Comparison of PD-L1 expression and MMR status between primary and matched metastatic lesions in patients with cervical cancer.

PURPOSE: Programmed death-ligand 1 (PD-L1) and DNA mismatch repair (MMR) are considered predictive biomarkers for immunotherapy in cervical cancer. However, their expression in primary tumors and metastases does not always match affecting the course of treatment. We investigated the consistency of their expression in primary and matched recurrent/metastatic lesions from patients with cervical cancer. METHODS: Primary and matched recurrent/metastatic specimens from patients with recurrent cervical cancer (n = 194) were stained for PD-L1 and MMR (MLHI, MSH6, MSH2, and PMS2) using immunohistochemistry. The degree of consistency of PD-L1 and MMR expression in these lesions was analyzed. RESULTS: The inconsistency rate of PD-L1 expression in primary and recurrent/metastatic lesions was 33.0%, and it varied between the recurrence sites. Positive PD-L1 rate in primary lesions was lower (15.4%) than that in recurrent/metastatic lesions (30.4%). The discordance rate of MMR expression between primary and recurrent/metastatic lesions was 4.1%. CONCLUSION: We conclude that to use PD-L1 as a predictive biomarker for immunotherapy, analysis of both metastatic and primary lesions may be required. High consistency rate of MMR expression between primary and metastatic lesions suggests that testing primary lesions alone can be sufficient for guiding the course of therapy, thereby solving the difficulty of obtaining recurrent/metastatic specimens in clinic.

HEATR1 promotes proliferation in gastric cancer in vitro and in vivo.

HEAT repeat-containing protein 1 (HEATR1) is related to the progression of several cancers. However, the role of HEATR1 in gastric cancer (GC) remains unknown. In the present study, we aimed to detect the expression of HEATR1 in GC and identify its role. The expressions of HEATR1 in GC tissues were analyzed using The Cancer Genome Atlas database and by western blot analysis and immunohistochemistry. Furthermore, the HEATR1 expressions in GC cell lines MGC-803 and AGS were knocked down by using lentivirus-mediated HEATR1 shRNA. Cell proliferation and apoptosis were detected by CCK-8 and Caspase-Glo® 3/7 assays, respectively. PathScan® Signaling Antibody Array kit and Kyoto Encyclopedia of Genes and Genomes enrichment were used to study the pathways related to HEATR1. The influence of HEATR1 shRNA on the in vivo growth of GC cells was assessed by establishing a nude mouse xenograft model and conducting bioluminescence imaging. Our results showed that HEATR1 was highly expressed in GC tissues. Higher expression of HEATR1 is related to cancer progression and metastasis. Knocking down HEATR1 significantly suppressed the cell proliferation and colony formation and promoted cell apoptosis. The expression levels of phosphorylated p53, p38 MAPK, Chk2, and IKBa in shHEATR1-transfected MGC-803 cells exceeded those in shCtrl-transfected cells. HEATR1 shRNA treatment also significantly inhibited tumor growth in the mouse model. This study suggested that HEATR1 may be an oncogene and a target for GC therapy.

RNA methyltransferase NSUN2 promotes gastric cancer cell proliferation by repressing p57Kip2 by an m5C-dependent manner.

The RNA methyltransferase NSUN2 has been involved in the cell proliferation and senescence, and is upregulated in various types of cancers. However, the role and potential mechanism of NSUN2 in gastric cancer remains to be determined. Our study showed that NSUN2 was significantly upregulated in gastric cancers, compared to adjacent normal gastric tissues. Moreover, NSUN2 could promote gastric cancer cell proliferation both in vitro and in vivo. Further study demonstrated that CDKN1C (p57Kip2) was the potential downstream gene of regulated by NSUN2 in gastric cancer. NSUN2 could promote gastric cancer cell proliferation through repressing p57Kip2 in an m5C-dependent manner. Our findings suggested that NSUN2 acted as an oncogene through promoting gastric cancer development by repressing p57Kip2 in an m5C-dependent manner, which may provide a novel therapeutic target against gastric cancer.

The optimum marker for the detection of lymphatic vessels.

