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Cholelithiasis is a common disease of the digestive system. The risk factors for cholelithiasis have been reported and summarized many times in the published literature, which primarily focused on cross-sectional studies. Due to the inherent limitations of the study design, the reported findings still need to be validated in additional longitudinal studies. Moreover, a number of new risk factors for cholelithiasis have been identified in recent years, such as bariatric surgery, hepatitis B virus infection, hepatitis C virus infection, kidney stones, colectomy, osteoporosis, etc. These new findings have not yet been included in published reviews. Herein, we reviewed the 101 cholelithiasis-associated risk factors identified through research based on longitudinal investigations, including cohort studies, randomized controlled trials, and nested case control studies. The risk factors associated with the pathogenesis of cholelithiasis were categorized as unmodifiable and modifiable factors. The unmodifiable factors consist of age, sex, race, and family history, while the modifiable factors include 37 biological environmental factors, 25 socioenvironmental factors, and 35 physiochemical environmental factors. This study provides thorough and comprehensive ideas for research concerning the pathogenesis of cholelithiasis, supplying the basis for identifying high-risk groups and formulating relevant prevention strategies.

Epidemiological and genetic evidence for the relationship between ABO blood group and human cancer.

To comprehensively evaluate the etiological role of ABO blood group in human cancer, we conducted a large-scale meta-analysis of 127 publications totaling 20 million participants including 231 737 patients of 20 cancers, supplemented by genetic evidence. Effects of A, AB and B groups on cancer risk were investigated by respectively comparing with O group and their combined counterparts, and subgroup analysis by ethnicity was conducted for O-referent models. For cancer categories, A group increased risk of cancers of oral cavity and nasopharynx, digestive and female genital organs, while both AB and B groups showed associations with cancers of digestive and female genital organs. For individual cancers, A group significantly increased the risk of nine cancers including oral cavity (OR = 1.17, P = .013), stomach (OR = 1.19, P = 3.90 × 10-15 ), pancreas (OR = 1.33, P = 9.89 × 10-33 ), colorectum (OR = 1.09, P = .001), liver (OR = 1.23, P = .011), ovary (OR = 1.13, P = .001), cervix (OR = 1.17, P = .025), bladder (OR = 1.12, P = .025) and breast (OR = 1.06, P = .043). AB group showed associations with only three cancers: stomach (OR = 1.10, P = .007), pancreas (OR = 1.21, P = .001) and ovary (OR = 1.28, P = .006). B group, except for shared associations with A group on pancreas (OR = 1.20, P = 2.27 × 10-5 ) and cervix cancers (OR = 1.13, P = .011), had two distinct associations with esophagus (OR = 1.17, P = .002) and nonmelanoma skin cancers (OR = 0.96, P = .017). Ethnicity-specific analyses revealed the notable effects of non-O groups on pancreatic cancer both in Caucasians and Asians. In genetic analysis, four SNPs were associated with the risk of pancreatic cancer, with rs505922 corresponding to O group showing the strongest protective effect (P = 1.16 × 10-23 ). Our study provided comprehensive evidence of ABO blood group associated with cancers and highlighted its carcinogenic role.

S100A1 expression is increased in spinal cord injury and promotes inflammation, oxidative stress and apoptosis of PC12 cells induced by LPS via ERK signaling.

Spinal cord injury (SCI) is a severe neurological disorder and the molecular mechanisms leading to its poor prognosis remain to be elucidated. S100A1, a mediator of Ca2+ handling of sarcoplasmic reticulum and mitochondrial function, operates as an endogenous danger signal (alarmin) associated with inflammatory response and tissue injury. The aim of the present study was to investigate the expression and biological effects of S100A1 in SCI. A rat model of SCI and a PC12 cell model of lipopolysaccharide (LPS)­induced inflammation were established to examine S100A1 expression at the mRNA and protein levels. The inflammation level, which was mediated by S100A1, was determined based on inflammatory factor (IL­1ß, IL­6 and TNF­α) and anti­inflammatory factor (IL­10) expression. The effects of S100A1 on cellular oxidation and anti­oxidation levels were observed by detecting the levels of reactive oxygen species, superoxide dismutase, catalase activities and nuclear factor erythroid 2­related factor 2 expression. The protein levels of Bax, Bcl2 and cleaved caspase­3 were used for the evaluation of the effects of S100A1 on apoptosis. Phosphorylated (p­)ERK1/2 expression was used to evaluate the effects of S100A1 on ERK signaling. The results revealed that S100A1 expression was significantly upregulated in vivo and in vitro in the PC12 cell model of LPS­inflammation. The silencing and overexpression of S100A1 helped alleviate and aggravate LPS­induced inflammation, oxidative stress and apoptosis levels, respectively. S100A1 was found to regulate the ERK signaling pathway positively. An inhibitor of ERK signaling (MK­8353) partially abolished the promoting effects of the overexpression of S100A1 on inflammation, oxidative stress damage and apoptosis. In conclusion, S100A1 expression was elevated in model of SCI and in the PC12 cell model of LPS­induced inflammation. Furthermore, the overexpression/silencing S100A1 aggravated/mitigated the inflammation, oxidative stress damage and the apoptosis of LPS­stimulated PC12 cells via the ERK signaling pathway. The present study revealed the mechanism of S100A1 in SCI, which provided a new theoretic reference for future research on SCI.

