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Human umbilical cord-derived mesenchymal stem/stromal cells (UMSCs) demonstrate great therapeutic potential in regenerative medicine. The use of UMSCs for clinical applications requires high quantity and good quality of cells usually by in vitro expansion. However, the heterogeneity and the characteristics of cultured UMSCs and the cognate human umbilical cord tissue at single-cell resolution remain poorly defined. In this study, we created a single-cell transcriptome profile of human umbilical cord tissue and the cognate culture-expanded UMSCs. Based on the inferred characteristics of cell clusters and trajectory analysis, we identified three subgroups in culture-expanded UMSCs and putative novel transcription factors (TFs) in regulating UMSC state transition. Further, putative ligand-receptor interaction analysis demonstrated that cellular interactions most frequently occurred in epithelial-like cells with other cell groups in umbilical cord tissue. Moreover, we dissected the transcriptomic differences of in vitro and in vivo subgroups and inferred the telomere-related molecules and pathways that might be activated in UMSCs for cell expansion in vitro. Our study provides a comprehensive and integrative study of the transcriptomics of human umbilical cord tissue and their cognate-cultured counterparts, which paves the way for a deeper understanding of cellular heterogeneity and offers fundamental biological insight of UMSCs-based cell therapy.

The lid margins are essential to maintain a healthy tear film and distribute it over the ocular surface to achieve an optimal refractive interface. Alterations in the lid margin structures and func...

OBJECTIVES Prader-Willi syndrome (PWS) increases the risk of obstructive sleep apnea (OSA) due to obesity, hypotonia, and abnormal ventilatory responses. We evaluated post-adenotonsillectomy complications, polysomnography changes, and quality of life in children with OSA and PWS. STUDY DESIGN Systematic review and meta-analysis. METHODS We conducted a systematic review and meta-analysis by searching PubMed, Embase, Cochrane, Web of Science, and Scopus. Two researchers independently reviewed studies about adenotonsillectomy for OSA in patients

Previous studies have shown that single‐nucleotide polymorphisms (SNPs) of a disintegrin and metalloproteinase with thrombospondin type 1 motif 4 (ADAMTS4) may involve in the pathogenesis of some diseases. However, it is not clear whether they are associated with hepatocellular carcinoma (HCC). A hospital‐based case‐control study, including 862 cases with HCC and 1120 controls, was conducted to assess the effects of 258 SNPs in the coding regions of ADAMTS4 on HCC risk and prognosis. We found that six SNPs in ADAMTS4 were differential distribution between cases and controls via the primary screening analyses; however, only rs538321148 and rs1014509103 polymorphisms were further identified to modify the risk of HCC (odds ratio: 2.73 and 2.95; 95% confidence interval, 2.28‐3.29 and 2.43‐3.58; P‐value, 5.73 × 10−27 and 1.36 × 10−27, respectively). Significant interaction between these two SNPs and two known causes of hepatitis B virus and aflatoxin B1 were also observed. Furthermore, rs538321148 and rs1014509103 polymorphisms were associated not only with clinicopathological features of tumor such as tumor stage and grade, microvessel density, and vessel metastasis, but with poor overall survival. Additionally, these SNPs significantly downregulated ADATMS4 expression in tumor tissues. These data suggest that SNPs in the coding region of ADAMTS4, such as rs538321148 and rs1014509103, may be potential biomarkers for predicting HCC risk and prognosis., This relatively large‐size retrospective study was conducted to investigate the association between ADAMTS4 single‐nucleotide polymorphisms and the risk and prognosis of hepatocellular carcinoma (HCC). Both rs538321148 and rs1014509103 polymorphisms were identified to increase HCC risk and change tumor outcome, and they may be potential biomarkers for predicting HCC risk and prognosis.

Objectives/hypothesis Adenotonsillectomy is first-line treatment for pediatric obstructive sleep apnea syndrome (OSAS) when not otherwise contraindicated. There is concern severe OSAS increases risk of comorbid cardiopulmonary abnormalities, such as ventricular hypertrophy or pulmonary hypertension, which preoperative testing could detect. Our objective is to determine if there is a severity of pediatric OSAS where previously undetected cardiopulmonary comorbidities are likely. Study design Retrospective chart review. Methods We performed a retrospective review of 358 patients ≤21 years with severe OSAS who underwent adenotonsillectomy at a tertiary hospital June 1, 2016 to June 1, 2018. We extracted demographics, comorbidities, polysomnography, and preoperative tests. Wilcoxon rank-sum and logistic regression estimated associations of OSAS severity (based on obstructive apnea-hypopnea index [OAHI], hypoxia, hypercarbia) with preoperative echocardiograms and chest X-rays (CXRs). Results Mean age was 5.9 (±3.6) years and 52% were male. Mean OAHI and oxygen saturation nadir were 30.3 (±23.8) and 80.7% (±9.2), respectively. OAHI ≥60 was associated with having a preoperative echocardiogram (OR, 3.8; 95% CI, 1.7-8.5) or CXR (OR, 3.0; 95% CI, 1.4-6.8) compared to OAHI 10-59. There were no significant associations between OSAS severity and test abnormalities. The presence of previously diagnosed cardiopulmonary comorbidities was associated with abnormalities on echocardiogram (OR, 36; 95% CI, 4.1-320.1) and CXR (OR, 4.1; 95% CI, 1.2-14.4). Conclusions Although pediatric patients with very severe OSAS (OAHI ≥60) underwent more pre-adenotonsillectomy cardiopulmonary tests, OSAS severity did not predict abnormal findings. Known cardiopulmonary comorbidities may be a better indication for cardiopulmonary testing than polysomnographic parameters, which could streamline pre-adenotonsillectomy evaluation and reduce cost. Level of evidence 4 Laryngoscope, 131:2361-2368, 2021.

Objective: Effective delivery of discharge instructions and access to postoperative care play a critical role in outcomes after pediatric surgery. Previous studies in the pediatric emergency department suggest that caregivers with language barriers have less comprehension of discharge instructions despite use of interpretation services. However, the impact of language barriers during discharge on surgical outcomes in a pediatric surgical setting has not been studied. This study examined the effect of parental language during discharge on number and mode of healthcare contact following pediatric adenotonsillectomy. Methods: A retrospective cohort study was conducted on children who underwent adenotonsillectomy at a tertiary care pediatric academic medical center from July 1, 2016 to June 1, 2018. Data were collected on consecutive patients with non-English-speaking caregivers and a systematic sampling of patients with English-speaking caregiver. Surgery-related complications and healthcare contacts within 90 days after discharge were collected. Two-tailed t tests, χ2 tests, and logistic regression were performed to assess the association between parental primary language and incidence of healthcare contact after surgery. Results: A total of 136 patients were included: 85 English-speaking and 51 non-English-speaking. The groups were comparable in age, sex, and comorbidities. The non-English group had more patients with public insurance (86% vs. 56%; P Conclusion: Language barriers at discharge following pediatric otolaryngology surgery is associated with a meaningful difference in how patients utilized medical care. Interventions to improve comprehension and access may help reduce preventable emergency department visits and healthcare costs.

