The Pathogenicity of Fusobacterium nucleatum Modulated by Dietary Fibers-A Possible Missing Link between the Dietary Composition and the Risk of Colorectal Cancer.

The dietary composition has been approved to be strongly associated with the risk of colorectal cancer (CRC), one of the most serious malignancies worldwide, through regulating the gut microbiota structure, thereby influencing the homeostasis of colonic epithelial cells by producing carcinogens, i.e., ammonia or antitumor metabolites, like butyrate. Though butyrate-producing Fusobacterium nucleatum has been considered a potential tumor driver associated with chemotherapy resistance and poor prognosis in CRC, it was more frequently identified in the gut microbiota of healthy individuals rather than CRC tumor tissues. First, within the concentration range tested, the fermentation broth of F. nucleatum exhibited no significant effects on Caco-2 and NCM460 cells viability except for a notable up-regulation of the expression of TLR4 (30.70%, p < 0.0001) and Myc (47.67%, p = 0.021) and genes encoding proinflammatory cytokines including IL1B (197.57%, p < 0.0001), IL6 (1704.51%, p < 0.0001), and IL8 (897.05%, p < 0.0001) in Caco-2 cells exclusively. Although no marked effects of polydextrose or fibersol-2 on the growth of F. nucleatum, Caco-2 and NCM460 cells were observed, once culture media supplemented with polydextrose or fibersol-2, the corresponding fermentation broths of F. nucleatum significantly inhibited the growth of Caco-2 cells up to 48.90% (p = 0.0003, 72 h, 10%) and 52.96% (p = 0.0002, 72 h, 10%), respectively in a dose-dependent manner. These two kinds of fibers considerably promoted butyrate production of F. nucleatum up to 205.67% (p < 0.0001, 6% polydextrose at 24 h) and 153.46% (p = 0.0002, 6% fibersol-2 at 12 h), which explained why and how the fermentation broths of F. nucleatum cultured with fibers suppressing the growth of Caco-2 cells. Above findings indicated that dietary fiber determined F. nucleatum to be a carcinogenic or antitumor bacterium, and F. nucleatum played an important role in the association between the dietary composition, primarily the content of dietary fibers, and the risk of CRC.

Prenatal predictors of need for cerebrospinal fluid diversion in infants following prenatal repair of open spina bifida; systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate prenatal predictors of the need for cerebrospinal fluid diversion in infants following prenatal repair of open spina bifida. DATA SOURCES: A systematic search was performed to identify relevant studies published from inception until June 2022 in the English language using the databases PubMed, Scopus, and Web of Science. STUDY ELIGIBILITY CRITERIA: We included retrospective and prospective cohort studies and randomized controlled trials reporting on prenatal repair of open spina bifida. METHODS: The random-effects model was used to pool the mean differences or odds ratios and the corresponding 95% confidence intervals. Heterogeneity was assessed using the I2 value. RESULTS: A total of 9 studies including 948 pregnancies undergoing prenatal repair of open spina bifida were included in the final analysis. Prenatal factors that were significantly associated with the need for postnatal cerebrospinal fluid diversion were gestational age at surgery ≥25 weeks (odds ratio, 4.2; 95% confidence interval, 1.8-9.9; I2=54%; P=.001), myeloschisis (odds ratio, 2.2; 95% confidence interval, 1.1-4.1; I2=0.0%; P=.02), preoperative lateral ventricle width ≥15 mm (odds ratio, 4.5; 95% confidence interval, 2.9-6.9; I2=0.0%; P<.0001), predelivery lateral ventricle width (mm) (mean difference, 8.3; 95% confidence interval, 6.4-10.2; I2=0.0%; P<.0001), and preoperative lesion level at T12-L2 (odds ratio, 2.5; 95% confidence interval, 1.03-6.3; I2=68%; P=.04). Factors that significantly reduced the need for postnatal shunt placement were gestational age at surgery <25 weeks (odds ratio, 0.3; 95% confidence interval, 0.15-0.6; I2=67%; P=.001) and preoperative lateral ventricle width <15 mm (odds ratio, 0.3; 95% confidence interval, 0.2-0.4; I2=0.0%; P<.0001). CONCLUSION: This study demonstrated that among fetuses that underwent surgical repair of open spina bifida, having gestational age at surgery of ≥25 weeks, preoperative lateral ventricle width of ≥15 mm, myeloschisis lesion type, and preoperative lesion level above L3 was predictive of the need for cerebrospinal fluid diversion during the first year of life.

Ranking Breast Cancer Drugs and Biomarkers Identification Using Machine Learning and Pharmacogenomics.

