GREM1 is a potential biomarker for the progression and prognosis of bladder cancer.

BACKGROUND: Gremlin-1 (GREM1) is a protein closely related to tumor growth, although its function in bladder cancer (BCa) is currently unknown. Our first objective was to study the GREM1 treatment potential in BCa. METHODS: BCa tissue samples were collected for the detection of GREM1 expression using Western blot analysis and Immunofluorescence staining. Association of GREM1 expression with clinicopathology and prognosis as detected by TCGA (The Cancer Genome Atlas) database. The functional investigation was tested by qRT-PCR, western blot analysis, CCK-8, cell apoptosis, wound healing, and transwell assays. The interaction between GREM1 and the downstream PI3K/AKT signaling pathway was assessed by Western blot analysis. RESULTS: GREM1 exhibited high expression in BCa tissues and was linked to poor prognosis. Stable knockdown of GREM1 significantly inhibited BCa cell (T24 and 5637) proliferation, apoptosis, migratory, invasive, as well as epithelial-mesenchymal transition (EMT) abilities. GREM1 promotes the progression in BCa via PI3K/AKT signaling pathway. CONCLUSION: Findings demonstrate that the progression-promoting effect of GREM1 in BCa, providing a novel biomarker for BCa-targeted therapy.

Agenesis of the dorsal pancreas with chronic suppurative pancreatitis: Case report and literature review.

RATIONALE: Agenesis of the dorsal pancreas (ADP) is a rare congenital anomaly of the pancreas. ADP is associated with some other medical problems such as diabetes mellitus, abdominal pain/bloating, pancreatitis, pancreatic neuroendocrine tumor and so on. In this study, we present a case of ADP with chronic suppurative pancreatitis, summarize the clinical characteristics of the reported cases in China and review the correlative literature. PATIENT CONCERNS: A 51-year-old Chinese man, with a history of impaired fasting glucose, presented with jaundice, pruritus and dark urine. Laboratory analysis showed abnormal liver function and elevated carbohydrate antigen 19-9. DIAGNOSES: Contrast-enhanced computed tomography demonstrated a mass located at the head of pancreas and complete absence of the body and tail of pancreas. Endoscopic retrograde cholangiopancreatography demonstrated an eccentric malignant stricture about 1.6cm of distal common bile duct. INTERVENTIONS: The patient underwent pancreaticoduodenectomy because of the suspicion of pancreatic tumor. The postoperative pathological result was chronic suppurative pancreatitis, with moderate hyperplasia in focal ductal epithelium. OUTCOMES: A long-term follow-up shows that the patient is asymptomatic with well-controlled diabetes mellitus and pancreatic exocrine insufficiency. LESSONS: ADP is a quite rare congenital malformation of the pancreas with poorly-understood pathogenesis. The diagnosis of ADP depends on the imaging examination. The therapeutic strategy varies from person to person due to the different accompanying conditions.

Adenovirus-mediated OX40Ig gene transfer induces long-term survival of orthotopic liver allograft in rats.

BACKGROUND: To discuss the effect and mechanism of adenovirus-mediated OX40Ig gene transfer in inducing long-term survival of liver allografts in rats. METHODS: Orthotopic liver transplantation was performed from Lewis to Brown Norway (BN) rats through the modified two-cuffed technique, and all rats were randomly divided equally into four groups: control, AdEGFP, AdOX40Ig, and FK506. The survival times of the rats were recorded. The rats' liver function, serum cytokines, hepatocyte pathology, OX40Ig protein level, and mixed lymphocyte reaction (MLR) with or without recombinant interleukin-2 (rIL-2) were evaluated. RESULTS: Compared with the control and AdEGFP groups, the rats in the AdOX40Ig and FK506 groups survived longer (P < 0.05), experienced less damage to hepatic function (P < 0.05), and showed milder hepatic cellular rejection and less hepatic cellular apoptosis. Interferon (IFN)-γ and IL-2 content in the serum were lower after operation (P < .05) in the AdOX40Ig and FK506 groups. On the contrary, IL-4 and IL-10 content in the serum was higher after operation (P < 0.05) in the AdOX40Ig and FK506 groups. OX40Ig protein was significantly expressed in the AdOX40Ig group and reached the highest level on the 7th day after operation. With respect to the MLR between BN and Lewis rats, the AdOX40Ig group showed a lighter reaction for the same strain than the control and AdEGFP groups (P < 0.05), which is different from the MLR between BN and F344 rats. After adding rIL-2 to the MLR system between BN rats in the AdOX40Ig group and Lewis rats, MLR was aggravated. CONCLUSION: Through OX40/OX4OL pathways, OX40Ig created an immunosuppressive effect after liver transplantation in rats. This immunosuppressive effect is associated with reduced IL-2 and can be reversed by adding IL-2 with antigen specificity.

