Uni-directional release of ibuprofen from an asymmetric fibrous membrane enables effective peritendinous anti-adhesion.

Drug-loaded porous membranes have been deemed to be effective physicochemical barriers to separate postoperative adhesion-prone tissues in tendon healing. However, cell viability and subsequent tissue regeneration might be severely interfered with the unrestricted release and the locally excessive concentration of anti-inflammatory drugs. Herein, we report a double-layered membrane with sustained and uni-directional drug delivery features to prevent peritendinous adhesion without hampering the healing outcome. A vortex-assisted electrospinning system in combination with ibuprofen (IBU)-in-water emulsion was utilized to fabricate IBU-loaded poly-ʟ-lactic-acid (PLLA) fiber bundle membrane (PFB-IBU) as the anti-adhesion layer. The resultant highly porous structure, oleophilic and hydrophobic nature of PLLA fibers enabled in situ loading of IBU with a concentration gradient across the membrane thickness. Aligned collagen nanofibers were further deposited at the low IBU concentration side of the membrane for regulating cell growth and achieving uni-directional release of IBU. Drug release kinetics showed that the release amount of IBU from the high concentration side reached 79.32% at 14 d, while it was only 0.35% at the collagen side. Therefore, fibroblast proliferation at the high concentration side was successfully inhibited without affecting the oriented growth of tendon-derived stem cells at the other side. In vivo evaluation of the rat Achilles adhesion model confirmed the successful peritendinous anti-adhesion of our double-layered membrane, in that the macrophage recruitment, the inflammatory factor secretion and the deposition of pathological adhesion markers such as α-SMA and COL-III were all inhibited, which greatly improved the peritendinous fibrosis and restored the motor function of tendon.

Dietary 5-hydroxytryptophan improves sheep growth performance by enhancing ruminal functions, antioxidant capacity, and tryptophan metabolism: in vitro and in vivo studies.

Background: Hydroxytryptophan (5-HTP) can regulate the synthesis of 5-Hydroxytryptamine (5-HT) and melatonin (MT). In a previous metabolome analysis, we found that 5-HTP is an effective ingredient in yeast culture for regulating rumen fermentation. However, research on the effect of this microbial product (5-HTP) as a functional feed additive in sheep production is still not well explained. Therefore, this study examined the effects of 5-HTP on sheep rumen function and growth performance using in vitro and in vivo models. Methods: A two-factor in vitro experiment involving different 5-HTP doses and fermentation times was conducted. Then, in the in vivo experiment, 10 sheep were divided into a control group which was fed a basal diet, and a 5-HTP group supplemented with 8 mg/kg 5-HTP for 60 days. Results: The results showed that 5-HTP supplementation had a significant effect on in vitro DMD, pH, NH3-N, acetic acid, propionic acid, and TVFA concentrations. 5-HTP altered rumen bacteria composition and diversity indices including Chao1, Shannon, and Simpson. Moreover, the in vivo study on sheep confirmed that supplementing with 8 mg/kg of 5-HTP improved rumen fermentation efficiency and microbial composition. This led to enhanced sheep growth performance and increased involvement in the tryptophan metabolic pathway, suggesting potential benefits. Conclusion: Dietary 5-HTP (8 mg/kg DM) improves sheep growth performance by enhancing ruminal functions, antioxidant capacity, and tryptophan metabolism. This study can provide a foundation for the development of 5-HTP as a functional feed additive in ruminants' production.

Longitudinal varying coefficient single-index model with censored covariates.

It is of interest to health policy research to estimate the population-averaged longitudinal medical cost trajectory from initial cancer diagnosis to death, and understand how the trajectory curve is affected by patient characteristics. This research question leads to a number of statistical challenges because the longitudinal cost data are often non-normally distributed with skewness, zero-inflation, and heteroscedasticity. The trajectory is nonlinear, and its length and shape depend on survival, which are subject to censoring. Modeling the association between multiple patient characteristics and nonlinear cost trajectory curves of varying lengths should take into consideration parsimony, flexibility, and interpretation. We propose a novel longitudinal varying coefficient single-index model. Multiple patient characteristics are summarized in a single-index, representing a patient's overall propensity for healthcare use. The effects of this index on various segments of the cost trajectory depend on both time and survival, which is flexibly modeled by a bivariate varying coefficient function. The model is estimated by generalized estimating equations with an extended marginal mean structure to accommodate censored survival time as a covariate. We established the pointwise confidence interval of the varying coefficient and a test for the covariate effect. The numerical performance was extensively studied in simulations. We applied the proposed methodology to medical cost data of prostate cancer patients from the Surveillance, Epidemiology, and End Results-Medicare-Linked Database.

