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Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin

Liang, Wen-Wei; Lu, Rita Jui-Hsien; Jayasinghe, Reyka G; Foltz, Steven M; Porta-Pardo, Eduard; Geffen, Yifat; Wendl, Michael C; Lazcano, Rossana; Kolodziejczak, Iga; Song, Yizhe; Govindan, Akshay; Demicco, Elizabeth G; Li, Xiang; Li, Yize; Sethuraman, Sunantha; Payne, Samuel H; Fenyö, David; Rodriguez, Henry; Wiznerowicz, Maciej; Shen, Hui; Mani, D R; Rodland, Karin D; Lazar, Alexander J; Robles, Ana I; Ding, Li; Clinical Proteomic Tumor Analysis Consortium
DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.
PMID: 37582362
ISSN: 1878-3686
CID: 5558572

Proteogenomic insights suggest druggable pathways in endometrial carcinoma

Dou, Yongchao; Katsnelson, Lizabeth; Gritsenko, Marina A; Hu, Yingwei; Reva, Boris; Hong, Runyu; Wang, Yi-Ting; Kolodziejczak, Iga; Lu, Rita Jui-Hsien; Tsai, Chia-Feng; Bu, Wen; Liu, Wenke; Guo, Xiaofang; An, Eunkyung; Arend, Rebecca C; Bavarva, Jasmin; Chen, Lijun; Chu, Rosalie K; Czekański, Andrzej; Davoli, Teresa; Demicco, Elizabeth G; DeLair, Deborah; Devereaux, Kelly; Dhanasekaran, Saravana M; Dottino, Peter; Dover, Bailee; Fillmore, Thomas L; Foxall, McKenzie; Hermann, Catherine E; Hiltke, Tara; Hostetter, Galen; Jędryka, Marcin; Jewell, Scott D; Johnson, Isabelle; Kahn, Andrea G; Ku, Amy T; Kumar-Sinha, Chandan; Kurzawa, Paweł; Lazar, Alexander J; Lazcano, Rossana; Lei, Jonathan T; Li, Yi; Liao, Yuxing; Lih, Tung-Shing M; Lin, Tai-Tu; Martignetti, John A; Masand, Ramya P; Matkowski, Rafał; McKerrow, Wilson; Mesri, Mehdi; Monroe, Matthew E; Moon, Jamie; Moore, Ronald J; Nestor, Michael D; Newton, Chelsea; Omelchenko, Tatiana; Omenn, Gilbert S; Payne, Samuel H; Petyuk, Vladislav A; Robles, Ana I; Rodriguez, Henry; Ruggles, Kelly V; Rykunov, Dmitry; Savage, Sara R; Schepmoes, Athena A; Shi, Tujin; Shi, Zhiao; Tan, Jimin; Taylor, Mason; Thiagarajan, Mathangi; Wang, Joshua M; Weitz, Karl K; Wen, Bo; Williams, C M; Wu, Yige; Wyczalkowski, Matthew A; Yi, Xinpei; Zhang, Xu; Zhao, Rui; Mutch, David; Chinnaiyan, Arul M; Smith, Richard D; Nesvizhskii, Alexey I; Wang, Pei; Wiznerowicz, Maciej; Ding, Li; Mani, D R; Zhang, Hui; Anderson, Matthew L; Rodland, Karin D; Zhang, Bing; Liu, Tao; Fenyö, David; Clinical Proteomic Tumor Analysis Consortium
We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.
PMID: 37567170
ISSN: 1878-3686
CID: 5558742

Cis-regulatory arbitrators of regeneration

Konieczny, Piotr; Naik, Shruti
Mammals favor healing with scaring over functional tissue regeneration.1 In this issue of Cell Stem Cell, Mack et al. use "super-healer" mice to identify cis-regulatory variations that direct regenerative versus fibrotic gene expression in wound fibroblasts and they uncover complement factor H as a molecular driver of skin regeneration.2.
PMID: 37714155
ISSN: 1875-9777
CID: 5557772