Exosomes-mediated transfer of long noncoding RNA ZFAS1 promotes gastric cancer progression.

BACKGROUND: ZFAS1 is a newly identified long noncoding RNA (lncRNA) that promotes tumor growth and metastasis. Exosomes mediate cellular communications in cancer by transmitting active molecules. The presence of ZFAS1 in the circulating exosomes and the roles of exosomal ZFAS1 in gastric cancer (GC) remains unknown. The aim of this study was to investigate the potential roles of exosomal ZFAS1 in GC. METHODS: The expression of ZFAS1 was examined in the tumor tissues, serum samples, serum exosomes of GC patients and cell lines using qRT-PCR. The correlation between ZFAS1 expression and the clinicopathological characteristics was analyzed. The characteristics of exosomes were identified using transmission electron microscope (TEM), Nanoparticle Tracking Analysis (NTA), and western blot. The biological roles of ZFAS1 in GC cell growth and mobility were investigated using cell counting, cell colony formation, and transwell migration assay. The potential mechanism of ZFAS1 was demonstrated using flow cytometry, western blot, and qRT-PCR. RESULTS: ZFAS1 expression was elevated in GC cells, tumor tissues, serum and serum exosomes of GC patients. The increased ZFAS1 expression was significantly correlated with lymphatic metastasis and TNM stage. ZFAS1 knockdown inhibited the proliferation and migration of GC cells by suppressing cell cycle progression, inducing apoptosis, and inhibiting epithelial-mesenchymal transition (EMT). On the contrary, ZFAS1 overexpression promoted the proliferation and migration of GC cells. Moreover, ZFAS1 was present in exosomes and could be transmitted by exosomes to enhance GC cell proliferation and migration. CONCLUSION: ZFAS1 could be delivered by exosomes to promote GC progression, which suggests that ZFAS1 may serve as a potential diagnostic and prognostic biomarker for GC.

E6/E7-P53-POU2F1-CTHRC1 axis promotes cervical cancer metastasis and activates Wnt/PCP pathway.

Cervical cancer is an infectious cancer and the most common gynecologic cancer worldwide. E6/E7, the early genes of the high-risk mucosal human papillomavirus type, play key roles in the carcinogenic process of cervical cancer. However, little was known about its roles in modulating tumor microenvironment, particular extracellular matrix (ECM). In this study, we found that E6/E7 could regulate multiple ECM proteins, especially collagen triple helix repeat containing 1 (CTHRC1). CTHRC1 is highly expressed in cervical cancer tissue and serum and closely correlated with clinicopathological parameters. CTHRC1 promotes cervical cancer cell migration and invasion in vitro and metastasis in vivo. E6/E7 regulates the expression of CTHRC1 in cervical cancer by E6/E7-p53-POU2F1 (POU class 2 homeobox 1) axis. Futhermore, CTHRC1 activates Wnt/PCP signaling pathway. Take together, E6/E7-p53-POU2F1-CTHRC1 axis promotes cervical cancer cell invasion and metastasis and may act as a potential therapeutic target for interventions against cervical cancer invasion and metastasis.

RANK rs1805034 T>C Polymorphism Is Associated with Susceptibility to Gastric Cardia Adenocarcinoma in a Chinese Population.

BACKGROUND: Gastric cardia adenocarcinoma (GCA) is a common malignant tumor of the digestive tract with a high incidence in China. Genetic factors such as single nucleotide polymorphisms (SNPs) may contribute to the carcinogenesis of GCA. METHODS: We conducted a hospital-based case-control study to evaluate the genetic association of functional SNPs with susceptibility to GCA development. A total of 330 GCA cases and 608 controls were recruited for this study. The SNPs OPG rs3102735 T>C and rs2073618 G>C, RANK rs1805034 T>C, and RANKL rs9533156 T>C and rs2277438 A>G were determined using the ligation detection reaction method. RESULTS: Our findings suggest that RANK rs1805034 T>C is associated with susceptibility to GCA, which is more evident among male patients, elderly patients (≥ 60 years), smokers, and patients who do not consume alcohol. CONCLUSION: Based on our findings, the functional SNP RANK rs1805034 T>C may be an indicator for individual susceptibility to GCA. However, further larger studies with other ethnic populations and tissue-specific biological characterization are required to confirm the current findings.