Podoplanin, lymphatic vessel endothelial hyaluronic acid receptor-1, prospero-related homeobox-1 and vascular endothelial growth factor receptor 3 have been demonstrated to have crucial roles in the development of the lymphatic system and lymphangiogenesis process by combining with their corresponding receptors. Thus, the four markers have been widely used in labelling lymphatic vessels for the detection of lymphangiogenesis and lymphatic vessel invasion. Numerous authors have aimed to identify the roles of these four markers in the lymphatic system and the mechanisms have been partly clarified at the molecular level. The aim of the present review was to comprehensively clarify the characteristics and latent action modes of the four markers in order to determine which is the best one for the detection of lymphangiogenesis and lymphatic vessel invasion.

Total versus subtotal gastrectomy for distal gastric cancer: meta-analysis of randomized clinical trials.

OBJECTIVES: This meta-analysis of randomized controlled trials was conducted to give a more precise estimation of the efficacy and drawbacks of total gastrectomy (TG) versus subtotal gastrectomy (SG) for proven distal gastric cancer. METHODS: The electronic databases Cochrane and PubMed (updated on April 10, 2016) were searched for randomized controlled trials comparing TG with SG as surgical procedures for distal gastric cancer. Five outcome variables were analyzed, including postoperative complications, anastomotic fistula rate, hospital mortality rate, mortality rate of recurrence (the patient's death is caused by the recurrence of gastric cancer, rather than caused by other diseases), and 5-year survival rate. Random or fixed effect model was used to perform this meta-analysis. RESULTS: Six trials, including 573 cases treated with TG and 791 cases treated with SG, were included. Compared with patients in the SG group, patients in the TG group did not show a higher rate of postoperative complications (odds ratio [OR]: 1.46, 95% confidence interval [CI]: 0.71-3.03, P=0.30). However, patients in the TG group showed a significantly higher rate of anastomotic fistula than patients in the SG group (OR: 3.78, 95% CI: 1.97-7.27, P<0.0001). Hospital mortality rate, which was analyzed in four trials, including 510 TG versus 729 SG patients, showed no significant difference between the two groups (OR: 1.80, 95% CI: 0.85-3.78, P=0.12). Importantly, there was no significant difference in the 5-year survival between the two groups (OR: 0.68, 95% CI: 0.39-1.19, P=0.18). Mortality rate of recurrence, which was also analyzed in three trials, including 396 TG versus 407 SG patients, showed a significantly higher rate in the TG group (OR: 0.07, 95% CI: 0.01-0.13, P=0.03). CONCLUSION: This meta-analysis demonstrated that postoperative complications, hospital mortality rate, and 5-year survival rate in TG patients was similar to the SG group. Furthermore, SG was associated with significantly fewer anastomotic fistula and lower mortality rate of recurrence compared with TG. However, lower mortality rate of recurrence was probably related to the criteria of these two procedures.

Emerging role of microRNA-21 in colorectal cancer.

Colorectal cancer (CRC) is one of the most common types of cancers worldwide. In spite of much progress in surgery, chemotherapy and molecular targeted therapy, the mortality rate has only decreased slightly over the past years. MicroRNAs are 18-25 nucleotide, noncoding RNA molecules that regulate the translation of many genes. Evidence suggests that miRNAs may play an important role in a variety of cellular biological processes, such as cell growth, differentiation, metabolism, invasion, angiogenesis. Recently, miR-21 is found to be aberrantly expressed in CRC and miR-21 has been recognized to perform significantly in CRC, where miR-21 can regulate several different target genes and pathways involving tumor proliferation, invasion and metastasis. In this study, we will focus on the critical role of miR-21 in CRC. Hopefully, the information obtained may lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for this disease.

Integrative genomic analyses of the histamine H1 receptor and its role in cancer prediction.

