Bayesian Approaches in Exploring Gene-environment and Gene-gene Interactions: A Comprehensive Review.

Rapid advancements in high-throughput biological techniques have facilitated the generation of high-dimensional omics datasets, which have provided a solid foundation for precision medicine and prognosis prediction. Nonetheless, the problem of missing heritability persists. To solve this problem, it is essential to explain the genetic structure of disease incidence risk and prognosis by incorporating interactions. The development of the Bayesian theory has provided new approaches for developing models for interaction identification and estimation. Several Bayesian models have been developed to improve the accuracy of model and identify the main effect, gene-environment (G×E) and gene-gene (G×G) interactions. Studies based on single-nucleotide polymorphisms (SNPs) are significant for the exploration of rare and common variants. Models based on the effect heredity principle and group-based models are relatively flexible and do not require strict constraints when dealing with the hierarchical structure between the main effect and interactions (M-I). These models have a good interpretability of biological mechanisms. Machine learning-based Bayesian approaches are highly competitive in improving prediction accuracy. These models provide insights into the mechanisms underlying the occurrence and progression of complex diseases, identify more reliable biomarkers, and develop higher predictive accuracy. In this paper, we provide a comprehensive review of these Bayesian approaches.

Detection of Sodium Formaldehyde Sulfoxylate, Aluminum, and Borate Compounds in Bread and Pasta Products Consumed by Residents in Jilin Province, China.

ABSTRACT: Food additives are widespread in the human diet; however, their excessive intake can have an impact on the quality of health. This study evaluated food additives in bread and pasta products consumed by residents in various regions of Jilin Province, People's Republic of China, from 2019 to 2021. We collected samples of bread and six types of pasta products from farmers' markets and morning markets and used high-performance liquid chromatography, UV-visible spectrophotometry, and graphite furnace atomic absorption spectrometry to detect the content of the following food additives: sodium formaldehyde sulfoxylate, aluminum, and borate compounds. For 836 samples in total, we detected the presence of sodium formaldehyde sulfoxylate, aluminum, and borate compounds in excess rates reaching 3.5, 10, and 4.7%, respectively. Aluminum in fried breadsticks exceeded the standard by 40%. The results of this study can be used to assess the overall pass rate of bread and pasta products sold in Jilin Province and support the detection of possible food safety problems.

Survival After Minimally Invasive Surgery in Older Women With Endometrial Carcinoma.

BACKGROUND/AIM: To analyze the impact of minimally invasive surgery for endometrial cancer on overall survival among age >65. PATIENTS AND METHODS: We examined women who underwent hysterectomy from 2010 to 2015 from the U.S. National Cancer Data Base (NCDB). We evaluated the impact of surgical approach on survival. RESULTS: Of 243,601 endometrial cancer cases, 42,458 met the inclusion criteria. Laparoscopic approach was associated with improved survival by 14% (HR=0.86; 95%CI=0.80-0.92; p<0.001) and robotic approach was associated with improved survival by 12% (HR=0.88; 95%CI=0.83-0.93; p<0.0001), compared to the open approach. Similarly, the weighted adjusted 5-year overall survival was 73.1% (95%CI=72%-74.2%), 76.4% (95%CI=75.1-77.7%), and 75.5% (95%CI=74.7-76.4%) for open, laparoscopic, and robotic approaches, respectively (p<0.001). CONCLUSION: Minimally invasive surgery improved overall survival in women over 65 years with endometrial cancer.

Efficacy of YAP1-gene Knockdown to Inhibit Alveolar-Epithelial-Cell Senescence and Alleviate Idiopathic Pulmonary Fibrosis (IPF).