Prostate cancer in New York City: impact of neighborhood level social determinants of care.

Social determinants of health may impact prostate cancer presentation. Since neighborhoods may influence adjacent neighborhoods across often porous and arbitrary borders, we performed generalized spatial two stage least squares cross sections regression to assess direct and indirect (via adjacent neighborhoods) impact of neighborhood level independent variables. Using the New York State Public Access Cancer Epidemiology Data and the NYC Open neighborhood-level dataset, we discovered a direct association between Race and poverty with the likelihood of presenting with advanced prostate cancer. There were no indirect impacts of neighborhood variables, indicating the need to directly target neighborhoods to improve outcomes.

Comparisons of Medical Cost Trajectories Between Non-Hispanic Black and Non-Hispanic White Patients With Newly Diagnosed Localized Prostate Cancer.

OBJECTIVES: This study applied a recently developed statistical method to compare the mean cost trajectories between non-Hispanic White (NHW) and non-Hispanic Black (NHB) patients with localized prostate cancer conditioning on patients' survival. METHODS: In this observational study, we modeled cost trajectories of NHW and NHB patients with localized prostate cancer for 3 survival durations: 24, 48, and 72 months. We also compared the cost trajectories between NHW and NHB, stratified by comorbidities scores. RESULTS: We find that the mean cost trajectories of NHB were significantly higher than the trajectories of NHW in the last 12 months before death, regardless of the survival duration and patients' baseline comorbidity scores. For patients with comorbidity score ≥2, mean cost trajectories within the first year of diagnosis for NHB were significantly higher than those for NHW, except for the subgroup of patients with comorbidity 2-3 and whose survival length was 72 months. CONCLUSIONS: Our results suggested that a higher proportion of NHB patients with high comorbidity scores are likely contribute to their higher end-of-life costs than those for NHW patients. To narrow the gap in healthcare-related financial burden between NHB and NHW patients with localized prostate cancer, policy makers need to explore different strategies to better manage comorbidities.

[Lamin B1 regulates the growth of hepatocellular carcinoma cells by influencing telomerase activity].

Lamin B1 (LMNB1) is highly expressed in liver cancer tissues, and its influence and mechanism on the proliferation of hepatocellular carcinoma cells were explored by knocking down the expression of the protein. In liver cancer cells, siRNAs were used to knock down LMNB1. Knockdown effects were detected by Western blotting. Changes in telomerase activity were detected by telomeric repeat amplification protocol assay (TRAP) experiments. Telomere length changes were detected by quantitative real-time polymerase chain reaction (qPCR). CCK8, cloning formation, transwell and wound healing were performed to detect changes in its growth, invasion and migration capabilities. The lentiviral system was used to construct HepG2 cells that steadily knocked down LMNB1. Then the changes of telomere length and telomerase activity were detected, and the cell aging status was detected by SA-ß-gal senescence staining. The effects of tumorigenesis were detected by nude mouse subcutaneous tumorigenesis experiments, subsequent histification staining of tumors, SA-ß-gal senescence staining, fluorescence in situ hybridization (FISH) for telomere analysis and other experiments. Finally, the method of biogenesis analysis was used to find the expression of LMNB1 in clinical liver cancer tissues, and its relationship with clinical stages and patient survival. Knockdown of LMNB1 in HepG2 and Hep3B cells significantly reduced telomerase activity, cell proliferation, migration and invasion abilities. Experiments in cells and tumor formation in nude mice had demonstrated that stable knockdown of LMNB1 reduced telomerase activity, shortened telomere length, senesced cells, reduced cell tumorigenicity and KI-67 expression. Bioinformatics analysis showed that LMNB1 was highly expressed in liver cancer tissues and correlated with tumor stage and patient survival. In conclusion, LMNB1 is overexpressed in liver cancer cells, and it is expected to become an indicator for evaluating the clinical prognosis of liver cancer patients and a target for precise treatment.