Addictive behavior and incident gallstone disease: A dose-response meta-analysis and Mendelian randomization study.

Background: Previous studies have suggested associations between addictive behavior and gallstone disease (GSD) risk, yet conflicting results exist. It also remains unclear whether this association is causal or due to confounding or reverse associations. The present study aims to systematically analyze the epidemiological evidence for these associations, as well as estimate the potential causal relationships using Mendelian randomization (MR). Methods: We analyzed four common addictive behaviors, including cigarette smoking, alcohol intake, coffee, and tea consumption (N = 126,906-4,584,729 participants) in this meta-analysis based on longitudinal studies. The two-sample MR was conducted using summary data from genome-wide associations with European ancestry (up to 1.2 million individuals). Results: An observational association of GSD risk was identified for smoking [RR: 1.17 (95% CI: 1.06-1.29)], drinking alcohol [0.84 (0.78-0.91)], consuming coffee [0.86 (0.79-0.93)], and tea [1.08 (1.04-1.12)]. Also, there was a linear relationship between smoking (pack-years), alcohol drinking (days per week), coffee consumption (cups per day), and GSD risk. Our MRs supported a causality of GSD incidence with lifetime smoking [1.008 (1.003-1.013), P = 0.001], current smoking [1.007 (1.002-1.011), P = 0.004], problematic alcohol use (PAU) [1.014 (1.001-1.026), P = 0.029], decaffeinated coffee intake (1.127 [1.043-1.217], P = 0.002), as well as caffeine-metabolism [0.997 (0.995-0.999), P = 0.013], and tea consumption [0.990 (0.982-0.997), P = 0.008], respectively. Conclusion: Our study suggests cigarette smoking, alcohol abuse, and decaffeinated coffee are causal risk factors for GSD, whereas tea consumption can decrease the risk of gallstones due to the effect of caffeine metabolism or polyphenol intake.

Penile metastasis from rectal carcinoma: A case report.

BACKGROUND: Metastasis to the penis is an unusual event, and penile metastasis from rectal carcinoma (PMRC) is extremely rare and associated with a dismal prognosis. Thus far, approximately 80 cases have been reported. CASE SUMMARY: Herein, we report the case of a 49-year-old man with PMRC. The patient presented to the urology clinic with a complaint of penile pain during urination. The patient underwent the Dixon operation for rectal carcinoma 2 mo before the presentation. During hospitalisation, abdominal computed tomography revealed a nodular lesion on the left penis. The postoperative pathological examination revealed a typical intestinal-type adenocarcinoma. Previous cases of PMRC were retrieved from PubMed to characterise the clinicopathological features and identify the prognostic factors of PMRC. CONCLUSION: The analysis suggested that approximately 24 mo is the median time to metastasis occurrence and 150 d is the survival time after diagnosis. Furthermore, poor pathological differentiation, lymph node involvement of the primary RC, metastasis time < 6 mo, penile metastatic nodule diameter > 1 cm, and treatment abandonment are negative predictors of survival outcomes. Close follow-up, surgical resection, chemotherapy, and radiotherapy may potentially improve the prognosis of patients.

Ibuprofen on Proliferation and Apoptosis of Sarcoma Cells via PI3K/Akt/mTOR Signaling Pathway.