Characteristics of bacterial vaginosis infection in cervical lesions with high risk human papillomavirus infection.

UNLABELLED: High risk human papillomavirus (HPV) infection is the major cause of cervical cancer. Bacterial vaginosis (BV) is considered as the most prevalent vaginal imbalance affecting women of reproductive age. However, the relationship between HPV and BV infection is unclear. This study aimed to assess the prevalence of human papillomavirus (HPV) infection combined with bacterial vaginosis (BV) infection in Shanghai suburbs and evaluate associations between bacterial vaginosis with HPV infection, cervical intraepithelial neoplasia (CIN) and cervical cancer. METHODS: From October 1, 2009 to October 31, 2013, a total number of 3502 women who visited Fengxian Hospital, Southern Medical University were enrolled in this study. All participants gave informed consent and agreed to HPV, BV, chlamydia, mycoplasma and thinprepcytologic test (TCT). In addition, all women took histopathologic examination under colposcopy. Statistical analyses were done using SPSS 17.0 for windows (IBM). In present study the overall BV-positive rate was 9.25%. The top three high risk HPV types were listed as follows (in descending order): HPV16, 52, 58. Moreover, our data showed BV infection tended to occur in the HPV positive women, HPV infection also tended to occur in the BV positive women. Most of the women who present HPV with BV infection were younger than 30 years old. We also found that CIN and cervical cancer occurred mainly in HPV/BV positive and HPV with BV positive group. BV infection and HPV infection may haveconsistency or synergies. HPV with BV infection may increase the incidence of CIN and cervical cancer.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility.

AIM: To identify the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and gastric cancer (GC) susceptibility. METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I (2) statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed. RESULTS: Increased risk was found for the MTHFR C677T polymorphism under four genetic models (TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations (CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04). CONCLUSION: MTHFR C677T polymorphism is a risk factor for GC, and the A1298C polymorphism may be a protective factor against GC in eastern populations.

Kinetic analysis of the immunity in a pregnant patient infected with avian influenza H7N9.

BACKGROUND: Human infection with avian influenza A H7N9 has emerged in China since February, 2013. The immunologic changes in pregnant women infected with H7N9 are not known. OBJECTIVE: To report the clinical data and kinetic changes of immunity in a pregnant woman infected with H7N9 virus in Zhenjiang, Jiangsu, China. METHODS: The clinical data were collected and immunity status was monitored in this patient. RESULTS: H7N9 virus became undetectable in sputum from 14 days since onset of symptoms after effective antiviral therapy with oseltamivir and symptomatic/supporting treatments. The symptoms and signs in this patient gradually improved from 15 days since onset of symptoms. Peripheral lymphocytes initially decreased and gradually increased. The percentage of CD4+ T cells increased since 16 days after onset of symptoms. The kinetic changes of cytokines including IFN-γ, IFN-α, TNF-α, IL-10 and TGF-ß1 matched the development and recovery of illness. Her family members, including her parents exposed to H7N9 positive materials in poultry market, were H7N9 negative. CONCLUSIONS: Our results indicate that pregnant women are susceptible to H7N9 virus and H7N9 infection in pregnant women is curable without significant impact on fetus. Kinetic changes of pro-inflammatory and anti-inflammatory cytokines play a role in the pathogenesis and clinical outcome in the pregnant patient with H7N9 infection.

Clinicopathological and biological significance of cripto overexpression in human colon cancer.

