Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

[Banxia Xiexin Decoction inhibiting colitis-associated colorectal cancer infected with Fusobacterium nucleatum by regulating Wnt/ß-catenin pathway].

This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and ß-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, ß-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3ß(GSK-3ß) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and ß-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3ß and an increased protein content of Wnt3a, ß-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and ß-catenin was downregulated. The protein content of E-cadherin and GSK-3ß increased, while that of Wnt3a, ß-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/ß-catenin pathway.

[Tongxie Yaofang regulates tumor-associated macrophage polarization in colorectal cancer under chronic stress].

This study aims to investigate the intervention effect and mechanism of Tongxie Yaofang in regulating tumor-associated macrophage polarization on colorectal cancer under chronic stress. BALB/C mice were randomized into blank, control, model, mifepristone, and low-, medium-, and high-dose Tongxie Yaofang groups. The other groups except the blank and model groups were subjected to chronic restraint stress and subcutaneous implantation of colon cancer cells for the modeling of colon cancer under stress. Du-ring this period, the body mass and tumor size of each group of mice were recorded. The degree of depression in mice was assessed by behavioral changes. Enzyme-linked immunosorbent assay was employed to determine the levels of cortisol(CORT), 5-hydroxytryptamine(5-HT), norepinephrine(NE), M1-associated inflammatory cytokines [interleukin(IL)-1ß, IL-12, and tumor necrosis factor(TNF)-α], and M2-associated inflammatory cytokines(IL-4 and IL-10) in the serum. The tumor growth of mice in each group was regularly monitored by in vivo imaging. The histopathological changes of tumors in each group of mice were observed by hematoxylin-eosin staining. The proportions of CD86 and CD206 in the tumor tissue were detected by flow cytometry and immunofluorescence staining. Western blot was employed to determine the protein levels of Janus kinase(JAK)1, JAK2, JAK3, signal transducer and activator of transcription(STAT)3, and STAT6 in the tumor tissue. The results showed that chronic stress increased the immobility time of mice, elevated the serum levels of CORT, IL-4, and IL-10, lowered the levels of 5-HT, NE, IL-1ß, IL-12, and TNF-α, and promoted the growth of subcutaneous tumors. The tumor cells in the tumor tissue grew actively, with obvious atypia and up-regulated protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and down-regulated protein level of CD86. The treatment with Tongxie Yaofang shortened the immobility time of mice, lowered the serum levels of CORT, IL-4, and IL-10, elevated the serum levels of 5-HT, NE, IL-1ß, IL-12, and TNF-α, and inhibited the growth of subcutaneous tumors in mice. Moreover, the treatment caused different degrees of necrosis in the tumor tissues, down-regulated the protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and up-regulated the protein level of CD86. In summary, Tongxie Yaofang can promote the transformation of M2 macrophages to M1 macrophages and change the tumor microenvironment under chronic stress to inhibit the development of colorectal cancer, which may be related to the JAK/STAT signaling pathway.

Correlation of Great Chinese Famine Exposure During Early Life to Prevalence of Kidney Stone in Adulthood.

Background: The Great Chinese Famine, as the famine of 1959-1961 was often known. Famine exposure during early life was proven to be associated with some kidney diseases but has not been studied with kidney stone. We aimed to investigate the relationship between exposure to the Great Chinese Famine in early life and the incidence of kidney stone in adulthood. Methods: From 1 January 2017 to 31 December 2018, a total of 19,658 eligible adults were recruited in a cross-sectional survey who were born between 1 October 1952 and 30 September 1964 in Guangdong, China. Participants were separated into kidney stone and none-kidney stone groups based on kidney stone status. According to birth data, participants were divided into non-exposed, fetal-exposed, early-, mid-, and late-childhood-exposed groups. Multivariate logistic regression, subgroup analysis and interaction test were used to estimate the odds ratios (ORs) and confidence intervals (CIs) between famine exposure and kidney stone. Results: In total, 19,658 (12,246 female, mean age 59.31 ± 3.68 years) subjects were enrolled, and 3219 (16.38%) participants with kidney stone. The prevalence of kidney in none-, fetal-, early-, mid-, and late-childhood-exposed groups were 645 (14.9%), 437 (15.9%), 676 (16.3%), 743 (17.0%), and 718 (17.6%), respectively (P<0.001). When compared with the unexposed group, the fully adjusted ORs for kidney stone from fetal-exposed, early-, mid- to late-childhood-exposed groups were 1.37 (95% CI: 1.13, 1.68, P=0.002), 1.98 (95% CI: 1.45, 2.72, P<0.001), 2.94 (95% CI: 1.96, 4.42, P<0.001), and 3.48 (95% CI: 2.11, 5.72, P<0.001), respectively (P for trend<0.001). Subgroup analyses revealed no interactions between the famine effect on kidney stones and body mass index, gender, smoking status, history of diabetes or hypertension (all P for interaction >0.05). Conclusion: This study found that exposure to the Great Chinese Famine during early life was independently associated with the increased incidence of kidney stone in adulthood.

