Plasminogen Activator Inhibitor-1 4G/5G (rs1799889) Polymorphism in Chinese Patients with Diabetes Mellitus and Hypertension.

Objective: To determine the plasminogen activator inhibitor-1 (PAI-1) 4G/5G (rs1799889) genotype of the subjects in a robust detection method and to explore the association of the PAI-1 4G/5G polymorphism with susceptibility to diabetes mellitus (DM) and hypertension (HTN) as well as clinical characteristics. Methods: This study recruited 208 patients (68 patients were diagnosed with DM, 70 patients with HTN and 70 patients with DM combined with HTN) and 132 healthy controls (HC). A subset of the population was selected to evaluate the accuracy of the Real-time PCR (RT-PCR) method for detecting PAI-1 4G/5G polymorphism by using the sequencing method as the gold standard. Furthermore, the association of the PAI-1 4G/5G polymorphism with genetic susceptibility to DM and HTN was explored. Moreover, variations in clinical characteristics among individuals with various PAI-1 genotypes were also analyzed in the DM group, the HTN group and the DM+HTN group. Results: There was a high concordance between the RT-PCR method and the sequencing method in determining the PAI-1 4G/5G polymorphism. No association was observed between the PAI-1 4G/5G polymorphism and susceptibility to DM, HTN and DM+HTN, respectively. There were no statistical differences in all study indicators among individuals that carrying various genotypes in the HC group. There were several variations in clinical characteristics among individuals harboring different PAI-1 4G/5G genotypes in the DM group, the HTN group and the DM+HTN group. Conclusion: The RT-PCR method can accurately identify the PAI-1 4G/5G genotype in different individuals. The PAI-1 4G/5G polymorphism may not be associated with genetic susceptibility to DM, HTN and DM+HTN, but differences in clinical characteristics among individuals with various genotypes may provide a reference for disease assessment and personalized treatment of patients.

Predicting Diabetes in Patients with Metabolic Syndrome Using Machine-Learning Model Based on Multiple Years' Data.

Purpose: To evaluate the performance of machine-learning models based on multiple years of continuous data to predict incident diabetes among patients with metabolic syndrome. Patients and Methods: The dataset comprises the health records from 2008 to 2020 including 4510 nondiabetic participants with metabolic syndrome (MetS) at baseline and with at least 6 years of records. MetS was defined according to the International Diabetes Federation (IDF) criteria. Overall, 332 patients developed incident diabetes during the 7±1.4 years of follow-up. Three popular classification algorithms were evaluated on the dataset: logistic regression, random forest, and Xgboost. Five models including single-year models (year 1, year 2, and year 3) and multiple-year models (year 1-2 and year 1-3) were developed for each algorithm. Results: The model performances improved with the increasing longitudinal dataset as the area under the receiver operating characteristic curve (AUROC) was boosted for both random forest (year 1-3: AUROC=0.893; year 3: AUROC=0.862; year 1-2: AUROC=0.847; year 2: AUROC=0.838) and Xgboost (year 1-3: AUROC=0.897; year 3: AUROC=0.833; year 1-2: AUROC=0.856; year 2: AUROC=0.823) model. In the multiple-year models, the highest fasting plasma glucose, followed by the mean or lowest level of HbA1c and BMI had the most important predictive value for the onset of diabetes. In the "1-3" year model, "delta weight" which reflects the fluctuations of yearly change of weight was the fourth-most important feature. Conclusion: This study demonstrated improved performance with the accumulation of longitudinal data when using machine learning for diabetes prediction in MetS patients. For individuals with similar clinical parameters, the variation trends of these parameters could change the risk of future diabetes. This result indicated that models based on longitudinal multiple years' data may provide more personalized assessment tools for risk evaluation.

Nedd4-2-dependent Ubiquitination Potentiates the Inhibition of Human NHE3 by Cholera Toxin and Enteropathogenic Escherichia coli.

