Browsing by Author "Singh, Ruchi"

Now showing 1 - 4 of 4
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    Colorectal Dysplasia and Cancer in Pediatric-Onset Ulcerative Colitis Associated With Primary Sclerosing Cholangitis
    (Elsevier, 2021) El-Matary, Wael; Guthery, Stephen L.; Amir, Achiya Z.; DiGuglielmo, Matthew; Draijer, Laura G.; Furuya, Katryn N.; Gupta, Nitika; Hochberg, Jessica T.; Horslen, Simon; Kerkar, Nanda; Koot, Bart G. P.; Laborda, Trevor J.; Loomes, Kathleen M.; Mack, Cara; Martinez, Mercedes; Miethke, Alexander; Miloh, Tamir; Mogul, Douglas; Mohammed, Saeed; Moroz, Stacy; Ovchinsky, Nadia; Perito, Emily R.; Rao, Girish; Ricciuto, Amanda; Sathya, Pushpa; Schwarz, Kathleen B.; Shah, Uzma; Singh, Ruchi; Soufi, Nisreen; Valentino, Pamela L.; Zizzo, Andréanne; Deneau, Mark R.; Pediatrics, School of Medicine
    Inflammatory bowel disease (IBD), especially when associated with primary sclerosing cholangitis (PSC), is a risk factor for developing colorectal cancer (CRC). We aimed to determine the incidence of CRC in a large cohort of pediatric-onset PSC-ulcerative colitis (UC) patients.
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    Nucleotide-resolution Mapping of RNA N6-Methyladenosine (m6A) modifications and comprehensive analysis of global polyadenylation events in mRNA 3’ end processing in malaria pathogen Plasmodium falciparum
    (bioRxiv, 2025-01-08) Catacalos-Goad, Cassandra; Chakrabarti, Manohar; Salem, Doaa Hassan; Camporeale, Carli; Somalraju, Sahiti; Tegowski, Matthew; Singh, Ruchi; Reid, Robert W.; Janies, Daniel A.; Meyer, Kate D.; Janga, Sarath Chandra; Hunt, Arthur G.; Chakrabarti, Kausik; Biomedical Engineering and Informatics, Luddy School of Informatics, Computing, and Engineering
    Plasmodium falciparum is an obligate human parasite of the phylum Apicomplexa and is the causative agent of the most lethal form of human malaria. Although N6-methyladenosine modification is thought to be one of the major post-transcriptional regulatory mechanisms for stage-specific gene expression in apicomplexan parasites, the precise base position of m6A in mRNAs or noncoding RNAs in these parasites remains unknown. Here, we report global nucleotide-resolution mapping of m6A residues in P. falciparum using DART-seq technology, which quantitatively displayed a stage-specific, dynamic distribution pattern with enrichment near mRNA 3' ends. In this process we identified 894, 788, and 1,762 m6A-modified genes in Ring, Trophozoite and Schizont stages respectively, with an average of 5-7 m6A sites per-transcript at the individual gene level. Notably, several genes involved in malaria pathophysiology, such as KAHRP, ETRAMPs, SERA and stress response genes, such as members of Heat Shock Protein (HSP) family are highly enriched in m6A and therefore could be regulated by this RNA modification. Since we observed preferential methylation at the 3' ends of P. falciparum transcripts and because malaria polyadenylation specificity factor PfCPSF30 harbors an m6A reader 'YTH' domain, we reasoned that m6A might play an important role in 3'-end processing of malaria mRNAs. To investigate this, we used two complementary high-throughput RNA 3'-end mapping approaches, which provided an initial framework to explore potential roles of m6A in the regulation of alternative polyadenylation (APA) during malaria development in human hosts.
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    Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis
    (Wolters Kluwer, 2021) Deneau, Mark R.; Mack, Cara; Mogul, Douglas; Perito, Emily R.; Valentino, Pamela L.; Amir, Achiya Z.; DiGuglielmo, Matthew; Draijer, Laura G.; El-Matary, Wael; Furuya, Katryn N.; Gupta, Nitika; Hochberg, Jessica T.; Horslen, Simon; Jensen, M. Kyle; Jonas, Maureen M.; Kerkar, Nanda; Koot, Bart G. P.; Laborda, Trevor J.; Lee, Christine K.; Loomes, Kathleen M.; Martinez, Mercedes; Miethke, Alexander; Miloh, Tamir; Mohammad, Saeed; Ovchinsky, Nadia; Rao, Girish; Ricciuto, Amanda; Sathya, Pushpa; Schwarz, Kathleen B.; Shah, Uzma; Singh, Ruchi; Vitola, Bernadette; Zizzo, Andréanne; Guthery, Stephen L.; Pediatrics, School of Medicine
    Background and aims: Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. Approach and results: We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. Conclusions: We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.
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    The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children
    (Wolters Kluwer, 2021) Deneau, Mark R.; Mack, Cara; Perito, Emily R.; Ricciuto, Amanda; Valentino, Pamela L.; Amin, Mansi; Amir, Achiya Z.; Aumar, Madeleine; Auth, Marcus; Broderick, Annemarie; DiGuglielmo, Matthew; Draijer, Laura G.; Druve Tavares Fagundes, Eleonora; El-Matary, Wael; Ferrari, Federica; Furuya, Katryn N.; Gupta, Nitika; Hochberg, Jessica T.; Homan, Matjaz; Horslen, Simon; Iorio, Raffaele; Jensen, M. Kyle; Jonas, Maureen M.; Kamath, Binita M.; Kerkar, Nanda; Kim, Kyung Mo; Kolho, Kaija-Leena; Koot, Bart G. P.; Laborda, Trevor J.; Lee, Christine K.; Loomes, Kathleen M.; Martinez, Mercedes; Miethke, Alexander; Miloh, Tamir; Mogul, Douglas; Mohammad, Saeed; Mohan, Parvathi; Moroz, Stacy; Ovchinsky, Nadia; Palle, Sirish; Papadopoulou, Alexandra; Rao, Girish; Rodrigues Ferreira, Alexandre; Sathya, Pushpa; Schwarz, Kathleen B.; Shah, Uzma; Shteyer, Eyal; Singh, Ruchi; Smolka, Vratislav; Soufi, Nisreen; Tanaka, Atsushi; Varier, Raghu; Vitola, Bernadette; Woynarowski, Marek; Zerofsky, Melissa; Zizzo, Andréanne; Guthery, Stephen L.; Pediatrics, School of Medicine
    Background and aims: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. Approach and results: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. Conclusions: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.