Rationale, Aims, and Objectives: To determine the extent to which nurses reportedly assess evidence-based falls risk factors and identify targeted prevention implemented for medical and surgical patients in China. Method: This was a multicenter retrospective observational study. Respondents were nurses working in medical and surgical units of Chinese 662 hospitals. Fall-risk factors assessments and targeted interventions by health professionals were collected online by the Nursing Management Committee of Chinese Nursing Association in China, in 2019. Results: A total of 68527 valid questionnaires were recovered (95.0%). In medical and surgical units, nurses were most likely to report assessing balance, mobility and strength (81.6%) and orthostatic hypotension (76.4%) for falls and least likely to continence (61.3%) and feet and footwear (55.8%). Appropriate footwear (79.3%) and managing syncope, dizziness and vertigo (73.8%) were the most frequently falls multiple interventions, while managing postural hypotension (48.8%) and cognitive imparement (48.4%) were the least. Nine fall-risk factors with clearly matched multifactorial interventions were determined in medical and surgical units (68.2%~ 97.5%). On comparative analysis, Cognitive therapy, Toileting-assistance, Indwelling catheter, Monitor postural blood pressure, Dizziness and vertigo interventions, Minimise asthma triggers, Educating medication use, Keeping floor surface clean and dry were more common in medical ward, while With the head of the bed raised, Assessments and referrals and Bed brakes locked in surgical ward. Conclusion: Health professionals are generally concerned about risk factors and prevention for falls with their patients in much of China, however limited attention was directed at the continence, feet and footwears assessment and managing cognitive imparement. Evidence-based prevention should be further tailored to the individual, based on an individual risk factors.

Summary Background & aims Although fruits and vegetable consumption has been shown to be associated with lower risks of mortality, cancers, and cardiovascular disease (CVD), there are limited data from China on the shape of the association. This study aimed to quantify the relationship between levels of fruit, vegetable, and legume consumption with the risk of major CVD, CVD mortality, cancer incidence, cancer mortality, and all-cause mortality. Methods In the baseline survey, participants attended 1 of 115 (45 urban and 70 rural) communities from 12 provinces to complete a standardized questionnaire, and undergo a physical examination between 2005 and 2009, and were followed up till 2017 (for the current analysis). Diet was assessed through in-person interviews by using validated food-frequency questionnaires. The clinical outcomes were adjudicated centrally by trained physicians using standardized definitions. Cox frailty models were used to explore the associations between fruit, vegetable, and legume consumption with the risk of all-cause, CVD, and cancer mortality. Results A total of 41 243 participants were eligible for inclusion in the analyses. The average combined average daily intake of fruit, vegetable, and legume was 2.97 [standard deviation (SD) 1.22] servings per day. During a median follow-up of 8.9 years [interquartile range (IQR) 6.7–9.9 years], we recorded 1893 major CVDs, 794 cancer events, and 1324 deaths, with 411 CVD deaths and 429 cancer deaths. In the models adjusted for age, sex, and center (random effect), a higher total intake of fruit, vegetable, and legume was inversely associated with CVD mortality, cancer incidence, cancer mortality, and all-cause mortality. After adjusting for additional covariates, the associations were evidently attenuated and only the association with all-cause mortality (hazard ratio [HR] trend 0.92, 95% CI 0.86–0.98, p trend = 0.021) remained significant, with a non-significant trend for major CVD (HR trend 1.02, 95% CI 0.97–1.08, p trend = 0.449), CVD mortality (HR trend 0.94, 95% CI 0.84–1.06, p trend = 0.301), cancer incidence (HR trend 0.97, 95% CI 0.89–1.06, p trend = 0.540), or cancer mortality (HR trend 0.92, 95% CI 0.82–1.04, p trend = 0.174). Compared with the reference group, the risk of all-cause mortality was the lowest for four to five servings of total daily intake of fruit, vegetable, and legume (HR 0.73, 95% CI 0.55–0.97), and did not show a further decrease for the higher intake group. Separately, fruit intake was associated with a lower risk of all-cause mortality (HR trend 0.92, 95% CI 0.86–0.99, p trend = 0.020) and legume intake was associated with a lower risk of major CVD (HR trend 0.95, 95% CI 0.90–0.99, p trend = 0.028) and all-cause mortality (HR trend 0.94, 95% CI 0.89–0.99, p trend = 0.020) in the fully adjusted models. Conclusions This prospective study suggests that Chinese people with daily consumption of four to five servings (equivalent to 500–625 g/day) of fruit, vegetable, and legume demonstrated the lowest mortality, which conveys an encouraging message to the public that lifestyle modification to increase fruit, vegetable, and legume intakes may have greater beneficial effects on reducing all-cause mortality.

BackgroundPostprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of short-term postprandial glucose (PPG) excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD. However, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with acute coronary syndrome (ACS).MethodsA total of 144 diabetic patients with ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 49 patients with plaque rupture and 95 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBG), hemoglobin A1c(HbA1c) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F2α(8-iso-PGF2α) level was measured and corrected by creatinine clearance.ResultsPatients with ruptured plaque had significantly lower serum 1,5-AG levels, longer duration of diabetes, higher HbA1cand FBG levels than patients without ruptured plaque in our study population. In multivariate analysis, low 1,5-AG levels were an independent predictor of plaque rupture (odds ratio 3.421; P = 0.005) in diabetic patients with ACS. The area under the receiver-operating characteristic curve for 1,5-AG (0.658, P = 0.002) to predict plaque rupture was superior to that for HbA1c(0.587, P = 0.087). Levels of 1,5-AG were significantly correlated with urinary 8-iso-prostaglandin F2αlevels (r = − 0.234, P = 0.005).ConclusionsSerum 1,5-AG may identify high risk for coronary plaque rupture in diabetic patients with ACS, which suggests PPG excursions are related to the pathogenesis of plaque rupture in diabetes.

Objective The goal of this survey-based study is to explore patients’ knowledge of and expectations for radiologists in the outpatient setting. Materials and Methods A comprehensive survey was distributed to adult patients undergoing knee magnetic resonance imaging (MRI) over a one-year period from September 2015 through August 2016 at an urban, quaternary care academic medical center. Results The survey results demonstrate that only a subset of patients undergoing knee MRI at the institution during the survey period are aware of the role of the radiologist, which is a well-documented fact described in the literature. Approximately one-third of patients expected to meet the radiologist during their visit to the department of radiology to undergo a knee MRI. The vast majority of patients surveyed wanted to be able to contact the person who read their exam, but only one patient actually contacted the radiologist during the study period. Conclusion While the vast majority of surveyed patients wanted to be able to contact the person who read their knee MRI, only one patient actually did reach out to the radiologist to discuss findings. However, six of 36 follow-up respondents reported that they had contacted the person “who interpreted/read your exam:” two in person, one by email, three by phone, and one by other. Survey results demonstrated that only a subset of patients correctly understood the role of the radiologist (46% in the 1st survey and 63% in the 2nd survey, which does not represent a statistically significant difference), which suggests that perhaps the patients did have a conversation with a member of the radiology department staff whom they believed was actually the radiologist. The fact that patients expressed a desire to communicate with the person reading their reports, but then did not take advantage of the opportunity to contact the radiologist, suggests that the issue is more complicated than just a lack of a pathway for communication between patients and radiologists. Perhaps the lack of a clear understanding of the role of the radiologist hinders patients from contacting radiologists, as they feel uncertain as to whom they are actually attempting to reach. Or perhaps patients are sufficiently reassured by having a means through which they could contact the radiologist and do not require the actual communication in order to feel comfortable. There remains a significant amount of work to be done in understanding the barriers in patient-radiologist communications.