Single-Cell Analysis of CX3CR1+ Cells Reveals a Pathogenic Role for BIRC5+ Myeloid Proliferating Cells Driven by Staphylococcus aureus Leukotoxins

Loredan, Denis G; Devlin, Joseph C; Lacey, Keenan A; Howard, Nina; Chen, Ze; Zwack, Erin E; Lin, Jian-Da; Ruggles, Kelly V; Khanna, Kamal M; Torres, Victor J; Loke, P'ng
Our previous studies identified a population of stem cell-like proliferating myeloid cells within inflamed tissues that could serve as a reservoir for tissue macrophages to adopt different activation states depending on the microenvironment. By lineage-tracing cells derived from CX3CR1+ precursors in mice during infection and profiling by single-cell RNA sequencing, in this study, we identify a cluster of BIRC5+ myeloid cells that expanded in the liver during chronic infection with either the parasite Schistosoma mansoni or the bacterial pathogen Staphylococcus aureus. In the absence of tissue-damaging toxins, S. aureus infection does not elicit these BIRC5+ cells. Moreover, deletion of BIRC5 from CX3CR1-expressing cells results in improved survival during S. aureus infection. Hence the combination of single-cell RNA sequencing and genetic fate-mapping CX3CR1+ cells revealed a toxin-dependent pathogenic role for BIRC5 in myeloid cells during S. aureus infection.
PMID: 37466391
ISSN: 1550-6606
CID: 5535762

Suboptimal Guideline Adherence and Biomarker Underutilization in Monitoring of Post-operative Crohn's Disease

Li, Terry; Click, Benjamin; Bachour, Salam; Sachs, Michael; Barnes, Edward L; Cohen, Benjamin L; Contreras, Susell; Axelrad, Jordan
BACKGROUND:Crohn's disease recurrence after ileocecal resection is common. Guidelines suggest colonoscopy within 6-12 months of surgery to assess for post-operative recurrence, but use of adjunctive monitoring is not protocolized. We aimed to describe the state of monitoring in post-operative Crohn's. METHODS:We conducted a retrospective study of patients with Crohn's after ileocolic resection with ≥ 1-year follow-up. Patients were stratified into high and low risk based on guidelines. Post-operative biomarker (C-reactive protein, fecal calprotectin), cross-sectional imaging, and colonoscopy use were assessed. Biomarker, radiographic, and endoscopic post-operative recurrence were defined as elevated CRP/calprotectin, active inflammation on imaging, and Rutgeerts ≥ i2b, respectively. Data were stratified by surgery year to assess changes in practice patterns over time. P-values were calculated using Wilcoxon test and Fisher exact test. RESULTS:Of 901 patients, 53% were female and 78% high risk. Median follow-up time was 60 m for LR and 50 m for high risk. Postoperatively, 18% low and 38% high risk had CRPs, 5% low and 10% high risk had calprotectins, and half of low and high risk had cross-sectional imaging. 29% low and 38% high risk had colonoscopy by 1 year. Compared to pre-2015, time to first radiography (584 days vs. 398 days) and colonoscopy (421 days vs. 296 days) were significantly shorter for high-risk post-2015 (P < 0.001). Probability of colonoscopy within 1 year increased over time (0.48, 2011 vs. 0.92, 2019). CONCLUSION:Post-operative colonoscopy completion by 1 year is low. The use of CRP and imaging are common, whereas calprotectin is infrequently utilized. Practice patterns are shifting toward earlier monitoring.
PMID: 37548896
ISSN: 1573-2568
CID: 5563092

Endolysin inhibits skin colonization by patient-derived Staphylococcus aureus and malignant T cell activation in cutaneous T cell lymphoma

