Deficiency of IQCH causes male infertility in humans and mice.

IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.

HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice.

Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno-associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.

Resurfacing of multiple adjacent defects with free multipaddle SCIAP flaps.

BACKGROUND: The efficient resurfacing of multiple adjacent defects (MADs) requires precise reconstructive strategy. Various approaches (e.g., several flap transferring or prelamination of the recipient site) have been reported, but recipient-site impairments, pain, long hospitalization, and low cost-benefit results fatefully considered them as compromise approaches. This study aims to evaluate the feasibility of MADs reconstruction with free multipaddle superficial circumflex iliac artery perforator (SCIAP) flaps. METHODS: From Dec 2015 to Dec 2020, we enrolled patients with upper and lower extremity defects treated with various multipaddle SCIAP flaps (2-paddle, 3-paddle, and 4-paddle). Patient demographics and outcomes of each group were collected. RESULTS: Thirty-two, 21, and 6 patients underwent 2-paddle, 3-paddle, and 4-paddle SCIAP flaps transfers, respectively. All multipaddle SCIAP flaps survived without vascular problems, and the donor sites were closed directly. Except for 3 cases of 2-paddle SCIAP flaps drained by superficial circumflex iliac vein venous return, most cases (n = 56) were drained by venae comitans. Minor complications, including partial flap necrosis (4 cases) and lateral femoral cutaneous nerve palsies (11 cases), were treated conservatively. All patients were satisfied with the reconstructive outcome. CONCLUSION: Multiple adjacent defects reconstruction is still a Gordian knot and lacks a golden standard. The free multipaddle SCIAP flap was demonstrated as a promising alternative, not only enriching its versatility but also initially highlighting the "replace need with need" reconstructive demand.

Novel variations in TENT5D lead to teratozoospermia in infertile patients.

PURPOSE: Teratozoospermia is the main pathogenic factor of male infertility. However, the genetic etiology of teratozoospermia is largely unknown. This study aims to clarify the relationship between novel variations in TENT5D and teratozoospermia in infertile patients. MATERIALS AND METHODS: Two infertile patients were enrolled. Routine semen analysis of patients and normal controls was conducted with the WHO guidelines. Whole-exome sequencing (WES) was conducted to identify pathogenic variants in the two patients. Morphology and ultrastructure analysis of spermatozoa in the two patients was determined by Papanicolaou staining, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The functional effect of the identified variants was analyzed by immunofluorescence staining and western blotting. The expression of TENT5D in different germ cells was detected by immunofluorescence staining. RESULTS: Two new hemizygous variations, c.101C > T (p.P34L) and c.125A > T (p.D42V), in TENT5D were detected in two patients with male infertility. Morphology analysis showed abnormalities in spermatozoa morphology in the two patients, including multiple heads, headless, multiple tails, coiled, and/or bent flagella. Ultrastructure analysis showed that most of the spermatozoa exhibited missing or irregularly arranged '9+2' structures. Further functional experiments confirmed the abrogated TENT5D protein expression in patients. In addition, both p.P34L and p.D42V substitutions resulted in a conformational change of the TENT5D protein. We precisely analyzed the subcellular localization of TENT5D in germ cells in humans and mice. And we found that TENT5D was predominantly detected in the head and flagellum of elongating spermatids and epididymal spermatozoa. CONCLUSIONS: Our results showed further evidence of a relationship between TENT5D mutation and human male infertility, providing new genetic insight for use in the diagnosis and treatment of male infertility.

A Bibliometrics of the Treatment of Alopecia Areata in the Past Twenty Years.

BACKGROUND: Alopecia areata (AA) is an autoimmune disorder characterized by hair loss on the scalp, face, and other body areas. Despite affecting approximately 2% of the global population, there has been no previous bibliometric analysis specifically focusing on AA treatment that can guide researchers in exploring promising treatment options and directing future research efforts. SUMMARY: This study conducted a bibliometric analysis of AA treatment research, encompassing publications from 2003 to 2022. A total of 1,323 papers from 65 countries, predominantly led by the USA and China, were included in the analysis. The number of publications related to AA treatment showed a notable increase over the years. Prominent research institutions included the University of Manchester, Icahn School of Medicine at Mount Sinai, University of Miami, and Columbia University. Among the journals, Dermatologic Therapy stood out as the most popular, while the Journal of the American Academy of Dermatology appeared as the most frequently co-cited publication.

