Advances in Neuromodulation for Bowel Dysfunction : Opening New Frontiers

Neurostimulation in the form of sacral nerve stimulation has been used in the treatment of bowel dysfunction since the past 17-18 years. However, our knowledge on the alternative forms of neurostimulation such as pudendal nerve stimulation and posterior tibial nerve stimulation are limited. In addition, there exist several patient groups where sacral nerve stimulation is not effective. This thesis incorporates a series of studies done with the aim of expanding our existing knowledge on neurostimulation as well as exploring alternate forms of neurostimulation in treating bowel dysfunction. The role of pudendal nerve stimulation in faecal incontinence and the steps in the development of a new technique including cadaveric dissection, for stimulating the pudendal nerve are discussed. The new technique developed is subsequently used to successfully stimulate the pudendal nerve in two specific subgroups of patients where sacral nerve stimulation has not been effective in: patients with complete cauda equina syndrome and those who failed to improve with sacral nerve stimulation. The thesis explores additional routes of neurostimulation using the posterior tibial nerve and discusses the findings of a single blinded randomised placebo controlled clinical trial of percutaneous, transcutaneous and sham posterior tibial nerve stimulation in a group of faecal incontinent patients. Our knowledge on the effects of sacral nerve stimulation in constipation is relatively new. The results of a double blinded crossover study of sacral nerve stimulation in constipation sheds more light on the possible actions and effects of sacral nerve stimulation in this group of patients. The effects of sacral nerve stimulation in the elderly is discussed in the subsequent chapter through the presentation of the findings of a single center retrospective analysis on the safety and long term efficacy of sacral nerve stimulation in the elderly subgroup

Mutation spectrum of the CYP1B1 gene in Indian primary congenital glaucoma patients

Purpose: The human Cytochrome P450 gene CYP1B1 has been implicated in primary congenital glaucoma worldwide. The aim of this study was to understand the role of CYP1B1 mutations in causing primary congenital glaucoma in Indian populations. Methods: The study included 64 new and unrelated cases of primary congenital glaucoma from different ethnic groups of India. Direct sequencing screened the coding and the promoter regions of CYP1B1. Results: Sixteen pathogenic mutations were observed in 24 cases, of which 7 were novel. These included two frameshift mutations leading to deletions of 23 bp (g.3905del23bp) and 2 bp (g.7900-7901delCG) in exons II and III, respectively. Four novel missense mutations viz. A115P, M132R, Q144P, S239R were noted in exon II, and one in exon III (G466D), whose residue is a part of the "signature sequence" (NH2-FXXGXXXCXG-COOH) and is present in all heme binding cytochromes. Overall, CYP1B1 was involved in 37.50% (24/64) cases and homozygosity of the mutant allele was seen in 29.68% (19/64) and compound heterozygosity in 3.12% (2/64) of the cases, respectively. The frequency of CYP1B1 mutations was comparatively lower than Saudi Arabian, Slovakian Gypsys, and Turkish populations, largely due to genetic heterogeneity and ethnic diversities in Indian populations. Genotype-phenotype correlation indicated variable prognosis that could be due to the type of mutation, leading to alteration of CYP1B1 protein. Conclusions: This study provides a mutation spectrum of CYP1B1 causing primary congenital glaucoma in Indian populations that has implications in devising molecular diagnostics for rapid screening