Nowadays, there is a serious lack of information about the value-added apoptosis of sarcoma cells in China. Especially in clinical medicine, exploring the effect of ibuprofen on the growth and apoptosis of fibrosarcoma cells under the PI3K/Akt/mTOR signaling pathway can not only effectively prevent us in advance, but also be a great way to break through this field. The main purpose of this study was to investigate the effects of ibuprofen on the proliferation, cell cycle and apoptosis of fibrosarcoma cells through the PI3K/Akt/mTOR signaling pathway. We divided the HTl080 cell line into zero control group, control group and experimental group. The withering group was not inoculated with any cells, while the control group was only added with the same amount of culture medium, while the experimental group was added with 5,10,15,20 concentrations respectively. We found that the apoptosis rate of sarcoma cells in the control group increased from 5.66% to 7.12%, while the apoptosis rate of sarcoma cells in the experimental group increased significantly faster than that in the control group, with an overall increase of 7.16%, from 4.56% to 11.72%. Therefore, we can be surer that ibuprofen has a very good inhibitory effect on the proliferation, cell cycle and apoptosis of fibrosarcoma cells under the PI3K/Akt/mTOR signaling pathway. Therefore, when ibuprofen was injected into the body, it could not only observe the sarcoma cells well but also reflect the good inhibitory effect of ibuprofen on other substances in vivo under the PI3K/Akt/mTOR signaling pathway.

Causal effect of autoimmune liver diseases on cancer: Meta-analyses of cohort studies and Mendelian randomization study.

BACKGROUND AND AIMS: Prior studies suggested that patients with autoimmune liver diseases (AiLDs) had an increased risk of cancer, whereas the causal effect remained unclear. METHODS: Meta-analyses concerning the relationship between AiLD and cancer risk were performed to calculate the pooled relative risk (RR) and corresponding 95% confidence intervals (CIs). Then, the associations with a p value of <.05 were further validated by two-sample Mendelian randomization studies. RESULTS: A total of 37 cohort studies covering more than 34 558 patients were included, and we observed an increased risk of overall cancers (pooled RR = 3.64, 95% CI: 2.64-5.03, p < .001) and cancer-related death (pooled RR = 2.48, 95% CI: 1.73-3.53, p < .001) for patients with AiLD. Besides, overall and several site-specific cancers risk were found in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC) (p < .05). However, associations between genetically predisposed AIH, PBC, and PSC and the risk of specific cancers did not reach a significant level, except for PBC and gastric cancer (OR = 0.96, 95% CI: 0.93-0.99; p = .02). CONCLUSIONS: In addition to hepatobiliary cancer, results from the meta-analyses suggest that patients with AiLD might have an increased risk of several extrahepatobiliary cancers. However, the causal role of AiLD in cancer development needs to be further investigated.

X-ray source design optimization using differential evolution algorithms-A case study.

Traditional x-ray sources used today for multiple applications, such as medical imaging (computed tomography, radiography, mammography, and interventional radiology) or industrial inspection, are vacuum based electron beam devices that include several key components, such as electron emitters, electron guns/cathodes, and anodes/targets. The associated electronics for electron beam generation, focusing and control, and beam acceleration are located outside the vacuum chamber. The general topology of these tubes has been directionally unchanged for more than 100 years; however, tube design remains a long, inefficient, tedious, and complex process; blind design of experiments do not necessarily make the process more efficient. As a case study, in this paper, we introduce the differential evolution (DE), an artificial intelligence-based optimization algorithm, for the design optimization of x-ray source beam optics. Using a small-scale design problem, we demonstrate that DE can be an effective optimization method for x-ray source beam optics design.

Association Between Systemic Lupus Erythematosus and Cancer Morbidity and Mortality: Findings From Cohort Studies.

Background: Observational studies suggested that systemic lupus erythematosus (SLE) might be associated with increased cancer incidence and cancer-related death, however, the results are inconsistent. We aim to comprehensively estimate the causal relationships between SLE and cancer morbidity and mortality using a meta-analysis of cohort studies and Mendelian randomization. Methods: A systematic search was conducted using PubMed to identify cohort studies published before January 21, 2021. Meta-analysis was performed to calculate relative risk (RR) and corresponding 95% confidence intervals (CI). In addition, we further evaluated the potentially causal relationships identified by cohort studies using two-sample Mendelian randomization. Results: A total of 48 cohort studies involving 247,575 patients were included. We performed 31 main meta-analysis to assess the cancer risk and three meta-analyses to evaluate cancer mortality in SLE patients. Through meta-analyses, we observed an increased risk of overall cancer (RR=1.62, 95%CI, 1.47-1.79, P<0.001) and cancer-related death (RR=1.52, 95%CI, 1.36-1.70, P<0.001) in patients with SLE. Subgroup analysis by site-specific cancer showed that SLE was a risk factor for 17 site-specific cancers, including six digestive cancers (esophagus, colon, anus, hepatobiliary, liver, pancreatic), five hematologic cancers (lymphoma, Hodgkin's lymphoma, non-Hodgkin lymphoma, leukemia, multiple myeloma), as well as cancer in lung, larynx, cervical, vagina/vulva, renal, bladder, skin, and thyroid. In addition, further mendelian randomization analysis verified a weakly association between genetically predisposed SLE and lymphoma risk (odds ratio=1.0004, P=0.0035). Conclusions: Findings from our study suggest an important role of SLE in carcinogenesis, especially for lymphoma. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, CRD42021243635.