BACKGROUND & AIMS: Diarrhea is one of the most common illnesses and is often caused by bacterial infection. Recently, we have shown that human Na+/H+ exchanger NHE3 (hNHE3), but not non-human NHE3s, interacts with the E3 ubiquitin ligase Nedd4-2. We hypothesize that this property of hNHE3 contributes to the increased severity of diarrhea in humans. METHODS: We used humanized mice expressing hNHE3 in the intestine (hNHE3int) to compare the contribution of hNHE3 and mouse NHE3 to diarrhea induced by cholera toxin (CTX) and enteropathogenic Escherichia coli (EPEC). We measured Na+/H+ exchange activity and fluid absorption. The role of Nedd4-2 on hNHE3 activity and ubiquitination was determined by knockdown in Caco-2bbe cells. The effects of protein kinase A (PKA), the primary mediator of CTX-induced diarrhea, on Nedd4-2 and hNHE3 phosphorylation and their interaction were determined. RESULTS: The effects of CTX and EPEC were greater in hNHE3int mice than in control wild-type (WT) mice, resulting in greater inhibition of NHE3 activity and increased fluid accumulation in the intestine, the hallmark of diarrhea. Activation of PKA increased ubiquitination of hNHE3 and enhanced interaction of Nedd4-2 with hNHE3 via phosphorylation of Nedd4-2 at S342. S342A mutation mitigated the Nedd4-2-hNHE3 interaction and blocked PKA-induced inhibition of hNHE3. Unlike non-human NHE3s, inhibition of hNHE3 by PKA is independent of NHE3 phosphorylation, suggesting a distinct mechanism of hNHE3 regulation. CONCLUSIONS: The effects of CTX and EPEC on hNHE3 are amplified, and the unique properties of hNHE3 may contribute to diarrheal symptoms occurring in humans.

Predictive Value of GAD Antibody for Diabetes in Normal Chinese Adults: A Retrospective Cohort Study in China.

PURPOSE: To investigate the prevalence of GAD antibody (GADA) in the general adult population and to evaluate its predictive value for diabetes in China. PATIENTS AND METHODS: We searched the PUMCH-HM database and identified 36,731 adult subjects with GADA test results from 2012 to 2015. We then established a retrospective cohort of 4835 nondiabetic subjects at baseline with complete annual health evaluation records through 2019. The median follow-up time was 4.8 (3.0-7.3) years. RESULTS: The overall prevalence of GADA was 0.53% and was higher in diabetic subjects (1.25%) than in nondiabetic subjects (0.47%). We found a decrease in baseline body mass index (BMI) from the GADA- to GADAhigh subgroups among baseline diabetic and prediabetic patients and also those who developed diabetes later in the cohort study. A total of 136 subjects (2.8%) developed diabetes after a median follow-up of 3.5 years. For GADA+ participants, BMI was not associated with the risk for diabetes. In the Cox regression model, the GADAlow and GADAhigh exhibited 2.63-fold and 4.16-fold increased risk for diabetes, respectively. This increased risk for diabetes by GADA-positivity is only found in male adults (HR 4.55, 95% CI 2.25-9.23). CONCLUSION: GADA has a low prevalence in China but is associated with a 2.63-4.16-fold increased risk for diabetes.

Reference Intervals for Thyroid-Associated Hormones and the Prevalence of Thyroid Diseases in the Chinese Population.