Our previous reports have shown that microRNA‐4651 is a potential early diagnostic and prognostic marker for hepatocellular carcinoma. We aimed to investigate whether microRNA‐4651 modified postoperative adjuvant transarterial chemoembolization (pa‐TACE) to improve the prognosis of hepatocellular carcinoma. A hospital‐based retrospective study, including 302 patients with advanced‐stage hepatocellular carcinoma who received tumor resection or tumor resection plus pa‐TACE as an initial therapy, was conducted to assess the effects of microRNA‐4651 on pa‐TACE treatment. MicroRNA‐4651 expression in tumor tissues was tested using the TaqMan‐PCR technique. The sensitivity of tumor cells to doxorubicin (an anticancer drug used in pa‐TACE procedure) was analyzed by the half‐maximal inhibitory concentration (IC50). Upregulated microRNA‐4651 expression in tumor tissues can improve the therapeutic response of patients with hepatocellular carcinoma on pa‐TACE (hazard ratios [95% confidence intervals] = 0.32 [0.22‐0.46] for death risk and 0.39 [0.28‐0.56] for tumor‐recurrence risk, respectively), but downregulated expression cannot. Functional analyses–displayed microRNA‐4651 mimics decreased while its inhibitor increased the IC50 of tumor cells to doxorubicin (0.65 [0.61‐0.69] versus 2.17 [1.98‐2.37] µM). Cytochrome P450 2W1 was shown as a possible target of microRNA‐4651. Additionally, dysregulation of microRNA‐4651 also affected the clinical pathological features of hepatocellular carcinoma and was an independent prognostic factor for this cancer. Conclusion: These results indicate that increasing microRNA‐4651 expression may be beneficial for pa‐TACE in improving hepatocellular carcinoma prognosis.

In vitro development of monkey embryos Owing to technical and ethical limitations, the molecular and cellular mechanisms underlying primate gastrulation are far from clear (see the Perspective by Tam). Two independent studies used an in vitro culture system to study cynomolgus monkey embryo postimplantation development up to and beyond gastrulation (day 9 to day 20). Niu et al. observed in vivo morphogenetic events and used single-cell RNA sequencing and single-cell chromatin accessibility to study the distinct cell lineages in developing embryos. Ma et al. also observed that key events of in vivo early development were recapitulated in their system, and single-cell RNA-sequencing analysis revealed molecular signatures of postimplantation cell types. These systems will help elucidate the dynamics and regulation of gastrulation in primates, including possible relevance to human development. Science , this issue p. eaaw5754 , p. eaax7890 ; see also p. 798

Constant exposure to allergen triggers destructive type 2 cell-mediated inflammation. The effect of allergen specific immunotherapy (SIT) in maintaining airway epithelial barrier function in asthma remains unknown. In the current study, we showed that SIT maintained airway epithelial homeostasis in mice exposed to dermatophagoides farinae (Der f), which induced increased expression of IL-25, endoplasmic reticulum (ER) stress and airway epithelial apoptosis. Meanwhile, SIT treatment ameliorated airway inflammatory infiltration and hyper-responsiveness in allergic mice. SIT treatment restored the airway epithelial integrity, attenuated Der f -induced airway epithelial ER stress and epithelial apoptosis. We also found that 4-PBA, an inhibitor of ER stress, suppressed airway epithelial ER stress and apoptosis in vitro. The pathological changes were partially induced by IL-25-induced ER stress, epithelial tight junction damage, and cell apoptosis in airways following allergen exposure. Furthermore, IL-25 induced ER stress in airway epithelial cells in vitro. The IL-25-induced airway epithelial apoptosis dependent on PERK activity was inhibited by 4-PBA. Taken together, we demonstrate that SIT is effective in allergic asthma and dependent on its depressive effect on the expression of IL-25, epithelial integrity damage, and epithelial ER stress.

Aims To analyze the left ventricular longitudinal function in a rabbit model of myocardial ischemia reperfusion with morphine preconditioning through strain rate imaging and to evaluate the effect of morphine preconditioning. Methods A myocardial ischemia-reperfusion model was induced by occlusion and recanalization of the coronary artery in 40 male New Zealand white rabbits, which were divided into a sham group, morphine group, and vehicle control group. Routine echocardiography data were recorded 1 day before and within 28 days after the operation. Dynamic images were also collected and analyzed off-line using Doppler tissue imaging software. Results On the first day after the operation, the global and regional systolic functions of the left ventricle in the morphine and vehicle control groups were lower than those in the sham group. After ischemia reperfusion, some of the values of the above-mentioned parameters decreased over time, which was more obvious in the vehicle control group at each examined time point. Conclusions The current study revealed that detection of changes in regional myocardial function after myocardial ischemia reperfusion by strain rate imaging is objective and accurate. In addition, our results indicated that morphine preconditioning significantly attenuates myocardial ischemia-reperfusion injury in rabbits.

© 2017, Association of Food Scientists & Technologists (India). Biofortification of crops with exogenous iodine is a novel strategy to control iodine deficiency disorders (IDD). The bioaccessibility of iodine (BI) in the biofortified vegetables in the course of soaking, cooking and digestion, were examined. Under hydroponics, the concentration of iodine in leafstalks of the celery and pakchoi increased with increasing exogenous iodine concentration, 54.8–63.9% of the iodine absorbed by pakchoi was stored in the soluble cellular substance. Being soaked in water within 8 h, the iodine loss rate of the biofortified celery was 3.5–10.4% only. More than 80% of the iodine in the biofortified celery was retained after cooking under high temperature. The highest BI of the biofortified vegetables after digestion in simulated gastric and intestinal juice amounted to 74.08 and 68.28%, respectively. Factors influencing BI included pH, digestion duration, and liquid-to-solid ratio. The high BI of the biofortified vegetables provided a sound reference for the promotion of iodine biofortification as a tool to eliminate the IDD.

Polyphenols have long been used as functional compounds and are beneficial for host immunity and gut health. This three-phased study investigated the function of Ouli fermented juice (OF) in improving the immunity of cyclophosphamide (CTX)-immunosuppressed mice and regulating their intestinal microbiota and mucosal barrier. Lactobacillus plantarum fermentation increased the phenolic content in the OF. OF effectively improved host immunity and the intestinal mucosal barrier, including increasing serum immunoglobulin (Ig)A, IgG, and IgM levels and secreted IgA (sIgA) levels in the colon, and reduced CTX-induced pathological damage to the spleen and jejunum. Importantly, OF effectively increased the abundance of Lachnospiracea, Roseburia, Akkermansia, and butyric acid-producing microbes, subsequently increasing the levels of short chain fatty acids in the colon. OF with polyphenols exhibited better efficacy at altering the intestinal flora, which might affect the host immunity by changing the host-mucosal barrier-microbiota interaction.