The Causal Relationships Between Extrinsic Exposures and Risk of Prostate Cancer: A Phenome-Wide Mendelian Randomization Study.

BACKGROUND: Prostate cancer is the second most common cancer in males worldwide, and multitudes of factors have been reported to be associated with prostate cancer risk. OBJECTIVES: We aim to conduct the phenome-wide exposed-omics analysis of the risk factors for prostate cancer and verify the causal associations between them. METHODS: We comprehensively searched published systematic reviews and meta-analyses of cohort studies and conducted another systematic review and meta-analysis of the Mendelian randomization studies investigating the associations between extrinsic exposures and prostate cancer, thus to find all of the potential risk factors for prostate cancer. Then, we launched a phenome-wide two-sample Mendelian randomization analysis to validate the potentially causal relationships using the PRACTICAL consortium and UK Biobank. RESULTS: We found a total of 55 extrinsic exposures for prostate cancer risk. The causal effect of 30 potential extrinsic exposures on prostate cancer were assessed, and the results showed docosahexaenoic acid (DHA) [odds ratio (OR)=0.806, 95% confidence interval (CI): 0.661-0.984, p=0.034], insulin-like growth factor binding protein 3 (IGFBP-3) (OR=1.0002, 95%CI: 1.00004-1.0004, p=0.016), systemic lupus erythematosus (SLE) (OR=0.9993, 95%CI: 0.9986-0.99997, p=0.039), and body mass index (BMI) (OR=0.995, 95%CI: 0.990-0.9999, p=0.046) were associated with prostate cancer risk. However, no association was found between the other 26 factors and prostate cancer risk. CONCLUSIONS: Our study discovered the phenome-wide exposed-omics risk factors profile of prostate cancer, and verified that the IGFBP-3, DHA, BMI, and SLE were causally related to prostate cancer risk. The results may provide new insight into the study of the pathogenesis of prostate cancer.

Effect of Interventional Therapy on Iliac Venous Compression Syndrome Evaluated and Diagnosed by Artificial Intelligence Algorithm-Based Ultrasound Images.

In order to explore the efficacy of using artificial intelligence (AI) algorithm-based ultrasound images to diagnose iliac vein compression syndrome (IVCS) and assist clinicians in the diagnosis of diseases, the characteristics of vein imaging in patients with IVCS were summarized. After ultrasound image acquisition, the image data were preprocessed to construct a deep learning model to realize the position detection of venous compression and the recognition of benign and malignant lesions. In addition, a dataset was built for model evaluation. The data came from patients with thrombotic chronic venous disease (CVD) and deep vein thrombosis (DVT) in hospital. The image feature group of IVCS extracted by cavity convolution was the artificial intelligence algorithm imaging group, and the ultrasound images were directly taken as the control group without processing. Digital subtraction angiography (DSA) was performed to check the patient's veins one week in advance. Then, the patients were rolled into the AI algorithm imaging group and control group, and the correlation between May-Thurner syndrome (MTS) and AI algorithm imaging was analyzed based on DSA and ultrasound results. Satisfaction of intestinal venous stenosis (or occlusion) or formation of collateral circulation was used as a diagnostic index for MTS. Ultrasound showed that the AI algorithm imaging group had a higher percentage of good treatment effects than that of the control group. The call-up rate of the DMRF-convolutional neural network (CNN), precision, and accuracy were all superior to those of the control group. In addition, the degree of venous swelling of patients in the artificial intelligence algorithm imaging group was weak, the degree of pain relief was high after treatment, and the difference between the artificial intelligence algorithm imaging group and control group was statistically considerable (p < 0.005). Through grouped experiments, it was found that the construction of the AI imaging model was effective for the detection and recognition of lower extremity vein lesions in ultrasound images. To sum up, the ultrasound image evaluation and analysis using AI algorithm during MTS treatment was accurate and efficient, which laid a good foundation for future research, diagnosis, and treatment.