BACKGROUND: Thyroid diseases are highly prevalent worldwide, but their diagnosis remains a challenge. We established reference intervals (RIs) for thyroid-associated hormones and evaluated the prevalence of thyroid diseases in China. METHODS: After excluding outliers based on the results of ultrasound screening, thyroid antibody tests, and the Tukey method, the medical records of 20,303 euthyroid adults, who visited the Department of Health Care at Peking Union Medical College Hospital from January 2014 to December 2018, were analyzed. Thyroid-associated hormones were measured by the Siemens Advia Centaur XP analyzer. The RIs for thyroid-associated hormones were calculated according to the CLSI C28-A3 guidelines, and were compared with the RIs provided by Siemens. The prevalence of thyroid diseases over the five years was evaluated and compared using the chi-square test. RESULTS: The RIs for thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3) were 0.71-4.92 mIU/L, 12.2-20.1 pmol/L, 3.9-6.0 pmol/L, 65.6-135.1 nmol/L, and 1.2-2.2 nmol/L, respectively. The RIs of all hormones except TT4 differed significantly between males and females. The RIs of TSH increased with increasing age. The prevalence of overt hypothyroidism, overt hyperthyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism was 0.5% and 0.8%, 0.2% and 0.6%, 3.8% and 6.1%, and 3.3% and 4.7% in males and females, respectively, which differed from those provided by Siemens. CONCLUSIONS: Sex-specific RIs were established for thyroid-associated hormones, and the prevalence of thyroid diseases was determined in the Chinese population.

The effect of ALDH2 rs671 gene mutation on clustering of cardiovascular risk factors in a big data study of Chinese population: associations differ between the sexes.

BACKGROUND: The ALDH2 rs671 genetic polymorphism has been linked with cardiovascular diseases (CVDs), but comprehensive epidemiological studies are lacking. An observational, retrospective big data study was carried out to evaluate the associations between this polymorphism and clustering cardiovascular risk factors (CRFs) in a Chinese population. METHODS: A total of 13,101 individuals (8431 males and 4670 females) were enrolled. Genetic polymorphism was assessed using gene mutation detection kits, coupled with an automatic fluorescent analyzer. Other data were obtained from the records of the Department of Health Care at Peking Union Medical College Hospital. RESULTS: Comparing the concentrations of common biochemical analytes, including BMI, SBP, DBP, ALT, AST, γ-GT, TBil, Cr, Glu, TC, TG, and HDL-C among individuals with the GG, GA, and AA genotypes of ALDH2 rs671, we found significant differences in males (all p < 0.001), but not in females. For males, the frequencies of hypertension, diabetes, and obesity were significantly higher for GG than for GA or AA (all p < 0.05). However, there was no significant difference for dyslipidemia, and no significant associations were observed for all frequencies in females. The prevalence of individuals with 1-4 CRFs was significantly higher among GG males than those carrying GA or AA, and fewer GG males had non-CRFs (all p < 0.05). CONCLUSION: Polymorphisms of ALDH2 rs671 are associated with clustering CRFs, especially hypertension and diabetes in males, but not in females. These associations are likely mediated by alcohol intake, which is also associated with this gene.

Establishment of variation source and age-related reference interval models for 22 common biochemical analytes in older people using real-world big data mining.

BACKGROUND: the ageing population has increased in many countries, including China. However, reference intervals (RIs) for older people are rarely established because of difficulties in selecting reference individuals. Here, we aimed to analyse the factors affecting biochemical analytes and establish RI and age-related RI models for biochemical analytes through mining real-world big data. METHODS: data for 97,220 individuals downloaded from electronic health records were included. Three derived databases were established. The first database included 97,220 individuals and was used to build age-related RI models after identifying outliers by the Tukey method. The second database consisted of older people and was used to establish variation source models and RIs for biochemical analytes. Differences between older and younger people were compared using the third database. RESULTS: sex was the main source of variation of biochemical analytes for older people in the variation source models. The distributions of creatinine and uric acid were significantly different in the RIs of biochemical analytes for older people established according to sex. Age-related RI models for biochemical analytes that were most affected by age were built and visualized, revealing various patterns of changes from the younger to older people. CONCLUSION: the study analysed the factors affecting biochemical analytes in older people. Moreover, RI and age-related RI models of biochemical analytes for older people were established to provide important insight into biological processes and to assist clinical use of various biochemical analytes to monitor the status of various diseases for older people.

Association between lipoprotein(a) concentration and the risk of stroke in the Chinese Han population: a retrospective case-control study.