// Jun Lu 1, 2, * , Xing-Zhizi Wang 2, * , Tian-Qi Zhang 2, * , Xiao-Ying Huang 2 , Jin-Guang Yao 2 , Chao Wang 3 , Zhong-Hong Wei 4 , Yun Ma 5 , Xue-Min Wu 2 , Chun-Ying Luo 2 , Qiang Xia 1 and Xi-Dai Long 1, 2 1 Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R.China 2 Department of Pathology, Youjiang Medical University for Nationalities, Baise 533000, P.R.China 3 Department of Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, P.R.China 4 Department of Tumor, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, P.R.China 5 Department of Pathology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, P.R.China * These authors have contributed equally to this work Correspondence to: Xi-Dai Long, email: sjtulongxd@263.net Keywords: XRCC4, hepatocarcinoma, prognosis, TACE Received: May 01, 2017 Accepted: August 29, 2017 Published: September 28, 2017 ABSTRACT Background: Our previous investigations have shown that the variants of X-ray repair complementing 4 (XRCC4) may be involved in hepatocellular carcinoma (hepatocarcinoma) tumorigenesis. This study aimed to investigate the possible prognostic significance of XRCC4 expression for hepatocarcinoma patients and possible value for the selection of transarterial chemoembolization (TACE) treatment. Materials and Methods: We conducted a hospital-based retrospective analysis (including 421 hepatocarcinoma cases) to analyze the effects of XRCC4 on hepatocarcinoma prognosis and TACE. The levels of XRCC4 expression were tested using immunohistochemistry. The sensitivity of cancer cells to anti-cancer drug doxorubicin was evaluated using the half-maximal inhibitory concentration (IC50). Results : XRCC4 expression was significantly correlated with pathological features including tumor stage, liver cirrhosis, and micro-vessel density. XRCC4 expression was an independent prognostic factor of hepatocarcinoma, and TACE treatments had no effects on prognosis of hepatocarcinoma patients with high XRCC4 expression. More intriguingly, TACE improved the prognosis of hepatocarcinoma patients with low XRCC4 expression. Functionally, XRCC4 overexpression increased while XRCC4 knockdown reduced the IC50 of cancer cells to doxorubicin. Conclusions : These results suggest that XRCC4 may be an independent prognostic factor for hepatocarcinoma patients, and that decreasing XRCC4 expression may be beneficial for post-operative adjuvant TACE treatment in hepatocarcinoma.

// Xue-Min Wu 1,* , Zhi-Feng Xi 2,* , Pinhu Liao 3,* , Hong-Dong Huang 4,* , Xiao-Ying Huang 1,* , Chao Wang 3,* , Yun Ma 5 , Qiang Xia 2 , Jin-Guang Yao 1 and Xi-Dai Long 1,2 1 Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China 2 Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 3 Department of Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China 4 Division of Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 5 Department of Pathology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, China * These authors have contributed equally to the manuscript Correspondence to: Xi-Dai Long, email: // Keywords : microRNA-4651, aflatoxin B1, hepatocellular carcinoma, diagnostic and prognostic biomarkers Received : November 22, 2016 Accepted : February 18, 2017 Published : March 08, 2017 Abstract Background: The serum microRNAs have been reported as potential biomarkers for hepatitis virus-related hepatocellular carcinoma (HCC); however, their role in aflatoxin B1 (AFB1)-related HCC to has not yet been evaluated. Materials and Methods: We conducted a case-control study, including 366 HCC cases and 662 controls without any evidence of tumors, to identify and assess diagnostic and prognostic potential of serum microRNAs for AFB1-related HCC. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to elucidate diagnostic performance, and to compare the microRNAs with α-fetoprotein (AFP) at a cutoff of 20 ng/mL (AFP20) and 400 ng/mL (AFP400). Results: We found 8 differentially expressed microRNAs via the microRNA array analysis; however, only microRNA-4651 was further identified to detect AFB1-positive HCC but not AFB1-negative HCC. For AFB1-positive HCC, microRNA-4651 showed higher accuracy and sensitivity than AFP400 (AUC, 0.85 vs . 0.72; Sensitivity, 78.1% vs. 43.0%). Compared to AFP20, microRNA-4651 exhibited higher potential in identifying small-size (0.68 vs. 0.84 for AUC and 36.7% vs . 75.5% for sensitivity, respectively) and early-stage HCC (0.69 vs . 0.84 for AUC and 38.7% vs . 75.7% for sensitivity, respectively). Additionally, miR-4651 was also associated with HCC prognosis (hazard risk value, 2.67 for overall survival and 3.62 for tumor recurrence analysis). Conclusions: These data suggest that serum microRNA-4651 may be a useful marker for HCC diagnosis and prognosis, especially AFB1-positive cases.

In asthma, mucus hypersecretion is thought to be a prominent pathological feature associated with widespread mucus plugging. However, the current treatments for mucus hypersecretion are often ineffective or temporary. The potential therapeutic targets of mucus hypersecretion in asthma remain unknown. Here, we show that Lyn is a central effector of endoplasmic reticulum stress (ER stress) and mucous hypersecretion in asthma. In Lyn-transgenic mice (Lyn-TG) and wild-type (WT) C57BL/6J mice exposed to ovalbumin (OVA), Lyn overexpression attenuates mucus hypersecretion and ER stress. Interleukin 13 (IL-13) induced MUC5AC expression by enhancing ER stress in vitro. Lyn serves as a negative regulator of IL-13-induced ER stress and MUC5AC expression. We further find that an inhibitor of ER stress, which is likely involved in the PI3K p85α/Akt pathway and NFκB activity, blocked MUC5AC expression in Lyn-knockdown cells. Furthermore, PI3K/Akt signaling is required for IL-13-induced ER stress and MUC5AC expression in airway epithelial cells. The ER stress regulation of MUC5AC expression depends on NFκB in Lyn-knockdown airway epithelial cells. Our studies indicate not only a concept of mucus hypersecretion in asthma that involves Lyn kinase but also an important therapeutic candidate for asthma., Highlights • ER stress may be critical for the pathogenesis of bronchial asthma, especially the steroid-resistant neutrophilic asthma. • We confirmed that Lyn serves as a negative regulator of ER stress and MUC5AC through PI3K p85α/Akt/NFκB pathway in asthma. • This indicates not only a concept of mucus hypersecretion that involves Lyn but also a therapeutic candidate for asthma.

Drug repositioning, or the identification of new indications for approved therapeutic drugs, has gained substantial traction with both academics and pharmaceutical companies because it reduces the cost and duration of the drug development pipeline and the likelihood of unforeseen adverse events. To date there has not been a systematic effort to identify such opportunities, in part because of the lack of a comprehensive resource for an enormous amount of unsystematic drug repositioning information to support scientists who could benefit from this endeavor. To address this challenge, we developed a new database, the Experimental Knowledge-Based Drug Repositioning Database (EK-DRD), by using text and data mining as well as manual curation. EK-DRD contains experimentally validated drug repositioning annotation for 1861 FDA-approved and 102 withdrawn small-molecule drugs. Annotation was done at four levels using 30 944 target assay records, 3999 cell assay records, 585 organism assay records, and 8889 clinical trial records. Additionally, approximately 1799 repositioning protein or target sequences coupled with 856 related diseases and 1332 pathways are linked to the drug entries. Our web-based software displays a network of integrative relationships between drugs, their repositioning targets, and related diseases. The database is fully searchable and supports extensive text, sequence, chemical structure, and relational query searches. EK-DRD is freely accessible at http://www.idruglab.com/drd/index.php .