The human histamine receptor H1 (HRH1) gene is located on chromosome 3p25 and encodes for a 487 amino acid G protein-coupled receptor (GPCR) with a long third intracellular loop (IL3). The HRH1 predominantly couples to Gαq/11 proteins, leading to the activation of phospholipase C (PLC) and subsequent release of the second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG) followed by the activation of PKC and the release of [Ca2+]i. In the present study, we identified HRH1 genes from 14 vertebrate genomes and found that HRH1 exists in all types of vertebrates including fish, amphibians, birds and mammals. We identified 88 SNPs including 4 available alleles disrupting an existing exonic splicing enhancer and 84 SNPs causing missense mutation, which may impact the effect of histamine on the HRH1 protein. We found that the human HRH1 gene was expressed in many tissues or organs, and predominant expression of HRH1 was shown in the bone marrow, whole blood, lymph node, thymus, brain, cerebellum, retina, spinal cord, heart, smooth muscle, skeletal muscle, small intestine, colon, adipocytes, kidney, liver, lung, pancreas, thyroid salivary gland, skin, ovary, uterus, placenta, prostate and testis. When searched in the PrognoScan database, human HRH1 was also found to be expressed in bladder cancer, blood cancer, brain cancer, breast cancer, colorectal cancer, eye cancer, head and neck cancer, lung cancer, ovarian cancer, skin cancer and soft tissue cancer tissues. The relationship between the expression of HRH1 and prognosis was found to vary in different types of cancers, even in the same cancer from different databases. This implies that the function of HRH1 in these tumors may be multidimensional. GR, STAT5A and c-Myb regulatory transcription factor binding sites were identified in the HRH1 gene upstream (promoter) region, which may be involved in the effect of HRH1 in tumors.

Acute kidney injury after radical gastrectomy: a single center study.

OBJECTIVES: To investigate the incidence of acute kidney injury (AKI) and identify risk factors for AKI in patients who undergo radical gastrectomy. METHODS: This study included 536 patients underwent radical gastrectomy. Primary outcome was AKI, defined as a ≥ 50 % increase in serum creatinine relative to baseline during the first three postoperative days. Secondary outcomes were duration of hospitalization and all-cause hospital mortality within 30 days after radical gastrectomy. RESULTS: A total of 37 (6.9 %) patients developed postoperative AKI. Age, body mass index (BMI), presence of hypertension, hyperlipidemia, poor blood glucose control, and preoperative higher cystatin C were associated with increased frequency of AKI. By multivariable analyses, the independent risk factors for AKI were age, BMI, hypertension, hyperlipidemia, and preoperative cystatin C. CONCLUSIONS: Postoperative AKI is not infrequent after radical gastrectomy. Age, BMI, hypertension, hyperlipidemia, and preoperative cystatin C are independently associated with increased risk of postoperative AKI.

Methylation of DLEC1 promoter is a predictor for recurrence in Chinese patients with gastric cancer.

PURPOSE: To investigate promoter methylation in the deleted in lung and esophageal cancer 1 (DLEC1) gene in Chinese patients with gastric cancer. METHODS: A total of 227 patients with gastric cancer were enrolled. The methylations of the promoter regions of DLEC1 and ACTB were determined using quantitative methylation-specific PCR. The DLEC1 methylation was compared to the clinicopathological variables of gastric cancer. RESULTS: DLEC1 methylation was not associated with the clinicopathological variables of gastric cancer. Patients with DLEC1-hypermethylated gastric cancer had significantly higher recurrence rate than those with DLEC1-hypomethylated gastric cancer (P = 0.025; hazard ratio = 2.43). CONCLUSIONS: Methylation of DELC1 promoter may be a valuable predictor for recurrence in Chinese patients with gastric cancer.

[Experimental study on early pulmonary injury induced by severe acute pancreatitis in rats].

OBJECTIVE: To investigate the injury to pulmonary tissue induced by severe acute pancreatitis (SAP) during its early period. METHODS: Forty adult male Sprague-Dawley (SD) rats weighing 300-400 g were randomly divided into 4 groups with 8 animals in each group: sham operation group and 30, 60, 120 and 360 minutes after SAP groups. The model of SAP was reproduced by retrograde injection of 5% sodium taurocholate into the pancreatic duct of rats. Rats were sacrificed at different time points, and blood gas analysis, pulmonary pathological changes and wet dry weight ratio (W/D) of the lung were conducted. RESULTS: A large amount of polymorphonuclear neutrophils were observed in pulmonary tissue within 360 minutes after reproduction of SAP with obvious changes, and water content of pulmonary tissue was increased significantly, while base excess (BE) decreased significantly in rats with SAP (P<0.05 or P<0.01 ). But no obvious change was observed in arterial partial pressure of oxygen (PaO(2)) and partial pressure of carbon dioxide (PaCO(2), both P>0.05). CONCLUSION: SAP causes significant inflammation in rat lung with injury to pulmonary tissue in its early period.