BACKGROUND: Lipoprotein(a) [Lp(a)] is a risk factor of coronary heart disease, however, its effects on stroke are less well-defined. METHODS: We performed a single-center, retrospective case-control study in 1,953 and 196 ischemic stroke and hemorrhagic stroke in-hospital patients, respectively. Controls were healthy individuals that were matched for sex and age (±5 years) for the ischemic (1:1 ratio) and hemorrhagic (1:2 ratio) stroke. Lp(a) concentration was measured using the latex agglutination turbidimetric method. Logarithmic transformation and quartile categorization were applied to adjust for the skewed distribution of Lp(a). Conditional logistic regression models were used to assess the association between Lp(a) and stroke risk. RESULTS: Median Lp(a) concentration was higher in stroke patients when compared with controls (12.2 vs. 8.60 mg/dL) and hemorrhagic strokes (14.40 vs. 13.40 mg/dL). The conditional multivariate analysis revealed a positive association between Lp(a) and ischemic stroke (OR =2.03, 2.36, and 2.03 for quartiles 2, 3 and 4, respectively, vs. quartile 1; P<0.001). In addition, elevated Lp(a) was also significantly associated with increased hemorrhagic stroke risk, after adjusted for potential covariates (OR =1.93, 3.24, and 2.19 for quartile 2, 3 and 4 respectively vs. quartile 1, P<0.05). The stratified analyses for ischemic and hemorrhagic stroke revealed significant association between elevated log-transformed Lp(a) and ischemic stroke in men. Furthermore, there was a trend towards a higher stroke risk for younger patients compared with older patients. CONCLUSIONS: Elevated serum Lp(a) is significantly positively correlated with ischemic and hemorrhagic stroke risk in the Chinese Han population, especially among men and younger patients.

ApEn for assessing hypoxemia severity in obstructive sleep apnea hypopnea syndrome patients.

OBJECTIVE: A new index, approximate entropy (ApEn) of oxygen saturation, was used to assess the severity of hypoxemia in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), determine the correlation with other parameters, and explore its clinical value. METHODS: A retrospective analysis was performed on 1200 patients with OSAHS and snorers (normal control). All subjects underwent sleep apnea monitoring for 6 h. Subjects were divided into four subgroups by apnea-hypopnea index (AHI): normal control (AHI < 5), mild OSAHS (5 ≤ AHI < 15), moderate OSAHS (15 ≤ AHI < 30), and severe OSAHS 104 (AHI ≥ 30). ApEn was initially compared among the subgroups. Then a correlation analysis of AHI with ApEn and a correlation analysis of ApEn with oxygen desaturation index (ODI), lowest oxygen saturation (LO2), and T < 90% were performed. (2) The AHI was used as the gold standard, and an attempt was performed to determine the value of ApEn to assess the severity of hypoxemia in OSAHS. RESULTS: Among the 1200 subjects, 822 subjects were men (72%) and mean age was 53.2 ± 15.2 years (range 24-95 years). The ApEn in each group was significantly different (P <0.001), and the ApEn synchronously increased with AHI. Furthermore, a significant difference in ApEn was found among the groups (P <0.001). In addition, ApEn had a good correlation with ODI, LO2, and T <90%. According to the ROC analysis results, the boundary value of ApEn to judge OSAHS patients with mild, moderate, and severe hypoxia was 16.72, 17.84, and 20.06, respectively. CONCLUSION: ApEn synchronously increased with the AHI and had a good correlation with AHI, ODI, LO2, and T <90%. These findings suggest that ApEn may have clinical value for assessing hypoxia severity in OSAHS patients.