Background: Our previous studies have reported that polycomb chromobox 4 (CBX4) has a potential promoting hepatocellular carcinoma (HCC) angiogenesis and tumor progression. However, it is unclear whether genetic single-nucleotide polymorphisms (SNPs) in this gene are associated with HCC prognosis. Methods: We conducted a hospital-based two-phase study, including 598 patients with pathologically diagnosed HCC for the SNPs screening phase and 328 HCC patients for clinic significance validating phase, to elucidate the association between SNPs of CBX4 and the survival of HCC. The genotypes of CBX4 were tested using the SNaPshot method and the effects of CBX4 SNPs on HCC prognosis were analyzed using Kaplan-Meier survival model and Cox regression model. Results: A total of 33 SNPs were selected and genotyped in this study. We found the rs77447679 SNP was significantly related to survival in individuals with HCC. Specifically, survival was noticeably decreased in HCC patients who have mutant homozygote AA of this SNP (rs77447679-AA) compared with these with wild type (rs77447679-CC). An additive effect of rs77447679 polymorphism and aflatoxin B1 exposure level was also observed in the survival analyses of HCC cases. Furthermore, this SNP was positively correlated not only with tumor size, grade, stage, and microvessel density (correlation coefficient r = 0.17, 0.23, 0.23, and 0.42, respectively), but also with increasing CBX4 expression (r = 0.57). Interestingly, the mutant genotypes of rs77447679 can significantly improve the therapeutic response of HCC cases on post-operative adjuvant transarterial chemoembolization (pa-TACE), but wild type not. Conclusions: These data suggest that genetic polymorphisms in the CBX4 may be a prognostic biomarker for HCC, and the rs77447679 SNP is such a potential candidate.

Acute pancreatitis is characterized by zymogen preactivation. Severe inflammation caused by zymogen activation can eventually lead to multiple organ dysfunctions which contribute to the high mortality rate of severe acute pancreatitis. However, there is no specific treatment available for acute pancreatitis therapy. Here, we show that spautin-1, which effectively inhibits autophagy flux, ameliorated the pathogenesis of acute pancreatitis induced by cerulein or L-arginine. CaMKII phosphorylation due to cytosolic calcium overload was revealed in this paper. It was also demonstrated that autophagic protein aggregates degradation blockade accompanied by impaired autophagy correlated positively with intra-acinar cell digestive aymogen activation stimulated by cerulein or L-arginine. The role of spautin-1 in ameliorating acute pancreatitis was shown here to be associated with impaired autophagy inhibition and Ca2+ overload alleviation. We provide a promising therapy for acute pancreatitis through targeting both impaired autophagy and increased cytosolic calcium.

Iodine deficiency is an environmental health problem affecting one-third of the global population. An iodine biofortification hydroponic experiment was conducted to explore the iodide and iodate uptake characteristics of strawberry plants, to measure the dosage effects of iodine on plant growth and to evaluate the influence of I? or IO3? application on fruit quality. RESULTS After biofortification, the iodine contents of the fresh strawberry fruits were 600?4000 µg kg?1, covering the WHO dietary iodine allowance of 150 µg · day?1 for adults. The iodine uptake of the strawberry plants increased with increasing I? or IO3? concentration of the culture solution. At the same iodine concentration, the iodate uptakes of various plant organs under I? treatments were apparently more than those under IO3? treatments. Low-level exogenous iodine (I? ≤ 0.25 mg L?1 or IO3? ≤ 0.50 mg L?1) not only promoted plant growth and increased biomass per plant, but also improved fruit quality by enhancing the vitamin C and soluble sugar contents of the strawberry fruits. Nevertheless, excessive exogenous iodine inhibited plant growth and reduced biomass per plant. IO3? uptake apparently increased the total acidity and nitrate content of the fruits, reducing the quality of the strawberry fruits. Conversely, I? uptake obviously decreased the total acidity and nitrate content of the strawberry fruits, improving the fruit quality. CONCLUSION The strawberry can be used as a target crop for iodine biofortification. Furthermore, applying an appropriate dose of KI can improve the fruit quality of the strawberry plants. ? 2016 Society of Chemical Industry

Single nucleotide polymorphisms within microRNAs are known to affect the risk in development and prognosis of many diseases. This study was designed to investigate whether polymorphism of microRNA-499 (miR-499, rs3746444 AG) is associated with risk to biliary atresia (BA).A hospital-based cases-control study was performed on a total of 507 Han Chinese (207 BA cases and 300 ethnically-matched healthy controls without any evidence of liver diseases) so as to analyze the association between miR-499 rs3746444 polymorphism and BA risk as well as liver function remission (LFR) after liver transplantation.A significant higher frequency of the rs3746444 G alleles was found in the BA cases than the control group (odd ratio, 1.55, 95% confidence intervals [CIs], 1.15-2.10). This polymorphism was also observed to correlate with some clinic-pathological features of BA cases such as liver inflammatory. Further research found both higher levels of IL-6 (P0.05) and TNF-α (P0.05) in removed liver as well as in serum. What is more, the miR-499 rs3746444 polymorphism significantly affected the status of LFR (hazard ratio, 1.37; 95% CI, 1.08-1.83).MiR-499 (rs3746444) gene polymorphisms may be genetic determinants for increased risk of BA and prolonged recovery of BA patients after liver transplantation in Han Chinese.

Lung cancer is one of the most prevalent types of cancer worldwide, with a poor prognosis for patients and a concomitant financial burden on society. There are a number of different pathological subtypes, with non-small cell lung cancer (NSCLC) being the primary subtype. Although anticancer therapy has led to a marked improvement in the survival rate of patients in recent years, the survival rate remains poor. Potential reasons for this include a lack of early diagnosis and drug resistance, which is considered to be associated with mutations in components of signaling pathways, tumor suppressors and epidermal growth factor receptor, and certain other complex mechanisms to a certain extent. It is therefore imperative to develop novel therapies. In the present study, the pyrazolopyrimidine compound PP2 was used to inhibit Src family protein tyrosine kinases in A549 cells. It was demonstrated that PP2 was able to suppress cell viability, migration and invasion, and promote apoptosis via regulating the phosphoinositide 3-kinase/protein kinase B/B-cell lymphoma 2/caspase-3 signaling pathway. PP2 may therefore be useful in anti-NSCLC therapy in the future.

Honokiol is a natural compound with small molecular structure and extracted from bark of magnolia trees. The biological activities of honokiol include anti-oxidation, anti-inflammation as well as anti-tumor. However, their mechanism remains unknown. In this study, A549 cell line and EGFR-mutant cell line PC-9 with higher expression level of Lyn than A549 cells were used to assess the anti-tumor effects of honokiol. As shown in this study, honokiol is an effective drug on inhibiting proliferation and inducing apoptosis depended on Lyn and EGFR signal pathway regulated by Lyn, and its efficacy is stronger in PC-9 cells than A549 cells. In addition, this anti-tumor effect in PC-9 cells was weakened by Lyn-knockdown. Taken together, this study indicated the mechanism of honokiol on lung adenocarcinoma and provides a possibility of honokiol as an effective anti-tumor medicine.