Risk Factors for Bronchiolitis Obliterans Syndrome after Initial Detection of Pulmonary Impairment after Hematopoietic Cell Transplantation.

Pulmonary chronic graft-versus-host-disease (cGVHD), or bronchiolitis obliterans syndrome (BOS), is a highly morbid complication of hematopoietic cell transplantation (HCT). The clinical significance of a single instance of pulmonary decline not meeting the criteria for BOS is unclear. We conducted a retrospective analysis in a cohort of patients who had an initial post-HCT decline in the absolute value of forced expiratory volume in 1 second (FEV1) of ≥10% or mid-expiratory flow rate of ≥25% but not meeting the criteria for BOS (pre-BOS). We examined the impact of clinical variables in patients with pre-BOS on the risk for subsequent BOS. Pre-BOS developed in 1325 of 3170 patients (42%), of whom 72 (5%) later developed BOS. Eighty-four patients developed BOS without detection of pre-BOS by routine screening. Among patients with pre-BOS, after adjusting for other significant variables, airflow obstruction (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1 to 3.7; P = .02), percent-predicted FEV1 on decline (HR, .98; 95% CI, .97 to 1.0; P = .02), active cGVHD (HR, 7.7; 95% CI, 3.1 to 19.3; P < .001), peripheral blood stem cell source (HR, 3.8; 95% CI, 1.7 to 8.6; P = .001), and myeloablative conditioning (HR, 2.0; 95% CI, 1.1 to 3.5; P = .02) were associated with subsequent BOS. The absence of airflow obstruction and cGVHD had a negative predictive value of 100% at 6 months for subsequent BOS, but the positive predictive value of both factors was low (cGVHD, 3%; any obstruction, 4%; combined, 6%). Several clinical factors at the time of pre-BOS, particularly active cGVHD and airflow obstruction, increase the risk for subsequent BOS. These factors merit consideration to be included in screening practices to improve the detection of BOS, with the caveat that the predictive utility of these factors is limited by the overall low incidence of BOS among patients with pre-BOS.

Elevating Photooxidation of Methane to Formaldehyde via TiO2 Crystal Phase Engineering.

Photocatalytic conversion of methane to value-added products under mild conditions, which represents a long sought-after goal for industrial sustainable production, remains extremely challenging to afford high production and selectivity using cheap catalysts. Herein, we present the crystal phase engineering of commercially available anatase TiO2 via simple thermal annealing to optimize the structure-property correlation. A biphase catalyst with anatase (90%) and rutile (10%) TiO2 with the optimal phase interface concentration exhibits exceptional performance in the oxidation of methane to formaldehyde under the reaction conditions of water solvent, oxygen atmosphere, and full-spectrum light irradiation. An unprecedented production of 24.27 mmol gcat-1 with an excellent selectivity of 97.4% toward formaldehyde is acquired at room temperature after a 3 h reaction. Both experimental results and theoretical calculations disclose that the crystal phase engineering of TiO2 lengthens the lifetime of photogenerated carriers and favors the formation of intermediate methanol species, thus maximizing the efficiency and selectivity in the aerobic oxidation of methane to formaldehyde. More importantly, the feasibility of the scale-up production of formaldehyde is demonstrated by inventing a "pause-flow" reactor. This work opens the avenue toward industrial methane transformation in a sustainable and economical way.

Neural Peptide α-CGRP Coregulated Angiogenesis and Osteogenesis via Promoting the Cross-Talk between Mesenchymal Stem Cells and Endothelial Cells.

