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Background and aims The apolipoprotein A-I mimetic peptide D-4F, among its anti-atherosclerotic effects, improves vasodilation through mechanisms not fully elucidated yet. Methods Low-density lipoprotein (LDL) receptor null (LDLr−/−) mice were fed Western diet with or without D-4F. We then measured atherosclerotic lesion formation, endothelial nitric oxide synthase (eNOS) phosphorylation and its association with heat shock protein 90 (HSP90), nitric oxide (NO) and superoxide anion (O2•-) production, and tetrahydrobiopterin (BH4) and GTP-cyclohydrolase 1 (GCH-1) concentration in the aorta. Human umbilical vein endothelial cells (HUVECs) and aortas were treated with oxidized LDL (oxLDL) with or without D-4F; subsequently, BH4 and GCH-1 concentration, NO and O2•- production, eNOS association with HSP90, and endothelium-dependent vasodilation were measured. Results Unexpectedly, eNOS phosphorylation, eNOS-HSP90 association, and O2•- production were increased, whereas BH4 and GCH-1 concentration and NO production were reduced in atherosclerosis. D-4F significantly inhibited atherosclerosis, eNOS phosphorylation, eNOS-HSP90 association, and O2•- generation but increased NO production and BH4 and GCH-1 concentration. OxLDL reduced NO production and BH4 and GCH-1 concentration but enhanced O2•- generation and eNOS association with HSP90, and impaired endothelium-dependent vasodilation. D-4F inhibited the overall effects of oxLDL. Conclusions Hypercholesterolemia enhanced uncoupled eNOS activity by decreasing GCH-1 concentration, thereby reducing BH4 levels. D-4F reduced uncoupled eNOS activity by increasing BH4 levels through GCH-1 expression and decreasing eNOS phosphorylation and eNOS-HSP90 association. Our findings elucidate a novel mechanism by which hypercholesterolemia induces atherosclerosis and D-4F inhibits it, providing a potential therapeutic approach.

Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR‐483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with more severe disease. RNA‐seq and bioinformatics analyses showed that miR‐483 targets several PAH‐related genes, including transforming growth factor‐β (TGF‐β), TGF‐β receptor 2 (TGFBR2), β‐catenin, connective tissue growth factor (CTGF), interleukin‐1β (IL‐1β), and endothelin‐1 (ET‐1). Overexpression of miR‐483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF‐β, TGFBR2, β‐catenin, CTGF, IL‐1β, and ET‐1. In contrast, inhibition of miR‐483 increased these genes in ECs. Rats with EC‐specific miR‐483 overexpression exhibited ameliorated pulmonary hypertension (PH) and reduced right ventricular hypertrophy on challenge with monocrotaline (MCT) or Sugen + hypoxia. A reversal effect was observed in rats that received MCT with inhaled lentivirus overexpressing miR‐483. These results indicate that PAH is associated with a reduced level of miR‐483 and that miR‐483 might reduce experimental PH by inhibition of multiple adverse responses., This study reveals a protective role for miR‐483 in the development of pulmonary arterial hypertension (PAH). Overexpression of miR‐483 in endothelial cells (ECs) inhibits inflammatory and fibrogenic responses and leads to ameliorated pulmonary hypertension phenotypes in rats.

Extreme variation in lifetime cancer risk among tissues has been a riddle of cancer etiology. Considering that cancer risks were found to be contributed heavily by environmental factors, levels of environmental carcinogens, such as metal/metalloid in tissues, may be an explanation of the variation. We analyzed the correlations between metal/metalloid concentrations in different tissues and the lifetime cumulative cancer risks of the corresponding tissues using the data of National Health Standards and National Central Cancer Registry of China. Cadmium (Cd) and rubidium (Rb) were found to be correlated with the lifetime cancer risks in a positive linear relationship while a U-shaped relationship was observed for cesium (Cs) and tin (Sn). A positive linear trend between the mixture of metals/metalloids and lifetime cancer risks was observed and cadmium (Cd) may be the main driving element. Our results indicated that Cd-based metal/metalloid levels may be an explanation for the variation in lifetime cancer risk among tissues. Furthermore, the analytical strategy may in turn help identify environmental factors involved in cancer etiology.

Background Cyclophilin A is identified as a biomarker for inflammation. We elucidated prognostic significance of serum cyclophilin A (CypA) concentrations in acute pancreatitis (AP). Methods In this prospective and observational study, serum CypA concentrations were quantified in 210 AP patients and 100 healthy controls. We recorded local complication, in-hospital mortality and organ failure. Disease severity was assessed using the traditional predictors, namely Acute Physiology and Chronic Health Care Evaluation II score, Ranson score, multiple organ dysfunction score and sequential organ failure assessment score. Results Serum CypA concentrations were significantly lower in controls than in AP group. CypA concentrations after AP were highly correlated with the traditional predictors and other inflammatory mediators, including blood erythrocyte sedimentation rate, procalcitonin levels, white blood cell count and C-reactive protein levels. Serum CypA emerged as an independent predictor for in-hospital local complication, organ failure and mortality. Under receiver operating characteristic curve, serum CypA possessed similar prognostic ability, as compared to the traditional predictors. Its predictive ability was almost similar to that of procalcitonin levels and significantly exceeded those of the other inflammatory mediators. Also, it significantly improved prognostic performance of the traditional predictors. Conclusions Increased serum CypA concentrations have close relation to the severity, inflammation and prognosis, substantializing CypA as a potential prognostic biomarker of AP.