BACKGROUND/AIM: The prevalence of idiopathic pulmonary fibrosis (IPF) increases with age and is associated with senescence of alveolar epithelial cells (AECs). AEC senescence in pulmonary cells mediates IPF. We herein aimed to determine if YAP1 gene knockdown, a member of the Hippo/YAP signal pathway, in the bleomycin (BLM)-induced mouse model of IPF, inhibits onset of senescence of AECs and alleviates IPF. MATERIALS AND METHODS: Adeno-associated viruses (AAVs) expressing Yes-associated protein 1 (YAP1) short hairpin RNA (shRNA) were delivered into the lung of BLM-induced IPF mice via intratracheal injection, to knockdown the YAP1 gene in AECs. The mice were assigned to 4 groups: G1: control (normal mice); G2: IPF mice; G3: IPF + AAV/YAP1; G4: IPF + AAV/scramble. After 28 days, AECs were examined for senescence using H&E staining, Masson's trichrome Staining, senescence-associated ß-galactosidase (SA-ß-gal) staining, western blotting and co-immunofluorescence staining, to determine the expression of YAP1, Smad-3 and p21, in order to determine the induction of senescence of ACEs. RESULTS: The severity of IPF determined by H&E staining, Masson's staining and immunofluorescence (IF) staining was positively correlated with the senescence of AECs. Down-regulation of YAP1 expression of the Hippo-signaling pathway, determined by western blotting in AECs, alleviated pulmonary fibrosis as determined by Masson's staining. Down regulation of YAP1 expression reduced the senescence of AECs as determined by ß-galactosidase (SA-ß-gal) staining, which alleviated the clinical symptoms of IPF mice, as determined by body weight and lung index. CONCLUSION: Down-regulation of YAP1 expression in AECs inhibited AEC senescence which is thought to be the cause of IPF. Therefore, future studies can focus on inhibiting YAP1 to effectively treat IPF.

The Anti-oxidant Monoterpene p-Cymene Reduced the Occurrence of Colorectal Cancer in a Hyperlipidemia Rat Model by Reducing Oxidative Stress and Expression of Inflammatory Cytokines.

BACKGROUND/AIM: Overexpression of inflammatory cytokines and oxidative stress increase the risk of colorectal cancer (CRC) in obesity and hyperlipidemia. The aim of this study was to investigate whether the monoterpene antioxidant p-cymene would reduce the incidence of CRC in a rat model of hyperlipidemia. MATERIALS AND METHODS: The hyperlipidemic CRC rat model was established by a high-fat diet and dimethyl hydrazine (DMH) induction. All rats received 30 mg/kg DMH to induce CRC, and were then assigned to groups with a normal diet or high-fat diet with/without 30 mg/kg/day p-cymene orally during the entire experimental period. Tumor incidence in each group, and the level of serum inflammatory cytokines and oxidative stress-related markers in intestinal tissues were measured. RESULTS: p-Cymene significantly inhibited CRC occurrence in hyperlipemic rats (p=0.024) by reducing the expression of serum inflammatory cytokines (interleukin-1 by 54.5%; interleukin-6 by 28.3%; adiponectin by 26.3%; cyclo-oxygenase-2 by 48.4%) and intestinal oxidative-stress cytokines (total antioxidant capacity by 30.4%; superoxide dismutase by 30.3%; malondialdehyde by 47.1%). CONCLUSION: p-Cymene has clinical potential to reduce the incidence of CRC in hyperlipemia.

Elevated expression of KIF18A enhances cell proliferation and predicts poor survival in human clear cell renal carcinoma.

The function of kinesin family member 18A (KIF18A) in human renal cell carcinoma (RCC) is unclear. The purpose of the current study was to determine the expression and prognostic significance of KIF18A in RCC. Specimens from 273 RCC patients undergoing nephrectomies were studied. Expression of KIF18A mRNA was examined by reverse transcription-polymerase chain reaction (RT-PCR) or quantitative PCR, and the expression of KIF18A protein was examined by immunohistochemistry and western blotting. The expression of KIF18A in clear-cell RCC cell lines was decreased using small interfering RNA targeting KIF18A, and increased by transfection with KIF18A cDNA. The proliferative ability of RCC cells in vitro and in vivo was detected by WST-1 assay and an animal xenograft model with BALB/c nude mice, respectively. The association between KIF18A expression and overall survival was calculated using Kaplan-Meier analysis. The results showed that KIF18A expression was significantly increased in RCC tissues compared with normal kidney tissues. The level of KIF18A expression was significantly associated with tumor stage, histological grade, metastasis and tumor size. Moreover, KIF18A increased the proliferation of RCC cells in vitro and in vivo. KIF18A expression was upregulated in RCC and enhanced the proliferation of RCC cells. Therefore, it appears that KIF18A plays a key role in the carcinogenesis and progression of RCC, and is a novel candidate prognostic marker for RCC patients. Furthermore, silencing KIF18A expression may serve as a new therapeutic strategy against RCC.

