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关键词： AP-1   Chromatin remodeling   Human induced pluripotent stem cells   JDP2   PLURIPOTENT STEM-CELLS   RNA-SEQ DATA   CHROMATIN ACCESSIBILITY   EPITHELIAL TRANSITION   HIGH-EFFICIENCY   GENERATION   NAIVE   DERIVATION   MOUSE   FIBROBLASTS  

摘要： Human induced pluripotent stem cells (iPSCs) technology has been widely applied to cell regeneration and disease modeling. However, most mechanism of somatic reprogramming is studied on mouse system, which is not always generic in human. Consequently, the generation of human iPSCs remains inefficient. Here, we map the chromatin accessibility dynamics during the induction of human iPSCs from urine cells. Comparing to the mouse system, we found that the closing of somatic loci is much slower in human. Moreover, a conserved AP-1 motif is highly enriched among the closed loci. The introduction of AP-1 repressor, JDP2, enhances human reprogramming and facilitates the reactivation of pluripotent genes. However, ESRRB, KDM2B and SALL4, several known pluripotent factors promoting mouse somatic reprogramming fail to enhance human iPSC generation. Mechanistically, we reveal that JDP2 promotes the closing of somatic loci enriching AP-1 motifs to enhance human reprogramming. Furthermore, JDP2 can rescue reprogramming deficiency without MYC or KLF4. These results indicate AP-1 activity is a major barrier to prevent chromatin remodeling during somatic cell reprogramming.

摘要： Objectives: Despite recent advances in adjuvant therapy for various gynecologic malignancies, the prognosis of patients presenting with stage IVB uterine serous carcinoma (USC) remains extremely poor, with a reported 5-year survival of <20%. The goal of this study is to evaluate the survival impact of cytoreductive surgery and identify other prognostic factors in stage IVB USC. Methods: A multicenter retrospective analysis of patients with stage IVB USC was conducted from 2000 - 2018. Inclusion criteria were patients who had undergone comprehensive surgical staging/tumor debulking; followed by adjuvant chemotherapy±external beam radiation therapy (EBRT). Optimal cytoreduction (R1) was defined as residual disease <=1 cm at completion of surgery, and suboptimal cytoreduction (R2) was defined as >=1cm. Patients receiving neoadjuvant chemotherapy were excluded from analysis. Progression free survival (PFS) and overall survival (OS) analysis was performed using Kaplan-Meier estimates. Multivariate analysis (MVA) was performed using Cox proportional hazards model. Results: Final analysis included 68 patients. 50 (74%) patients were cytoreduced to R1 and 18 (26%) to R2. Additionally, 11 (16%) R1 patients were cytoreduced to no gross residual disease (R0). The mean age was 66 years (range 44-89) and 96% of patients were African American. The majority of patients, 56 (82%), received systemic chemotherapy alone and 12 (18%) received a combination of chemotherapy and EBRT±vaginal brachytherapy (chemoradiation). Adjuvant therapy regimens were well-balanced between R1 and R2 patients ( p =0.992). There was no difference in the frequency of treatment delays between regimens ( p =0.832). 96% of patients received platinum-based chemotherapy. There was no difference in the age ( p =0.227), race ( p =0.936), type of radiotherapy ( p =0.852) or chemotherapy regimen received ( p =0.996) between R1 and R2 cohorts. The median PFS for all patients was 8 months and the median OS was 13 mon

关键词： Vascular smooth muscle cells   Primary cell culture   RVSMCs   Phenotype   PROLIFERATION   CONTRACTION  

摘要： An efficient and simple method to obtain aortic media for primary culture of rat vascular smooth muscle cells (RVSMCs) is developed. The main steps to obtain aortic media include isolation of rat aortic artery, removal of the fat tissue and branches, separation of longitudinal cutting edge, and peeling off the adventitia. Then, aortic media was used to obtain RVSMCs by our tissue explants method and the enzyme digestion method. The removal efficiency of the intima and adventitia was confirmed by hematoxylin-eosin and immunohistochemical staining. Morphology and immunofluorescent staining were used to identify cells and cell purity. RVSMCs at the 3rd and 8th passages were isolated by our tissue explants method; the enzyme digestion method and the traditional tissue explants method were compared respectively. Western blotting and gel contraction assay were used to investigate the phenotype and contraction ability of RVSMCs obtained by the different methods. Compared with the other methods, RVSMCs isolated by our method showed higher purity and demonstrated "contractile" phenotype with retained contraction ability for more passages. And the aortic media obtained showed no visible damage with few endothelial cells and fibroblasts remained. An efficient and simple method was established to obtain rat aortic media for primary culture of RVSMCs with high purity, "contractile" phenotype characteristics, and more stable during subculturing.

关键词： Oral cancer   Routine follow-up   Postoperative surveillance   Head and neck cancer   Survivorship   Second primary tumours   CANCER INCIDENCE   NECK-CANCER   HEAD   TRENDS   MORTALITY   RISK  

摘要： Introduction: The aim of this study was to determine the incidence, location and timing of second primary tumours (SPT) after diagnosis of oral squamous cell carcinoma (OSCC) and relate the risk of SPT to that after head and neck squamous cell carcinoma (HNSCC) and the risks of those tumours in the general population in order to assess the need for a separate follow-up programme for OSCC patients and to aid development of an evidence-based and individualized follow-up programme for OSCC patients. Materials and methods: All patients diagnosed with OSCC or HNSCC in the Netherlands in 1991-2015 were selected from the Netherlands Cancer Registry. Cumulative incidence rates and Standardized Incidence Ratios (SIR) were calculated. Analyses were stratified by incidence period and age at primary diagnosis of the index tumour, follow-up time, and site of the SPT. Results: We included 11263 patients with OSCC from a population of 34244 patients with HNSCC, of which the median follow-up time was 4.0 years. OSCC SPT develop in different patterns and at different locations than after HNSCC. The 5-year risk of SPT and SIR (95% confidence intervals) were respectively 0.13 (0.13-0.14) and 3.0 (2.9-3.1) for OSCC. The risk of a SPT was continuous over follow-up time and calendar period but decreased with an increasing age at diagnosis of the index tumour up to the age of 75 and there were differences in sites of SPT. Conclusion: A specific follow-up protocol for OSCC is needed, which can be individualized on the basis of, among others, age. (C) 2021 Published by Elsevier Ltd.

关键词： Primary Sclerosing Cholangitis   Immune-mediated liver disease   Single-cell sequencing   Atlas   T cells   Naive T cells   T(H)17 cells   Tissue residency   GENOME-WIDE ASSOCIATION   TRANSCRIPTION FACTORS   FACTOR-I   EXPRESSION   DIFFERENTIATION   TISSUE   RECRUITMENT   PROMOTES   SUPPORTS   CCL21  

摘要： Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver. Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs. Results: We identified a population of intrahepatic naive-like CD4(+) T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (T(H)17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards T(H)17 cells. Conclusion: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4(+) T cells in PSC harbour the propensity to develop into T(H)17 cells. Lay summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-r

关键词： Beta cell mass   Beta cell number   Beta cell size   Human pancreas   Japanese  

摘要： Aims/hypothesis Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. Methods Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. Results Both beta cell size (548.7 +/- 58.5 vs 606.7 +/- 65.0 mu m(3), p < 0.01) and number (5.10 x 10(8) +/- 2.35 x 10(8) vs 8.16 x 10(8) +/- 4.27 x 10(8), p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA(1c) (r = -0.45, p < 0.01). Conclusions/interpretation Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes.

关键词： Surgery   Gastroenterology  

关键词： Intravascular large B-cell lymphoma   Intravascular lymphoma   Peritubular capillary   Renal lymphoma  

摘要： We report on a 70-year-old woman with intravascular large B-cell lymphoma, in whom the renal lesion was localized in the peritubular capillaries. The patient complained of fatigue, general malaise, and unsteadiness when walking. Laboratory tests showed anemia, increased C-reactive protein, and mild renal failure, with a serum creatinine level of 1.31 mg/dL and no remarkable proteinuria or hematuria. Renal biopsy showed intravascular large B-cell lymphoma. The large atypical cells were mainly accumulated within the peritubular capillaries and no large atypical cells were found in the glomeruli. Skin and bone marrow biopsies confirmed intravascular large B-cell lymphoma. Brain magnetic resonance imaging showed multiple small infarctions in the cerebral white matter. The patient was treated with dexamethasone, methotrexate, and cytarabine followed by CHOP (combined cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-CHOP (CHOP with the recombinant anti-CD20 antibody rituximab), and her renal function improved soon after the start of chemotherapy.

摘要： Objectives: To compare overall survival, progression-free survival, and complication rate for women with squamous cell cancer of the vulva treated with curative intent radiation therapy compared to primary surgery. Methods: Retrospective cohort study of Kaiser Permanente Northern California (KPNC) members diagnosed with invasive squamous cell carcinoma of the vulva between 2008-2018 who were treated with either primary surgery (PS) or primary radiation therapy (PRT). Additional analyses were included for patients who underwent surgery alone (PS alone) vs surgery with adjuvant radiation (PS+RT). Exclusion criteria were synchronous primary cancer, palliative treatment, and lapse of KPNC membership during primary therapy. Women were identified using an internal cancer registry and variables were extracted through chart review. Bivariate analysis was completed using Kaplan Meier curves and Chi-square tests to compare 1- and 3-year overall and progression-free survival. Multivariable Cox proportional hazards regression adjusted for age, stage (FIGO 2009), Charlson comorbidity index, and smoking status. Results: 202 women were included in the analysis. Median follow-up was 3.3 years. 59 women (29.2%) underwent PRT, of whom 47 (79.7%) received concurrent chemotherapy. 143 women (70.8%) underwent PS, of whom 33 (23.1%) received adjuvant radiation with or without chemotherapy. 83.0% of PRT patients were stage II-IV, whereas 77.6% of PS patients were stage I (p<0.0001). One- and three-year overall survival for patients who received PRT vs PS was 74.6% vs 90.9% (p=0.002) and 57.4% vs 82.0% (p=0.029), respectively. Adjusted hazard ratio (aHR) of death for PRT vs PS was 1.05 (95% confidence interval (CI) 0.62-1.78). aHR for death or recurrence was 0.87 (CI 0.57-1.33). PS patients were additionally analyzed based on receipt of adjuvant therapy. One- and three-year overall survival for patients who received PS alone vs PS+RT was 96.4% vs 72.7% (p<0.0001) and 82% vs 50.0% (p<0.001)

关键词： case-control study   odd-chain saturated fatty acids   serine palmitoyl-transferase long-chain base subunit 3 gene polymorphism   SPTLC3   type 2 diabetes   T2D   very-long-chain saturated fatty acids   VLSFAs   SATURATED FATTY-ACIDS   DAIRY PRODUCT INTAKE   ADIPOSE-TISSUE   SERUM-LIPIDS   RISK   BIOMARKERS   CONSUMPTION   MELLITUS   MARKERS   FOOD  

摘要： Background: Several individual studies have shown that circulating levels of odd-chain SFAs and very-long-chain SFAs (VLSFAs) may have beneficial effects, but the results are mixed. While the dietary and metabolic factors that may influence VLSFAs are not well-known, a previous study observed associations of VLSFA concentrations with variants in serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3) gene. Objectives: We investigated the associations of individual plasma SFAs and SPTLC3 gene rs680379 polymorphism with metabolic risk factors and type 2 diabetes (T2D). Methods: We measured plasma SFAs using gas chromatography among 898 T2D cases and 1618 matched controls, and genotyped the SPTLC3 gene rs680379 polymorphism using the MassArray System among 1178 T2D cases and 1907 matched controls. Conditional logistic regression was used to estimate ORs and 95% CIs. Results: We found that plasma odd-chain SFAs and VLSFAs were correlated with favorable blood lipids and insulin resistance marker profiles. After multivariable adjustment, pentadecanoic acid (15:0) was inversely associated with the odds of T2D (OR per 1 SD difference: 0.63; 95% CI: 0.57, 0.70), as were measurements of 3 individual VLSFAs [arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)], with ORs ranging from 0.60 to 0.72 (95% CIs ranging between 0.52 and 0.79). The associations between 3 individual VLSFAs and T2D were attenuated after further adjustment for triglycerides. Meanwhile, compared with the rs680379 GG genotype carriers, the ORs of T2D for the GA and AA genotype carriers were 0.81 (95% CI: 0.68-0.97) and 0.76 (95% CI: 0.61-0.96), respectively. Conclusions: Plasma 15:0 and VLSFAs were inversely associated with T2D. Meanwhile, compared with the rs680379 GG genotype carriers, subjects with GA and AA genotypes were associated with decreased odds of T2D. More investigations are warranted to confirm our findings.