Marine fishery at Vizhinjam - A decadal analysis

The average annual marine fish landing of Vizhinjam during 2004-2013 fluctuated from 13,119 to 23,798 t registering an average catch of 1,9462 t. Standard effort fluctuated over the years with minimum of 53,772 during 2011 and maximum of 1,21,524 during 2005 with an average of 91,491 units. Pelagic finfishes contributed 78.4% to the total catch, followed by demersal finfishes (10.5%), crustaceans (0.8%) and molluscs (10.5%). Boat seine contributed 39% to the total catch, followed by drift gillnet (31%) and mechanised hooks and line (20%). Landings of major pelagic resources registered marginal increase till 2009, after which the catch decreased drastically. Tunas contributed 33.8% of the total pelagic landings followed by clupeids which formed 27.5%. Mackerel landings showed a gradual increase from 465 t in 2004 to 2,869 t in 2008 and subsequently declined with fluctuations in between. Carangids, one of the major resources also showed fluctuations in their landings with maximum landings during 2009. Trichiurids showed wide fluctuation, with peak landings during the period 2004-2007. Among demersal finfishes, perches formed 26.6% followed by elasmobranchs (21%) and flatfishes (10.4%). Crustacean landings which is highly seasonal showed a declining trend over the years. Penaeid prawns on an average formed 59.56% of total crustacean landings, followed by Acetes which constituted 20.7% and the rest by crabs. Total cephalopod production increased from 836 t in 2004 to 2,891 t in 2012 and comprised mainly squids and cuttlefish. Disappearance of gears such as Kolachivala, Achil and reduction in the effort of non-motorised crafts which operate gears like Chalavala, Netholivala as well as hooks & line were noticed during the present study

Integrated Multi-Omic Analysis of Low-Grade Ovarian Serous Carcinoma Collected From Short and Long-Term Survivors

BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as \u3c 40 and \u3e 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. METHODS: Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. RESULTS: We identified single-nucleotide variants (SNVs) (range: 5688-14,833 per sample), insertion and deletion variants (indels) (range: 880-1065), and regions with copy number variants (CNVs) (range: 62-335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. CONCLUSIONS: This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC

Classification of High-Grade Serous Ovarian Cancer Using Tumor Morphologic Characteristics

IMPORTANCE: Despite similar histologic appearance among high-grade serous ovarian cancers (HGSOCs), clinical observations suggest vast differences in gross appearance. There is currently no systematic framework by which to classify HGSOCs according to their gross morphologic characteristics. OBJECTIVE: To develop and characterize a gross morphologic classification system for HGSOC. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients with suspected advanced-stage ovarian cancer who presented between April 1, 2013, and August 5, 2016, to the University of Texas MD Anderson Cancer Center, a large referral center. Patients underwent laparoscopic assessment of disease burden before treatment and received a histopathologic diagnosis of HGSOC. Researchers assigning morphologic subtype and performing molecular analyses were blinded to clinical outcomes. Data analysis was performed between April 2020 and November 2021. EXPOSURES: Gross tumor morphologic characteristics. MAIN OUTCOMES AND MEASURES: Clinical outcomes and multiomic profiles of representative tumor samples of type I or type II morphologic subtypes were compared. RESULTS: Of 112 women (mean [SD] age 62.7 [9.7] years) included in the study, most patients (84% [94]) exhibited a predominant morphologic subtype and many (63% [71]) had a uniform morphologic subtype at all involved sites. Compared with those with uniform type I morphologic subtype, patients with uniform type II morphologic subtype were more likely to have a favorable Fagotti score (83% [19 of 23] vs 46% [22 of 48]; P = .004) and thus to be triaged to primary tumor reductive surgery. Similarly, patients with uniform type II morphologic subtype also had significantly higher mean (SD) estimated blood loss (639 [559; 95% CI, 391-887] mL vs 415 [527; 95% CI, 253-577] mL; P = .006) and longer mean (SD) operative time (408 [130; 95% CI, 350-466] minutes vs 333 [113; 95% CI, 298-367] minutes; P = .03) during tumor reductive surgery. Type I tumors had enrichment of epithelial-mesenchymal transition (false discovery rate [FDR] q-value, 3.10 × 10-24), hypoxia (FDR q-value, 1.52 × 10-5), and angiogenesis pathways (FDR q-value, 2.11 × 10-2), whereas type II tumors had enrichment of pathways related to MYC signaling (FDR q-value, 2.04 × 10-9) and cell cycle progression (FDR q-value, 1.10 × 10-5) by integrated proteomic and transcriptomic analysis. Abundances of metabolites and lipids also differed between the 2 morphologic subtypes. CONCLUSIONS AND RELEVANCE: This study identified 2 novel, gross morphologic subtypes of HGSOC, each with unique clinical features and molecular signatures. The findings may have implications for triaging patients to surgery or chemotherapy, identifying outcomes, and developing tailored therapeutic strategies

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment