ARID1A expression in gastric adenocarcinoma:Clinicopathological significance and correlation with DNA mismatch repair status

AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas.The results were further correlated with clinicopathological variables.RESULTS:The loss of any MMR protein expression,indicative of MMR deficiency,was observed in 38cases(7.8%)and was significantly associated with an older age(68.6±9.2 vs 60.4±11.7,P0.001),a female sex(55.3%vs 31.3%,P=0.004),an antral location(44.7%vs 25.7%,P=0.021),and a differentiated histology(57.9%vs 39.7%,P=0.023).Abnormal ARID1A expression,including reduced or loss of ARID1A expression,was observed in 109 cases(22.3%)and was significantly correlated with lymphatic invasion(80.7%vs 69.5%,P=0.022)and lymph node metastasis(83.5%vs 73.7%,P=0.042).The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency(47.4%vs 20.2%,P0.001).A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor(HR=1.36,95%CI:1.01-1.84;P=0.040).CONCLUSION:Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion,lymph node metastasis,poor prognosis,and MMR deficiency in gastric adenocarcinomas.     

Long-term oncologic outcomes of laparoscopic vs open surgery for stages II and III rectal cancer: A retrospective cohort study

AIM: To evaluate the 5-year survival after laparoscopic surgery vs open surgery for stages II and III rectal cancer.METHODS: This study enrolled 406 consecutive patients who underwent curative resection for stages II and III rectal cancer between January 2000 and December 2009 [laparoscopic rectal resection (LRR), n = 152; open rectal resection (ORR), n = 254]. Clinical characteristics, operative outcomes, pathological outcomes, postoperative recovery, and 5-year survival outcomes were compared between the two groups.RESULTS: Most of the clinical characteristics were similar except age (59 years vs 55 years, P = 0.033) between the LRR group and ORR group. The proportion of anterior resection was higher in the LRR group than that in the ORR group (81.6% vs 66.1%, P = 0.001). The LRR group had less estimated blood loss (50 mL vs 200 mL, P < 0.001) and a lower rate of blood transfusion (4.6% vs 11.8%, P = 0.019) compared to the ORR group. The pathological outcomes of the two groups were comparable. The LRR group was associated with faster recovery of bowel function (2.8 d vs 3.7 d, P < 0.001) and shorter postoperative hospital stay (11.7 d vs 13.7 d, P < 0.001). The median follow-up time was 63 mo in the LRR group and 65 mo in the ORR group. As for the survival outcomes, the 5-year local recurrence rate (16.0% vs 16.4%, P = 0.753), 5-year disease-free survival (DFS) rate (63.0% vs 63.1%, P = 0.589), and 5-year overall survival (OS) rate (68.1% vs 63.5%, P = 0.682) were comparable between the LRR group and the ORR group. Stage by stage, there were also no statistical differences between the LRR group and the ORR group in terms of the 5-year local recurrence rate (stage II: 6.3% vs 8.7%, P = 0.623; stage III: 26.4% vs 23.2%, P = 0.747), 5-year DFS rate (stage II: 77.5% vs 77.6%, P = 0.462; stage III: 46.5% vs 50.9%, P = 0.738), and 5-year OS rate (stage II: 81.4% vs 74.3%, P = 0.242; stage III: 53.9% vs 54.1%, P = 0.459).CONCLUSION: LRR for stages II and III rectal cancer can yield comparable long-term survival while achieving short-term benefits compared to open surgery.     

A high density of PD-L1-expressing immune cells is significantly correlated with favorable disease free survival in nonmetastatic colorectal cancer