Periplocin inhibits hepatocellular carcinoma progression and reduces the recruitment of MDSCs through AKT/NF-κB pathway.

AIMS: We aimed to evaluate the effect of periplocin on inhibiting hepatocellular carcinoma (HCC) and further determine its mechanisms. MAIN METHODS: Cytotoxic activity of periplocin against HCC cells was tested by CCK-8 and colony formation assays. The antitumor effects of periplocin were evaluated in human HCC SK-HEP-1 xenograft and murine HCC Hepa 1-6 allograft mouse models. Flow cytometry was used to measure cell cycle distribution, apopotosis, and the number of myeloid-derived suppressor cells (MDSCs). Hoechst 33258 dye was applied to observe the nuclear morphology. Network pharmacology was performed to predict possible signaling pathways. Drug affinity responsive target stability assay (DARTS) was used to evaluate AKT binding of periplocin. Western blotting, immunohistochemistry, and immunofluorescence were used to examine the protein expression levels. KEY FINDING: Periplocin inhibited cell viability with IC50 values from 50 nM to 300 nM in human HCC cells. Periplocin disrupted cell cycle distribution and promoted cell apoptosis. Moreover, AKT was predicted as the target of periplocin by network pharmacology, which was confirmed by that AKT/NF-κB signaling was inhibited in periplocin-treated HCC cells. Periplocin also inhibited the expression of CXCL1 and CXCL3, leading to decreased accumulation of MDSCs in HCC tumors. SIGNIFICANCE: These findings reveal the function of periplocin in inhibiting HCC progression by G2/M arrest, apoptosis and suppression of MDSCs accumulation through blockade of the AKT/NF-κB pathway. Our study further suggests that periplocin has the potential to be developed as an effective therapeutic agent for HCC.

LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability.

Genomic instability (GIN) is pivotal in regulating tumor drug resistance, which blocked the treatment of triple negative breast cancer (TNBC). Although recent studies implied that non-coding RNA (ncRNA)-mediated autophagy abolishment promoted tumorigenesis by up-regulation of GIN, autophagy was known as a risk factor in tumor drug resistance. However, previous study also pointed that up-regulation of autophagy promoted GIN. Therefore, the relationship between autophagy and GIN is not clear, and more work is needed. And, if an ncRNA is identified to be a co-regulator of autophagy and GIN, it will be a potential therapy target of chemotherapy resistance in TNBC. In our study, we recognized both autophagy-GIN-associated microRNA (mi-26a-5p) by big data analysis, which was prognosis-correlated in breast cancer. Next, we identified the up-stream regulators (long non-coding RNA, lncRNA) and down-stream targets of miR-26a-5p by bioinformatics analysis (online public databases). Finally, we established lncRNA OTUD6B-AS1/miR-26a-5p/MTDH signaling pathway, and verified their functions by cytological, molecular biological and zoological experiments. In general, our study found (1) miR-26a-5p was a protective factor of breast cancer, while OTUD6B-AS1 and MTDH were risk factors; (2) OTUD6B-AS1 was the up-stream regulator of miR-26a-5p verified by luciferase; (3) up-regulation of miR-26a-5p and down-regulation of MTDH promoted cellular cytotoxicity of paclitaxel (PTX) in vitro and in vivo. (4) down-regulation of miR-26a-5p, overexpression of MTDH and OTUD6B-AS1 promoted autophagy and DNA damage; (5) up-regulation of OTUD6B-AS1 and MTDH inhibited DNA damage response (DDR) by inhibiting the phosphorylated activation of RAD51, ATR and ATM.