Evaluation of miR-302c-3p as prognostic biomarkers in glioma patients.

OBJECTIVE: This study aimed to explore the clinicopathological and prognostic significance of miR-302c-3p in glioma. MATERIALS AND METHODS: The expression of miR-302c-3p in glioma tissues and normal brain tissues was measured using real-time PCR. Clinicopathological associations of miR-302c-3p expression in glioma were analyzed. The Kaplan-Meier method was used to determine the survival curves. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis. RESULTS: The relative expression of miR-302c-3p in glioma tissues was significantly lower than that in non-neoplastic brain tissues (p < 0.001). The decreased expression of miR-302c-3p in glioma was positively associated with WHO grade (p < 0.001) and Karnofsky performance status (KPS) score (p = 0.016). We found patients with low miR-302c-3p expression had significantly poorer OS (p = 0.0057) and PFS (p = 0.0092) by Kaplan-Meier method. Furthermore, multivariate regression analysis identified low miR-302c-3p expression as an independent predictor of poor survival. CONCLUSIONS: Our results revealed that miR-302c-3p may serve as a tumor suppressor of malignant glioma and be used as a novel biomarker to predict the clinical prognostic of patients with gliomas.

TPX2 in human clear cell renal carcinoma: Expression, function and prognostic significance.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein. TPX2 is considered to be an important gene in tumorigenesis; however, the particular function of TPX2 in the development of human renal cell carcinoma (RCC) is unknown. In the present study, the expression, function and prognostic significance of TPX2 in human RCC was analyzed. A total of 286 tissue samples from patients with RCC who had undergone nephrectomies were utilized. Subsequently, the expression of TPX2 protein was investigated using immunohistochemistry and western blotting, and TPX2 mRNA expression was examined using reverse transcription-quantitative polymerase chain reaction. To establish the effect of TPX2 on the proliferation and invasion of the RCC cells, TPX2 expression was increased by stable transfection with a TPX2 vector and TPX2 expression was decreased using small interfering RNA. Proliferation of the RCC cells was analyzed using a WST-1 assay and an animal xenograft model with BALB/c nude mice, whilst invasion of the RCC cells was examined using a Matrigel-coated invasion chamber. It was demonstrated that TPX2 expression was significantly higher in the RCC tissues compared with normal kidney tissues (P<0.05). Furthermore, TPX2 expression was associated with tumor size, histological grade and tumor stage (P<0.05), and was observed to markedly increase the proliferation and invasion of the RCC cells. It may be concluded that the expression of TPX2 is significantly upregulated in RCC tissue, subsequently increasing the proliferative and invasive ability of RCC cells. Therefore, the protein may serve as a therapeutic target and independent prognostic factor in the treatment of human RCC.

Upregulation of ULK1 expression in PC-3 cells following tumor protein P53 transfection by sonoporation.