Ras-related C3 botulinum toxin substrate 1 (RAC1) is a member of the Rho family of small GTPases. Recent studies have reported that RAC1 serves an important role in colon cancer cell proliferation. The present study aimed to investigate the effects of RAC1 knockdown on cell proliferation, cell cycle progression and apoptosis of colon cancer cells. Lentivirus-mediated short hairpin RNA (shRNA) was used to knockdown RAC1 expression in colon cancer cell lines, and cell proliferation, apoptosis, cell cycle progression were evaluated by MTT assays and flow cytometry. The differences in mRNAs expression were identified between RAC1-knockdown cells and control cells using a mRNA microarray, following which quantitative PCR (qPCR) and western blot were employed to confirm the results of the mRNA microarray. The proliferative ability of colon cancer cells was significantly decreased following RAC1 knockdown, and RAC1 knockdown increased the apoptotic rate and enhanced cell cycle arrest at G1 phase in colon cancer cells. In addition, >1,200 known genes were demonstrated to be involved in RAC1-associated tumorigenic functions in SW620 colon cancer cells, as determined by gene chip analysis; these genes were associated with cell proliferation, cell cycle, apoptosis and metastasis. Furthermore, western blot analysis indicated that cyclin D1 was downregulated, whereas B-cell lymphoma 2-associated agonist of cell death (BAD) was upregulated following RAC1 knockdown in colon cancer cells. In conclusion, RAC1 silencing may suppress the proliferation of colon cancer cells by inducing apoptosis and cell cycle arrest. In addition, a large number of genes were revealed to be involved in the process, including BAD, which was upregulated and cyclin D1, which was downregulated. Further studies on these differentially expressed genes may provide a better understanding of the potential roles of RAC1 in colon carcinogenesis.

Developmental dyslexia is a complex reading and writing disorder with strong genetic components. In previous genetic studies about dyslexia, a number of candidate genes have been identified. These include DCDC2, which has repeatedly been associated with developmental dyslexia in various European and American populations. However, data regarding this relationship are varied according to population. The Uyghur people of China represent a Eurasian population with an interesting genetic profile. Thus, this group may provide useful information about the association between DCDC2 gene polymorphisms and dyslexia. In the current study, we examined genetic data from 392 Uyghur children aged 8-12 years old from the Xinjiang Uyghur Autonomous Region of China. Participants included 196 children with dyslexia and 196 grade-, age-, and gender-matched controls. DNA was isolated from oral mucosal cell samples and fourteen single nucleotide polymorphisms (rs6456593, rs1419228, rs34647318, rs9467075, rs793862, rs9295619, rs807701, rs807724, rs2274305, rs7765678, rs4599626, rs6922023, rs3765502, and rs1087266) in DCDC2 were screened via the SNPscan method. We compared SNP frequencies in five models (Codominant, Dominant, Recessive, Heterozygote advantage, and Allele) between the two groups by means of the chi-squared test. A single-locus analysis indicated that, with regard to the allele frequency of these polymorphisms, three SNPs (rs807724, rs2274305, and rs4599626) were associated with dyslexia. rs9467075 and rs2274305 displayed significant associations with developmental dyslexia under the dominant model. rs6456593 and rs6922023 were significantly associated with developmental dyslexia under the dominant model and in the heterozygous genotype. Additionally, we discovered that the T-G-C-T of the four-marker haplotype (rs9295619-rs807701-rs807724-rs2274305) and the T-A of the two-marker haplotype (rs3765502-1087266) were significantly different between cases and controls. Thus, we conclude that DCDC2 gene polymorphisms are associated with developmental dyslexia in Chinese Uyghur children.

Becker's Nevus (BN) is a benign hamartoma with an esthetically troublesome condition secondary to hyperpigmentation and hypertrichosis. Many treatment modalities have been utilized with variable outcomes.To evaluate the efficacy and safety of intense pulsed light (IPL) in the treatment of BN.IPL was used at filter of 590 nm, fluence of 18-22 J/cmTwenty-four patients (9 females, 15 males) with BN (16 hypertrichotic, 8 atrichotic) completed the study. The mean number of treatment sessions was 5 ± 2.17. The improvement in atrichotic BN group (4.87 ± 0.35) was significantly greater than that observed in hypertrichotic BN group (3.63 ± 0.89) (IPL is an effective and well-tolerated treatment option for patients with hypertrichotic and atrichotic BN.