The Potential Immunomodulatory Properties of Levornidazole Contribute to Improvement in Experimental Ulcerative Colitis.

The use of an antibiotic with immunomodulatory properties could be fascinating in treating multifactorial inflammatory conditions such as ulcerative colitis (UC). We report our investigations into the immunomodulatory properties of levornidazole, the S-enantiomer of ornidazole, which displayed a tremendous therapeutic potential in UC induced by dextran sodium sulfate (DSS). Levornidazole administration to DSS-colitic mice attenuated the intestinal inflammatory process, with an efficacy better than that shown by 5-amino salicylic acid. This was evidenced by decreased disease activity index, ameliorated macroscopic and microscopic colon damages, and reduced expression of inflammatory cytokines. Additionally, levornidazole displayed anti-inflammatory activity through Caveolin-1-dependent reducing IL-1ß and IL-18 secretion by macrophages contributing to its improvement of the intestinal inflammation, as confirmed in vitro and in vivo. In conclusion, these results pointed out that the immunomodulatory effects of levornidazole played a vital role in ameliorating the intestinal inflammatory process, which would be crucial for the translation of its use into clinical settings.

A Non-Linear Association of High-Density Lipoprotein Cholesterol with All-Cause and Cause-Specific Mortality in Diabetic Patients.

BACKGROUND: The association between high-density lipoprotein cholesterol (HDL-C) and the risk of death among people with diabetes remains to be verified. METHODS: This was a nationwide, population-based cohort study in United States. A total of 6549 diabetes patients were included from the National Health and Nutrition Examination Surveys (NHANES). HDL-C concentration was divided into quintiles, and the lowest risk group (Q4: 1.32 to 1.53 mmol/L) was used as reference. Multivariate Cox proportional hazards models and restrictive cubic curves were performed to estimate hazard ratios (HRs) with 95% confidence interval (CI) for all-cause and cause-specific mortality. RESULTS: During a median follow-up of 82.36 ± 50.11 months, 1546 (23.61%) cases of all-cause, 389 (5.94%) cardiovascular and 262 (4.00%) cancer mortality have occurred, respectively. After adjusting for potential covariates, a U-shaped association was found between HDL-C and all-cause mortality (minimum mortality risk at 1.37 mmol/L); the risk for all-cause mortality was significantly higher in the groups with HDL-C concentration <0.96 mmol/L (HR: 1.30; 95% CI: 1.09, 1.56; P=0.0046) and with HDL-C concentration ≥1.55 mmol/L (HR: 1.20; 95% CI: 1.00, 1.44; P=0.0481) than participants with HDL-C concentrations ranging from 1.32 to 1.53mmol/L. Nonlinear associations of HDL-C levels with both cardiovascular and cancer mortality were also observed. CONCLUSION: A non-linear association was observed association of HDL-C with all-cause, cardiovascular and cancer mortality among diabetic patients.

A nonlinear association of total cholesterol with all-cause and cause-specific mortality.