Importance: Bronchoscopic lung volume reduction (BLVR) offers alternative novel treatments for patients with emphysema. Comprehensive evidence for comparing different BLVR remains unclear. Objective: To estimate the effects of different BLVR on patients with emphysema. DataSources: PubMed, EMBASE, Cochrane Library, and Web of Science databases from January 2001 to August 2017were searched. Study Selection: Randomized clinical trials (RCT) evaluated effects of BLVR on patients with emphysema. Data Extraction and Synthesis: The relevant information was extracted from the published reports with a predefined data extraction sheet, and the risk of bias was assessed with the Cochrane risk of bias tools. Main Outcomes and Measures: Pair-wise meta-analyses were made using the random-effects model. A random-effects network meta-analysis was applied within a Bayesian framework. The quality of evidence contributing to each network estimate was assessed using the GRADE framework. Results: 13 trials were deemed eligible, including 1993 participants. The quality of evidence was rated as moderate in most comparisons. Medical care (MC)was associated with the lowest adverse events compared with intra-bronchial valve (IBV)(-2.5,[-4.70 to -0.29]), endobronchial valve (EBV) (-1.73, [-2.37 to -1.09]), lung volume reduction coils (LVRC) (-0.76, [-1.24 to -0.28]), emphysematous lung sealant (ELS) (-1.53, [-2.66 to -0.39]), and airway bypass(-1.57, [-3.74 to 0.61]).Adverse events in LVRC were lower compared with ELS (-0.77,[-2.00 to 0.47]).Bronchoscopic thermal vapor ablation (BTVA) showed significant improvement inFEV1 compared with MC (0.99, [0.37 to 1.62]), IBV (1.25, [0.25 to 2.25]), and LVRC (0.72,[0.03 to 1.40]).6 MWT in ELS was significantly improved compared with other four BLVR, sham control, and MC (-1.96 to 1.99).Interestingly, MC showed less improvement in FEV1 and 6 MWT compared with EBV (-0.45, [-0.69 to -0.20] and -0.39, [-0.71 to -0.07], respectively).The mortality in MC and EBV was lower compared with LVRC alone (-0.38, [-1.16 to 0*41] and -0.50, [-1.68 to 0*68], respectively). BTVA and EBV led to significant changes in SGRQ compared with MC alone (-0.74, [-1.43 to -0.05] and 0.44, [0.11 to 0.78], respectively). Conclusions and Relevance: BLVR offered a clear advantage for patients with emphysema. EBV had noticeable beneficial effects on the improvement of FEV1, 6MWTand SGRQ, and was associated with lower mortality compared with MC in different strategies of BLVR. Funding: This project was supported by National major research program on Natural Science of China (91542164). Competing interests: The authors declare that they have no competing financial interests. Ethics Approval Statement: ??

Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell cancer associated with poor clinical prognosis and lacks targeted agents. PD-1 and PD-L1 play a critical role in cancer immune. However, genomic alterations associated with PD-1 and PD-L1 expression in LUSC have not been comprehensively characterized. To characterize genomic landscape, we integrally analyzed related genomic and clinical prognostic value associated with PD-1 and PD-L1 in Cancer Genome Atlas (TCGA) and GEO data. Here, we showed that PD-1 and PD-L1 expression were found to demonstrate the existence of heterogeneity in tumor samples. The degrees of PD-1 and PD-L1 expression did not show prognostic significance in patients with LUSC in TCGA. Higher tumor mutation burden (TMB) showed significantly increased expression of PD-1. NFE2L2 mutations led to higher PD-L1 expression in LUSC. The expression of PD-1 and PD-L1 were correlated with tumor microenvironment cells and immune-related molecules such as CTLA4, ICOS, FOXP3, HAVCR2, CD3G, CD8A, LAG3, and PDCD1LG2. The over-expression of PD-1 and PD-L led to genomic alterations of cell adhesion molecules cams; natural killer cell mediated cytotoxicity, antigen processing and presentation, and toll-like receptor signaling pathway. Moreover, survival analysis of PD-1 related module genes shows that ITIH3, EDEM1, EPS15, SETDB2, EHD1, and ANK26 are potent predictors of prognosis in patients with LUSC. Our results indicated that PD-1 and PD-L1 alterations were involved in crucial steps of tumor immune process, and present new therapeutic opportunities for manipulation of PD-1 and PD-L1 to achieve optimal immune responses in LUSC. Funding Statement: This project was supported by National major research program on Natural Science of China (91542164). Declaration of Interests: The authors declare that they have no competing financial interests.

The altered expression of some microRNAs (miRNAs) is observed in hepatocellular carcinoma (HCC); however, the genetic polymorphisms in the precursor miRNAs (pre-miRNAs) in aflatoxin B1 (AFB1)-related HCC have not yet been investigated. A hospital-based case-control study, including 1,706 HCC cases and 2,270 controls without any liver diseases or tumors, was conducted in a high AFB1 exposure area of China to assess the relationship between 48 polymorphisms in the pre-miRNAs and AFB1-related HCC risk and prognosis. Among 48 polymorphisms, only rs28599926 (in the miRNA 1268a) affected HCC risk. Compared with the homozygote of rs28599926C alleles (rs28599926-CC), the genotypes of rs28599926 T alleles (namely rs28599926-CT or -TT) increased HCC risk (odds ratio [OR]: 1.63 and 5.52, 95% confidence interval [CI]: 1.40-1.90 and 4.27-7.14, respectively). Significant interactive effects between risk genotypes and AFB1 exposure status were also observed in the joint effects analysis. This polymorphism was associated not only with larger tumor size, higher portal vein tumor risk, and tumor dedifferentiation, but also with higher AFB1 adducts levels and increasing the mutation risk of TP53 gene. Furthermore, rs28599926 modified the tumor recurrence-free survival (hazard ratio [HR]: 2.86, 95% CI: 2.36-3.43) and overall survival (HR: 2.12, 95% CI: 1.86-2.41) of cases. Additionally, one target of miR-1268a was show to be the ADAMTS4 mRNA and rs28599926 polymorphism might modify ADAMTS4 expression. These findings indicate that polymorphisms in the pre-miRNAs may be risk and prognostic biomarkers of AFB1-related HCC, and rs28599926 in miR-1268a is such a potential candidate. © 2015 Wiley Periodicals, Inc.

UNLABELLED Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71) ≤ Pmeta ≤ 9.92 × 10(-7) ). CONCLUSION Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.

Epidemiological, preclinical and cellular studies in the last 5 years have shown that metformin exerts anti-tumoral properties, but its mode of action in cancer remains unclear. Here, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and tumor-associated T cell immune responses. Oral metformin administration led to a significant reduction of tumor growth, which was accompanied by decreased interleukin-22 (IL-22). Meanwhile, IL-22-induced STAT3 phosphorylation and upregulation of downstream genes Bcl-2 and cyclin D1 were inhibited by metformin. At the cellular level, metformin attenuated Th1- and Th17-derived IL-22 production. Furthermore, metformin inhibited de novo generation of Th1 and Th17 cells from naive CD4(+) cells. These observations were further supported by the fact that metformin treatment inhibited CD3/CD28-induced IFN-γ and IL-17A expression along with the transcription factors that drive their expression (T-bet [Th1] and ROR-γt [Th17], respectively). The effects of metformin on T cell differentiation were mediated by downregulated STAT3 and STAT4 phosphorylation via the AMP-activated kinase-mammalian target of rapamycin complex 1 pathway. Notably, metformin led to a reduction in glucose transporter Glut1 expression, resulting in less glucose uptake, which is critical to regulate CD4(+) T cell fate. Taken together, these findings provide evidence for the growth-inhibitory and immune-modulatory effects of metformin in HCC and thus, broaden our understanding about the action of metformin in liver cancer treatment.