Fatal myositis and spontaneous haematoma induced by combined immune checkpoint inhibitor treatment in a patient with pancreatic adenocarcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have achieved unprecedented success in cancer treatment over the past decade. The application of ICIs hasled to the discovery of various types of immune-related adverse events (irAEs). Here, we report a case of fatal myositis and spontaneous haematoma following concurrent treatment of nivolumab and ipilimumab for pancreatic adenocarcinoma. CASE PRESENTATION: A 71-year-old gentleman with pancreatic adenocarcinoma underwent the Whipple procedure in September 2014. The patient received 8 cycles of adjuvant chemotherapy with gemcitabineand achieved a complete responsein April 2015. Treatment with the PD-1 inhibitor nivolumab was started due to suspected tumour recurrence in November 2015. In August 2016, the CTLA-4 inhibitor ipilimumab was added to nivolumab for 2 cycles. Eight weeks after the last dose, the patient developed severe myositis complicated with spontaneous haematomain skeletalmuscle. Pathology of the skeletal muscle autopsy revealed lymphocytic infiltration. Intense immunosuppressive therapy, including high-dose corticosteroids and methotrexate, resulted in clinical success in the treatment of myositis. However, the patient died of cancer recurrence. CONCLUSION: Myositis due to immunotherapy can be a fatal adverse event of ICIs, which requires close monitoring and cautious management.

Clinically-approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia.

Cystic Fibrosis (CF) is a multi-organ progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. Previously, we identified a significant dysfunction in CF cells and model mice of the transcription factor nuclear-factor-E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report that approved F508del CFTR correctors VX809/VX661 recover diminished Nrf2 function and colocalization with CFTR in CF human primary bronchial epithelia by proximity ligation assay, immunoprecipitation, and immunofluorescence, concordant with CFTR correction. F508del CFTR correctors induced Nrf2 nuclear translocation, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Rescue of Nrf2 function by VX809/VX661 was dependent on significant correction of F508del and was blocked by inhibition of corrected channel function, or high-level shRNA knockdown of CFTR or F508del-CFTR. Mechanistically, F508del-CFTR modulation restored Nrf2 phosphorylation and its interaction with the coactivator CBP. Our findings demonstrate that sufficient modulation of F508del CFTR function corrects Nrf2 dysfunction in CF.

Autotaxin determines colitis severity in mice and is secreted by B cells in the colon.

Autotaxin (ATX or ENPP2) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a pleiotropic lipid mediator acting on specific GPCRs. ATX and LPA have been implicated in key (patho)physiologic processes, including embryonic development, lymphocyte homing, inflammation, and cancer progression. Using LPA receptor knockout mice, we previously uncovered a role for LPA signaling in promoting colitis and colorectal cancer. Here, we examined the role of ATX in experimental colitis through inducible deletion of Enpp2 in adult mice. ATX expression was increased upon induction of colitis, whereas ATX deletion reduced the severity of inflammation in both acute and chronic colitis, accompanied by transient weight loss. ATX expression in lymphocytes was strongly reduced in Rag1-/- and µMT mice, suggesting B cells as a major ATX-producing source, which was validated by immunofluorescence and biochemical analyses. ATX secretion by B cells from control, but not Enpp2 knockout, mice led to ERK activation in colorectal cancer cells and promoted T cell migration. We conclude that ATX deletion suppresses experimental colitis and that B cells are a major source of ATX in the colon. Our study suggests that pharmacological inhibition of ATX could be a therapeutic strategy in colitis.-Lin, S., Haque, A., Raeman, R., Guo, L., He, P., Denning, T. L., El-Rayes, B., Moolenaar, W. H., Yun, C. C. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon.

Inhibition of autotaxin alleviates inflammation and increases the expression of sodium-dependent glucose cotransporter 1 and Na+/H+ exchanger 3 in SAMP1/Fc mice.