Prevalence and associated metabolic factors for thyroid nodules: a cross-sectional study in Southwest of China with more than 120 thousand populations.

OBJECTIVE: To explore the prevalence and its associated metabolic factors of thyroid nodules (TNs) among subjects who participated in the physical examinations in Chongqing, China. METHODS: The participants from the Health Management Center of JinShan Hospital of Chongqing Medical University, between September 2015 and May 2020, were included in this study. All of the participants underwent thyroid ultrasonography, anthropometric measurements, and serum examinations. Differences in the TNs prevalence were compared with the chi-square test or Wilcoxon rang-sum test. Multivariable logistic regression analyses were used to estimate the metabolic factors associated with TNs and multiple thyroid nodules (MTNs). RESULTS: Of the included 121,702 participants, 41,547 had TNs, and 20,899 had MTNs, with the prevalence of 34.1 and 17.0 %, respectively. Women had a significantly higher prevalence of TNs than men (40.6 % vs. 29.8 %; χ2 = 1517.33, P < 0.001), and TNs prevalence was gradually increased with age (P for trend < 0.001). Female gender, advanced age, and metabolic factors including central obesity, hypertension, diabetes and fatty liver were positively associated with TNs; BMI, hyperlipoidemia and hyperuricemia were not independent risk factors of TNs. While female gender, advanced age, central obesity, hypertension and diabetes were independent risk factors of MTNs. CONCLUSIONS: The prevalence of thyroid nodules was relatively high. The associated factors identified in this study could help the clinicians to detect the high-risk patients and make targeted screening strategies for the preventing of the occurrence of TNs.

Nomogram based on homogeneous and heterogeneous associated factors for predicting distant metastases in patients with colorectal cancer.

BACKGROUND: The identification of the homogeneous and heterogeneous risk factors for different types of metastases in colorectal cancer (CRC) may shed light on the aetiology and help individualize prophylactic treatment. The present study characterized the incidence differences and identified the homogeneous and heterogeneous risk factors associated with distant metastases in CRC. METHODS: CRC patients registered in the SEER database between 2010 and 2016 were included in this study. Logistic regression was used to analyse homogeneous and heterogeneous risk factors for the occurrence of different types of metastases. Nomograms were constructed to predict the risk for developing metastases, and the performance was quantitatively assessed using the receiver operating characteristics (ROC) curve and calibration curve. RESULTS: A total of 204,595 eligible CRC patients were included in our study, and 17.07% of them had distant metastases. The overall incidences of liver metastases, lung metastases, bone metastases, and brain metastases were 15.34%, 5.22%, 1.26%, and 0.29%, respectively. The incidence of distant metastases differed by age, gender, and the original CRC sites. Poorly differentiated grade, more lymphatic metastasis, higher carcinoembryonic antigen (CEA), and different metastatic organs were all positively associated with four patterns of metastases. In contrast, age, sex, race, insurance status, position, and T stage were heterogeneously associated with metastases. The calibration and ROC curves exhibited good performance for predicting distant metastases. CONCLUSIONS: The incidence of distant metastases in CRC exhibited distinct differences, and the patients had homogeneous and heterogeneous associated risk factors. Although limited risk factors were included in the present study, the established nomogram showed good prediction performance.

Sex Disparities in the Clinical Characteristics, Synchronous Distant Metastasis Occurrence and Prognosis: A Pan-cancer Analysis.