The aim of the present study was to investigate whether ultrasound combined with microbubbles was able to enhance liposome-mediated transfection of genes into human prostate cancer cells, and to examine the association between autophagy and tumor protein P53 (P53). An MTT assay was used to evaluate cell viability, while flow cytometry and fluorescence microscopy were used to measure gene transfection efficiency. Autophagy was observed using transmission electron microscopy. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis were used to assess the expression of autophagy-associated genes. The results of the present study revealed that cell viability was significantly reduced following successfully enhanced transfection of P53 by ultrasound combined with microbubbles. In addition, serine/threonine-protein kinase ULK1 levels were simultaneously upregulated. Castration-resistant prostate cancer is difficult to treat and is investigated in the present study. P53 has a significant role in a number of key biological functions, including DNA repair, apoptosis, cell cycle, autophagy, senescence and angiogenesis. Prior to the present study, to the best of our knowledge, increased transfection efficiency and reduced side effects have been difficult to achieve. Ultrasound is considered to be a 'gentle' technique that may be able to achieve increased transfection efficiency and reduced side effects. The results of the present study highlight a potential novel therapeutic strategy for the treatment of prostate cancer.

Multiple courses of immunotherapy with different immune cell types for patients with hepatocellular carcinoma after microwave ablation.

The aim of the present study was to investigate the therapeutic efficacy of immunotherapy after microwave ablation (MWA), which was used to improve liver function, reduce the recurrence rate and enhance survival period in patients with hepatocellular carcinoma (HCC). Between February 2009 and December 2010, 14 patients received immunotherapy after MWA (immunotherapy group) and 15 patients received MWA alone with no post-ablated adjuvant therapy (control group). Immune and liver parameters, recurrence rate and survival time were recorded. The absolute lymphocyte count in the immunotherapy group exceeded that in the control group after 3 courses of immunotherapy (P<0.05). No significant differences were detected in the lymphocyte subset distribution in the control and immunotherapy patients prior to ablation (P>0.05); however, certain cytotoxic subsets (CD3+/CD8+, CD8+CD28+ and CD3+CD16+CD56+ T cells) were over-represented and negative regulatory or helper subsets (CD4+CD8+, CD4+, CD4+CD25+) were under-represented in the immunotherapy group between 1 and 12 months after immunotherapy (P<0.05). After 2 courses of immunotherapy the proliferation rate of myeloid dendritic cells and T lymphocytes, including CD3+/CD8+ lymphocytes, significantly increased (P<0.05 and P<0.01, respectively). In addition, the level of albumin in the immunotherapy group exceeded that in the control group after 3 courses of immunotherapy (P<0.05). However, the rate of disease-free survival and overall survival within 16 months of MWA did not differ significantly between the two groups (P>0.05). In conclusion, the results of the present study indicate that immunotherapy improves the immune status and liver function of patients with HCC.

Upregulation of Beclin-1 expression in DU-145 cells following low-frequency ultrasound irradiation combined with microbubbles.

Castration-resistant prostate cancer (PCa) is difficult to treat. Autophagy, which is an evolutionarily conserved mechanism, plays an important role in cancer development. The balance between cell death and survival in different stages varies in cancer development. The role of autophagy in PCa development has not yet been fully elucidated. Ultrasound may be of value in the treatment of PCa. The aim of the present study was to investigate the association between autophagy and ultrasound combined with microbubbles. The MTT assay was used to evaluate cell viability. Autophagy was observed by transmission electron microscopy. Reverse transcription-polymerase chain reaction and western blot analysis were used to assess the expression of autophagy-related genes. The results revealed that cell viability was significantly reduced by ultrasound combined with microbubbles in DU145 PCa cells. The present study demonstrated that ultrasound combined with microbubbles induced autophagy and autophagy-related DU-145 cell death. Notably, these findings highlighted additional mechanisms that suggest the potential of ultrasound-modulated autophagy as a novel therapeutic strategy for PCa.

Characteristics of gastrointestinal hemorrhage associated with pancreatic cancer: A retrospective review of 246 cases.