The impact of immune cells (ICs) expressing various markers remains poorly understood in nonmetastatic colorectal cancer patients who have undergone colectomy. Here, we aimed to clarify the correlation between IC density and clinical parameters and survival.Programmed death protein-1 (PD-1), programmed cell death protein ligand-1 (PD-L1), clusters of differentiation (CD)-3, CD-8, and CD45RO immunostaining was performed for 421 patients using tissue microarray and automatic counting. Tumor stroma area immune density was assessed in comparison to clinical histological factors and surgical outcomes.High-density CD-8 expression was significantly associated with current smoking habits or a smoking history (P = .006). High-density of PD-1 expression was correlated with Lynch syndrome patients (P < .001) and with patients who did not consume alcohol (P = .034). A significant decrease in CR45RO expression density was associated with aging (P = .002 and r = –0.014), and high-density CD-3, CD-8, and PD-1 expression was significantly associated with right colon tumor location (P < .001). High CD-3 and PD-L1 expression was significantly associated with early tumor T-staging (P = .018 and P = .002). High-density PD-1 expression was significantly correlated with mucinous type adenocarcinoma (P = .027) and poor differentiation (P < .001). For treatment outcomes, multivariate analysis confirmed that patients exhibiting high-density PD-L1 expression possessed significantly longer disease free survival (adjusted hazard ratio: 0.752, 95% confidence interval [CI]: 0.61–0.92, P = .006) and overall survival (adjusted hazard ratio: 0.872, 95% CI: 0.75–1.91, P = .064)Significantly varied density in IC subsets was related to distinct demographic or clinic-histological factors. The presence of high-density PD-L1-expressing ICs is an independent favorable prognostic factor for disease free survival and overall survival among stage I to III colorectal cancer patients.     

Esophagojejunostomy after laparoscopic total gastrectomy by Or VilTM or hemi-double stapling technique

AIM: To investigate the feasibility, advantages and disadvantages of two types of anvil insertion techniques for esophagojejunostomy after laparoscopic total gastrectomy.METHODS: This was an open-label prospective cohort study. Laparoscopy-assisted radical total gastrectomy with D2 lymph node dissection was performed in 84 patients with primary non-metastatic gastric cancer confirmed by pre-operative histological examination. Overweight patients were excluded, as well as patients with peritoneal dissemination and invasion of adjacent organs. After total gastrectomy, all patients were randomized into two groups. Patients in Group Ⅰ underwent esophagojejunostomy using a transorally-inserted anvil(Or VilTM), while patients in Group Ⅱ underwent esophagojejunostomy using the hemi-double stapling technique(HDST). Both types of esophagojejunostomy were performed under laparoscopy. Patients' baseline characteristics, preoperative characteristics, perioperative characteristics, short-term postoperative outcomes and operation cost were comparedbetween the two groups. The primary endpoint was evaluation of the surgical outcome(operating time, time of digestive tract reconstruction and time of anvil insertion) and the medical cost of each operation(operation cost and total cost of hospitalization). The secondary endpoints were time to solid diet, post-surgical hospitalization time, time to defecation, time to ambulation and intra-operative blood loss. In addition, complications were assessed and compared. RESULTS: Laparoscopic total gastrectomy and esophagojejunostomy were successfully performed in all 84 patients, without conversion to laparotomy. There were no significant differences in the operative time and time for total gastrectomy between the two groups(287.8 ± 38.4 min vs 271.8 ± 46.1 min, P = 0.09, and 147.7 ± 31.6 min vs 159.8 ± 33.8 min, P = 0.09, respectively). The time for digestive tract reconstruction and for anvil insertion were significantly decreased in Group Ⅱ compared with Group I(47.8 ± 12.1 min vs 55.4 ± 15.7 min, P = 0.01, and 12.6 ± 4.7 min vs 18.7 ± 7.5 min, P = 0.001, respectively). Intraoperative blood loss(96.4 ± 32.7 m L vs 88.2 ± 36.9 m L, P = 0.28), time to defecation(3.5 ± 0.9 d vs 3.2 ± 1.1 d, P = 0.12), time to ambulation(3.9 ± 0.7 d vs 3.6 ± 1.1 d, P = 0.12), time to solid diet(7.6 ± 1.4 d vs 8.0 ± 2.7 d, P = 0.31) and total hospitalization(10.6 ± 2.6 d vs 10.8 ± 3.5 d, P = 0.80) were similar between the two groups. In addition, the total costs of hospitalization were similar between the two groups(73848.7 ± 11781.0 RMB vs 70870.3 ± 14003.5 RMB, P = 0.296), but operation cost was significantly higher in Group I compared with Group Ⅱ(32401.9 ± 1981.6 RMB vs 26961.9 ± 2293.8 RMB, P 0.001).CONCLUSION: Anvil insertion was faster and easier using the HDST technique compared with Or VilTM, and was more cost-effective. There was no significant difference in safety.     