Antiphospholipid syndrome (APS) is an acquired thrombophilia with an uncertain role in the development of chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to assess the association of APS with the clinical phenotype of CTEPH. We retrospectively reviewed data of CTEPH patients referred to our center. Clinical, angiographic, and hemodynamic data were available for all patients. APS was diagnosed in the presence of one or more positive antiphospholipid (aPL) tests confirmed more than 12 weeks apart. Data were compared between APS-positive and APS-negative patients. From May 2013 to December 2018, 297 patients with CTEPH were enrolled. Twenty-three (7.7%) were positive for laboratory tests exploring aPL antibodies. Among them, 17 patients (74%) had a triple positive aPL profile. When compared with the APS-negative group, APS patients were significantly younger (30.0 ± 11.1 vs. 55.6 ± 12.9 years, p

How thrombophilia may contribute to the development of chronic thromboembolic pulmonary hypertension (CTEPH) is unknown. We searched on PubMed and EMBASE (until 15 April 2018), studies on CTEPH reporting data on inherited or acquired thrombophilia. Starting from 367 articles mentioning the search terms, 347 were excluded mainly as duplicate articles or articles not in English. After reading the full text of remaining articles, ten were excluded for being reviews, editorials, letters or case reports, and two were further removed from the analysis because of the potential selection bias. All the eight considered studies provided the proportion of patients positive for antiphospholipid (aPL) antibodies. The crude rate of aPL in CTPEH patients is 11.8% (95% CI 10.09–13.8%). The meta-analysis considering the weighted mean proportion and 95% confidence intervals (CIs) yields a rate of aPL antibody-positive profile of 12.06% (95% CI 8.12–16.65%) among the patients with CTEPH in the random effects model (I2 76.33%; 95% CI 52.75–88.14%, p = 0.0001). The sensibility analysis confirms the result. No predictors of heterogeneity are found in a meta-regression analysis. Our results suggest that aPL antibodies are frequently associated with CTEPH underlining the need to test for aPL antibodies in young patients with “idiopathic” and “provoked” PE caused by mild provoking risk factors.

Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell undergoes a series of molecular events that result in a mesenchymal cell phenotype, plays an important role in atherosclerosis. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), derived from the oxidation of 1-Palmitoyl-2- arachidonoyl-sn-glycero-3-phosphatidylcholine, is a pro-inflammatory lipid found in atherosclerotic lesions. Whether POVPC promotes EndMT, and how simvastatin influences POVPC-mediated EndMT remains unclear. Here, we treated human umbilical vein endothelial cells with POVPC, simvastatin, or both, and determined their effect on endothelial cell viability, morphology, tube formation, proliferation, and generation of nitric oxide (NO) and superoxide anion (O2●-). Expression of specific endothelial and mesenchymal markers was detected by immunofluorescence and immunoblotting. POVPC did not affect endothelial cell viability, but altered cellular morphology from cobblestone-like endothelial cells to a spindle-like mesenchymal cell morphology. POVPC increased O2- generation and expression of alpha-smooth muscle actin, vimentin, Snail-1, Twist-1, transforming growth factor-beta (TGF-β), TGF-β receptor II, p-Smad2/3, and Smad2/3. POVPC also decreased NO production, and expression of CD31 and endothelial nitric oxide synthase. Simvastatin inhibited POVPC-mediated effects on cellular morphology, production of O2●- and NO, and expression of specific endothelial and mesenchymal markers. These data demonstrate that POVPC induces EndMT by increasing oxidative stress, which stimulates TGF-β/Smad signaling, leading to Snail-1 and Twist-1 activation. Simvastatin inhibited POVPC-induced EndMT by decreasing oxidative stress, suppressing TGF-β/Smad signaling, and inactivating Snail-1 and Twist-1. Our findings reveal a novel mechanism of atherosclerosis that can be inhibited by simvastatin.

Septal deviation constitutes an important component of both esthetic deformity and airway compromise in patients with cleft lip and palate (CLP). The posterior parts of the nasal septum presented greater deviation than the anterior parts in patients with complete unilateral CLP. Le Fort I down-fracture provides better access to the nasal septum than intranasal incision during rhinoplasty, especially to the posterior part. This study objectively and subjectively evaluated the nasal function after Le Fort I osteotomy combined with septoplasty in patients with complete unilateral CLP. Twenty-three patients with complete unilateral CLP presenting with nasal obstruction and septum deviation were included (12—combined surgery group; 11—control group). Types of septum deviation in the patients were analyzed. Presurgical and 6-month-postsurgical acoustic rhinometry (AR) was performed for objective assessment; and the nasal obstruction symptom evaluation (NOSE) scale was used for subjective assessment. The authors used SPSS to compare the baseline and follow-up results. Acoustic rhinometry assessment showed improvements in the nasal minimal cross-sectional area (MCA), nasal resistance, and nasal volumes in 12 patients who received combined surgery. For the 2 groups, significant improvements in nasal breathing were documented (by NOSE scores) at 6 months after surgery. Simultaneous management of the maxillary dysplasia (Le Fort I osteotomy) and intranasal pathology (septoplasty) were effective for relief of nasal airway obstruction in patients with complete unilateral CLP. The combination of objective (AR) and subjective (NOSE scale) assessments allowed better evaluation of the nasal function.