Crohn's disease (CD) is a chronic, relapsing, inflammatory disease that is often associated with malnutrition because of inflammation in the small intestine. Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidic acid. Increasing evidence suggests that ATX is upregulated during inflammation, and inhibition of ATX has been effective in attenuating chronic inflammatory conditions, such as arthritis and pulmonary fibrosis. This study aims to determine whether inhibition of ATX alleviates CD-associated inflammation and malnutrition by using SAMP1/Fc mice, a model of CD-like ileitis. SAMP1/Fc mice were treated the ATX inhibitor PF-8380 for 4 wk. Inhibition of ATX led to increased weight gain in SAMP1/Fc mice, decreased T helper 2 cytokine expression, including IL-4, IL-5, and IL-13, and attenuated immune cell migration. SAMP1/Fc mice have low expression of Na+-dependent glucose transporter 1 (SGLT1), suggesting impaired nutrient absorption associated with ileitis. PF-8380 treatment significantly enhanced SGLT1 expression in SAMP1/Fc mice, which could reflect the increased weight changes. However, IL-4 or IL-13 did not alter SGLT1 expression in Caco-2 cells, ruling out their direct effects on SGLT1 expression. Immunofluorescence analysis showed that the expression of sucrase-isomaltase, a marker for intestinal epithelial cell (IEC) differentiation, was decreased in inflamed regions of SAMP1/Fc mice, which was partially restored by PF-8380. Moreover, expression of Na+/H+ exchanger 3 was also improved by PF-8380, suggesting that suppression of inflammation by PF-8380 enhanced IEC differentiation. Our study therefore suggests that ATX is a potential target for treating intestinal inflammation and restoration of the absorptive function of the intestine. NEW & NOTEWORTHY This study is the first, to our knowledge, to determine whether autotoxin (ATX) inhibition improves inflammation and body weights in SAMP1/Fc mice, a mouse model of ileitis. ATX inhibition increased body weights of SAMP1/Fc mice and increased Na+-dependent glucose transporter 1 (SGLT1) expression. Increased SGLT1 expression in the inflamed regions was not a direct effect of cytokines but an indirect effect of increased epithelial cell differentiation upon ATX inhibition.

Lysophosphatidic Acid Receptor 1 Is Important for Intestinal Epithelial Barrier Function and Susceptibility to Colitis.

Intestinal epithelial cells form a barrier that is critical in protecting the host from the hostile luminal environment. Previously, we showed that lysophosphatidic acid (LPA) receptor 1 regulates proliferation of intestinal epithelial cells, such that the absence of LPA1 mitigates the epithelial wound healing process. This study provides evidence that LPA1 is important for the maintenance of epithelial barrier integrity. The epithelial permeability, determined by fluorescently labeled dextran flux and transepithelial resistance, is increased in the intestine of mice with global deletion of Lpar1, Lpar1-/- (Lpa1-/-). Serum liposaccharide level and bacteria loads in the intestinal mucosa and peripheral organs were elevated in Lpa1-/- mice. Decreased claudin-4, caudin-7, and E-cadherin expression in Lpa1-/- mice further suggested defective apical junction integrity in these mice. Regulation of LPA1 expression in Caco-2 cells modulated epithelial permeability and the expression levels of junctional proteins. The increased epithelial permeability in Lpa1-/- mice correlated with increased susceptibility to an experimental model of colitis. This resulted in more severe inflammation and increased mortality compared with control mice. Treatment of Caco-2 cells with tumor necrosis factor-α and interferon-γ significantly increased paracellular permeability, which was blocked by cotreatment with LPA, but not LPA1 knockdown cells. Similarly, orally given LPA blocked tumor necrosis factor-mediated intestinal barrier defect in mice. LPA1 plays a significant role in maintenance of epithelial barrier in the intestine via regulation of apical junction integrity.

Clinical Analysis of Unicentric Castleman's Disease with Paraneoplastic Pemphigus and Bronchiolitis Obliterans.