BACKGROUND: The link between total cholesterol (TC) and all-cause and specific mortality has not been elucidated. Herein, we aimed to evaluate the effect of TC levels on all-cause, cardiovascular disease (CVD), and cancer mortality. METHODS: All data analyzed were obtained from the National Health and Nutrition Examination Survey 1999-2014. The relationship between levels of TC and mortality was determined through Cox proportional hazard regression analysis coupled with multivariable adjustments. Two-piecewise linear regression models and Cox models with penalized splines were applied to explore nonlinear and irregular shape relationships. Kaplan-Meier survival curve and subgroup analyses were conducted. RESULTS: The sample studied comprised 14,662 men and 16,025 women, categorized as 25,429 adults aged 18-65 and 5,258 adults over 65 years old. A total of 2,570 deaths were recorded. All-cause, cardiovascular, and cancer mortality showed U-curve associations after adjusting for confounding variables in the restricted cubic spline analysis. Hazard ratios (HRs) of all-cause and cancer mortality were particularly negatively related to TC levels in the lower range < 200 mg/dL, especially in the range < 120 mg/dL (HR 1.97; 95% CI 1.38, 2.83, HR 2.39; 95% CI 1.21, 4.71, respectively). However, the HRs of cardiovascular disease mortality in the range < 120 mg/dL were the lowest (HR 0.60; 95% CI 0.15, 2.42). In the upper range, a TC range of ≥ 280 mg/dL was correlated with mortality as a result of CVD and cancer (HR 1.31; 95% CI 0.87, 1.97 and HR 1.22; 95% CI 0.82, 1.79). The lowest cumulative survival rate of all-cause mortality was recorded in the lowest TC-level group, while the lowest cumulative survival rate of CVD mortality was recorded in the highest TC-level group. CONCLUSIONS: A nonlinear association of TC level with all-cause, cancer, and CVD mortality in the American population was observed, suggesting that too low or too high serum total cholesterol levels might correlate with adverse outcomes.

Early-life exposure to the Chinese famine and risk of carotid intima-media thickness increased in adulthood.

BACKGROUND AND AIMS: Little was known about the effect of famine exposure on carotid intima-media thickness (cIMT). The present study aimed to explore the relationship in a Chinese population. METHODS AND RESULTS: Participants were divided into five groups: not exposed to famine, exposed to famine in fetal, early, mid or late childhood. Elevated cIMT was defined as a thickness of >0.9 mm measured by carotid ultrasound. Multivariate logistic regression was performed to calculate odds ratio (OR) and confidence interval (CI) between famine exposure and cIMT. A total of 2637 (970 male, mean age 59.1 ± 3.65 years) participants were recruited, and 491 (18.62%) of them had elevated cIMT. When compared with the non-exposure group, the fully adjusted ORs for increased cIMT for exposure in fetal, early, mid to late childhood were 1.321 (95%CI: 0.872, 1.994, P = 0.186), 1.713 (95% CI: 1.188, 2.483, P = 0.004), 2.359 (95% CI: 1.674, 3.357, P < 0.001) and 2.485 (95% CI: 1.773, 3.518, P < 0.001), respectively. Subgroup analyses showed that the exposure to famine did not interact with body mass index, gender, smoking status, hypertension and diabetes history on its effect on cIMT. CONCLUSION: Our findings indicated that early-life exposure to the Chinese famine might be associated with an increased risk of increased cIMT in adulthood.

Effects of waist to height ratio, waist circumference, body mass index on the risk of chronic diseases, all-cause, cardiovascular and cancer mortality.

BACKGROUND: Given the fat redistribution in later stages of life, how the associations between abdominal obesity and the risk of morbidity and mortality have changed with age have not been elucidated, especially for waist to height ratio (WHtR). OBJECTIVE: To compare the strength of association between obesity indices and chronic diseases at baseline, and the subsequent mortality risk among US adults. METHODS: We included 21 109 participants from National Health and Nutrition Examination Survey 1999-2014. We performed logistic regression and receiver operating curve analysis to examine the discriminatory power of obesity indicators on cardiometabolic diseases and cancer at baseline. Sex-stratified and age-stratified Cox models were constructed to explore the prospective association between obesity indices and all-cause, cardiovascular and cancer mortality. RESULTS: Elevated WHtR, elevated waist circumference (WC) and body mass index (BMI)-classified obesity are associated with higher odds of hypertension (OR: 1.37-2.13), dyslipidemia (OR: 1.06 to 1.75, all p<0.05) and diabetes (OR: 1.40-3.16, all p<0.05). WHtR had significantly better discriminatory power to predict cardiometabolic health than BMI, especially for diabetes (area under the curve: 0.709 vs 0.654). After multivariable adjustment, all obesity indicators are associated with lower risk of all-cause mortality among females aged ≥65 years (HR: 0.64 to 0.85), but the association was only significant for BMI when obesity indicators were mutually adjusted (HR: 0.79). CONCLUSIONS: WHtR and WC appeared to be the better indicators for cardiometabolic health than BMI. However, BMI had a stronger and inverse association with a greater risk of all-cause mortality among older females.