A novel splicing mutation identified in a DMD patient: a case report.

Background: Duchenne muscular dystrophy (DMD, ORPHA:98896) is a lethal X-linked recessive disease that manifests as progressive muscular weakness and wasting. Mutations in the dystrophy gene (DMD) are the main cause of Duchenne muscular dystrophy. Case presentation: This study aims to determine novel mutations of DMD and help preimplantation genetic diagnosis (PGD) for family planning. Here present a 4-year-old Chinses boy with DMD, whole-exome sequencing (WES) was performed to identify the molecular basis of the disease. It was confirmed that the boy carried a novel hemizygous mutation of NC_000023.11(NM_004006.3): c.5912_5922 + 19delinsATGTATG in DMD which inherited from his mother. This led to the aberrant splicing of DMD which demonstrated by a minigene splicing assay and further resulted in the impairment of the dystrophy protein. Conclusions: Our study discovered a novel splicing mutation of DMD in a DMD patient, which expands the variant spectrum of this gene and provide precise genetic diagnosis of DMD for timely therapy. Meanwhile, this finding will supply valuable information for preimplantation genetic diagnosis.

Negative pressure wound therapy (NPWT) is superior to conventional moist dressings in wound bed preparation for diabetic foot ulcers: A randomized controlled trial.

OBJECTIVES: To compare the efficacy of negative pressure wound therapy (NPWT) and alginate dressings on wound bed preparation prior to split thickness skin graft (STSG) surgery for patients with chronic diabetic foot ulcers (DFUs). METHODS: Between September 2022 and March 2023, we completed a randomized controlled trial in Nanjing First Hospital and PLA 454 Hospital. Patients were divided into 2 groups: i) the NPWT group (with vacuum-assisted closure, n=50); ii) the control group (with alginates dressings, n=50). Once DFU wound was filled with healthy granulation tissues, STSG surgery was performed. The time to STSG surgery was regarded as the primary outcome. The survival rates of skin graft, the wound blood perfusion, the wound neutrophil extracellular traps (NETs) formation, and polarization of M1 and M2 macrophages in DFU wounds were regarded ad secondary outcomes. RESULTS: Patients in the NPWT group had less time to STSG surgery than the control group. The patients in the NPWT group had prominently increased survival rates of skin graft, increased wound blood perfusion, and decreased NET formation in comparison with the control group. The macrophages in DFU wounds switched from M1 to M2 phenotype in the NPWT group. CONCLUSION: Negative pressure wound therapy is superior to conventional moist dressings in wound bed preparation prior to STSG surgery for patients with chronic DFUs.

Sutures positioning technique enhances the predictability and concordance between preoperative simulation and actual outcomes in rhinoplasty.

BACKGROUND: The predictability and concordance between simulated and actual outcomes in rhinoplasty are uncertain. Here, we introduce a suture positioning technique (SPT), a simple and low-cost method to minimize the gap between the simulated and actual outcomes of rhinoplasty. METHODS: Seventy patients were enrolled in this study between January 2018 and January 2021. Preoperative simulations were performed using Adobe Photoshop. The control group underwent surgery using simulation and intuition. In the SPT group, sutures were used to assist in the preoperative identification of the ideal nasal tip position. The SPT effectiveness was tested by measuring the nasal parameters and using the patient's subjective satisfaction questionnaire at T1 (Time 1, immediately postoperatively) and T2 (Time 2, at least 1 year postoperatively). RESULTS: The intraclass correlation coefficient test showed a satisfactory correlation between simulation and postoperative outcomes in both groups. However, the SPT group had a higher correlation than the control group, especially for the nasal length (16% higher at T1 and 15% higher at T2). The mean absolute difference (MAD) between the outcomes and simulation indicated that the MAD of nasal tip projection between T2 and simulation and MAD of nasal length between T1 (or T2) and simulation were statistically significant between groups. Additionally, the SPT group was more satisfied with the postoperative outcomes and were consistent with the preoperative simulation. CONCLUSION: This study demonstrated the effectiveness of SPT in intraoperative quality control. This technique may be adopted by surgeons to achieve good concordance between simulated and actual surgical outcomes.