Pallesen, Emil M H; Gluud, Maria; Vadivel, Chella K; Buus, Terkild B; de Rooij, Bob; Zeng, Ziao; Ahmad, Sana; Willerslev-Olsen, Andreas; Röhrig, Christian; Kamstrup, Maria R; Bay, Lene; Lindahl, Lise; Krejsgaard, Thorbjørn; Geisler, Carsten; Bonefeld, Charlotte M; Iversen, Lars; Woetmann, Anders; Koralov, Sergei B; Bjarnsholt, Thomas; Frieling, Johan; Schmelcher, Mathias; Ødum, Niels
Staphylococcus aureus (S. aureus) is suspected to fuel disease activity in cutaneous T cell lymphomas (CTCL). Here we investigate the effect of a recombinant, anti-bacterial protein, endolysin, XZ.700, on S. aureus skin colonization and malignant T cell activation. We show that endolysin strongly inhibits proliferation of S. aureus isolated from CTCL skin and significantly decreases S. aureus bacterial cell counts in a dose-dependent manner. Likewise, ex vivo colonization of both healthy and lesional skin by S. aureus is profoundly inhibited by endolysin. Moreover, endolysin inhibits the patient-derived S. aureus induction of Interferon-gamma (IFNγ) and IFNγ-inducible chemokine CXCL10 in healthy skin. Whereas patient-derived S. aureus stimulates activation and proliferation of malignant T cells in vitro through an indirect mechanism involving non-malignant T cells, endolysin strongly inhibits the effects of S. aureus on activation (reduced CD25 and STAT5 phosphorylation) and proliferation (reduced Ki67) of malignant T cells and cell lines in the presence of non-malignant T cells. Taken together, we provide evidence that endolysin XZ.700 inhibits skin colonization, chemokine expression, and proliferation of pathogenic S. aureus, and blocks their potential tumor-promoting effects on malignant T cells.
PMID: 36889662
ISSN: 1523-1747
CID: 5432822

Structured versus non-structured reporting of pelvic MRI for ileal pouch evaluation: clarity and effectiveness

Ginocchio, Luke A; Dane, Bari; Smereka, Paul N; Megibow, Alec J; Remzi, Feza H; Esen, Eren; Huang, Chenchan
PURPOSE/OBJECTIVE:Given that ileal pouch-anal anastomosis (IPAA) surgery is a technically challenging and high-morbidity procedure, there are numerous pertinent imaging findings that need to be clearly and efficiently communicated to the IBD surgeons for essential patient management and surgical planning. Structured reporting has been increasingly used over the past decade throughout various radiology subspecialties to improve reporting clarity and completeness. We compare structured versus non-structured reporting of pelvic MRI for ileal pouch to evaluate for clarity and effectiveness. METHODS:164 consecutive pelvic MRI's for ileal pouch evaluation, excluding subsequent exams for the same patient, acquired between 1/1/2019 and 7/31/2021 at one institution were included, before and after implementation (11/15/2020) of a structured reporting template, which was created with institutional IBD surgeons. Reports were assessed for the presence of 18 key features required for complete ileal pouch assessment: anastomosis (IPAA, tip of J, pouch body), cuff (length, cuffitis), pouch body (size, pouchitis, stricture), pouch inlet/pre-pouch ileum (stricture, inflammation, sharp angulation), pouch outlet (stricture), peripouch mesentery (position, mesentery twist), pelvic abscess, peri-anal fistula, pelvic lymph nodes, and skeletal abnormalities. Subgroup analysis was performed based on reader experience and divided into three categories: experienced (n = 2), other intra-institutional (n = 20), or affiliate site (n = 6). RESULTS:57 (35%) structured and 107 (65%) non-structured pelvic MRI reports were reviewed. Structured reports contained 16.6 [SD:4.0] key features whereas non-structured reports contained 6.3 [SD:2.5] key features (p < .001). The largest improvement following template implementation was for reporting sharp angulation of the pouch inlet (91.2% vs. 0.9%, p < .001), tip of J suture line and pouch body anastomosis (both improved to 91.2% from 3.7%). Structured versus non-structured reports contained mean 17.7 versus 9.1 key features for experienced readers, 17.0 versus 5.9 for other intra-institutional readers, and 8.7 versus 5.3 for affiliate site readers. CONCLUSION/CONCLUSIONS:Structured reporting of pelvic MRI guides a systematic search pattern and comprehensive evaluation of ileal pouches, and therefore facilitates surgical planning and clinical management. This standardized reporting template can serve as baseline at other institutions for adaptation based on specific radiology and surgery preferences, fostering a collaborative environment between radiology and surgery, and ultimately improving patient care.
PMID: 36871233
ISSN: 2366-0058
CID: 5428752

Preoperative Risk Factors for Adverse Events in Adults Undergoing Bowel Resection for Inflammatory Bowel Disease: 15-Year Assessment of ACS-NSQIP

Fernandez, Cristina; Gajic, Zoran; Esen, Eren; Remzi, Feza; Hudesman, David; Adhikari, Samrachana; McAdams-DeMarco, Mara; Segev, Dorry L; Chodosh, Joshua; Dodson, John; Shaukat, Aasma; Faye, Adam S
IntroductionOlder adults with IBD are at higher risk for postoperative complications as compared to their younger counterparts, however factors contributing to this are unknown. We assessed risk factors associated with adverse IBD-related surgical outcomes, evaluated trends in emergency surgery, and explored differential risks by age.MethodsUsing the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, we identified adults ≥18 years of age who underwent an IBD-related intestinal resection from 2005-2019. Our primary outcome included a 30-day composite of mortality, readmission, reoperation, and/or major postoperative complication.ResultsOverall, 49,746 intestinal resections were performed with 9,390 (18.8%) occurring among older adults with IBD. Nearly 37% of older adults experienced an adverse outcome as compared to 28.1% among younger adults with IBD (p<0.01). Among all adults with IBD, the presence of preoperative sepsis (aOR, 2.08; 95%CI 1.94-2.24), malnutrition (aOR, 1.22; 95%CI 1.14-1.31), dependent functional status (aOR, 6.92; 95%CI 4.36-11.57), and requiring emergency surgery (aOR, 1.50; 95%CI 1.38-1.64) increased the odds of an adverse postoperative outcome, with similar results observed when stratifying by age. Further, 8.8% of surgeries among older adults were emergent, with no change observed over time (p=0.16).DiscussionPreoperative factors contributing to the risk of an adverse surgical outcome are similar between younger and older individuals with IBD, and include elements such as malnutrition and functional status. Incorporating these measures into surgical decision-making can reduce surgical delays in older individuals at low-risk and help target interventions in those at high risk, transforming care for thousands of older adults with IBD.
PMID: 37410929
ISSN: 1572-0241
CID: 5539322

A Review of Available Medical Therapies to Treat Moderate to Severe Inflammatory Bowel Disease in 2023

Chang, Shannon; Murphy, Megan; Malter, Lisa
The treatment armamentarium for inflammatory bowel disease (IBD) has expanded rapidly in the past several years with new biologic and small molecule agents approved for moderate to severe ulcerative colitis and Crohn's disease. This has made treatment selection more challenging with limited but evolving guidance as to where to position each medication. In this review, we discuss the efficacy data for each agent approved in the United States by reviewing their phase III trial data and other comparative effectiveness studies. Additionally, safety considerations and use in special populations is summarized with proposed algorithms for positioning therapies. The aim is to provide a synopsis of high impact data and aid in outpatient treatment decision making for IBD patients.
PMID: 37615291
ISSN: 1572-0241
CID: 5564362

Messaging Clearly and Effectively About Hearing Loss and Increased Dementia Risk

Blustein, Jan; Weinstein, Barbara E; Chodosh, Joshua
PMID: 37615946
ISSN: 2168-619x
CID: 5564382