain damage in preterm infants with BPD.

Clinicopathological characteristics and prognosis of Epstein-Barr virus-associated gastric cancer.

OBJECTIVE: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS). METHODS: A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis. RESULTS: Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%. CONCLUSION: EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.

Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies.

Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8+ CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8+ T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8+ CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.

Investigating the role of county-level colorectal cancer screening rates on stage at diagnosis of colorectal cancer in rural Georgia.

BACKGROUND: To examine the impact of county-level colorectal cancer (CRC) screening rates on stage at diagnosis of CRC and identify factors associated with stage at diagnosis across different levels of screening rates in rural Georgia. METHODS: We performed a retrospective analysis utilizing data from 2004 to 2010 Surveillance, Epidemiology, and End Results Program. The 2013 United States Department of Agriculture rural-urban continuum codes were used to identify rural Georgia counties. The 2004-2010 National Cancer Institute small area estimates for screening behaviors were applied to link county-level CRC screening rates. Descriptive statistics and multinominal logistic regressions were performed. RESULTS: Among 4,839 CRC patients, most patients diagnosed with localized CRC lived in low screening areas; however, many diagnosed with regionalized and distant CRC lived in high screening areas (p-value = 0.009). In multivariable analysis, rural patients living in high screening areas were 1.2-fold more likely to be diagnosed at a regionalized and distant stage of CRC (both p-value < 0.05). When examining the factors associated with stage at presentation, Black patients who lived in low screening areas were 36% more likely to be diagnosed with distant diseases compared to White patients (95% CI, 1.08-1.71). Among those living in high screening areas, patients with right-sided CRC were 38% more likely to have regionalized disease (95% CI, 1.09-1.74). CONCLUSION: Patients living in high screening areas were more likely to have a later stage of CRC in rural Georgia. IMPACT: Allocating CRC screening/treatment resources and improving CRC risk awareness should be prioritized for rural patients in Georgia.

Construction of carbon sequestration ecological network in Linyi City based on supply and demand of ecosystem service.

The increasing carbon emissions is one of the important reasons for global warming. As a key area of carbon emissions, carbon sequestration capacity of cities is urgently needed to be improved. Carbon sequestration ser-vices can be transferred between supply and demand areas due to the circulation of atmosphere. With Linyi City as an example, we used the minimum cumulative resistance model to extract the matching path of supply and demand, and constructed a carbon sequestration ecological network. The results showed that the regions with high supply of carbon sequestration services were located in the north and south of the study area, and that current total supply could solve about 60% of the total demand. Although the spatial distribution of supply and demand was uneven, 54% of the areas that could meet the surrounding carbon sequestration demand were still idle. The optimized supply-demand matching paths could maintain good transmission efficiency of material and energy, with lower costs. Paths with strong potential carbon sequestration capacity were located in the central and northwest part of the research area. In the construction of carbon sequestration ecological network, it is necessary to strengthen the protection and restoration of the supply side of carbon sequestration services, realize carbon reduction and strengthen carbon sequestration on the demand side, and optimize the matching path of supply and demand. This method provided services to the demand areas through the oversupply of ecosystem services, optimized the overall resource allocation, which could advance regional carbon sequestration capacity.

Metabolomic Analysis Reveals the Association of Severe Bronchopulmonary Dysplasia with Gut Microbiota and Oxidative Response in Extremely Preterm Infants.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease mainly affecting premature infants needing ventilation or oxygen for respiratory distress. This study aimed to evaluate the molecular linkages for BPD in very and extremely preterm infants using a metabolomics-based approach. A case-control study of enrolling preterm infants born before 32 weeks gestational age (GA) was prospectively performed. These preterm infants were subsequently stratified into the following two groups for further analysis: no or mild BPD, and moderate or severe BPD based on the 2019 NICHD criteria. Urinary metabolomic profiling was performed using 1H-Nuclear magnetic resonance (NMR) spectroscopy coupled with partial least squares discriminant analysis (PLS-DA) at a corrected age of 6 months. Metabolites significantly differentially related to GA and BPD severity were performed between groups, and their roles in functional metabolic pathways were also assessed. A total of 89 preterm infants born before 32 weeks gestation and 50 infants born at term age (above 37 completed weeks' gestation) served as controls and were enrolled into the study. There were 21 and 24 urinary metabolites identified to be significantly associated with GA and BPD severity, respectively (p < 0.05). Among them, N-phenylacetylglycine, hippurate, acetylsalicylate, gluconate, and indoxyl sulfate were five metabolites that were significantly higher, with the highest importance in both infants with GA < 28 weeks and those with moderate to severe BPD, whereas betaine and N,N-dimethylglycine were significantly lower (p < 0.05). Furthermore, ribose and a gluconate related pentose phosphate pathway were strongly associated with these infants (p < 0.01). In conclusion, urinary metabolomic analysis highlights the crucial role of gut microbiota dysbiosis in the pathogenesis of BPD in preterm infants, accompanied by metabolites related to diminished antioxidative capacity, prompting an aggressive antioxidation response in extremely preterm infants with severe BPD.

Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3ß Signaling Pathway.

Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3ß (GSK3ß) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.

Colorectal cancer survival disparities in the five regions of Georgia.

BACKGROUND/OBJECTIVE: The objective of this study was to examine 5-year colorectal cancer survival rates. We also determined whether demographics, tumor characteristics, and treatment modality were associated with 5-year CRC survival in the Clayton, West Central, East Central, Southeast, and Northeast Georgia regions because the significant higher CRC mortality rates in these regions in comparison to the overall rates in the State of Georgia. METHODS: We conducted a retrospective cohort analysis using data from the 1975-2016 Surveillance, Epidemiology, and End Results program aggregated CRC patients to these five regions. Five-year CRC survival was calculated and stratified by the five regions of Georgia, using the Kaplan-Meier method with log-rank test. Cox proportional hazard regression was used to examine the mentioned association in these five regions. RESULTS: Among 11,023 CRC patients, 5-year CRC survival was lowest in Clayton (65.9%) compared to the West Central (69.0%), East Central (68.2%), Southeast (70.5%), and Northeast regions (69.5%) (p-value = 0.02). In multivariable analysis, greater risk of CRC death was found in the Clayton region compared to the West Central (HR, 1.12; 95%, 1.00-1.25) region when adjusting for demographics, tumor characteristics, and treatment modality. Among Clayton Georgians, age of 75+ years (HR, 2.13; 95%, 1.56-2.89), grade 3 & 4 tumors (HR, 2.22; 95%, 1.64-3.00), and distant stage (HR, 20.95; 95%, 15.99-27.45) were negatively associated with CRC survival. CONCLUSION: We observed place-based differences in CRC survival with significantly lower survival rates in the Clayton region. Factors associated with higher risk of CRC death include older age at diagnosis, high-grade tumors, and distant stage CRC among Clayton Georgians. Our study provides important evidence to all relevant stakeholders in furthering the development of culturally tailored CRC screening interventions aimed at CRC early detection and improved outcomes.