Identification of biallelic variations of CEP70 in patients with male infertility.

Introduction: Male infertility is a severe health issue caused by complex and multifactorial pathological conditions. Genetic factors are a major cause of male infertility. CEP70, a centrosomal protein, has been reported to play an important role in male reproduction in mice. However, the role of CEP70 in human male infertility is limited. Methods: Whole exome sequencing and Sanger sequencing were used to identify the genetic cause of the infertile patients. Papanicolaou staining, scanning electron microscopy and transmission electron microscopy were further conducted to explore morphological and ultrastructural defects in spermatozoa from the patient. Immunofluorescence staining was used to detect the pathogenicity of the identified variants and the particular expression of CEP70 in testis. Results: In this study, we identified biallelic mutations of CEP70 in two unrelated infertile male individuals with oligoasthenoteratozoospermia that followed a recessive inheritance pattern. Papanicolaou staining, scanning electron microscopy and transmission electron microscopy showed that morphological and ultrastructural defects in the acrosome and flagellum of sperm from the patient in a pattern strikingly similar to that in Cep70-/- male mice. The results of immunofluorescence staining suggested that CEP70 was normally expressed in the acrosome and flagellum of control sperm but was hardly detected in the sperm of patient carrying CEP70 variation. We also explored the particular expression pattern of CEP70 during spermatogenesis in humans and mice. Conclusions: Biallelic mutations of CEP70 might be a novel genetic cause of human male infertility, which could potentially serve as a basis for genetic counseling and diagnosis of male infertility.

Identification of nonfunctional SPATA20 causing acephalic spermatozoa syndrome in humans.

Acephalic spermatozoa syndrome (ASS) is a rare and severe type of teratozoospermia characterized by the predominance of headless spermatozoa in the ejaculate. However, knowledge about the causative genes associated with ASS in humans is limited. Loss-of-function of SPATA20 has been suggested to result in the separation of the sperm head and flagellum in mice, whereas there have been no cases reporting SPATA20 variants leading to human male infertility. In this study, a nonsense mutation in SPATA20 (c.619C > T, p.Arg207*) was first identified in an ASS patient. Moreover, this variant contributed to the degradation of SPATA20 and was associated with decreased expression of SPATA6, which plays a vital role in the assembly of the sperm head-tail conjunction in humans. In addition, the infertility caused by loss-of-function mutation of SPATA20 might not be rescued by intracytoplasmic sperm injection (ICSI). Collectively, our findings suggested that SPATA20 might be required for sperm head-tail conjunction formation in humans, the nonfunction of which may lead to male infertility related to ASS. The discovery of the loss-of-function mutation in SPATA20 enriches the gene variant spectrum of human ASS, further contributing to improved diagnosis, genetic counseling and prognosis for male infertility.

Predictive value of circulating cystatin C level in patients with acute coronary syndrome: a meta-analysis.

Circulating cystatin C level has been identified as a predictor of adverse outcomes in patients with coronary artery disease (CAD). This meta-analysis aimed to investigate the value of circulating cystatin C level for predicting adverse outcomes in patients with acute coronary syndrome (ACS). We comprehensively searched articles indexed in Pubmed and Embase databases from their inceptions to 30 November 2019. All available observational studies that investigated the association between circulating cystatin C level and major adverse cardiovascular events [MACE] (including death, heart failure, re-infarction, target vascular revascularization, angina and stroke) or all-cause mortality in patients with ACS were included. The prognostic value was expressed by pooling the multivariable-adjusted hazard risk (HR) with 95% confidence interval (CI) for the highest versus the lowest category of cystatin C level. Eleven eligible studies (12 articles) with 4600 ACS patients were identified. Meta-analysis indicated that the highest versus lowest category of cystatin C level was associated with higher risk of MACE (HR 2.28; 95% CI 1.92-2.71) and all-cause mortality (HR 2.89; 95% CI 1.43-5.83) after adjustment for estimated glomerular filtration rate (eGFR) or creatinine. Subgroup analysis by subtypes of patients, study design, follow-up duration and cutoff level of cystatin C further confirmed the value of cystatin C level for predicting MACE. Elevated circulating cystatin C level at baseline is strongly and independently associated with an increased risk of MACE and all-cause mortality in patients with ACS. Determination of circulating cystatin C level has potential to improve risk stratification of ACS patients.

