Alterations of antioxidant enzymes in preeclampsia

Background: Pregnancy is a stressful condition in which many physiological and metabolic functions are altered to considerable extent and hypertension is the most common problem encountered during pregnancy, complicating 5-10% of pregnancies.  Recent reports suggest that free radical induced endothelial damage as an important factor in the pathogenesis of preeclampsia. Such cell injury might in turn is counteracted by the action of several in vivo antioxidants. The aim of present study was to determine the activity of enzymatic antioxidants - glutathione peroxidase and catalase in preeclampsia.Methods: Thirty cases of preeclampsia and thirty gestational age matched normotensive pregnant women attending Narayana General Hospital, Nellore were included in the study. The antioxidant enzymes - RBC glutathione peroxidase and catalase   activities   were determined by the respective laboratory methods in preeclampsia cases and compared with that of normotensive pregnant women.Results: The activity of catalase was significantly decreased (mean ± SEM 5.6 ± 0.26 vs. 8.5 ± 0.32 k/ml) and that of glutathione peroxidase was significantly increased (mean ± SEM 103.9 ± 1.67 vs. 83.8 ± 1.85 U/gm of Hb) in preeclamptic cases when compared with that of normotensive pregnant women.Conclusions: We conclude that activities of antioxidant enzymes-glutathione peroxidase and catalase are altered   in preeclampsia. The increased activity of the antioxidant enzymes may be a compensatory regulation in response to increased oxidative stress while the decreased activity supports that lipid peroxidation is an important causative factor in the pathogenesis of preeclampsia.

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

A study on Clinical diagnosis, hormonal profile and radiological correlation with Histopathology in MNG

Background and Objective: Nodular goiter is the most common pathology of the thyroid gland. The disease is hyperplastic in nature. Palpable thyroid nodules are found in 3-7% of adult population and are more frequent in women. The basic objective of this study is - To evaluate the accuracy of radiology, and clinical diagnosis with respect to histopathology and role of hormonal data analysis for early diagnosis and treatment. Methodology: The study period is from Jan 2017 to Jan 2020, carried out in Department of Pathology, Gayathri Vidya Parishad institute of healthcare and medical technology(GVPIHC&MT), on the thyroidectomy specimens for detailed analysis of diagnostic efficacy, accuracy of radiology, clinical diagnosis with histopathology in detection of nodules in thyroid and their co-existent lesions. Results: A total of 180 histopathological case details were collectively analyzed. Out of these, 155 cases had hormonal profile data, 56 cases had radiological data. The study showed strong female preponderance with 41-60 years being the most common age group. Out of 180 nodular goiters studied, most of them were benign with only 12.22% malignant cases. The diagnostic accuracy for radiology- 89.5%, and clinical diagnosis- 92.1% were noted. Conclusion: Prior examination of thyroid by clinician, hormonal profile assessment, radiology of the lesion provides additional diagnostic aid to the conventional thyroidectomy. Though, histopathology remains the gold standard for diagnosing thyroid lesions, all these together minimize the unwanted surgeries and provide greater diagnostic yield

The acute surgical unit: improving emergency care

Background:  Acute care surgical teams are a new concept in the provision of emergency general surgery. Juggling emergency patients around the surgeons\u27 and staffs\u27 elective commitments resulted in semi-emergency procedures routinely being delayed. In an era of increasing financial pressure and the recent introduction of \u27safe work hours\u27 practices, the need for a new system which optimized available resources became apparent. Methods:  At Fremantle Hospital we developed a new system in a concerted effort to minimize the waiting time for general surgical referrals in the Emergency Department, as well as to move semi-urgent operating from the afterhours to the daytime. To analyse the impact of the ASU, data were collected during February, March, and April 2009 and compared with data from the same period in 2008. Results:  Although most referrals were received afterhours, over 85% of operations were performed during working hours compared with 72% in the 2008 period. The time from referral to review decreased from an average of 3.2 h in 2008 to 2.1 h. The mean duration of stay in 2009 was 3 days, which was a reduction from 4.2 days in 2008. An increase in weekend discharge rates was seen after the introduction of the ASU. Conclusion:  Despite an increased workload, more referrals were seen and more operations performed during working hours and the time from referral to review was reduced. Higher discharge rates and reduced length of stays increased the availability of beds. We have demonstrated a successful new model which continues to evolve

ROR1 and ROR2 expression in pancreatic cancer

Background: The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ beta-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC.Methods: Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated.Results: High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort.Conclusion: ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq

Hypermutation In Pancreatic Cancer

© 2017 AGA Institute Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer

Whole genomes redefine the mutational landscape of pancreatic cancer

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded

Corrigendum: Whole-genome landscape of pancreatic neuroendocrine tumours

This corrects the article DOI: 10.1038/nature21063