Objectives Sleep has been closely linked to breast cancer risk. However, the association between sleep and breast cancer prognosis remains unclear. The aim of this study was to evaluate the separate and joint effects of multiple sleep characteristics on breast cancer prognosis among Chinese women. Methods A total of 1580 breast cancer patients were recruited between October 2008 and December 2014 and followed up until December 31, 2017 in Guangzhou. Multivariate Cox models were conducted to estimate the hazard ratios (HR) and 95% confidence intervals (95%CI) for breast cancer prognosis in association with sleep characteristics. Results Long sleep duration at night (>9 h) (HR = 2.33, 95%CI: 1.01–5.42), poor sleep quality (HR = 3.08, 95%CI: 1.74–5.47), and impaired daytime function (HR = 2.49, 95%CI: 1.65–3.79) after diagnosis were associated with an increased risk of breast cancer progression. Both short sleep duration ( 9 h) (HR = 4.69, 95%CI: 1.31–16.78, P interaction = 0.187) increased the progression risk only among patients with impaired but not normal daytime function. In addition, daytime napping significantly modified the effect of short sleep duration on the progression (HR = 3.55, 0.59, 95%CI: 1.55–7.97, 0.23–1.53 for patients without and with daytime napping, respectively, P interaction = 0.005). Stratification results suggested that the associations were more evident among pre-menopausal patients, although no significant interaction was observed. Conclusion Our findings suggested that inadequate sleep duration to feel one's best and poor sleep quality after diagnosis were associated with an increased risk of breast cancer progression, particularly for pre-menopausal women.

Three new pimarane diterpenes, eutypellenoids A–C (1–3), together with a known compound, eutypenoid C (4), were isolated from the culture extract of Eutypella sp. D-1 derived from the Arctic region. Compounds 1–3 possessed an uncommon tetrahydrofuran-fused pimarane diterpene skeleton. The structures of all compounds were determined by detailed spectroscopic analysis, electronic circular dichroism (ECD) analysis, as well as a comparison with the literature data. Antibacterial, antifungal, and cytotoxic activities of these compounds were evaluated. Compound 2 displayed antibacterial activity against Staphylococcus aureus and Escherichia coli with MIC values of 8 and 8 μg/mL, respectively. Additionally, compound 2 showed antifungal activity against Candida parapsilosis, Candida albicans, Candida glabrata, and Candida tropicalis with MIC values of 8, 8, 16, and 32 μg/mL, respectively. Furthermore, compound 2 exhibited moderate cytotoxic activity against HCT-116 cell line with IC50 value of 3.7 μM.

Background Mesenchymal stem cells (MSCs) have demonstrated significant potentials for the treatment of inflammatory bowel disease. Clinical feasible methods to individually document the MSC recruitment to intestinal mucosa is lacking. Here, we proposed that endomicroscopy could noninvasively track MSCs in vivo at cellular resolution. Method Isolated Sprague Dawley rat MSC was characterized, fluorescently labeled, and imaged ex vivo using an endomicroscope. Then enhanced green fluorescent protein (eGFP)-labeled MSC was tracked in vivo, and acquired images were compared with immunofluorescence, immunohistology, and fluorescent in situ hybridization results. Results Endomicroscopy visualized clearly the eGFP-labeled or carboxyfluorescein succinimidyl ester-stained MSC ex vivo. Endomicroscopy using the FIVE1 system could track eGFP-labeled MSC with distinct in vivo features. Immunofluorescence, immunohistochemistry, and fluorescent in situ hybridization confirmed the presence of eGFP-positive cells. In vivo endomicroscopy could quantify the transplanted MSCs that homed to colonic mucosa of the recipient rat in multiple models, including the rat-to-rat allograft, human-to-rat xenograft, hypoxia-induced MSC, and busulfan immunosuppressed recipient rat models. After hypoxia induction, there was a trend of enhanced rat MSC homing to the inflamed mucosa as visualized by endomicroscopy (114.1 in hypoxia group versus 34.3 in other 3 groups combined, t = 2.14, P = 0.0644). Conclusions Endomicroscopy is a novel and promising tool to track transplanted MSCs to the colonic mucosa. This clinical available noninvasive cellular tracking method may provide new insight to individualize each recipient's regimen in the future.

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, is a disease of immune microenvironment. Chronic Hepatitis B virus (HBV) infection, also an immune-related disease, is the major etiological factor for HCC especially in Asia. As an immune regulator, which has pleiotropic activities on T cells, nature killer cells and dendritic cells and so on, the efficacy of thymalfasin on HCC patients has been proven by several pilot studies as an adjuvant therapy. Combination of thymalfasin significantly improved survival and prolonged the time to tumor recurrence in patients who received transcatheter arterial chemoembolization after tumor resection. An improvement in patients' immunity has also been demonstrated. However, there is no large-scale randomized controlled study so far in resectable HCC patients. To confirm the role of thymalfasin adjuvant therapy in patients with HBV-related HCC after curative resection, a large-scale multicenter randomized controlled trial has been planned in China to investigate the effect of thymalfasin (1.6 mg twice a week for 12 months) on 2-year recurrence-free survival rate and tumor immune microenvironment. Here is the first announcement of the study protocol (ClinialTrials.gov Identifier: NCT02281266).

To calibrate and standardise an animal model of graded optic nerve injury (ONI) in rats to facilitate future inter-laboratory data comparisons, focussing on quantification of injury intensity, injury severity, and the correlation between them.A pair of cross-action forceps or a pair of artery clips was used to induce optic nerve (ON) crush injuries. A lever principle and a simplified method were used to measure the crushing force. The simplified method directly measured weights as an external force exerted on the tip of the forceps or clips, which was just sufficient to maintain a gap and was equivalent to the closing (crush) force. The impulse and averaged impulse were explored as physical quantities to compare injury intensities. Graded ONIs were made by crushing the ON for 3, 6, 12, 30 or 60 seconds by the cross-action forceps, or 5, 10 or 15 seconds by the artery clips. The injury severity was evaluated by counting surviving retinal ganglion cell (RGC) through applied FluoroGold to the superior colliculus and lateral geniculate body before ON crush, intact RGC counting by applied FluoroGold after ON crush, and ON axon counting.Similar results were obtained by the lever principle method and the simplified method. The crushing force of the cross-action forceps and the artery clips was 148.0 gram force (gf) and 32.4 gf, respectively. The graded ONI animal models were successfully created in rats without retinal ischaemia post-trauma. The averaged impulse produced by the artery clips for 15 seconds was equal to that produced by a 3-second crush of the cross-action forceps. The correlation between injury intensity and injury severity was fitted for a power function.Our results provide a simplified and effective means to quantify and analyse data from ON crush studies compared with previously reported animal models.

We isolated and identified a new sesquiterpene lactone which we named eut-Guaiane sesquiterpene (1), along with four cytochalasins from the fungus Eutypella sp. derived from the soil of high latitude of Arctic. The new structure was determined by spectroscopic studies such as 1D and 2D NMR and MS analyses, while the known compounds were identified by comparison of the NMR data with those in literatures. New compound 1 exhibited strong antibacterial activity against Escherichia coli, Bacillus subtilis and Staphylococcus aureus. Besides, it showed a little cytotoxicity against SGC7901 cell line.

In vitro and in vivo studies have identified that low-frequency ultrasound (US) and microbubbles (MBs) mediate tumor inhibitory effects. However, the application of US in the clinical setting remains unclear. The aim of the present study was to investigate the clinically therapeutic effect of 20 kHz US in combination with MBs for the treatment of hepatic carcinoma. A 71-year-old male with a hepatic malignant tumor was admitted to Nantong University Affiliated Nantong Tumor Hospital (Nantong, China). The patient was subsequently sonicated with 20 kHz US and MBs over a period of five days. The low-frequency US parameters were set at 20 kHz, 2 W/cm2, duty cycle 40% (on 2 sec, off 3 sec) for a duration of 5 min each day for a total of five days. Computed tomography (CT), contrast-enhanced US (CEUS) and carbohydrate antigen 19-9 (CA19-9) tests were performed to evaluate the therapeutic effects. Although the tumor size increased marginally on CT from 5.4 to 5.6 cm after US treatment, the intensity and enhanced-areas on the CT scans and CEUS decreased. The abdominal lymph node decreased in size, from 2.2 to 1.9 cm, and CA19-9 levels decreased from the pretreatment value of 2,007 to 734 U/ml. Therapy with low-frequency US combined with MBs may exhibit an antivasculature effect and may be used as a palliative treatment for patients with unresectable hepatic malignant tumors.

Purpose In this article,we revisited the anatomy of the distal perforator of the descending genicular artery (DGA) and report the clinical application of its perforator propeller flap in the reconstruction of soft tissue defects around the knee. Methods Forty fresh human lower limbs were dissected to redefine the anatomy of the branches of the DGA and their perforators and the anatomical landmarks for clinical applications. Five patients underwent “propeller” distal anteromedial thigh (AMT) flaps based on DGA perforators for the reconstruction of post-traumatic (n = 4) and post-oncologic (n = 1) soft tissue defects occurring near the knee with a size ranging from 4.8 cm × 6.2 cm to 10.5 cm × 18.2 cm. Results A constant cutaneous perforator of the osteoarticular branch (OAB) of the DGA was found in the distal AMT fossa with a mean caliber of 1.2 ± 0.4 mm. It arose 9.4 ± 3.1 cm distally to the origin of the OAB and 4.0 ± 0.4 cm above the knee joint. The size of the harvested flaps ranged from 6.0 cm × 7.1 cm to 11.0 cm × 20.1 cm. All the flaps healed uneventfully at a mean period of 7.4 months. All the patients regained full range motion of the knee-joint. Conclusion Our study provided evidence of the vascular supply and the clinical application of the distal AMT flap based on a constant perforator arising from the OAB of the DGA. This flap may be a versatile alternative for the reconstruction of the defects around the knee because of its consistent vascular pedicle, pliability and thinness, adequate retrograde perfusion, and the possible direct suture of the donor site. © 2014 Wiley Periodicals, Inc. Microsurgery 35:370–379, 2015.

Mechanisms underlying female gonadal dysgenesis remain unclarified and relatively unstudied. Whether X-chromosome inactivation (XCI)-escaping genes and microRNAs (miRNAs) contribute to this condition is currently unknown. We compared 45,X Turner Syndrome women with 46,XX normal women, and investigated differentially expressed miRNAs in Turner Syndrome through plasma miRNA sequencing. We found that miR-320a was consistently upregulated not only in 45,X plasma and peripheral blood mononuclear cells (PBMCs), but also in 45,X fetal gonadal tissues. The levels of miR-320a in PBMCs from 45,X, 46,XX, 46,XY, and 47,XXY human subjects were inversely related to the expression levels of XCI-escaping gene KDM5C in PBMCs. In vitro models indicated that KDM5C suppressed miR-320a transcription by directly binding to the promoter of miR-320a to prevent histone methylation. In addition, we demonstrated that KITLG, an essential gene for ovarian development and primordial germ cell survival, was a direct target of miR-320a and that it was downregulated in 45,X fetal gonadal tissues. In conclusion, we demonstrated that downregulation of miR-320a by the XCI-escaping gene KDM5C contributed to ovarian development by targeting KITLG.

Population-based cancer survival is an improved index for evaluating the overall efficiency of cancer health services in a given region. The current study analysed the observed survival and relative survival of leading cancer sites from a population-based cancer registry between 1972 and 2011 in Qidong, China. A total of 92,780 incident cases with cancer were registered and followed-up for survival status. The main sites of the cancer types, based on the rank order of incidence, were the liver, stomach, lung, colon and rectum, oesophagus, breast, pancreas, leukaemia, brain and central nervous system (B and CNS), bladder, blood [non-Hodgkin's lymphoma (NHL)] and cervix. For all malignancies combined, the 5-year observed survival was 13.18% and the relative survival was 15.80%. Females had higher observed survival and relative survival (19.32 and 22.71%, respectively) compared with males (9.63 and 11.68%, respectively). The cancer sites with the highest five-year relative survival rates were the female breast, bladder, cervix and colon and rectum; followed by NHL, stomach, B and CNS cancer and leukaemia. The poorest survival rates were cancers of oesophagus, lung, pancreas and liver. Higher survival rates were observed in younger patients compared with older patients. Cancers of the oesophagus, female breast and bladder were associated with higher survival in middle-aged groups. Improved survival rates in the most recent two 5-year calendar periods were identified for stomach, lung, colon and rectum, oesophagus, female breast and bladder cancer, as well as leukaemia and NHL. The observations of the current study provide the opportunity for evaluation of the survival outcomes of frequent cancer sites that reflects the changes and improvement in a rural area in China.

Objective To evaluate the application of transvaginal hydrolaparoscopy for exploration of the pelvic cavity exploration in infertile women. Study design A total of 510 infertile women were included in this study from May 1st, 2009 to April 30, 2012 in the clinic of the Hebei Research Institute for Family Planning. Results In 495 of 510 of the patients (97.06%), a successful operation was achieved at the first puncture. Of these 495 patients, 286 (57.78%) showed bilateral patency. Completely normal tubo-ovarian and pelvic structures were observed only in 79 patients (15.96%): 16 patients (3.23%) had bilateral tube obstruction, 18 (3.64%) had hydrosalpinx, and 8 (1.62%) had fimbrial stenosis. Pelvic abnormalities occurred in 240 patients (44.04%), including bilateral and/or unilateral tubo-ovarian adhesions in 80 patients (16.16%) and 160 (32.32%) found with adhesions in other parts of the pelvic cavity. Pelvic endometriosis was found in 82 patients (16.57%) and 19 (3.84%) had two or more lesions in the pelvic cavity. In addition, 9 cases (1.82%) of ovarian cysts, 7 (1.41%) of bilateral vesicular appendices and 43 cases (6.69%) of a unilateral vesicular appendix were observed. In addition, convoluted tubes such as bent or twisted tubes were found in 4 cases of bilateral fallopian tube occlusion patients (0.81%) and 17 cases of unilateral tubal occlusion patients (3.43%). Conclusions Transvaginal hydrolaparoscopy is a feasible, safe, and cost-effective microinvasive technique. This technique can be considered as an alternative procedure for evaluating female infertility.

Aims Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated. Methods and results We screened six candidate genes ( CAV1 , KCNJ2 , KCNQ1 , NKX2.5 , PITX2 , and TBX5 ) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1 , KCNJ2 , KCNQ1 , NKX2.5 , and PITX2. These mutations increased the expression of atrial natriuretic peptide ( ANP ) and connexin-40 ( CX40) in the primarily cultured rat atrial myocytes, but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α ( MHC-α ) and myosin light chain-2α ( MLC-2α ) . Over-expression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. In order to replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (AEAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects. Conclusion Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40 .

The aim of this meta-analysis is to demonstrate whether diffusion-weighted magnetic resonance imaging (DWI) could assist in the precise diagnosis of cervical cancer or not. Both English and Chinese electronic databases were searched for potential relevant studies followed by a comprehensive literature search without any language restriction. Two reviewers independently assessed the methodological quality of the included trials. Standardized mean difference (SMD) and its corresponding 95 % confidence interval (95 % CI) were calculated in this meta-analysis. We chose Version 12.0 STATA statistical software to analyze our statistical data. Thirteen eligible cohort studies were selected for statistical analysis, including 645 tumor tissues and 504 normal tissues. Combined SMD of apparent diffusion coefficient (ADC) suggested that the ADC value in cervical cancer tissues was significantly lower than that of normal tissue (SMD = 2.80, 95 % CI = 2.64 ~ 2.96, P

Pigmented paravenous retinochoroidal atrophy (PPRCA) is an uncommon disease characterized by perivenous aggregations of pigment clumps associated with peripapillary and radial zones of retinochoroidal atrophy that are distributed along the retinal veins. Patients are usually asymptomatic and the disease process is non-progressive or slow and subtly progressive. It is commonly bilateral and symmetric. The cause of the condition may be unknown or idiopathic, although a dysgenetic, degenerative, hereditary etiology or even an inflammatory cause has been hypothesized. A non-inflammatory cause is referred to as primary, while inflammation-associated PPRCA is referred to as secondary or pseudo PPRCA. The present study reviewed and summarized the features of PPRCA.

The aim of this study is to explore the inhibitory effects of RNA interference (RNAi) targeting NET-1 or combined with sorafenib on HCCin vitroandin vivoand the possible underlying mechanisms. The expressions of NET-1 mRNA and protein were detected by RT-QPCR and western blot. The ability of proliferation was determined by CCK-8 assay. Apoptosis was examined by flow cytometry (FCM). Abilities of migration and invasion were measured by scratch-wound assay and transwell assay. MHCC97H cells with stable transfection of NET-1shRNA were injected subcutaneously to prepare nude mice model of HCC and Caspase-3, Caspase-8, and Caspase-9 mRNAs of tumor tissues in different groups were examined. NET-1 mRNA and protein were reduced sharply in MHCC97H cells transfected with NET-1shRNA. The abilities of proliferation and migration were inhibited and apoptosis was promoted in either NET-1shRNA or sorafenib as compared with untreated cellsin vitroandin vivo(P<0.05). The mRNA levels of caspase-3, caspase-8, and caspase-9 of tumor tissues were reduced in different treatment groups compared with untreated group, particularly in combination group. (P<0.05). The combination NET-1shRNA with sorafenib dramatically enhanced the effects of sorafenib antitumor ,which may involve in blocking ras signaling pathway and stimulating apoptotic pathways simultaneously.

To explore the effect of NET-1 on the proliferation, migration and endocytosis in the hepatocellular carcinoma (HCC) cell line SMMC-7721, we constructed the pU6H1-NET-1-siRNA (NET-1siRNA) and pcDNA3.1/myc-NET-1 (myc-NET-1) vectors and transfected them into SMMC-7721 cells. The expression levels of NET-1 mRNA and protein were detected using real-time quantitative RT-QPCR and western blotting. The proliferation rates of SMMC-7721 cells were determined by CCK-8 assays, flow cytometry (FCM) and immunohistochemistry staining. The migration in two or three dimensional space of SMMC-7721 cells were determined by wound-healing assay and in vitro invasion assay. The extent of endocytosis in SMMC-7721 cells was estimated by observing the amount of transferrin (Tfn) absorbed with capture ELISA assays, and Tfn endocytosis was observed under confocal immunofluorescence microscopy. The results show that: i) after transfecting NET-1 siRNA, the expression of NET-1 mRNA and protein in SMMC-7721 cells decreased significantly, the growth of cells was suppressed, which induced cell cycle arrest, the proliferation rates were dramatically reduced and the expression of Ki67 declined, and migration and endocytosis in cells were inhibited, compared with untreated cells (every P

To evaluate the clinical significance of CpG island methylator phenotype (CIMP) in plasma and its association with hepatocellular carcinoma (HCC) progress.CIMP status of 108 HCC patients was analyzed using a methylation marker panel in tumor tissues and plasma with methylation-specific polymerase chain reaction. Fifteen samples of non-neoplastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examined genes included APC, WIF-1, RUNX-3, DLC-1, SFRP-1, DKK and E-cad.The frequencies of high-level methylation in HCC tissue and plasma were at least 15% for the seven genes: APC, 48/108, 44.44% in tissue and 26/108, 24.07% in plasma; WIF-1, 53/108, 49.07% in tissue and 35/108, 32.41% in plasma; RUNX-3, 52/108, 48.14% in tissue and 42/108, 38.89% in plasma; DLC-1, 38/108, 35.18% in tissue and 23/108, 21.30% in plasma; SFRP-1, 40/108, 37.04% in tissue and 31/108, 28.7% in plasma; DKK, 39/108, 36.1% in tissue and 25/108, 23.14% in plasma; and E-cad, 37/108, 34.3% in tissue and 18/108, 16.67% in plasma. CIMP+ (≥ 3 methylated genes) was detected in 68 (60.2%) tumor tissue samples and 62 (57.4%) plasma samples. CIMP was not detected in non-neoplastic liver tissues or plasma of healthy persons. CIMP status in tumor tissues differed significantly in gender, hepatitis B surface antigen, alpha-fetoprotein, and tumor-node-metastasis stage (P0.05). Similar results were obtained with plasma samples (P0.05). There was no difference in CIMP status in age, presence of hepatitis C virus antibody, cirrhosis, number of nodes, number of tumors, tumor size, or Edmondson-Steiner stage. A one-year follow-up found that the metastatic rate and recurrence rate in the CIMP+ group were significantly higher than in the CIMP- group as assessed with plasma samples (P0.05).Plasma DNA can be a reliable sample source for CIMP analysis. CIMP in plasma may serve as a molecular marker of late-stage and poor-prognosis HCC.

Toll-like receptor 3 (TLR3) is a member of the Toll-like receptors which recognize pathogen-associated molecular patterns leading to the activation of the innate immune response. Recent reports have strongly indicated that they play important roles in cancer cells. Since TLR3 has been recently suggested as a possible therapeutic target in certain types of cancers, in the present study, TLR3 expression and its function were explored in hepatocellular carcinoma (HCC) and human umbilical vein endothelial cells (HUVECs). The expression of TLR3 in various HCC cell lines and HUVECs was detected using quantitative real-time PCR (qRT-PCR) and immunocytochemistry. TLR3 activity was determined by Luciferase reporter assays. The effects of TLR3 double-stranded RNA (dsRNA) agonists on angiogenesis were tested by aortic ring assay and HUVEC tube formation experiments. After dsRNA treatment, cell apoptosis was assessed by Annexin V and PI staining through FACS, and the migration ability was measured by a migration assay. The results showed that TLR3 was expressed in HCC cell lines and HUVECs at the mRNA and protein level. Luciferase reporter assays demonstrated that TLR3 was activated by the dsRNA analog BM-06 or poly(I:C). Rat aortic ring outgrowth and endothelial cell tube formation were suppressed after treatment with dsRNA. In addition, dsRNA triggered apoptosis in MHCC97H, SMMC-7721 and HUVEC cell lines and inhibited cell migration. In conclusion, TLR3 agonists not only affect tumor microenvironment by suppressing angiogenesis but also directly induce tumor cell apoptosis and inhibit tumor cell migration. TLR3 may be a new target for HCC therapy.

The foot offers numerous useful options for hand reconstruction. Hallux transfer, dorsalis pedis flap, second toe transfers, and toe joint transfers offer good functional results in reconstructed hands. However, when the donor site is repaired with skin grafts, delayed wound healing, scarring, and contractures often result. Poor cosmesis of the donor site and altered gait are the main drawbacks of the procedures. The authors propose a new concept of primary reconstruction of the donor foot using a reverse-flow anterior tibial flap from the same leg. Two flaps are raised from the same anterior tibial vessel system in continuity as a distal free flap for hand reconstruction and as a proximal reverse-flow pedicled flap to resurface the donor defect. This technique allows good flap reconstruction of the foot donor site, reducing morbidity and limiting the operation to the same limb. The authors report their experience of 33 cases. There were no failures. Primary wound healing was achieved in the foot donor site, with acceptable cosmesis and satisfactory function.

Background A role for autophagy, a conserved cellular response to stress, has recently been demonstrated in human cancers. Aberrant expression of Beclin-1, an important autophagic gene, has been reported in various human cancers. In the present study, we investigated the significance and relationship between Beclin-1 expression and cell proliferation, apoptosis, microvessel density (MVD) and clinical pathological changes or prognosis in human hepatocellular carcinoma (HCC). Methods A total of 103 primary HCC patients were involved in the study. Expression of Beclin-1, PCNA, NET-1, Bcl-2, Bax, Survivin in cancer cells and CD34 in stromal microvessels were evaluated immunohistochemically in tissue microarrays comprising 103 cases of HCC and 57 matched adjacent nontumor liver tissues. Correlations between clinicopathological characteristics and survival of HCC patients were explored. Results The positive rate of Beclin-1 was significantly lower in HCC tissues than adjacent tissues (72.8 vs. 89.5%, χ2 = 6.085, P = 0.015). In HCC, Beclin-1 expression was negatively correlated with cirrhosis background (r = −0.216, P = 0.029), Edmondson grade (r = −0.249, P = 0.011), vascular invasion (r = −0.246, P = 0.012), PCNA (r = −0.242, P = 0.014), NET-1 (r = −0.245, P = 0.013), anti-apoptosis protein Bcl-2 (r = −0.245, P = 0.013) and MVD (r = −0.292, P = 0.003), and positively correlated with pro-apoptosis protein Bax (r = 0.242, P = 0.014). Significant differences in the 5-year survival rates were seen among patients with Beclin-1 strong positive (++) (59.1%, 13/22), moderate positive (+) (28.3%, 15/53) and weak negative expression (−) (14.6%, 7/28) (P = 0.043). Significant differences were detected between Beclin-1 (++) and either Beclin-1 (+) (P = 0.036) or Beclin-1 (−) groups (P = 0.008), but no significant difference between Beclin-1 (+) and Beclin-1 (−) groups (P = 0.281) was observed. Survival rates were positively related to high Beclin-1 co-expressed with low PCNA, NET-1, or Bcl-2, lower MVD, and high Bax. Univariate and multivariate Cox regression analysis revealed that Beclin-1 expression was an independent indicator for overall survival in HCC patients (P

Background Totally laparoscopic distal gastrectomy (TLDG) has been developed in the hope of improving surgical quality and overcoming the limitations of conventional laparoscopic assisted distal gastrectomy (LADG) for gastric cancer. The aim of this study was to determine the extent of evidence in support of these ideals. Methods A systematic review of the two operation types (LADG and TLDG) was carried out to evaluate short-term outcomes including duration of operation, retrieved lymph nodes, estimated blood loss, resection margin status, technical postoperative complications, and hospital stay. Results Twelve non-randomized observational clinical studies involving 2,255 patients satisfied the eligibility criteria. Operative time was not statistically different between groups (P > 0.05). The number of retrieved lymph nodes and the resection margin length in TLDG were comparable with those in LADG. Estimated blood loss was significantly less in TLDG than that in LAG (P