Expression of insulin-like growth factor binding protein-2 in gastric carcinoma and its relationship with cell proliferation.

AIM: To investigate the expression of insulin-like growth factor binding protein-2 (IGFBP-2) in gastric carcinoma and its clinical significance and to explore its relationship with cell proliferation. METHODS: Expressions of IGFBP-2 and Ki-67 in 118 cases of gastric carcinoma and 40 cases of normal gastric mucosa were detected by EnVision immunohistochemical technique. RESULTS: Expression of IGFBP-2 in gastric carcinoma was higher than that in normal gastric mucosa (P < 0.01). There was no difference between high- and low-grade gastric carcinoma (P > 0.05). Expression of IGFBP-2 in advanced gastric carcinoma was higher than that in early gastric carcinoma (P < 0.05). Expression of IGFBP-2 in gastric carcinoma with lymph node metastasis was higher than that without lymph node metastasis (P < 0.01). IGFBP-2 expression was a positively related to the clinical stage of gastric carcinoma (P < 0.01). There was a positive correlation between IGFBP-2 and Ki-67 (P < 0.05). CONCLUSION: IGFBP-2 may be involved in carcino-genesis and progression of gastric carcinoma by promoting cell proliferation.

Relationship between inactivation of p16 gene and gastric carcinoma.

AIM: To investigate the relationship between inactivation of p16 gene and gastric carcinoma, and the mechanism of inactivation of p16 gene in gastric carcinogenesis. METHODS: 40 fresh tumor tissue specimens were taken from primary gastric cancer patients. Expression of P16 protein was detected by immunohistochemical method. Deletion and point mutation of p16 gene were analyzed by polymerase chain reaction (PCR) and DNA sequencing, respectively. RESULTS: The frequency of loss of P16 protein expression in the gastric cancer tissue, adjacent nontumor tissue, and distal normal tissue was 77.5 % (31/40), 55.0 % (22/40), and 17.5 % (7/40), respectively (P<0.005). Homozygous deletion of exon 1 and exon 3 was observed in two and three cases, respectively, giving an overall frequency of homozygous deletion of 12.5 %. All five cases had diffuse type gastric carcinoma. No p16 gene point mutation was detected. CONCLUSION: These findings suggest a close correlation between inactivation of p16 gene and gastric carcinoma. Further investigations are needed to testify the mechanism of inactivation of p16 gene in gastric carcinogenesis.

A ten-year study on non-surgical treatment of postoperative bile leakage.

AIM: To summarize systematically our ten-year experience in non-surgical treatment of postoperative bile leakage, and explore its methods and indications. METHODS: The clinical data of 57 patients with postoperative bile leakage treated non-surgically from January 1991 to December 2000 were reviewed retrospectively. RESULTS: The site of the leakage was mainly the disrupted or damaged fistulous tracts of T tube in 25 patients (43.9 %), the fossae of gallbladder in 14 cases (24.6 %), the cut surface of liver in 7 cases(12.3 %), and it was undetectable in the other 2 cases. Besides bile leakage, the wrong ligation of bile ducts was found in 3 patients, residual stones of the distal bile duct in 5 patients, benign papillary strictures in 3, and biloma resulting from bile collections in 2. The diagnoses were made according to the history of surgery, clinical situation, abdominal paracentesis, ultrasonography, ERCP, PTC, MRI/MRCP, gastroscopy and percutaneous fistulography. All 57 patients were treated non-surgically at the beginning of bile leakage. The non-surgical methods included keeping original drainage unobstructed, percutaneous abdominal paracentesis or drainage, percutaneous transhepatic cholangial/biliary drainage (PTCD/PTBD),endoscopic management, traditional Chinese medicine and so on. Of the 57 patients,2 patients died,5 were converted to reoperation later, the other 50 were directly cured by non-surgical methods without any complication. The cure rate of the non-surgery was 82.5 %(50/57). CONCLUSION: Many nonoperative methods are available to treat postoperative bile leakage. Non-surgical treatment may serve as the first choice for the treatment of bile leakage for its advantages in higher cure rate, convenience and safety in practice. It is important to choose the specific non-surgical method according to the volume, site of bile leakage and patient's condition.