Background: This study aims to assess the sex disparities in clinical characteristics and synchronous distant metastasis occurrence at diagnosis, as well as the subsequent prognosis in non-sex-specific cancers. Methods: The study included details from patients diagnosed with non-sex-specific cancers, during the period from 2010 to 2016, in the Surveillance, Epidemiology, and End Results (SEER) program. The distant metastasis prevalence and subsequent survival time were summarized in the total population and the population with specific cancers of different systems. The multivariable logistic and the Cox proportional hazards regressions were applied to evaluate the sex effect on distant metastasis occurrence and prognosis. The results were combined using meta-analysis. Results: Across all non-sex-specific cancers, the pooled prevalence of distant metastasis was 15.2% (95% CI: 14.7-15.7%) and 7.1% (95% CI: 6.8-7.3%) for males and females, respectively. The pooled median survival time was 8.40 months (95% CI: 7.99-8.81) for male patients and 9.40 months (95% CI: 8.84-10.02) for female patients. After combining all non-sex-specific cancers, male patients displayed a higher distant metastasis occurrence than females (pooled OR=1.06, 95% CI: 1.04-1.08; P<0.01), as well as worse overall survival after distant metastasis (pooled HR=1.08, 95% CI: 1.05-1.10; P<0.01). The sex differences were more significant in patients younger than 65 years (P<0.01). Additionally, the sex influence on prognosis was most predominant amongst patients from Asian or Pacific Islander ethnic groups. Conclusion: Male gender appears to be an independent risk factor associated with the occurrence and prognosis of synchronous distant metastasis. Therefore, sex-specific preventions and treatments should become the focus of future research.

The construction and validation of the model for predicting the incidence and prognosis of brain metastasis in lung cancer patients.

BACKGROUND: Brain metastasis (BM) causes high morbidity and mortality rates in lung cancer (LC) patients. The present study aims to develop models for predicting the development and prognosis of BM using a large LC cohort. METHODS: A total of 266,522 LC cases diagnosed between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) Program cohort. Risk factors for developing BM and prognosis were calculated by univariable and multivariable logistic and Cox regression analysis, respectively, and nomograms were constructed based on risk factors. Nomogram performance was evaluated with receiver operating characteristics (ROC) curve, or C-index and calibration curve. RESULTS: The prevalence of BM was 13.33%. Associated factors for developing BM include: advanced age; Asian or Pacific Islander race; uninsured status; primary tumor site; higher T stage; higher N stage; poorly differentiated grade; the presence of lung, liver, and bone metastases; and adenocarcinoma histology. Median overall survival (OS) was 4 months; associated prognosis factors were similar to risk factors plus female gender, unmarried status, and surgery. The calibration curve showed good agreement between predicted and actual probability, and the AUC/C-index was 73.1% (95% CI: 72.6-73.6%) and 0.88 (95% CI: 0.87-0.89) for risk and prognosis predictive models, respectively. CONCLUSIONS: BM was highly developed in LC patients, and homogeneous and heterogeneous factors were found between risk and prognosis for BM. The nomogram showed good performance in predicting BM development and prognosis.

Pan-metastatic cancer analysis of prognostic factors and a prognosis-based metastatic cancer classification system.

We aimed to perform a pan-metastatic cancer analysis on survival and prognostic factors and to create a prognosis-based classification system. We selected distant metastasis patients from the Surveillance, Epidemiology, and End Results (SEER) database. The associations between the characteristics of the patients at admission and overall survival were determined. A prognosis-based metastatic cancer classification was established based on the identified prognostic factors. The differences in prognosis among these categories were tested. The survival rate and prognostic factors were not consistent across cancers. Three metastatic cancer categories were generated, each with different prognoses. The prognostic differences among the categories were satisfactorily validated. Different metastatic cancer types had homogeneous and heterogeneous survival rates and prognostic factors. A prognosis-based classification system for synchronous distant metastasis cancer patients at admission was created. This classification system reflects the grade of malignancy in metastatic cancers and may guide the prediction of survival and individualized treatment. Moreover, it may have important implications for the management of synchronous metastatic cancers and aid clinicians in properly allocating medical resources to metastatic patients.

[Prokaryotic expression and purification of mouse recombinant myelin proteolipid protein polypeptide].

Objective To establish and optimize the prokaryotic expression method for the recombinant mouse myelin proteolipid protein (PLP, 139-208 aa) which is a critical immunogenic polypeptide of PLP. Methods The sequence coding for PLP139-208 polypeptide was cloned into pET-32a(+) vector. Afterwards, the expression vector prepared in this research was transformed into E. coli BL21, and the recombinant PLP polypeptide was induced to express by isopropyl-ß-D-thiogalactoside (IPTG). Two key prokaryotic expression conditions, IPTG's induction length and temperature, were analyzed for further optimization. The recombinant PLP polypeptide was induced to express by the expression method under the optimal expression conditions, and then was purified by Ni-NTA agarose and amylose resin. Finally, the gain of PLP139-208 polypeptide was verified by Western blot analysis. Results The results in the combinatorial optimization revealed that the expression of PLP139-208 was obtained at a satisfactory level when it was incubated at 23DegreesCelsius for 20 hours with the IPTG concentration of 0.5 mmol/L. Conclusion The optimized prokaryotic expression method for the recombinant mouse PLP139-208 was successfully established and effectively performed. This will shed light on the further researches on the improved preparation for experimental autoimmune encephalitis (EAE, an animal model of multiple sclerosis) and the underlying mechanism underlying PLP-induced autoimmune demyelination.