// Xing-Zhizi Wang 1, * , Xiao-Ying Huang 1, * , Jin-Guang Yao 1, * , Chao Wang 2 , Qiang Xia 3 and Xi-Dai Long 1, 3, 4 1 Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China 2 Department of Digestive Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China 3 Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China 4 Guangxi Clinic Research Center of Hepatobiliary Diseases, Baise 533000, China * These authors contributed equally to this work Correspondence to: Xi-Dai Long, email: sjtulongxd@263.net Keywords: ataxin-3; polymorphism; liver cirrhosis; aflatoxin B1; Gerotarget Received: August 02, 2017 Accepted: November 07, 2017 Epub: February 19, 2018 Published: June 08, 2018 ABSTRACT Background: Altered expression of ataxin-3 (AT3) can modify DNA repair capacity and is observed in human diseases. The genetic polymorphisms of this gene in aflatoxin B1 (AFB1)–related liver cirrhosis (LC) have not yet been elucidated. Materials and Methods: We conducted a hospital-based case–control study, including 384 patients with LC and 851 controls without any liver diseases, to assess the association between 264 polymorphisms in AT3 and AFB1-related LC risk. Genotype were tested using TaqMan-PCR or sequencing technique. Results: We found three differentially distributed SNPs (rs8021276, rs7158733, and rs10146249) via the screening analysis; however, only rs8021276 polymorphism was further identified to modify the risk of LC. Compared with the homozygote of rs8021276 A alleles (rs8021276-AA), the genotypes of rs8021276 G alleles (rs8021276-AG or -GG) increased LC risk (OR: 2.48 and 6.98; 95% CI: 1.84–3.33 and 4.35–11.22, respectively). Significant interactive effects between risk genotypes and AFB1 exposure status were also observed in the joint effects analysis. Additionally, rs8021276 polymorphism was also associated with down-regulation of AT3 mRNA expression and increasing AFB1-DNA adducts in liver tissues with cirrhosis. Conclusions: These results suggest AT3 polymorphisms may be risk biomarkers of AFB1-related LC, and rs8021276 is a potential candidate.

An aerosolized liposome formulation for the pulmonary delivery of an anti-asthmatic medication was developed. Asthma treatment usually requires frequent administration of medication for a sustained bronchodilator response. Liposomes are known for their sustained drug release capability and thus would be a suitable delivery system for prolonging the therapeutic effect of anti-asthmatic medication. Liposomes prepared by thin film hydration were loaded with a model drug, R-terbutaline hydrochloride(R-TBH), using an ammonium sulfate-induced transmembrane electrochemical gradient. This technique provided an encapsulation efficiency of up to 71.35% and yielded R-TBH liposomes with a particle size of approximately 145 ± 20 nm. According to stability studies, these R-TBH liposomes should be stored at 4°C before usage. Compared to R-TBH solution, which showed 90.84% release within 8 h, liposomal R-TBH had a cumulative release of 73.53% at 37°C over 192 h. A next generation impactor (NGI) was used to analyze the particle size distribution in the lungs of R-TBH liposome aerosol in vitro at 5°C. The therapeutic efficacy of the nebulized aerosol of the R-TBH liposomes was assessed via pulmonary delivery in guinea pigs. The results showed that, compared to the R-TBH solution group, the R-TBH liposome group had a prolonged anti-asthma effect.

Alternative splicing occurs frequently in many genes, especially those involved in immunity. Unfortunately, the functions of many alternatively spliced molecules from immunologically relevant genes remain unknown. Classical HLA-I molecules are expressed on almost all nucleated cells and play a pivotal role in both innate and adaptive immunity. Although splice variants of HLA-I genes have been reported, the details of their functions have not been reported. In the current study, we determined the characteristics, expression, and function of a novel splice variant of HLA-A11 named HLA-A11svE4. HLA-A11svE4 is located on the cell surface without β2-microglobulin (β2m). Additionally, HLA-A11svE4 forms homodimers as well as heterodimers with HLA-A open conformers, instead of combining with β2m. Moreover, HLA-A11svE4 inhibits the activation of NK cells to protect target cells. Compared with β2m and HLA-A11, the heterodimer of HLA-A11svE4 and HLA-A11 protected target cells from lysis by NK cells more effectively. Furthermore, HLA-AsvE4 expression was upregulated by HIV-1 in vivo and by HSV, CMV, and hepatitis B virus in vitro. In addition, our findings indicated that HLA-A11svE4 molecules were functional in activating CD8+ T cells through Ag presentation. Taken together, these results suggested that HLA-A11svE4 can homodimerize and form a novel heterodimeric complex with HLA-A11 open conformers. Furthermore, the data are consistent with HLA-A11svE4 playing a role in the immune escape of HIV-1.

The relationship between tonsillar autoimmune response and the pathogenesis of IgA nephropathy (IgAN) has been previously demonstrated. However, the role of CD4 (+)CD25 (+)Treg cells, which play critical roles in maintaining peripheral tolerance and preventing autoimmunity, has not yet been defined in IgAN.Thirty-five patients with IgAN and 35 patients without renal disease were studied. The CD4 (+)CD25 (+)Treg cells were examined by flow cytometry. Clinical and laboratory data, such as serum creatinine and urinary samples, were obtained from each patient. Glomerular injury was assessed by histopathology. Serum IgA, C3, IL-2, IL-4 and IL-6 were analyzed by ELISA.CD4 (+)CD25 (+)Treg cells significantly decreased in IgAN patients compared with the controls before tonsillectomy (p0.05). CD4 (+)CD25 (+)Treg cells were negatively correlated with blood urea nitrogen, supernatant IL-4 and proteinuria in IgAN patients, and positively with estimated glomerular filtration rate. CD4 (+)CD25 (+)Treg cells gradually decreased as the severity of renal histology increased. In addition, serum IgA, IL-2, IL-6 and supernatant IL-4 elevated while CD4 (+)CD25 (+)Treg cells decreased in IgAN patients. CD4 (+)CD25 (+)Treg cells were significantly increased when serum IgA, IL-2, IL-6 and supernatant IL-4, urine protein and urine erythrocytes were decreased after tonsillectomy in patients with IgAN, but were still lower than those of the controls (p0.05).CD4 (+)CD25 (+)Treg cells were associated with IgAN, and tonsillectomy may increase CD4 (+)CD25 (+)Treg cells in IgAN patients, leading to clinical improvement.