The relationship between famine exposure during early life and carotid plaque in adulthood.

BACKGROUND: Famine exposure is a potential risk factor for adverse cardiometabolic health. However, the relationship between famine exposure during early life and carotid plaque in adulthood remains unclear. Therefore, the aim was to investigate the relationship between famine exposure during early life and the risks for carotid plaque in adulthood. METHODS: This was a cross-sectional study. Data were collected between 2017 and 2018 in Guangdong, China. Subjects who were born between 1 October 1952 and 30 September 1964, and had the carotid ultrasound measurement were enrolled. All included participants were divided into five groups: no exposure, fetal exposure, early-childhood exposure, mid-childhood exposure, and late-childhood exposure. Carotid plaque was assessed by carotid ultrasound examination. Multivariate logistic regression was used to estimate the odds ratio (OR) and confidence interval (CI) between famine exposure and carotid plaque. RESULTS: There were 2652 subjects enrolled, 973 (36.7%) of them were males, and the mean age was 59.1 ± 3.6 years. The prevalence of carotid plaque in unexposed, fetal-exposed, early-childhood, mid-childhood, and late-childhood exposed groups were 40.2%, 40.8%, 55.3%, 56.8%, and 62.1%, respectively. When compared with the unexposed group, the fully adjusted ORs for carotid plaque from fetal-exposed, early-childhood, mid-childhood to late-childhood exposed were 1.023 (95% CI: 0.771, 1.357, P = 0.872), 1.755 (95% CI: 1.356, 2.275, P < 0.001), 1.780 (95% CI: 1.391, 2.280, P < 0.001), and 2.119 (95% CI: 1.643, 2.739, P < 0.001), respectively. Subgroup analyses showed that the famine effect on carotid plaque did not interact with body mass index, gender, smoking status, hypertension, and diabetes history (all P for interaction > 0.500). CONCLUSIONS: Famine exposure during early life was significantly associated with an increased risk of carotid plaque in adulthood.

Association between pulse pressure and ischaemic stroke in elderly patients with hypertension.

BACKGROUND: The association between pulse pressure (PP) and the risk of first ischaemic stroke (IS) is inconsistent. Therefore, we evaluated the association between PP and the risk of first IS among elderly hypertensive population in China. METHODS: This was a retrospective cohort study. Patients with hypertension and aged ≥60 years were recruited. Multivariate Cox regression was performed to evaluate the association between PP and the risk of IS. We further stratified the regression models into subgroups and test for interaction to assess whether the associations were modified by other covariates. RESULTS: A total of 3315 patients with hypertension (44.49% male; mean age 71.41±7.20 years) were included, and 206 cases of IS occurred with a median follow-up of 5.5 years. The results showed that per SD mm Hg increment in PP was associated with a 17% (95% CI 1.05 to 1.40, p=0.0172) increased risk of IS. Moreover, the HR of IS for the highest quartile of PP was 1.46 (95% CI 1.18 to 1.73, p=0.0011, p for trend <0.001) comparing with the lowest quartile of PP. Subgroup analysis showed that population aged ≥70 years, male, patients with smoking or drinking habit, diabetes at baseline, being overweight, with uncontrolled blood pressure or did not take antihypertensive drugs have a higher risk for IS. CONCLUSIONS: We found that PP was significantly associated with IS and was an independent risk factor for IS.

Derivation and validation of a simple nomogram prediction model for all-cause mortality among middle-aged and elderly general population.