Background: The coupled vascularization and bone remodeling are key steps during bone healing, during which the cross-talk between mesenchymal stem cells (MSCs) and endothelial cells plays vital roles. Evidence indicates the well-characterized neuropeptide Calcitonin Gene-Related Peptide-α (CGRP) is proven to play an important role during bone regeneration. However, the regulatory effects of αCGRP on angiogenesis and osteogenesis, as well as underlying cellular and molecular mechanisms, remain unclear. Aim: The present study was performed to verify the availability of the CGRP for osteogenic capacity in MSCs and explore its potential underlying molecular mechanism. After that, the promoted angiogenic effect of CGRP as well as its underlying mechanisms was studied. Methods and Results: The results showed that CGRP could significantly increase the cyclic adenosine monophosphate (cAMP) level and promote the osteogenesis ability of MSCs via cAMP/PKA signaling pathway. Direct exposure to CGRP increased nitric oxide synthase expression, the release of NO, tube formation, and wound healing of human umbilical vein endothelial cells (HUVEC). The CGRP-treated MSCs were observed with high expression levels of angiogenic factors, such as bFGF and VEGF-α; the conditioned medium derived from CGRP-treated MSCs was also able to promote tube formation and transmembrane migration of HUVECs. Conclusion: These findings demonstrate the coregulated angiogenesis and osteogenesis effects of CGRP, especially for its regulation effects on the cross-talk between mesenchymal stem cells and endothelial cells.

MicroRNA engineered umbilical cord stem cell-derived exosomes direct tendon regeneration by mTOR signaling.

BACKGROUND: Exosomes are extracellular vesicles of nano-structures and represent an emerging nano-scale acellular therapy in recent years. Tendon regeneration is a sophisticated process in the field of microsurgery due to its poor natural healing ability. To date, no successful long-term solution has been provided for the healing of tendon injuries. Functional recovery requires advanced treatment strategies. Human umbilical cord mesenchymal stem cell-derived exosomes (HUMSC-Exos) are considered as promising cell-free therapeutic agents. However, few studies reported their potential in the tendon repair previously. In this study, we explored the roles and underlying mechanisms of HUMSC-Exos in the tendon regeneration. RESULTS: Expression of tendon-specific markers in, and collagen deposition by, tendon-derived stem cells (TDSCs) treated with HUMSC-Exos increased in vitro. In a rat Achilles tendon injury model, treatment with HUMSC-Exos improved the histological structure, enhanced tendon-specific matrix components, and optimized biomechanical properties of the Achilles tendon. Findings in miRNA sequencing indicated a significant increase in miR-29a-3p in HUMSC-Exo-treated Achilles tendons. Next, luciferase assay in combination with western blot identified phosphatase and tensin homolog (PTEN) as the specific target of miR-29a-3p. Furthermore, we applied a miR-29a-3p-specific agonist to engineer HUMSC-Exos. These HUMSC-Exos overexpressing miR-29a-3p amplified the gain effects of HUMSC-Exos on tendon healing in vivo. To explore the underlying mechanisms, a transforming growth factor-ß1 (TGF-ß1) inhibitor (SB-431542), mTOR inhibitor (rapamycin), and engineered HUMSC-Exos were employed. The results showed that TGF-ß1 and mTOR signaling were involved in the beneficial effects of HUMSC-Exos on tendon regeneration. CONCLUSION: The findings in our study suggest that PTEN/mTOR/TGF-ß1 signaling cascades may be a potential pathway for HUMSC-Exos to deliver miR-29a-3p for tendon healing and implicate a novel therapeutic strategy for tendon regeneration via engineered stem cell-derived exosomes.

Statistical modeling of longitudinal medical cost trajectory: renal cell cancer care cost analyses.

Estimating the current cost of cancer care is important to health policy makers. An indispensable step in cost projection is to estimate cost trajectories from an incident cohort of cancer patients using longitudinal medical cost data, accounting for terminal events such as death, and right censoring due to loss of follow-up. Since the cost of cancer care and survival are correlated, a scientifically meaningful quantity for inference in this context is the mean cost trajectory conditional on survival. We propose a two-stage semiparametric approach to estimate the longitudinal cost trajectories from a joint model of longitudinal medical costs and survival. The longitudinal cost trajectories corresponding to various survival times form a bivariate surface in a triangular area. The cost trajectories are estimated using the tensor products of discretized measurement time and survival, as well as effective ridge penalties for data in 2D arrays. The proposed approach balances the practical considerations of model flexibility, statistical efficiency, and computational tractability. We used the proposed method to estimate the cost trajectories of renal cell cancer patients using the Surveillance, Epidemiology, and End Results-Medicare linked database.