Aim: Treg cells are of critical importance for maintenance of tolerance. The purpose of the this study was to observe the number of Treg cells in the patients with thrombotic thrombocytopenic purpura (TTP) associated with systemic lupus erythematosus (SLE), and to study pathogenesis of TTP with SLE. Methods: Seven patients with TTP associated with SLE and seven healthy volunteers were studied. The Treg cells were examined by flow cytometry. Clinical and laboratory data, such as urinary protein, serum creatinine, endothelial markers and immunologic serologics, were obtained from each patient and healthy volunteer. Glomerular injury was assessed by histopathology. Serum IL-2, IL-4, IL-6 and anti-endothelial cell antibody were analyzed by ELISA and anti-ADAMTS13 antibody were detected by Western blotting. Results: Treg cells significantly decreased in TTP with SLE patients compared with controls (p

A series of novel fluorescent pyrazoline coumarin derivatives were synthesized. From them, we screened a compound possessing strong growth inhibitory effects on lung cancer cells. By taking advantage of fluorescence combined with LC-MS/MS and chemoinformatics technique, we successfully identified HSP90 as the target of the compound.

The DNA repair gene X-ray cross-complementary group 4 (XRCC4), an important caretaker of the overall genome stability, is thought to play a major role in human tumorigenesis. We investigated the association between an important polymorphic variant of this gene at codon 247 (rs373409) and diffusely infiltrating astrocytoma (DIA) risk and prognosis. This hospital-based case-control study investigated this association in the Guangxi population. In total, 242 cases with DIA and 358 age-, sex-, and race-matched healthy controls were genotyped using TaqMan-PCR technique. We found a significant difference in the frequency of XRCC4 genotypes between cases and controls. Compared with the homozygote of XRCC4 codon 247 Ala alleles (XRCC4-AA), the genotypes of XRCC4 codon 247 Ser alleles (namely XRCC4-AS or -SS) increased DIA risk (odds ratios [OR], 1.82 and 2.89, respectively). Furthermore, XRCC4 polymorphism was correlated with tumor dedifferentiation of DIA (r = 0.261, p &lt, 0.01). Additionally, this polymorphism modified the overall survival of DIA patients (the median survival times were 26, 14, and 8 months for patients with XRCC4-AA, -AS, and -SS, respectively). Like tumor grade, XRCC4 codon 247 polymorphism was an independent prognostic factor influencing the survival of DIA. These results suggest that XRCC4 codon 247 polymorphism may be associated with DIA risk and prognosis among the Guangxi population.

The purpose of the present study was to detect bacterial strains and antibiotic susceptibility in chronic tonsillitis patients with IgA nephropathy (IgAN) and without nephritis, in order to provide evidence for clinical therapy and pathogenesis of IgAN.A total of 53 patients with IgAN (group A) and 53 chronic tonsillitis patients without nephritis (group B) underwent tonsillectomy. The tonsil tissues of patients were collected under sterile condition. The bacteria in the tonsil crypt of patients in both groups were isolated and identified for antibiotic susceptibility test by the manual routine of the laboratory and also with the autoScan/Microscan system.There were bacteria in each specimen in both groups. The bacteria detection rate was 100%, but there was no significant difference between two groups (p 0.05). The 522 strains of bacteria in group A and 494 strains of bacteria in group B were isolated. Streptococcus. Neisseria, Hemophilus parainfluenzae. Staphylococcus. Bacillus proteus and Streptococcus pneumoniae were detected in both groups, but there was no significant difference in the types of bacteria between the two groups (all p 0.05). Alpha streptococcus was the most common in both groups. The antibiotic susceptibility test showed that there was no significant difference in the susceptibility to penicillin, chloramphenicol, macrolides, cephalosporin, gentamicin, amikacin sulphate, norfloxacin, ciprofloxacin, rifampicin and vancomycin between two groups (all p 0.05).Alpha streptococcus in both two groups can be detected and is the most common. There was no significant difference in bacterial strains and antibiotic susceptibility between two groups.

BACKGROUND Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity and may play an important role in carcinogenesis. We investigated the role of genetic polymorphisms at XRCC4 codon 247 (rs3734091, XRCC4P) and XRCC5 codon 180 (rs80309960, XRCC5P) in liver cancer (hepatocellular carcinoma) caused by aflatoxin B1 (AFB1). METHODS A hospital-based case-control study, including 1499 liver cancer cases and 2045 controls without any liver disease, was conducted in a high aflatoxin exposure area in the Guangxi region of China to assess the relationship between these two polymorphisms and aflatoxin-related liver cancer risk and prognosis. Genotypes, mRNA levels, and the hot-spot mutation of TP53 gene (TP53M) related to AFB1 exposure was tested using TaqMan-PCR technique. XRCC4 protein level was analyzed by immunohistochemistry. RESULTS For XRCC4P and XRCC5P, only XRCC4P modified liver cancer risk. Compared with the homozygote of XRCC4 codon 247 Ala alleles (XRCC4-AA), the genotypes of XRCC4 codon 247 Ser alleles (namely XRCC4-AS or -SS) increased liver cancer risk (odds ratio [OR] = 1.35 and 2.02, respectively). Significant interactive effects between risk genotypes (OR > 1) and aflatoxin exposure status were also observed in the joint effects analysis. Moreover, this polymorphism was associated not only with lower XRCC4 expression levels but also with higher AFB1-DNA adduct levels and increasing TP53M and portal vein tumor risk. Additionally, XRCC4P modified the recurrence-free survival and overall survival of cases, especially under conditions of high aflatoxin exposure. CONCLUSION XRCC4P may be a genetic modifier for the risk and outcome of hepatocellular carcinoma induced by AFB1 exposure.

X-ray repair complementing group 4 (XRCC4) is very important in maintaining overall genome stability and may play an important role in carcinogenesis. We aimed to investigate the role of polymorphisms in the coding region of this gene in hepatocellular carcinoma (HCC) caused by aflatoxin B1 (AFB1). A hospital-based case-control study, including 1,499 HCC cases and 2,045 controls without any liver diseases or tumors, was conducted in a high AFB1 exposure area (the Guangxi region) to assess the relationship between 21 polymorphisms in the coding region of XRCC4 and AFB1-related HCC risk and prognosis. Among these 21 polymorphisms, only rs28383151 modified HCC risk. These individuals with the genotypes of rs28383151 A alleles (rs28383151-GA/AA), compared with the homozygote of rs28383151 G alleles (rs28383151-GG), faced increasing risk of HCC (odds ratio [OR]: 2.17; 95% confidence interval: 1.77-2.67). Significant interactive effects between risk genotypes (OR, >1) and AFB1 exposure status were also observed in the joint-effects analysis. Furthermore, this polymorphism was correlated not only with lower XRCC4-expressing levels, but also with higher AFB1-DNA adducts levels and increasing TP53M and portal vein tumor risk. The rs28383151 polymorphism modified the recurrence-free survival and overall survival of HCC patients, especially under high AFB1 exposure conditions. Additionally, this polymorphism multiplicatively interacted with the glutathione S-transferase M1 polymorphism with respect to HCC risk (ORinteraction = 2.13). Conclusion: Genetic polymorphisms in the coding region of XRCC4 may be risk and prognostic biomarkers of AFB1-related HCC, and rs28383151 is such a potential candidate. (HEPATOLOGY 2013) © 147.

To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, P(meta) = 2.48 × 10(-10), odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, P(meta) = 2.72 × 10(-17), OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (P(trend) = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10(-14)).