Objective To investigate the clinical features of unicentric Castleman's disease(UCD)with paraneoplastic pemphigus(PNP)and bronchiolitis obliterans(BO).Method Data of UCD patients with PNP and BO from Peking Union Medical College Hospital were retrospectively analyzed,along with literatures review. Results Totally 23 cases(11 males and 12 females)were enrolled.The median age was 31 years(13-56 years).The most common pathological type was hyaline-vascular variant(91.4%),and most tumors located in abdominopelvic cavity(69.6%).Considerable cases presented bulky masses(26.3%).Most cases were first diagnosed on presentation with the symtoms of PNP(90.0%).BO was characterized by progressive dyspnea after excision of CD lesions.The average follow-up duration was 27.5 months(1-135 months).The median overall survival time was 36.0 months(95% CI=13.9-58.1).Respiratory failure was the dominant cause of death(91.7%).Conclusions PNP should be considered among those patients with specific oral or cutaneous lesions.Earlier diagnosis and treatment of latent UCD are important for reducing complications and deaths.

Expression of GRK2 and IGF1R in hepatocellular carcinoma: clinicopathological and prognostic significance.

AIM: It has been shown that G-protein-coupled receptor kinase 2 (GRK2) negatively regulates the insulin-like growth factor 1 receptor (IGF1R) signalling pathway in hepatocellular carcinoma (HCC). The aim of this study was to evaluate the clinicopathological and prognostic significance of GRK2 and IGF1R in HCC. METHODS: Expression of GRK2 and IGF1R was first detected by tissue microarray-based immunohistochemistry in 156 patients with HCC. Staining results, termed the H-score, were then correlated with clinicopathological variables and patient survival. Finally, the prognostic value of GRK2 and IGF1R was validated in the publically available TCGA (The Cancer Genome Atlas) RNA-sequencing database. RESULTS: The H-score of GRK2 staining (which was significantly lower in tumour than non-tumour tissue) was negatively associated with that of IGF1R with a reverse trend. No clinicopathological significance of the proteins was found except for a relationship between tumoral IGF1R expression and tumour-node-metastasis stage. In univariate analysis, high IGF1R expression predicted poor overall and disease-free survival, whereas GRK2 was not prognostic. In multivariate analysis, IGF1R was significant for overall survival. Furthermore, IGF1R was also of prognostic value in the TCGA database. CONCLUSIONS: Our data indicate that GRK2 and IGF1R show a negative correlation in HCC. IGF1R could be a potential marker of poor prognosis for this malignancy.

Effects of first-dose volume and exercise on the efficacy and tolerability of bowel preparations for colonoscopy in Chinese people.

AIM: This study was designed to compare the efficacy and tolerability of bowel preparations with and without the higher first-dose volume of polyethylene glycol (PEG) solution or exercise after drinking PEG solution in Chinese people. METHODS: A total of 330 participants who had a colonoscopy done in Peking Union Medical College Hospital were randomly and evenly assigned to three groups. Participants in Group A ingested 1 L PEG solution and then ingested 2 L PEG solution at a rate of 250 mL every 15 minutes. Participants in Group B ingested 3 L PEG solution at a rate of 250 mL every 15 minutes and then exercised more than 10 minutes after ingesting each liter of PEG solution. Participants in Group C ingested 3 L PEG solution at a rate of 250 mL every 15 minutes. Experienced gastrointestinal endoscopists rated the efficacy of bowel preparations based on the Boston Bowel Preparation Scale score. A questionnaire regarding participants' symptoms associated with bowel preparations was administered to evaluate participants' tolerability. RESULTS: The three groups had insignificant difference in the percentages of participants' symptoms including dizziness, nausea, stomach ache, bloating, and asthenia. However, the percentages of participants having hunger sensation, sleep disturbance, and anal discomfort were significantly higher in groups with the higher first-dose volume of PEG solution or exercise after drinking PEG solution than without them. The three groups had insignificant difference in the Boston Bowel Preparation Scale score. CONCLUSION: Whether to add the higher first-dose volume of PEG solution and exercise after drinking PEG solution or not, all participants achieved a similar quality of bowel preparations. Bowel preparations without the additional first-dose volume of PEG solution or exercise after drinking PEG solution showed the advantage of high participant tolerability.

Evaluation of Reliability and Validity of the Hendrich II Fall Risk Model in a Chinese Hospital Population.