While gastrointestinal (GI) hemorrhage is common in the general population, few studies have evaluated large numbers of GI hemorrhage patients with pancreatic cancer. The clinical features and potential risk factors of GI hemorrhage with pancreatic cancer was investigated in the present study and the effect of GI hemorrhage on survival rate was examined. Patients enrolled in the present study had pathologically proven pancreatic cancer, and received treatment between August 2006 and 2012. Their medical records were retrospectively reviewed. The data for the present study were obtained from a review of 246 patients with pancreatic cancer (average age, 63.4±10.92 years; 190 male cases, 56 female cases). In addition, 73 cases had stage I-II, 173 had stage III-IV, and only 67 cases (27.2%) were candidates for curative pancreatectomy. Among them, 32 cases (13.0%) were clinically diagnosed with GI hemorrhage. A total of 24 cases were male patients and the other 8 cases were female, the cases of hemorrhage history and alcoholism were 2 and 29 cases, respectively. The major initial clinical symptoms of GI hemorrhage included 18 patients with melena or blood stool (56.25%), 9 with haematemesis (28.13%), 3 with abdominal distention (9.37%) and 2 with stomach ache (6.25%). The independent risk factor for GI hemorrhage was tumor initial stage of IV. A continuous increase in carbohydrate antigen 19-9 (CA19-9) may be a warning of GI hemorrhage, particularly when it is >1,000 U/ml. The most frequent method of hemostasis was combination therapy (n=12, 37.5%). Only 3 cases (9.3%) of these 32 GI hemorrhage patients were blood stanched and only 10 patients (31.2%) received gastroscopy. The time from GI hemorrhage to fatality is extremely short (median 30 days, range from 1 h to 65 days), and the median overall survival time of the patients with GI hemorrhage was 9.0 months (range, 2.0-16.0 months) and was significantly shorter than that of patients without GI hemorrhage [14.5 months (range, 0.5-48.0 months)]. In conclusion, although GI hemorrhage was not common in patients with pancreatic cancer, it is critical. GI hemorrhage was controlled with endoscopic hemostasis. Clinicians should fully assess the risk factors of GI hemorrhage (such as alcohol, smoking, past hemorrhage history, initial stage, tumor location and CA19-9 level at diagnosis of pancreatic cancer) when the pancreatic cancer patients were on admission, particularly for patients of the late stage, preventive measures should be investigated to reduce suffering.

Association between B7-H1 expression and bladder cancer: a meta-analysis.

B7 homolog 1 (B7-H1), which is also known as programmed death-L1, is an important member of the B7/CD28 costimulatory factor superfamily, which are emerging as important mediators of various host immune responses. B7-H1 is differentially expressed in various cell subsets and to different extents in human and murine cells. Human B7-H1 is constitutively expressed at low levels in dendritic cells and activated T cells (compared with high expression in activated murine T cells) and is highly expressed in monocytes and tumor cells. We conducted a meta-analysis to explore the association between B7-H1 expression and bladder cancer risk. Two groups were examined, including 352 bladder cancer cases and 60 healthy controls. Meta-analysis results revealed that B7-H1 expression is positively associated with bladder cancer and is strongly associated with the clinical stage of bladder cancer. However, no significant difference was found with respect to gender and the pathological grade of bladder cancer.

Mesenchymal stem cells expressing interleukin-18 suppress breast cancer cells in vitro.

Breast cancer is the most common malignancy among females throughout the world. Current treatments have unsatisfactory outcomes due to the dispersed nature of certain types of the disease. The development of a more effective therapy for breast cancer has long been one of the most elusive goals of cancer gene therapy. In the present study, human mesenchymal stem cells derived from umbilical cord (hUMSCs) genetically modified with interleukin 18 (IL-18) gene were used to study the effect of hUMSCs/IL-18 on the growth, migration and invasion of MCF-7 and HCC1937 cells in vitro. The hUMSCs could be efficiently modified by lentiviral systems and stably expressed IL-18 protein. hUMSCs/IL-18, but not hUMSCs without the IL-18 gene transduction, significantly suppressed the proliferation, migration and invasion of the MCF-7 and HCC1937 cells. The mechanism of this proliferation suppression may have involved the induction of G1- to S-phase arrest of the breast cancer cells by the hUMSCs/IL-18. In conclusion, hUMSCs/IL-18 can suppress the proliferation, migration and invasion of breast cancer cells in vitro and may provide an approach for a novel antitumor therapy in breast cancer.