The prognostic value of lncRNA AGAP2-AS1 in cancer patients: A meta-analysis

Background:ArfGAP with GTPase domain, Ankyrin repeat and PH domain 2 Antisense 1 (AGAP2-AS1) is a promising long noncoding RNA that may possess prognostic value for different types of tumors. The objective of this meta-analysis is to evaluate the prognostic value of long noncoding RNA AGAP2-AS1 in cancer patients.Methods:A systematic literature search of the PubMed, Cochrane Library, EMBASE, Medline, Web of Science, CNKI, Weipu, and Wanfang electronic databases were carried out in this meta-analysis. Synthetic hazard ratios (HRs) or odd ratios (ORs) with 95% confidence intervals (CIs) were obtained to determine the prognostic and clinicopathological significance of AGAP2-AS1 expression in tumors.Results:The final meta-analysis included 10 studies that contained 948 patients. The pooled results provided evidence that AGAP2-AS1 overexpression predicted reduced overall survival (OS) (HR = 1.77, 95% CI: 1.49–2.09, P < .00001), disease-free survival (HR = 1.84, 95% CI: 1.40–2.41, P < .0001), and progression-free survival (HR = 1.84, 95% CI: 1.01–3.33, P = .04) and for various cancers. Additionally, the AGAP2-AS1 overexpression was concerned with lymph node metastasis (positive vs negative, OR = 2.95, 95% CI: 1.96–4.45, P < .00001), advanced tumor node metastasis stage (III/IV vs I/II, OR = 3.73, 95% CI: 2.71–5.13, P < .00001), and tumor size (larger vs smaller, OR = 2.28, 95% CI: 1.24–4.18, P = .008). Besides, data from gene expression profiling interactive analysis dataset verified the results in our meta-analysis. The results showed that the expression level of AGAP2-AS1 was higher in most tumor tissues than in the corresponding normal tissues and was linked to poor OS and disease-free survival.Conclusions:Our results indicated that AGAP2-AS1 overexpression was closely correlated with shorter OS in multiple cancer types, suggesting that AGAP2-AS1 might function as a promising predictor for clinical outcomes in cancer.     

Correlational research of Golgi phosphorylation protein 3 expression in colorectal cancer

AIM: To investigate the effect of Golgi phosphorylation protein 3 (GOLPH3) expression on cell apoptosis, angiogenesis and prognosis in colorectal cancer (CRC).METHODS: The expression of GOLPH3 in CRC tissues and normal colorectal mucosae was determined by immunohistochemistry in 62 patients. In addition, immunohistochemistry was also carried out to detect the expression of vascular endothelial growth factor (VEGF), CD34 and microvessel density (MVD). Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay was used to determine the apoptotic index (AI). The Kaplan-Meier method was used to analyze the relationship between GOLPH3 expression and survival in another 123 CRC cases.RESULTS: Compared with normal colorectal mucosae, a notably higher level of GOLPH3 protein expression was identified in CRC tissues (53.2% vs 24.2%, P < 0.05). Positive GOLPH3 expression was significantly associated with tumor invasion depth, TNM stage, and lymph node metastasis (P = 0.001; P = 0.020; P = 0.020; P < 0.05, respectively), but not with tumor length, tumor site, and age (P = 0.363; P = 0.819; P = 0.599; P > 0.05, respectively). VEGF expression and MVD in GOLPH3-positive CRC was significantly higher than in GOLPH3-negative CRC (VEGF: 69.7% vs 31.0%; MVD: 21.45 ± 9.39 vs 14.24 ± 8.97; P < 0.05). GOLPH3 expression was negatively correlated with AI in CRC as shown by Spearman correlation analysis (r = -0.320, P < 0.05). The 5-year survival rate in GOLPH3-negative CRC (69.4%) was significantly higher than in GOLPH3-positive CRC (48.6%) (log-rank test, P < 0.05).CONCLUSION: High expression of GOLPH3 is found in CRC tissues. GOLPH3 expression may be a novel prognostic marker for CRC patients.     

High expression of CD11c indicates favorable prognosis in patients with gastric cancer

AIM: To determine the relationship between CD11 c expression level and prognosis in patients with gastric cancer(GC).METHODS: This retrospective survival study was performed from July 31,2008 to June 30,2014. Our study inclusion criteria included all the patients with GC who underwent surgical resection between January 1998 and December 2009 in the Third Affiliated Hospital of Soochow University. CD11 c expression levels in 140 patients with GC at different UICC stages were evaluated using immunohistochemistry,and GC tissues from 16 cases were further verified by q RTPCR. The χ2 test was used to compare the patientand disease-related factors between the low CD11 c expression group and the high expression group. Univariate probabilities of overall survival(OS) and disease-free survival(DFS) were assessed using the Kaplan-Meier method. The log rank test was used to compare survival curves. Different multivariate COX models were used to estimate the association between CD11 c expression and both death and recurrence riskin GC patients.RESULTS: The average CD11 c expression level was 5.1 ± 1.8/high power field(HPF) in 10 gastritis samples,4.5 ± 2.3/HPF in 10 gastric polyp samples and 9.7 ± 6.3/HPF in 140 gastric cancer samples,respectively. The CD11 c expression level was significantly decreased from UICC stage Ⅰ to stage Ⅳ(stage Ⅰ: 16.0 ± 7.4,stage Ⅱ: 10.4 ± 5.5,stage Ⅲ: 9.4 ± 6.1,stage Ⅳ: 5.3 ± 3.2,P 0.001). Patients in the high CD11 c expression group had a greater 3- and 5-year OS probability and longer median survival time compared with the low CD11 c expression group,(67.7% vs 39.2%; 51.4% vs 29.0%; 67.0 mo vs 28.0 mo; χ2 = 6.80,P = 0.009),and had a greater 3- and 5-year DFS probability and longer median DFS time(63.7% vs 24.0%; 49.1% vs 11.9%; 64.0 mo vs 18.0 mo; χ2 = 15.39,P 0.001). Patients with high CD11 c high expression had a reduced risk of death(HR = 0.56,95%CI: 0.33-0.98,P 0.05) and relapse(HR = 0.39,95%CI: 0.23-0.67,P 0.01) compared with patients with low CD11 c expression after adjustment of potential confounders,with the exception of tumor size. However,the protective effect related to death(HR = 0.90,95%CI: 0.49-1.67,P = 0.749) and relapse(HR = 0.65,95%CI: 0.36-1.19,P = 0.160) disappeared when tumor size was incorporated into the model.CONCLUSION: High expression of CD11 c decreased the risk of death and relapse,and may be regarded as an alternative indicator of favorable prognosis in patients with GC.     

Expression of HSP90 and HIF-1α in human colorectal cancer tissue and its significance

Objective:To investigate the expression of HSP90 and HIF-1αin human colorectal cancer tissue,the influence of HSP90 and HIF-1αon human colorectal cancer biological behavior and their related factors.Methods:The expression of HSP90 and HIF-1 a protein in human colorectal cancer as well as normal tissue were detected by imnmnohistochemical method.Results:The positive expression rates of HSP90 and HIF-1αprotein in normal human colorectal tissue as well as colorectal cancer tissue were 30%vs.63.0%,15.0%vs.71.7%,respectively.There were significant difference(P=0.035 and P=0.005 respectively).The expression of HSP90 was significantly correlated with the differentiation,Dukes stages and lymph node metastasis(P0.05),while the expression of HIF-1 a was significantly correlated with the Dukes stages and lymph node metastasis(P0.05).Association analysis showed that the expression of HSF90 protein was significantly correlated with that of HIF-1αprotein(P0.01).Conclusions:The expression of HSP90 and HIF—1αprotein may be related to the development,metastasis and invasion of human colorectal cancer,and their synergistic effects may participate in the development of the colorectal carcinoma.     

Clinic image surveillance reduces mortality in patients with primary hepato-gastrointestinal cancer who develop second primary lung cancer: A STROBE-compliant retrospective study

Second primary cancer is prevalent in patients with gastrointestinal (GI) cancer, for which lung cancer is the most common and associated with high lethality. Image screening for lung cancer was proved to be effective in early diagnosis and lower mortality. However, trials of screen for lung cancer generally excluded patients with a previous diagnosis of malignancy. The study aimed to investigate the outcome of second primary lung cancer and the factor that improve survival in patients with hepato-GI cancer.A total of 276 patients with secondary lung cancer were found among 3723 newly-diagnosed lung cancer patients diagnosed in Chang Gung Memorial Hospital, between 2010 and 2014. Patients’ clinical characteristics, stages and survival were recorded and analyzed. The patients were separated into 2 groups: Group I was defined as lung cancer detected in original primary cancer clinic and group II patients defined as lung cancer detected in other medical places.Sixty-nine cases with primary GI-hepatic and secondary lung cancer were diagnosed (42 (60.8%) in Group I and 27 (39.1%) in Group II). Although both groups had comparable primary cancer stages and treatment, more patients in Group I than Group II were diagnosed as early stage lung cancer (stage I-II: 40.5% vs 11.1%; P = .023). Group II had larger lung tumor sizes than Group I (4.7 vs 3.5 cm; P = .025). Group I showed better 5-year overall survival than Group II (P = .014, median survival: 27 vs 10 months). Among Group II, only 37% had received image follow up in clinic compared with 67% of Group I cases (P = .025). Patients with chest image follow up in clinics also had better 5-year overall survival (P = .043).GI-hepatic cancer was the most common primary malignancy in the lung cancer cohort. Patients had better survival outcome when secondary lung cancer was diagnosed in original primary cancer clinic. Chest image screening strategy may contribute better survival in secondary lung cancer due to detection at an earlier stage.     

Clinical impact of COVID-19 on Turkish children with neurological and neuromuscular diseases: One center experience

This study aims to explore the effects of new type of coronavirus disease (COVID-19) in children with neurological and/or neuromuscular diseasesA retrospective study was conducted at State Hospital of Denizli. Pediatric patients diagnosed with COVID-19 who were hospitalized between March 18, 2020 and January 18, 2021 were included in the study. Children were divided into two groups: those with (group I) and without neurological and /or neuromuscular disorders (group II).Male cases were more than female cases in group I. The difference between group I and group II was significant in terms of seizure (47.3%; 1.7%), dyspnea (36.8%, 6.2%) and number of days with fever (2.6 ± 1.9; 1.58 ± 1.42) (P < .01, P < .01, P = .02). Hypoxemia (7, 11; 36.8%, 4.5%) and abnormal auscultation findings (8, 44; 42.1%, 18.1%) were more common in children in group I, hypertension was more common in group II (0, 8; 0%, 3.3%). Lung involvement of COVID-19 was found to be more severe in group I (P = .04). The frequency of hospitalization in the intensive care unit (P < .01) and application of noninvasive mechanical ventilation (NIMV) (P < .01); the number of days followed-up in the intensive care (P < .01) and in the hospital (P = .02) of the patients in group I were higher than those in group II.It is recognized that children with underlying neurological and/or neuromuscular diseases are severely affected by COVID-19.     

Prenatal and postnatal exposure to Tangshan earthquake and CRHR1 gene polymorphism influence risk of sleep disturbance in adulthood

To determine the effect of earthquake on sleep quality of adults who had experienced Tangshan Earthquake either as infants or fetuses and also investigate whether CRHR1 polymorphism influenced sleep quality in subjects exposed to seismic stress.Totally 556 subjects were enrolled in the current study and were divided into 3 groups, those who had experienced Tangshan Earthquake as infants (group I) or fetuses (group II), and those who had not experienced Tangshan Earthquake (group III). Sleep was evaluated using the Pittsburgh Sleep Quality Index (PQSI). Three single nucleotide polymorphisms of the CRHR1 gene were analyzed.Fifty two (9.4%) subjects had sleep disturbance, including 17 (9.9%) subjects in group I, 24 (13.4%) subjects in group II, and 11 (5.3%) subjects in group III (χ² = 7.373, P = .025). Moreover, subjects with CRHR1 genotype T/T had a significantly lower rate of sleep disturbance (7.8%) than subjects with genotype C/T and C/C (14.7%; χ² = 4.845, P = .028). Furthermore, subjects with rs7209436 genotype C had an approximately 2-fold increase in the risk of sleep disturbance versus those who were not genotype C (OR = 1.978, 95% CI (1.045, 3.744).Prenatal and postnatal exposure to seismic stress significantly increases subsequent risk of sleep disturbance in adulthood.     

Hepatitis B virus pre S1 deletion is related to viral replication increase and disease progression

AIM:To investigate the clinical implications of hepatitis B virus(HBV) pre S1 deletion.METHODS:We developed a fluorescence resonance energy transfer-based real-time polymerase chain reaction(RT-PCR) that can detect four genotypes(wild type, 15-bp, 18-bp and 21-bp deletion).The PCR method was used in two cohorts of Korean chronic HBV subjects with genotype C infections.Cohort Ⅰ included 292 chronic HBV subjects randomly selected from Cheju National University Hospital(Jeju, South Korea) or Seoul National University Hospital(Seoul, South Korea), and cohort Ⅱ included 90 consecutive chronic HBV carriers recruited from Konkuk University Hospital(Seoul, South Korea); the cohort Ⅱ patients did not have hepatocellular carcinoma or liver cirrhosis.RESULTS:The method proposed in this study identified 341 of 382 samples(89.3%).Deletion variants were identified in 100(29.3%) of the 341 detected samples.In both cohorts, the subjects with deletions had a significantly higher Hepatitis B virus e antigen(HBe Ag)-positive seroprevalence [cohort Ⅰ, wild(51.0%) vs deletion(75.0%), P 0.001; cohort Ⅱ, wild(69.2%) vs deletion(92.9%), P = 0.002] and higher HBV DNA levels [cohort Ⅰ, wild(797.7 pg/m L) vs deletion(1678.9 pg/m L), P = 0.013; cohort Ⅱ, wild(8.3 × 108 copies/m L) vs deletion(2.2 × 109 copies/m L), P = 0.049], compared to subjects with wild type HBV.CONCLUSION:HBV genotype C pre S1 deletion may affect disease progression in chronic HBV subjects through an extended duration of HBe Ag seropositive status and increased HBV replications.     

LKB1 expression and the prognosis of lung cancer: A meta-analysis

Background:In the past few decades, many lines of evidence implicate the importance of liver kinase B1 (LKB1) as a tumor suppressor gene in the development and progression of solid tumours. However, the prognostic and clinicopathological value of LKB1 in patients with lung cancer are controversial. This article aimed to investigate the latest evidence on this question.Methods:A systematic literature searched in the PubMed, Web of Science, Embase, Cochrane library, Scopus until September 20, 2020. The association between overall survival (OS), relapse-free survival (RFS), progression-free survival (PFS), clinicopathological features and LKB1 were analysed by meta-analysis.Results:Eleven studies including 1507 patients were included in this meta-analysis. The pooled results revealed that low LKB1 expression was significantly associated with poor overall survival (OS) (HR = 1.67, 95% CI: 1.07–2.60, P = .024) in lung cancer. However, no association was found between LKB1 expression and DFS/PFS (HR = 1.29, 95% CI: 0.70–2.39, P = .410). Pooled results showed that low LKB1 expression was associated with histological differentiation (poor vs moderate or well, OR = 4.135, 95% CI:2.524–6.774, P < .001), nodal metastasis (absent vs present, OR = 0.503, 95% CI: 0.303–0.835, P = .008) and smoking (yes vs no, OR = 1.765, 95% CI: 1.120–2.782, P = .014).Conclusion:These results suggest that low expression of LKB1 can be considered as a unfavorable prognostic biomarker for human lung cancer, which should be further researched.     

Myofibroblastic cell activation and neovascularization predict native liver survival and development of esophageal varices in biliary atresia

AIM:To study the relation between collagen 1,α-smooth muscle actin(α-SMA)and CD34 expression and the most essential portoenterostomy(PE)outcomes.METHODS:Liver specimens were obtained at PE from33 biliary atresia(BA)patients for immunohistochemical analysis of collagen 1,α-SMA and CD34.Liver biopsies from 35 organ donors were used as controls.Expression patterns were related to clinical data including age at PE,serum total and conjugated bilirubin concentration at the time of PE and during follow-up,incidence of esophageal varices in follow-up upper gastrointestinal endoscopies,and native liver survival as well as to detailed histopathological findings.RESULTS:Collagen 1(16.4%vs 4.5%,P<0.0001),α-SMA(17.9%vs 4.6%,P<0.0001)and CD34(4.9%vs 3.8%,P=0.017)were markedly overexpressed in BA patients compared with controls.Patients who underwent liver transplantation by age of two years had significantly higher expression of collagen 1(18.6%vs 13.7%,P=0.024),α-SMA(20.4%vs 15.4%,P=0.009)and CD34(5.9%vs 4.0%,P=0.029)at PE compared with native liver survivors.CD34-positive microvessels were identified in the centrizonal region close to central vein in every BA patient.In majority of BA cases(56%)neovascularization was frequent as CD34-positive microvessels were observed in over half of the hepatic lobules.In controls,the CD34-positive microvessels were rare as they were completely absent in 40%and were found in less than 5%of the hepatic lobules in the rest.The difference between BA patients and controls was significant(P<0.0001).Patients who developed esophageal varices by two years had significantly higher expression of CD34 at PE compared with patients without varices(5.6%vs 4.0%,P=0.019).Expression ofα-SMA(r=0.758,P<0.0001)and collagen 1(r=0.474,P=0.016),and the amount of CD34-positive microvessels(r=0.356,P=0.047)were related to patient age at PE.CONCLUSION:Hepatic myofibroblastic cell activation,fibrogenesis and neovascularization are enhanced in BA,progress with increasing PE age and relate to native liver survival and development of esophageal varices.     

Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance

In higher eukaryotes, the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) checkpoint kinases play distinct, but partially overlapping, roles in DNA damage response. Yet their interrelated function has not been defined for telomere maintenance. We discover in Drosophila that the two proteins control partially redundant pathways for telomere protection: the loss of ATM leads to the fusion of some telomeres, whereas the loss of both ATM and ATR renders all telomeres susceptible to fusion. The ATM-controlled pathway includes the Mre11 and Nijmegen breakage syndrome complex but not the Chk2 kinase, whereas the ATR-regulated pathway includes its partner ATR-interacting protein but not the Chk1 kinase. This finding suggests that ATM and ATR regulate different molecular events at the telomeres compared with the sites of DNA damage. This compensatory relationship between ATM and ATR is remarkably similar to that observed in yeast despite the fact that the biochemistry of telomere elongation is completely different in the two model systems. We provide evidence suggesting that both the loading of telomere capping proteins and normal telomeric silencing requires ATM and ATR in Drosophila and propose that ATM and ATR protect telomere integrity by safeguarding chromatin architecture that favors the loading of telomere-elongating, capping, and silencing proteins.     

Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model

AIM:To investigate whether transforming growth factor-β1(TGF-β1)signaling pathway is involved in the pathogenesis of primary biliary cirrhosis(PBC).METHODS:A murine model of PBC was developed by injection of polyinosinic polycytidylic acids(polyⅠ:C)in C57BL/6 mice,and the liver expressions of TGFβ1,TGF-βreceptorⅠ(TβRⅠ),TGF-βreceptorⅡ(TβRⅡ),p-Smad2/3,monoclonalα-smooth muscle actin antibody(α-SMA)andα1(Ⅰ)collagen in the mouse model and control mice were evaluated by immunohistochemistry,immunoblotting and real-time polymerase chain reaction(RT-PCR).Lymphocyte subsets in liver were analyzed using flow cytometry.RESULTS:The mouse model had several key phenotypic features of human PBC,including elevated levels of alkaline phosphatase,antimitochondrial antibodies,portal bile ducts inflammation,and progressive collagen deposition.Compared with control mice,protein and mRNA levels of TGFβ1,TβRⅠ,TβRⅡ,p-Smad2/3,α-SMA andα1(Ⅰ)collagen in liver(1.7±0.4 vs 8.9±1.8,0.8±0.2 vs 5.1±1.5,0.6±0.01 vs5.1±0.1,0.6±0.3 vs 2.0±0.3,0.9±0.4 vs 3.4±0.6,0.8±0.4 vs 1.7±0.3,1.1±1.2 vs 11.8±0.6,P<0.05),and the total number and percentage of CD4+CD25+FOXP3+and CD8+lymphocytes(0.01±0.001vs 0.004±0.00,0.12±0.04 vs 0.52±0.23,P<0.01)were higher in the mouse model.CONCLUSION:TGFβ1 might play a dual role in the development of PBC:it suppresses inflammatory response but operates to enhance fibrogenesis.The aberrant activity of TGF-β1 signaling contributes to the development of PBC.