To translate, validate and examine the reliability and validity of a Chinese version of the Hendrich II Fall risk Model (HFRM) in predicting falls in elderly inpatient. A sample of 989 Chinese elderly inpatients was recruited upon admission at the Peking Union Medical College Hospital. The inpatients were assessed for fall risk using the Chinese version of the HFRM at admission. The reliability of the Chinese version of the HFRM was determined using the internal consistency and test-rested methods. Validity was determined using construct validity and convergent validity. Receiver operating characteristic (ROC) curves were created to determine the sensitivity and specificity. The Chinese version of the HFRM showed excellent repeatability with an intra-class correlation coefficient (ICC) of 0.9950 (95% confidence interval (CI): 0.9923-0.9984). The inter-rater reliability was high with an ICC of 0.9950 (95%CI: 0.9923-0.9984). Cronbach's alpha coefficient was 0.366. Content validity was excellent, with a content validity ratio of 0.9333. The Chinese version of the HFRM had a sensitivity of 72% and a specificity of 69% when using a cut-off of 5 points on the scale. The area under the curve (AUC) was 0.815 (P<0.001). The Chinese version of the HFRM showed good reliability and validity in assessing the risk of fall in Chinese elderly inpatients.

Capturing the Direct Binding of CFTR Correctors to CFTR by Using Click Chemistry.

Cystic fibrosis (CF) is a lethal genetic disease caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel. F508del is the most prevalent mutation of the CFTR gene and encodes a protein defective in folding and processing. VX-809 has been reported to facilitate the folding and trafficking of F508del-CFTR and augment its channel function. The mechanism of action of VX-809 has been poorly understood. In this study, we sought to answer a fundamental question underlying the mechanism of VX-809: does it bind CFTR directly in order to exert its action? We synthesized two VX-809 derivatives, ALK-809 and SUL-809, that possess an alkyne group and retain the rescue capacity of VX-809. By using Cu(I) -catalyzed click chemistry, we provide evidence that the VX-809 derivatives bind CFTR directly in vitro and in cells. Our findings will contribute to the elucidation of the mechanism of action of CFTR correctors and the design of more potent therapeutics to combat CF.

CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells.

Respiratory syncytial virus (RSV) is a major cause of severe pneumonia and bronchiolitis in infants and young children, and causes disease throughout life. Understanding the biology of infection, including virus binding to the cell surface, should help develop antiviral drugs or vaccines. The RSV F and G glycoproteins bind cell surface heparin sulfate proteoglycans (HSPGs) through heparin-binding domains. The G protein also has a CX3C chemokine motif which binds to the fractalkine receptor CX3CR1. G protein binding to CX3CR1 is not important for infection of immortalized cell lines, but reportedly is so for primary human airway epithelial cells (HAECs), the primary site for human infection. We studied the role of CX3CR1 in RSV infection with CX3CR1-transfected cell lines and HAECs with variable percentages of CX3CR1-expressing cells, and the effect of anti-CX3CR1 antibodies or a mutation in the RSV CX3C motif. Immortalized cells lacking HSPGs had low RSV binding and infection, which was increased markedly by CX3CR1 transfection. CX3CR1 was expressed primarily on ciliated cells, and ∼50 % of RSV-infected cells in HAECs were CX3CR1+. HAECs with more CX3CR1-expressing cells had a proportional increase in RSV infection. Blocking G binding to CX3CR1 with anti-CX3CR1 antibody or a mutation in the CX3C motif significantly decreased RSV infection in HAECs. The kinetics of cytokine production suggested that the RSV/CX3CR1 interaction induced RANTES (regulated on activation normal T-cell expressed and secreted protein), IL-8 and fractalkine production, whilst it downregulated IL-15, IL1-RA and monocyte chemotactic protein-1. Thus, the RSV G protein/CX3CR1 interaction is likely important in infection and infection-induced responses of the airway epithelium, the primary site of human infection.