AIM: To assess the clinicopathological and biological significance of cripto in human colorectal cancer. METHODS: Real-time reverse-transcription polymerase chain reaction (PCR) was used to examine cripto mRNA levels in primary colon cancer and normal colon tissues as well as normal and metastatic lymph nodes from colon cancers. Human colon cancer LS-174T cells were transfected with cripto small interfering RNA (siRNA), and mRNA and protein levels were evaluated using real-time PCR and western blot analysis, respectively. The growth of cancer cells was evaluated using the MTT assay and colony formation in soft agar. Invasion was examined using a Transwell assay, and the expressions of matrix metalloproteinase (MMP)-7 and MMP-9 were determined using western blot assay. RESULTS: Cripto was significantly overexpressed in primary colon cancer and metastatic lymph nodes. Silencing cripto gene expression with cripto siRNA resulted in a significant decrease in colony formation in soft agar in the colon cancer cell line LS-174T. Cripto siRNA treatment decreased the migration and invasion capabilities of the colon cancer cell line LS-174T in vitro. Furthermore, cripto siRNA treatment inhibited the expression of matrix MMP-7 and MMP-9. CONCLUSION: The results provide evidence that cripto siRNA could be an effective approach for the inhibition of cancer cell invasion and migration and thus has potential for use in devising novel preventive and therapeutic strategies for colon cancer metastasis.

Can transanal tube placement after anterior resection for rectal carcinoma reduce anastomotic leakage rate? A single-institution prospective randomized study.

BACKGROUND: Anastomotic leakage is the most significant complication after low anterior resection (LAR) for rectal carcinoma, and it is the major cause of postoperative mortality and morbidity. The objective of the present study was to investigate whether the use of a transanal tube as an alternative endoluminal diversion technique for rectal carcinoma can reduce the 30-day leakage rate after LAR. METHODS: From June 2003 to December 2009, a total of 398 patients were randomized to a transanal tube or not after LAR. Inclusion criteria for randomization were biopsy-proven carcinoma of the rectum located ≤15 cm above the anal verge, measured with a rigid rectoscope; age≥18 years; informed consent; ability to understand the study information; estimated survival of >6 months; anterior resection for the lesion; final negative air leakage test; intact anastomotic stapler rings; and the absence of major intraoperative adverse events. RESULTS: Patient demographics, tumor size and location, Duke's stage, preoperative co-morbidity, and operative details were comparable between the two groups in general analysis and subgroup analysis (double-staple technique and handsewn technique). The overall rate of symptomatic leakage was 6.78% (27 of 398 patients). Patients randomized to a transanal tube (n=200) had leakage in 4.0% (8 of 200 patients) and those without a tube (n=198) in 9.6% (19 of 198 patients) (p=0.026). With regard to the double-staple technique subgroup, 3.7% (7 of 188) patients with a tube presented with a symptomatic anastomotic leakage, compared with 9.3% (17 of 182) of those without a tube (p=0.028). Of the patients with anastomotic leakage in the double-staple technique subgroup, the need for urgent abdominal reoperation was 28.6% (two of seven patients) in those randomized to a transanal tube and 82.4% (14 of 17) in those without (p=0.021). The 30-day mortality after LAR was nil. In the double-staple technique subgroup, a quicker resumption of gastrointestinal motility manifested by a smaller ratio of patients with flatus>postoperative day (POD) 3 (p=0.019) and a smaller ratio of poor gastrointestinal electromyogram on POD 3 (p<0.001) was associated with use of a transanal tube. Additionally, patients with a tube appeared to have a lower rectal resting pressure by POD 3 (4.0±2.2 vs. 5.0±2.2 kPa; p<0.001) or POD 5 (4.3±2.3 vs. 5.6±2.3 kPa; p<0.001), compared to the resting pressures patients without the device, respectively. A shorter length of hospital stay was associated with use of a transanal tube both in the double-staple technique subgroup (p<0.001) and the handsewn technique subgroup (p=0.011). Multivariate logistic regression analysis revealed that body mass index>25 kg/m2 and a poor gastrointestinal electromyogram on POD 3 were found to be independent risk factors for anastomotic leakage in the low anastomosis subgroup. CONCLUSIONS: The presence of a transanal tube is effective and safe in decreasing the rate of clinically significant anastomotic leaks and in mitigating the clinical consequences of leakage after anterior resection for rectal cancer with the technique of total mesorectal excision and double-staple anastomosis. The potential benefits of transanal tube placement are multifactorial, including drainage, reduction of endoluminal pressure, and promotion of gastrointestinal motility. Obesity and poor gastrointestinal electromyogram on POD 3 are independent risk factors for anastomotic leakage in patients with low anastomosis.

[Values of glycemic lability index in the prognostic evaluation of critically ill patients in intensive care unit].