BACKGROUND: A simple clinical model that can predict all-cause mortality in the middle-aged and older adults in general population based on demographics and physical measurement indicators. The aim of this study was to develop a simple nomogram prediction model for all-cause mortality in middle-aged and elderly general population based on demographics and physical measurement indicators. METHODS: This was a prospective cohort study. We used data from the 1999-2006 National Health and Nutrition Examination Survey (NHANES), which included adults aged ≥40 years with mortality status updated through 31 December 2015. Cox proportional hazards regression, nomogram and least absolute shrinkage and selection operator (LASSO) binomial regression model were performed to evaluate the prediction model in the derivation and validation cohort. RESULTS: A total of 13,026 participants (6,414 men, mean age was 61.59±13.80 years) were included, of which 6,671 (3,263 men) and 6,355 (3,151 men) were included in the derivation cohort and validation cohort, respectively. During an average follow-up period of 129.23±9.62 months, 4,321 died. We developed a 9-item nomogram mode included age, gender, smoking, alcohol intake, diabetes, hypertension, marriage status, education and poverty to income ratio (PIR). The area under the curve (AUC) was 0.842 and had good calibration. Internal validation showed good discrimination of the nomogram model with AUC of 0.849 and good calibration. Application of the LASSO regression model in the validation cohort also revealed good discrimination (AUC =0.854) and good calibration. A time-dependent and optimism-corrected AUC value for the model showed no significant relationship with the change of follow-up time. CONCLUSIONS: A simple nomogram model, including age, gender, smoking, alcohol intake, diabetes, hypertension, marriage, education and PIR, could predict all-cause mortality well in middle-aged and elderly general population.

The U Shaped Relationship Between High-Density Lipoprotein Cholesterol and All-Cause or Cause-Specific Mortality in Adult Population.

PURPOSE: The associations of high-density lipoprotein cholesterol (HDL-C) with mortality are still unclear. We explored the associations of HDL-C with all-cause and cause-specific mortality in an adult population. METHODS: Deaths were classified into all-cause, cardiovascular, and cancer mortality. Survival curve, multivariate Cox regression, and subgroup analyses were conducted, and hazard ratio (HR) and 95% confidence interval (CI) were performed. We fitted Cox regression models for all-cause, cardiovascular, and cancer mortality to evaluate their associations with categories of HDL-C (≤30, 31-40, 41-50, 51-60 [reference], 61-70, >70 mg/dL). RESULTS: A total of 42,145 (20,415 (48.44%) males, mean age 47.12±19.40 years) subjects were enrolled. At an average follow-up of 97.52±54.03 months, all-cause, cardiovascular, and cancer mortality numbers were 5,061 (12.01), 1,081 (2.56%), and 1,061 (2.52%), respectively. When compared with the reference group (HDL-C: 51-60 mg/dL), a U-shaped association was apparent for all-cause mortality, with elevated risk in participants with the lowest (≤30 mg/dL) (HR=1.33; 95% CI=1.14- 1.56) and highest (>70 mg/dL) (HR=1.14; 95% CI=1.02-1.27) HDL-C concentration. Associations for cardiovascular and cancer mortality were non-linear. An elevated risk for cancer mortality was observed in those with the highest HDL-C concentration (HR=1.06; 95% CI-0.84-1.34) compared with the reference group, although it was not statistically significant. The effect of HDL-C on mortality was adjusted by some traditional risk factors including age, gender, race, or comorbidities. CONCLUSION: A U-shaped association was observed between HDL-C and all-cause mortality among an adult population.

The Relationship Between Fasting Blood Glucose Levels and First Ischemic Stroke in Elderly Hypertensive Patients.