RET S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma.

Background: Inherited medullary thyroid carcinoma (MTC) is primarily caused by RET mutations that are commonly localized in exons 5, 8, 10, 11, and 13-16. In this study, we report pedigrees for individuals with MTC that harbor a germline S409Y variant within exon 6 of the RET proto-oncogene. Methods: Targeted sequencing was used to diagnose four apparently sporadic MTC index cases carrying the germline RET S409Y (c.1226 C>A) variant. Subsequently, 27 relatives of these individuals underwent clinical and genetic assessments and/or thyroid surgery. Furthermore, in silico analyses and in vitro assays were performed to predict or verify the potential oncogenic activity of the S409Y variant. Results: Overall, 15 of 31 participants were found to carry the RET S409Y variant. Of these, 6 presented with isolated MTC (mean age 50.2 years; range 41-75 years), of which 3 presented with neck lymph node metastases and 2 presented with distant liver or lung metastases. Among the remaining 9 carriers, 3 (mean age 56 years; range 41-76 years) had elevated serum calcium-stimulated calcitonin (sCtn) or concurrent marginally elevated serum calcitonin (Ctn) levels, whereas the other 6 (mean age 37.5 years; range 14-52 years) exhibited typical Ctn/sCtn levels (p < 0.05). None of the 15 carriers in these 4 families presented clinical evidence of pheochromocytoma, hyperparathyroidism, or Hirschsprung's disease. In silico analyses revealed that S409Y was a "possibly damaging" mutation that could affect the RET protein inter-domain interface. An in vitro assay revealed that the phosphorylation level of RET tyrosine 905 was relatively higher in the RET S409Y mutant than in wild-type (WT) RET. Moreover, transfection of HEK 293 cells with S409Y enhanced the phosphorylation activity of AKT, ERK pathways, and it increased cell proliferation compared with WT RET, but to a lesser degree than that for the RET C618Y and C634Y mutations. Conclusions: This study demonstrates that the novel germline RET S409Y variant is likely pathogenic and is associated with lower penetrance of MTC than that for the C618Y and C634Y mutations. Individuals with S409Y should be managed using a personalized approach, and additionally, "at-risk" family members should be evaluated. Additional studies are needed to elucidate the correlation between the S409Y mutation and multiple endocrine neoplasia type 2-specific tumors.

Classified status of smoking and quitting has different associations with dyslipidemia in residents in northeast China.

BACKGROUND: Various smoking status and high prevalence of dyslipidemia in residents exist in northeast China. However, associations of dyslipidemia with smoking status remain unclear. METHODS: A total of 17,114 participants selected by a multistage stratified cluster random sampling design were enrolled from a cross-sectional study conducted in northeast China. Associations of dyslipidemia with smoking/quitting status (smoking amount, smoking duration, and quitting duration) were investigated using multiple logistic regression. RESULTS: Prevalence (39.2%) of dyslipidemia existed in residents in northeast China. Smoking amount was associated with dyslipidemia (1-10 cigarettes daily: OR = 1.19, 95% CI: 1.08-1.32; 11-20 cigarettes daily: OR = 1.29, 95% CI: 1.16-1.42; and over 20 cigarettes daily: OR = 1.51, 95% CI: 1.25-1.83). Smoking duration was associated with dyslipidemia risk (6-10 years: OR = 1.75, 95% CI: 1.51-2.03; 11-15 years: OR = 1.85, 95% CI: 1.51-2.26; and ≥15 years: OR = 1.12, 95% CI: 1.02-1.23). Quitting duration (1-5 years) was associated with dyslipidemia (OR = 1.26, 95% CI: 1.07-1.48); however, we found no statistically significant associations between dyslipidemia and quitting duration (over 6 years). CONCLUSIONS: Dyslipidemia risk is positively associated with smoking/quitting status. Smoking amount and smoking duration may co-determine dyslipidemia risk, and quitting duration (>6 years) is necessary for reducing dyslipidemia risk.