Patient and Provider Variables Associated with Variation in the Systemic Treatment of Advanced Prostate Cancer.

PURPOSE: Six treatments have improved overall survival in men with metastatic castration-resistant prostate cancer (mCRPC), each differing in toxicities and cost. This study identified patient and provider factors associated with variation in treatment of men with mCRPC to identify potential barriers to treatments. METHODS: A claims database of commercially insured patients was used to identify patients with prostate cancer treated with abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223 between 2010 and 2016. Multinomial and binomial logistic regressions were conducted to determine patient and provider factors associated with treatment patterns. RESULTS: Among 5,575 patients identified, patients with a household income >$99,000 were less likely to receive an expensive oral androgen signaling inhibitor (abiraterone or enzalutamide) as first-line treatment versus docetaxel compared to patients with a household income <$50,000 (odds ratio, OR, 0.66, 95% confidence interval, CI, 0.48-0.92). Patients who are Black (OR 1.43, 95% CI 1.02-2.01), live in the Pacific region versus the South Atlantic (OR 2.68, 95% CI 1.74-4.11), received treatment from a urologist versus a medical oncologist (OR 16.05, 95% CI 6.01-42.86), or had pre-existing heart failure (OR 1.69, 95% CI 1.18-2.42) were more likely to receive first-line oral androgen signaling inhibitors over docetaxel, independent of other factors on multivariable analysis. CONCLUSION: Clinicians and policy makers should be aware of the potential barriers and provider factors that influence use of novel therapies among patients with advanced prostate cancer, including the paradoxical effect of income and the substantial effect of provider specialty on first-line treatment rendered to patients with mCRPC.

The predictive value of 18F-FDG PET for pathological response of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy: a meta-analysis.

OBJECTIVE: We want to review the value of 18-fluoro-deoxy-glucose positron emission tomography for response prediction of primary tumor in patients with esophageal cancer during or after neoadjuvant chemoradiotherapy. METHODS: Studies were searched in Pubmed, Embase and Cochrane Library with specific search strategy. The published articles were included according to the criteria established in advance. The included studies were divided into two groups according to the time of the repeat positron emission tomography: during (Group A) or after neoadjuvant chemoradiotherapy (Group B). The studies that performed the repeat positron emission tomography after neoadjuvant chemoradiotherapy were graded Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity, specificity and diagnostic odds ratio were obtained for both groups on the basis of no-existing of threshold effect. RESULTS: Fifteen studies were included in the present study. The threshold effect did not exist in both groups. The pooled sensitivity, specificity and diagnostic odds ratio were 85%, 59%, 6.82 with 95% confidence interval 76-91%, 48-69%, 2.25-20.72 in Group A. The equivalent values were 67%, 69%, 6.34 with 95% confidence interval 60-73%, 63-74%, 2.08-19.34 in Group B. The pooled sensitivity was 90% in four studies that enrolled patients with esophageal squamous cell carcinoma merely in Group B. CONCLUSIONS: According to the present data, positron emission tomography should not be used routinely to guide treatment strategy in esophageal cancer patients. We speculated that positron emission tomography could be used as a tool to predict treatment response after neoadjuvant chemoradiotherapy in patients with esophageal squamous cell carcinoma.

Retinoblastoma-binding protein 2 induces epithelial-mesenchymal transition in esophageal squamous cancer cells.

OBJECTIVES: To investigate the effect of retinoblastoma-binding protein 2 (RBP2) on epithelial-mesenchymal transition (EMT) in esophageal squamous cancer cells and to compare the effect of RBP2 in lung squamous cancer cells and esophageal squamous cancer cells. RESULTS: When transfected with RBP2 siRNA, the migrated cells were 36.3 ± 6.03 by transwell migration assay, compared to 107 ± 6.7 cells in the control group. The mRNA level of epithelial cadherin (E-cadherin) was 1.54 ± 0.14 times higher than in the control group, and that of neural cadherin (N-cadherin) fell to 0.76 ± 0.03 times. The relative luciferase activity of E-cadherin promoter rose to 3.84 ± 0.23 times. Correspondingly, the expression of E-cadherin protein increased and that of N-cadherin protein decreased. When SK-MES-1 cells were transfected with RBP2 siRNA, their relative mRNA level of E-cadherin was 8.6 ± 0.37 times as high as that in control group, which was higher than that in Eca-109 cells. The E-cadherin protein was also greater in SK-MES-1 cells. CONCLUSION: RBP2 could induce EMT in esophageal cancer cells and exert a greater effect on the expression of E-cadherin in lung squamous cells than in esophageal squamous cells.