Breast cancer is one of the major causes of death in women worldwide. It is a diverse illness with substantial intersubject heterogeneity, even among individuals with the same type of tumor, and customized therapy has become increasingly important in this sector. Because of the clinical and physical variability of different kinds of breast cancers, multiple staging and classification systems have been developed. As a result, these tumors exhibit a wide range of gene expression and prognostic indicators. To date, no comprehensive investigation of model training procedures on information from numerous cell line screenings has been conducted together with radiation data. We used human breast cancer cell lines and drug sensitivity information from Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases to scan for potential drugs using cell line data. The results are further validated through three machine learning approaches: Elastic Net, LASSO, and Ridge. Next, we selected top-ranked biomarkers based on their role in breast cancer and tested them further for their resistance to radiation using the data from the Cleveland database. We have identified six drugs named Palbociclib, Panobinostat, PD-0325901, PLX4720, Selumetinib, and Tanespimycin that significantly perform on breast cancer cell lines. Also, five biomarkers named TNFSF15, DCAF6, KDM6A, PHETA2, and IFNGR1 are sensitive to all six shortlisted drugs and show sensitivity to the radiations. The proposed biomarkers and drug sensitivity analysis are helpful in translational cancer studies and provide valuable insights for clinical trial design.

Mutational Impacts on the N and C Terminal Domains of the MUC5B Protein: A Transcriptomics and Structural Biology Study.

Cholangiocarcinoma (CCA) involves various epithelial tumors historically linked with poor prognosis because of its aggressive sickness course, delayed diagnosis, and limited efficacy of typical chemotherapy in its advanced stages. In-depth molecular profiling has exposed a varied scenery of genomic alterations as CCA's oncogenic drivers. Previous studies have mainly focused on commonly occurring TP53 and KRAS alterations, but there is limited research conducted to explore other vital genes involved in CCA. We retrieved data from The Cancer Genome Atlas (TCGA) to hunt for additional CCA targets and plotted a mutational landscape, identifying key genes and their frequently expressed variants. Next, we performed a survival analysis for all of the top genes to shortlist the ones with better significance. Among those genes, we observed that MUC5B has the most significant p-value of 0.0061. Finally, we chose two missense mutations at different positions in the vicinity of MUC5B N and C terminal domains. These mutations were further subjected to molecular dynamics (MD) simulation, which revealed noticeable impacts on the protein structure. Our study not only reveals one of the highly mutated genes with enhanced significance in CCA but also gives insights into the influence of its variants. We believe these findings are a good asset for understanding CCA from genomics and structural biology perspectives.

Pattern of hepatitis C virus genotypes and subtypes circulating in war-stricken Khyber Pakhtunkhwa, Pakistan: Review of published literature.

Infection due to hepatitis C virus (HCV) is a major cause of fibrosis and hepatocellular carcinoma in Pakistan. In the current review, pattern of HCV genotypes and subtypes in Khyber Pakhtunkhwa province was ascertained in light of the available literature. After thorough analysis, genotype 3 (58.27%) was determined to be the leading HCV genotype, followed by genotypes 2 (12.39%), 1 (9.54%) and 4 (0.86%). The proportions of genotypes 5 and 6 were recorded as 0.09% and 0.22% respectively. Subtype wise, 3a accounted for 48.67%, followed by subtype 2a (10.91%), 3b (9.43%), 1a (5.84%), 1b (3.66%), 2b (1.45%) and genotype 4 with its undefined subtypes contributed a portion of 0.86%. The cumulative share of subtypes 1c, 2c, 3c, 5a and 6a was less than 1%. In 11.51% cases, the subtype was untypeable while in 7.17% cases mixed subtypes were recorded. Gender wise, proportions of most HCV subtypes were marginally higher among males as compared to females. On the basis of studied groups, 3a was pervasive among all groups except in intravenous drug users where 2a was the major HCV subtype. Similarly, based on various geographical locations (provincial divisions), subtype 3a revealed a ubiquitous distribution. Conclusively, HCV 3a persists to be the principal subtype across the province of Khyber Pakhtunkhwa. The considerable number of untypeable subtypes in most studies urges for an improved genotyping system on the basis of local sequence data and practice of sequencing for determination of underlying subtype in untypeable cases. Further, studies on identification of subtypes transmission pattern are imperative for assessment of transmission origin and reinforcement of efficient control strategies. In addition, the current review emphasizes the need of attention toward HCV risk groups and ignored southern side of Khyber Pakhtunkhwa province for better holistic understanding of HCV genotype distribution pattern in the province.