Intrinsically altered lung-resident γδT cells control lung melanoma by producing interleukin-17A in the elderly.

Cancer is an age-associated disease, potentially related to the altered immune system of elderly individuals. However, cancer has gradually decreased incidence in the eldest globally such as the most common lung cancer, the mechanisms of which remain to be elucidated. In this study, it was found that the number of lung-resident γδT cells was significantly increased with altered gene expression in aged mice (20-24 months) versus young mice (10-16 weeks). Aged lung Vγ4+ and Vγ6+ γδT cells predominantly produced interleukin-17A (IL-17A), resulting in increased levels in the serum and lungs. Moreover, the aged mice exhibited smaller tumors and reduced numbers of tumor foci in the lungs after challenge with intravenous injection of B16/F10 melanoma cells compared with the young mice. Aged lung Vγ4+ and Vγ6+ γδT cells were highly cytotoxic to B16/F10 melanoma cells with higher expression levels of CD103. The markedly longer survival of the challenged aged mice was dependent on γδT17 cells, since neutralization of IL-17A or depletion of indicated γδT cells significantly shortened the survival time. Consistently, supplementation of IL-17A significantly enhanced the survival time of young mice with lung melanoma. Furthermore, the anti-tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota, as demonstrated through co-housing of the aged and young mice. Intrinsically altered lung γδT17 cells underlying age-dependent changes control lung melanoma, which will help to better understand the lung cancer progression in the elderly and the potential use of γδT17 cells in anti-tumor immunotherapy.

The Stromal Vascular Fraction Improves Maintenance of the Fat Graft Volume: A Systematic Review.

BACKGROUND AND OBJECTIVES: With the continued application of fat grafting in plastic surgery, many studies have focused on various factors to improve maintenance of the fat graft volume, such as platelet-rich plasma, adipose-derived stromal/stem cells, and the stromal vascular fraction (SVF). In addition, many review articles have investigated the functions of platelet-rich plasma and adipose-derived stromal/stem cells in fat grafting, although the usefulness of the SVF remains unclear. The aim of the present review was to determine whether SVF use could maintain a fat graft. METHODS: A systematic review was conducted of the PubMed, Cochrane Central Register of Controlled Trials, and Embase databases of original articles published up to February 2018. RESULTS: Relevant articles were identified by screening the abstracts. A total of 58 full texts were initially identified. After exclusion, 17 articles, including 6 animal studies and 11 clinical studies, were included for analysis. CONCLUSIONS: Most studies found a significant and measurable long-term effect of SVF-enhanced fat grafting on breast augmentation and defects, wound healing, scaring, and facial aesthetic outcomes. Stromal vascular fraction use did not result in a higher instance of complications and, thus, can be considered a safe option for fat grafting.

Clinicopathological and prognostic significance of circulating tumor cells in patients with lung cancer: a meta-analysis.

BACKGROUND: The prognostic significance of circulating tumor cells in patients with lung cancer is controversial. Therefore, we aimed to comprehensively and quantitatively assess the prognostic role of CTCs in patients with lung cancer. METHODS: The relevant literature was searched using PubMed, the Cochrane database and the China National Knowledge Internet database (up to June 2016). Using Review Manager 5.1.2, a meta-analysis was performed using hazard ratio (HR), odds ratio (OR) and 95% confidence interval (CI) as effect values. RESULTS: Thirty studies comprising 2,060 patients with lung cancer were analyzed. The pooled HR values showed that circulating tumor cells were significantly correlated with overall survival (HR =2.63, 95% CI [2.04, 3.39]) and progression-free survival (HR =3.74, 95% CI [2.49, 5.61]) in these patients. Further subgroup analyses were conducted and categorized by sampling time, detection method, and histological type; these analyses showed the same trend. The pooled OR values showed that circulating tumor cells were associated with non small cell lung cancer stage(OR = 2.11, 95% CI [1.42, 3.14]), small cell lung cancer stage (OR = 10.91, 95% CI [4.10, 29.06]), distant metastasis (OR =7.06, 95%CI [2.82, 17.66]), lymph node metastasis (OR =2.31, 95% CI [1.19,4.46]), and performance status(OR =0.42, 95%CI [0.22, 0.78]). CONCLUSION: The detection of circulating tumor cells in the peripheral blood of patients with lung cancer can be indicative of a poor prognosis.