RBP2 induces epithelial-mesenchymal transition in non-small cell lung cancer.

RBP2 has been found to actively participate in cancer progression. It inhibits the senescence of cancer cells, mediates cancer cell proliferation and promotes cancer metastasis. It is also essential to drug tolerance. However, the effects of RBP2 on epithelial-mesenchymal transition are still unknown. In this study, we analyzed the effects of RBP2 on epithelial-mesenchymal transition in non-small cell lung cancer. The results showed that RBP2 down-regulated the expression of E-cadherin by inhibiting the promoter activity of E-cadherin and up-regulated the expression of N-cadherin and snail via the activation of Akt signaling, and the overexpression of RBP2 induced epithelial-mesenchymal transition in non-small cell lung cancer cells. Our study further indicated that RBP2 may be a potential target for anti-lung cancer therapy.

Association between the telomerase reverse transcriptase (TERT) rs2736098 polymorphism and cancer risk: evidence from a case-control study of non-small-cell lung cancer and a meta-analysis.

BACKGROUND: A common genetic variant, telomerase reverse transcriptase (TERT) rs2736098, was recently reported to be associated with lung cancer risk in Caucasians. In addition, many studies have investigated the role of this polymorphism in the etiology of cancer of various organs. Nevertheless, the results of related case-control studies remain inconsistent. METHODS: We hypothesized that the genetic risk variant identified in Caucasians may potentially influence the susceptibility to lung cancer in the Chinese population. To test this hypothesis, a case-control study including 539 non-small-cell lung cancer (NSCLC) cases and 627 cancer-free controls was conducted. Furthermore, to investigate the association between rs2736098 and cancer risk, a meta-analysis based on previously published studies and our case-control study was also performed. RESULTS: Multivariate logistic regression demonstrated that individuals carrying the A allele or the AA genotype exhibited a significantly elevated risk of NSCLC compared with those carrying the G allele or GG genotype (A vs. G: OR = 1.21, 95% CI = 1.02-1.43, P = 0.028; AA vs. GG: OR = 1.48, 95% CI = 1.05-2.09, P = 0.025). Additionally, this association was stronger among adenocarcinoma cases (AA vs. GG: OR = 1.67, 95% CI = 1.12-2.50, P = 0.013; A vs. G: OR = 1.28, 95% CI = 1.05-1.57, P = 0.016). In the meta-analysis, a borderline significant association between the rs2736098 polymorphism and overall cancer risk was observed (AA vs. GG: OR = 1.25, 95% CI = 1.07-1.46; AA vs. AG+GG: OR = 1.22, 95% CI = 1.06-1.41; additive model: OR = 1.10, 95% CI = 1.02-1.18), and further stratifications demonstrated a moderately increased risk for lung and bladder cancer, Asian ethnicity and hospital-based studies. CONCLUSIONS: Our results suggest that the rs2736098 polymorphism may contribute to the risk of lung cancer, especially adenocarcinoma, in the Chinese population. In addition, the current meta-analysis indicates that this genetic variant is only weakly associated with overall cancer risk. However, the rs2736098 polymorphism may affect individual susceptibility to lung and bladder cancer. Further studies are needed to validate our findings.

Association of CHRNA5-A3-B4 variation with esophageal squamous cell carcinoma risk and smoking behaviors in a Chinese population.

BACKGROUND: CHRNA5-A3-B4, the gene cluster encoding nicotinic acetylcholine receptor subunits, is associated with lung cancer risk and smoking behaviors in people of European descent. Because cigarette smoking is also a major risk factor for esophageal squamous cell carcinoma (ESCC), we investigated the associations between variants in CHRNA5-A3-B4 and ESCC risk, as well as smoking behaviors, in a Chinese population. METHODS: A case-control study of 866 ESCC patients and 952 healthy controls was performed to study the association of polymorphisms (rs667282 and rs3743073) in CHRNA5-A3-B4 with cancer risk using logistic regression models. The relationships between CHRNA5-A3-B4 polymorphisms and smoking behaviors that can be quantified by cigarettes smoked per day (CPD) and pack-years of smoking were separately estimated with Kruskal-Wallis tests among all 840 smokers. RESULTS: CHRNA5-A3-B4 rs667282 TT/TG genotypes were associated with significantly increased risk of ESCC [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.03 - 1.69, P = 0.029]. The increased ESCC risk was even higher among younger subjects (≤60 years) (OR = 1.44, 95% CI = 1.04 - 1.98, P = 0.024). These effects were not found in another polymorphism rs3743073. No evident association between the two polymorphisms and smoking behaviors was observed. CONCLUSIONS: These results support the hypothesis that CHRNA5-A3-B4 is a susceptibility gene cluster for ESCC. The relationship between CHRNA5-A3-B4 and smoking behaviors in a Chinese population needs further investigation.

Is susceptibility locus for lung cancer in the 15q25 nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 associated with risk of gastric cancer?

An association between common variants in the 15q25 nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3-B4 (responsible for encoding nAChR subunits) and lung cancer risk has recently been reported in both Caucasian and Chinese population. Cigarette smoking is one of the major risk factors for both lung and gastric cancer. Moreover, nAChR plays an important role in cigarette smoke-related lung carcinogenesis as well as gastric cancer. Nevertheless, no study has evaluated the association between CHRNA5-A3-B4 gene cluster variants (rs667282 and rs3743073, two variants modifying lung cancer risk) and risk of gastric cancer. We genotyped these two single nucleotide polymorphisms(SNPs) and analyzed their associations with risk of gastric cancer in a case-control study of 637 gastric cancer patients and 855 healthy individuals matched by age and sex in a Chinese Han population. The differences in genotype distribution of the two SNPs (rs667282, rs3743073) between the cases and controls were not statistically significant (p = 0.468 and p = 0.495, respectively). Overall, we did not observe a significant association of each genotype of the two SNPs with risk of gastric cancer (TT/CT vs. CC: adjusted OR = 1.12,95 % CI = 0.86-1.45; p = 0.401 for rs667282 and GG/TG vs. TT: adjusted OR = 1.13,95 % CI = 0.90-1.43; p = 0.300 for rs3743073).The results of our study indicated that these two SNPs at the 15q25 locus did not modify gastric cancer risk and the reported risk SNP at 15q25 may be specific to lung cancer. Additional larger studies are needed to further confirm our findings.

TNF-α increases bone marrow mesenchymal stem cell migration to ischemic tissues.

The objective of this study was to analyze the influence of TNF-α on rat mesenchymal stem cells (MSCs) and to assess feasibility of MSC transplantation to repair ischemic injury. In this study, adhesion molecules and cell specific surface markers on MSCs were measured after exposure to different concentrations of TNF-α. MSCs stimulated with varying concentrations of TNF-α were cultured with aortic endothelial cells, and the adhesion rate was measured. MSCs were then stimulated with an optimum concentration of TNF-α as determined in vitro, and injected intravenously into rats with ischemic hind limb injury. The number of MSCs in muscle samples from the ischemic area was counted. The results showed that (1) TNF-α induced a concentration-dependent increase in VCAM-1 expression in MSCs, whereas the expression of L-selectin, ICAM-1 and VLA-4 did not change significantly. Expression of MSC-specific antigens was unchanged. (2) MSCs pretreated with 10 ng/ml TNF-α showed significantly increased adhesion to endothelial cells in vitro, and accumulated to a greater extent in the areas of ischemic damage in rat hind limbs. We were able to conclude that TNF-α has no effect on expression of MSC-specific markers, but can increase the expression of VCAM-1 on rat MSCs. Suitable concentrations of TNF-α can promote MSC adhesion to endothelial cells and migration to damaged tissue.