OBJECTIVE: The relationship between fasting blood glucose and first ischemic stroke in older adults was unclear, so we explored this association among older patients with hypertension in China. METHODS: We recruited hypertensive participants with 60 or more of age. Fasting blood glucose concentrations were categorized into quartiles. Hazard ratio (HR) and 95% confidence interval (CI) for ischemic stroke were estimated using multivariate Cox regression analysis and subgroup analysis. RESULTS: A total of 3310 (1474 (44.53%) male) patients with mean age of 71.41±7.20 years were included. During the mean follow-up period of 5.5 years, 206 cases of ischemic stroke occurred. After adjusting for potential confounding variables, multivariate adjusted HRs for each standard deviation increment of fasting blood glucose, the risk of ischemic stroke increased by 11% (95% CI: 1.03, 1.21; P= 0.008). In addition, when using the lowest group (Q1) as reference, the multivariate adjusted HRs for first ischemic stroke were 1.76 (95% CI: 1.08, 2.86; P=0.023), 1.73 (95% CI: 1.06, 2.81; P=0.027) and 2.42 (95% CI: 1.49, 3.93; P<0.001) (P for trend<0.001). Subgroup analysis revealed that the association between fasting blood glucose and the risk of ischemic stroke was higher in male (HR: 1.22 vs 1.10), those with uncontrolled hypertension (HR: 1.22 vs 1.10), subjects with diabetes (HR: 1.19 vs 1.10), overweight (HR: 1.19 vs 1.09), smoking habits (HR: 1.33 vs 1.13) and those whose eGFR< 90 (HR: 1.16 vs 1.09). CONCLUSION: Fasting blood glucose was an independent risk factor for the first ischemic stroke among older adults with hypertension. Managing fasting blood glucose may be beneficial for participants with diabetes, poorly controlled blood pressure, had smoking habits, being overweight, and with reduced renal function.

The correlation of circulating miR-29b and inflammatory markers with albuminuria in hypertensive patients.

AIMS: Circulating miR-29b and inflammatory process play a vital role in hypertension and hypertensive nephropathy. The aim of the present study was to investigate the association of circulating miR-29b and inflammatory markers with albuminuria and assess the predictive value of circulating miR-29b for albuminuria in essential hypertension. METHODS: This cross-sectional study was continuously enrolled 150 subjects and were divided into three groups based on random urinary albumin/creatinine ratio (UACR, mg/g), the patients with ACR<30 mg/g were classified as normal albuminuria, the values of 30< ACR<300 was defined as micro-albuminuria while the group with ACR over 300 mg/g are macro-albuminuria. Circulating miR-29b was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Multivariate logistic regression and area under the ROC curve (AUC) were used. RESULTS: We found miR-29b, C-reactive protein, and transforming growth factor-ß1 (TGF-ß1) in macro-albuminuria group were significantly higher than those in the micro-albuminuria and normal albuminuria group. The level of miR-29b was positively associated with TGF-ß1, C-reactive protein, and UACR, while negatively related to glomerular filtration rate. Circulating miR-29b was a significant independent determinant factor for albuminuria. CONCLUSION: Our results provided a clinical evidence of a positive association between circulating miR-29b, inflammatory markers, and UACR, and implied miR-29b was a significant independent determinant factor for albuminuria.

Short-term evaluation of the adjustable bulbourethral male sling for post-prostatectomy urinary incontinence.

OBJECTIVE: The Argus perineal sling is a minimally invasive surgical option to treat post-prostatectomy stress urinary incontinence (PPSUI). This study retrospectively evaluated the short-term clinical outcomes with the Argus sling for PPSUI management and determined the effects of potential preoperative parameters on intraoperative retrograde leak point pressure (RLPP). METHODS: In this retrospective review of 16 men with various degrees of stress incontinence after prostatic surgery who underwent Argus sling, PPSUI was evaluated by pad usage, urodynamics, 24-hour pad weight, and validated questionnaires. Findings before and a minimum of 6 months after sling placement were compared. "Cure" was defined as no pad usage or the use of 1 pad for security; "improvement" was defined as a reduction in daily pad use by >50%. RESULTS: After a mean (±SD) follow-up of 9.75 ± 3.51 months, 62.5% of patients were cured, 18.75% were improved, and 18.75% were still incontinent. Preoperative 24-hour pad weight was positively correlated with RLPP (P = .0121, r = 0.6286). Mean RLPP was 37.93 ± 3.45 cmH2 O. During follow-up, 44% of men had transient perineal or scrotal pain managed conservatively. Sling explantation, reported in 3 of 16 patients, was associated with urethral erosion or previous radiation therapy. CONCLUSION: The Argus male sling can lead to satisfactory results in carefully selected patients. Increased stress urinary incontinence severity based on 24-hour pad weight required higher RLPP to achieve continence. Favorable satisfaction variables and quality of life scores are affected by appropriate intraoperative tensioning pressure.