Commensal microbiota maintains alveolar macrophages with a low level of CCL24 production to generate anti-metastatic tumor activity.

Microbiota maintains host tissue homeostasis and influences tissue-resident macrophages. However, the mechanisms by which commensal bacteria in regulating the alveolar macrophages remain unclear. Here, by using an antibiotic-treated (Abt) mouse model, we found commensal bacteria depletion induced lower frequencies and numbers of alveolar macrophages. This effect was accompanied by the altered levels of genes involved in several biological pathways, including M2 macrophage polarization, as determined by gene expression analysis. Alveolar macrophages from the Abt mice had higher protein and gene levels of Arg1, CCL24, IL-13, IL-10, IL-6 and IL-1ß, which could be recovered to normal levels by reconstructing commensal bacteria in the upper respiratory of Abt mice. Moreover, alveolar macrophages performed significant enhancement of M2 functions, especially CCL24 secretion, in the Abt mice challenged with B16/F10 melanoma. Adoptive transfer of normal alveolar macrophages or antibody neutralization of CCL24 significantly recovered the decrease of γδT17 cells and rescued the defect anti-tumor response of Abt mice, indicating the elevated amount of alveolar macrophage-derived CCL24 inhibited γδT cell mediated anti-tumor response. In conclusion, we demonstrated the ability of commensal bacteria to maintain alveolar macrophages with a low level of CCL24 production, which was necessary for the normal anti-tumor response in the lung.

Thrombospondin-1 inhibits ossification of tissue engineered cartilage constructed by ADSCs.

Cartilage tissue engineering provides a new method in the treatment of cartilage defects, and adipose derived stem cells seem to be an ideal seed cell in cartilage tissue engineering because of its characteristics. However, ossification after in vivo implantation of tissue engineered cartilage remains a challenge. Thrombospondin-1 which has been reported to have an inhibitory effect on angiogenesis, may play an important role in inhibiting the ossification of tissue engineered cartilage constructed by adipose derived stem cells. Therefore, the effect of thrombospondin-1 in inhibiting the ossification of tissue engineered cartilage was evaluated in this study. Lentivirus vectors carrying thrombospondin-1 cDNA were transfected into adipose derived stem cells, and the transfected cells were used in the experiments. The expression of thrombospondin-1 was evaluated by quantitative reverse transcriptase-polymerase chain reaction and western blot, and the effects of thrombospondin-1 over-expression on angiogenesis were analyzed by angiogenesis assays. The quality of tissue engineered cartilage and the degree of ossification were assessed by biomechanical and molecular biology methods. The results showed that thrombospondin-1 infected cells have a high expression of thrombospondin-1 in mRNA and protein level, which inhibited the tube formation of endothelial cells, indicating the anti-angiogenic effects. Gene expression analyses in vitro showed that thrombospondin-1 inhibits the osteogenic differentiation of adipose derived stem cells significantly, and the results of in vivo study revealed that thrombospondin-1 significantly inhibits the expression of osteogenic genes. Compared to that in the control group, tissue engineered cartilage constructed by thrombospondin-1 transfected adipose derived stem cells in vivo showed a higher GAG content and lower compressive modulus, which indicating lower level of ossification. In conclusion, the current study indicated that the anti-angiogenic factor thrombospondin-1 suppresses the osteogenic differentiation of adipose derived stem cells in vitro, and inhibits ossification of tissue engineered cartilage constructed by adipose derived stem cells in vivo.

Relationship between epithelial cell adhesion molecule (EpCAM) overexpression and gastric cancer patients: A systematic review and meta-analysis.

OBJECTIVES: The epithelial cell adhesion molecule (EpCAM) is one of the most commonly used markers of cancer stem cells (CSCs), but the clinical and prognostic significance of EpCAM in gastric cancer (GC) remains disputable. Motivated by heterogeneous and inconclusive results, we conducted a systematic review and meta-analysis to systematically summarize and elucidate the association between EpCAM overexpression and GC patients. METHODS: The PubMed, Cochrane Library, Medline, Web of Knowledge and the China National Knowledge Infrastructure (CNKI) databases were searched to identify relevant studies. The RevMan 5.3 software was used for the meta-analysis. Fixed-effects or random-effects models were applied depending on the presence of heterogeneity. The pooled odds ratio (ORs) and 95% confidence intervals (CIs) were applied to estimate the associations between EpCAM and gastric cancer. For the significant heterogeneity studies, sensitivity analyses were applied based on the population to test the robustness of the pooled results and identify possible sources of heterogeneity. RESULTS: A total of 11 studies including 1960 GC patients met our inclusion criteria. The results of the meta-analyses revealed that there were significant differences in EpCAM overexpression and tumour size (OR = 2.97, 95% CI: 2.13~4.13, P < 0.00001), the nature of the tissue (OR = 80.30, 95% CI: 29.21~220.81, P < 0.00001), lymph node metastasis (OR = 2.78, 95% CI: 1.23~6.27, P = 0.01), and the cumulative 5-year overall survival rate (OR = 0.54, 95% CI:0.29~0.99, P = 0.05). No significant associations were identified between EpCAM overexpression and gender (OR = 0.89, 95% CI: 0.66~1.19, P = 0.43), age (OR = 1.13, 95% CI: 0.58~2.20, P = 0.73), tumour stage (OR = 2.26, 95% CI: 0.79~6.45, P = 0.13), distant metastasis (OR = 2.15, 95% CI: 0.20~22.69, P = 0.52), TNM stage (OR = 5.14, 95% CI: 0.77~34.37, P = 0.09), Lauren type (OR = 1.18, 95% CI: 0.08~16.45, P = 0.9), differentiation (OR = 1.88, 95% CI: 0.65~5.41, P = 0.24). However, due to significant heterogeneity in tumor stage, lymph node metastasis, TNM stage, differentiation and Lauren type, these results should be taken carefully. CONCLUSIONS: The meta-analysis demonstrated that the expression of EpCAM in the gastric cancer group was greater than that in the control group. Moreover, EpCAM overexpression was associated with larger tumour size, lymphnode metastasis and worse prognosis in gastric cancer. Due to significant heterogeneity, the sensitivity analysis suggests that population factor may be an important source of heterogeneity, and these results should be treated with caution. EpCAM may be useful as a novel prognostic factor, and large-scale and well-designed studies are needed to validate our results in the future.

Tumor suppressor genes and their underlying interactions in paclitaxel resistance in cancer therapy.

OBJECTIVES: Paclitaxel (PTX) is frequently used in the clinical treatment of solid tumors. But the PTX-resistance is a great obstacle in cancer treatment. Exploration of the mechanisms of drug resistance suggests that tumor suppressor genes (TSGs) play a key role in the response of chemotherapeutic drugs. TSGs, a set of genes that are often inactivated in cancers, can regulate various biological processes. In this study, an overview of the contribution of TSGs to PTX resistance and their underlying relationship in cancers are reported by using GeneMANIA, a web-based tool for gene/protein function prediction. METHODS: Using PubMed online database and Google web site, the terms "paclitaxel resistance" or "taxol resistance" or "drug resistance" or "chemotherapy resistance", and "cancer" or "carcinoma", and "tumor suppressor genes" or "TSGs" or "negative regulated protein" or "antioncogenes" were searched and analyzed. GeneMANIA data base was used to predict gene/protein interactions and functions. RESULTS: We identified 22 TSGs involved in PTX resistance, including BRCA1, TP53, PTEN, APC, CDKN1A, CDKN2A, HIN-1, RASSF1, YAP, ING4, PLK2, FBW7, BLU, LZTS1, REST, FADD, PDCD4, TGFBI, ING1, Bax, PinX1 and hEx. The TSGs were found to have direct and indirect relationships with each other, and thus they could contribute to PTX resistance as a group. The varied expression status and regulation function of the TSGs on cell cycle in different cancers might play an important role in PTX resistance. CONCLUSION: A further understanding of the roles of tumor suppressor genes in drug resistance is an important step to overcome chemotherapy tolerance. Tumor suppressor gene therapy targets the altered genes and signaling pathways and can be a new strategy to reverse chemotherapy resistance.

Protective effect of pyrroloquinoline quinine on ultraviolet A irradiation-induced human dermal fibroblast senescence in vitro proceeds via the anti-apoptotic sirtuin 1/nuclear factor-derived erythroid 2-related factor 2/heme oxygenase 1 pathway.

The aim of the present study was to determine whether pyrroloquinoline quinine (PQQ) exerts a protective effect on ultraviolet A (UVA) irradiation­induced senescence in human dermal fibroblasts (HDFs) and to elucidate its mechanism of action in vitro. A senescence model was constructed as follows: HDFs (1x10(4)­1x10(6)) were cultured in a six­well plate in vitro and then exposed to UVA irradiation at a dosage of 9 J/cm2. Various concentrations of PQQ (50, 100 and 200 ng/ml) were added to the culture medium 24 h prior to UVA exposure. Following 72 h of irradiation, senescence­associated ß­galactosidase staining was performed in order to evaluate the senescence state. Furthermore, mRNA expression of the senescence marker genes matrix­metalloprotease (MMP)1 and MMP3 was determined using reverse transcription quantitative polymerase chain reaction. Protein expression of sirtuin (SIRT)1, SIRT6, nuclear factor erythroid 2­related factor 2 (Nrf2) and heme oxygenase 1 (HO­1) were detected using western blot analysis. The results showed that the percentage of cells stained by X­gal following 9 J/cm2 UVA irradiation was markedly increased compared with that of the control group (53 and 8%, respectively), while 50 ng/ml PQQ attenuated the ratio of positive staining compared with that of the UVA­only cells (29 vs. 53%, respectively). Expression of fibroblast senescence marker genes MMP1 and MMP3 was decreased in cells treated with UVA and 50 ng/ml PQQ compared with that of cells in the UVA­only group. Western blot analysis revealed significant effects of PQQ on SIRT1 and SIRT6. Nrf2 and HO­1 exbibited mild changes with the same trend when treated with or without UVA and PQQ. In conclusion, the results of the present study showed that pyrroloquinoline quinine may have a protective effect on UVA irradiation­induced HDF aging, which may be associated with the anti­apoptotic SIRT1/Nrf2/HO­1 pathway as well as SIRT6 signaling.

Clinical practice guidelines for hypertension in China: a systematic review of the methodological quality.

OBJECTIVE: Clinical practice guidelines (CPGs) provide clinicians with specific recommendations for practice, but due to the increasing number of CPGs developed by diverse organisations over the past few years, there are concerns about the quality of some CPGs. This paper proposes a systematic review of the methodological quality of the CPGs for hypertension that were developed in China. DESIGN: A systematic review of CPGs for the management of hypertension in adult patients in China. DATA RESOURCES: Chinese electronic databases, Chinese guideline websites and Google Scholar were searched, and the reference lists of relevant publications were also screened for additional information. CPGs for the management of hypertension in adult patients were identified. The main characteristics of the CPGs were extracted, and the scaled Appraisal of Guidelines, REsearch and Evaluation II (AGREE II) domain percentages were independently evaluated by two reviewers. RESULTS: A total of 17 CPGs, with publication dates ranging from 2001 to 2011, were identified. There was considerable variation in the quality of the CPGs across the AGREE II domains. Overall, the domains of 'rigor of development' and 'editorial independence' were poorly addressed, with an average score of 18% and 16%, respectively. Also less well addressed were the 'stakeholder involvement' and 'applicability' domains, for which the average domain scores were 28% and 20%, respectively. The CPGs performance was less problematic in the domains of 'scope and purpose' and 'clarity and presentation', with a median of 41% for both. After considering the domain scores, 8 CPGs could be recommended with modification for use. CONCLUSIONS: There is considerable room for improvement of the methodological quality of CPGs for hypertension in China. Greater efforts should to be devoted to ensure the explicit and transparent reporting of potential conflicts of interest of stakeholders, and to consider the quality of the evidence and grade recommendations in the CPG development process.