OBJECTIVE: To access the predictive values of glycemic lability index (GLI) as an indicator of glucose variability in the prognosis of critically ill patients. METHODS: A prospective study of 72 critically ill patients admitted into intensive care unit (ICU) were performed. Capillary glucose was measured on admission and every 2 hrs afterward during the first 24 hrs. GLI, mean amplitude of glycemic excursion (MAGE), largest amplitude of glycemic excursions (LAGE), mean, standard deviation (SD) and coefficient of variability (CV) were calculated respectively. The 30 day mortality was selected as the end-point. Receiver operating curve (ROC) was drawn to explore the association between each indicator of glucose variability and prognosis. The subjects were subsequently divided into 4 subgroups according to the median of mean and GLI. The 30-day mortality was then compared between the subgroups. RESULTS: Thirty-one of 72 patients died with a mortality rate of 43.1%. The area under the curve (AUC) of GLI (0.798 ± 0.051) was superior to that of MAGE (0.785 ± 0.053), LAGE (0.772 ± 0.056), SD (0.761 ± 0.056), CV (0.729 ± 0.059) and mean (0.670 ± 0.065) under the determination of ROC respectively. GLI was significantly correlated with APACHE II (acute physiology and chronic health evaluation II) score assessed during the first 24 hrs after admission (R(2) = 0.787, P < 0.001). With the rise of GLI value, the 30-day mortality also increased gradually. Subgroup analysis demonstrated that the duration of mechanical ventilation, the incidence of multiple organ failure (MOF), the utilization rate of CRRT (continuous renal replacement therapy), the staying length of ICU and the 30 mortality rate was (3.3 ± 4.4) d, 41.6%, 12.5%, (4.6 ± 4.5) d and 16.7% respectively in the low mean +low GLI subgroup. They decreased obviously compared to the low mean +high GLI, high mean +low GLI and high mean +high GLI groups. Therefore the low mean +low GLI subgroup had the best prognosis while the high mean +high GLI subgroup worst. CONCLUSION: GLI of the first 24 hrs after ICU admission can serve as an indicator of glucose variability. And it is significantly correlated with the patient prognosis.

Radical microsurgical treatment of intramedullary spinal cord tumors / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The surgical treatment of intramedullary spinal cord tumor aims at complete removal and minimal postoperative deficit. This study was undertaken to evaluate the microsurgical features of intramedullary spinal cord tumors and the time for surgery and prognosis.</p><p><b>METHODS</b>Twenty-one patients with intramedullary spinal cord tumor who had been treated at Nanfang Hospital, Guangzhou, China since 2000 were studied retrospectively. Fifteen patients were men and 6 women, aged 2 - 60 years (mean 29.28 years). Thirteen patients had the tumor in the cervical segments, 4 in medulla-cervical segments, 1 in cervicothoracic segment, and 3 in thoracic spine. All the patients underwent microsurgery for the tumor through posterior approaches by laminectomy. The tumor was exposed through dorsal myelotomy, then tumor plane was removed carefully from the entire rostrocaudal area. The dura was sutured routinely. In case of tumors occupying too many spinal segments, titanium strip was applied to reconstruct the vertebral plate and keep the spinal column stable. All the patients were subjected to MR imaging early after operation.</p><p><b>RESULTS</b>Complete removal of the tumor was made in 15 patients, subtotal removal in 5, and partial resection in 1. Neurological recovery was related primarily to preoperative neurological conditions of the patients. Patients with minor neurological deficit showed stable sensory and motor function or minor loss in the early postoperative period, and neurological function tended to improve with time. But those with significant or long-standing deficit could hardly demonstrate any recovery. The dissection interface between the tumor and normal cord tissue was the most important factor influencing the extent of surgical removal.</p><p><b>CONCLUSIONS</b>Intramedullary spinal cord tumor mostly take place in cervical segments, with glioma as the commonest type. Microsurgery is the major treatment of choice, by which tumor plane could be totally resected. Excellent microsurgical expertise and careful recognition of tumor plane are essential to removal of the tumor while retaining neurological functions. Titanium strip fixation is helpful to reconstruct vertebral stability. Preoperative neurological conditions of patients are directly related to their postoperative recovery. We underscore the importance of early diagnosis and radical microsurgical treatment of intramedullary spinal cord tumor.</p>