[Effects of Reclamation on Soil Nutrients and Microbial Activities in the Huixian Karst Wetland in Guilin].

To investigate the effect of reclamation on soil quality in the Huixian Karst Wetland, samples from different soil levels were collected from marsh wetland, reclaimed paddy field, and reclaimed dry farmland, for analyzing soil nutrient (carbon, nitrogen, phosphorous, and potassium) contents, microbial biomass carbon/nitrogen (MBC/MBN), and microbial activity indicators[i.e. basal respiration (BR), potential respiration (PR), microbial quotient (qMB), and metabolic quotient (qCO2)]. The correlations between the soil nutrient contents and soil microbial activity indictors were examined. The results showed that:①Artificial reclamation led to the trend of slight acidity in the soil and a marked loss in soil nutrients, while, the pH value, soil water content (SWC), and the contents of soil organic carbon (SOC), total nitrogen (TN), available nitrogen (AN), total phosphorus (TP), available phosphorus (AP), total potassium (TK), and available potassium (AK) decreased with reclamation. ②Among all the microbes, bacteria were the most numerous, followed by actinomycetes, and fungi were the least numerous. The microbial quantity decreased with the increase in the soil depth on the whole. The proportion of bacteria and actinomycetes were much higher in the paddy field, and that of fungi was the highest in the dry farmland. ③ In total, protease, sucrase, urease, catalase, and polyphenol oxidase activities decreased with the increasing of soil depths. Soil reclamation reduced the soil enzyme activities. ④qCO2 decreased after an initial increase in the marsh wetland, while it rose gradually in the reclaimed paddy field and reclaimed dry farmland. The contents of MBC, MBN, BR, PR, and qMB were the highest in the marsh wetland, followed by those in the reclaimed paddy field, with the lowest contents occurring in the reclaimed dry farmland. The trend of qCO2 contents in the 0-10 cm and 10-20 cm soil layers followed the order of marsh wetland > paddy field > dry farmland, but in the 20-30 cm and 30-40 cm soil layers, it showed the order dry farmland > paddy field > marsh wetland. The continuation of reclamation resulted in the decrease in soil microbial activity, and soil quality as well, especially in the dry farmland. Meanwhile, we should reduce the areas of paddy fields and dry farmlands under reclamation during the process of wetland ecological restoration in future. Conversion of farmlands to wetlands or lakes, to improve and increase the size of wetland ecosystems of nearby lands, should be done gradually.

Clinicopathological and prognostic significance of SHP2 and Hook1 expression in patients with thyroid carcinoma.

Some thyroid carcinomas (TCs) have an aggressive biological behavior and poor prognosis, and lacking of effective molecular markers is still the main obstacle for clinical stratified diagnosis and treatment of TC. The aim of the study was to discover the clinicopathological and prognostic implications of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) and Hook microtubule tethering protein 1 (Hook1) expression in TC. The expression of SHP2 and Hook1 was detected by immunohistochemistry on tissue microarrays from 313 primary TCs who underwent surgery in January 2006 and January 2010 in Zhejiang Cancer Hospital. The χ2 test, Kaplan-Meier method, and Cox proportional-hazards regression models were used to analyze the associations between their expressions and clinicopathological features and prognosis. The expression rates of SHP2 and Hook1 in TC were 57.5% (180/313) and 22.0% (69/313), respectively. SHP2 was positively correlated with Hook1 in TC. SHP2 expression differed significantly by age, histologic variants, maximal tumor diameter, intrathyroidal dissemination, metastases, and disease stage (P < .05). Moreover, patients with high SHP2 expression had reduced risk for death of disease compared with those with low SHP2 expression (hazard ratio, 0.267; 95% confidence interval, 0.105-0.684; P = .006) in univariate analysis, but that multivariate analysis failed to suggest that SHP2 was an independent prognostic factor. Hook1 expression differed significantly by histologic variants, maximal tumor diameter, and intrathyroidal dissemination (P < .05). However, there was no significant correlation between Hook1 expression and outcome in TC (P > .05). Our results suggested that SHP2 may be a favorable indicator of prognosis in TC.