Sun A. Kim

Human noroviruses are a major cause of diarrheal disease, yet their pathogenesis remains poorly defined. We performed single-cell RNA sequencing of duodenal biopsies and matched stem cell–derived enteroids from immunodeficient individuals with chronic norovirus infection. Norovirus RNA was detected primarily in enterocytes, enteroendocrine cells, and macrophages, with the highest proportion of viral RNA-positive cells observed among M2 macrophages, followed by late enterocytes. Despite this distribution, late enterocytes produced higher viral yields than differentiated M2 macrophages in vitro. Norovirus infection was associated with the up-regulation of MHC class I-related genes and IL15 in duodenal macrophages and late enterocytes, together with increased IFNG expression by CD8 T cells. Macrophages and late enterocytes up-regulated CXCL9 and CXCL10/11 , respectively, consistent with CD8 and CD4 T cell recruitment to the duodenum. These findings show that noroviruses infect and persist across multiple permissive cell types during chronic infection, resulting in marked dysregulation of innate and adaptive immune responses that may drive pathogenesis.

Invasive fungal infections (IFI) are a significant cause of morbidity and mortality in hematologic malignancy patients and hematopoietic cell transplant (HCT) recipients. Mold cholecystitis has rarely been described. We present a case of disseminated Lomentospora prolificans , that had recrudescence of symptoms with acute cholecystitis. Treatment included a temporary cholecystostomy and administration of the novel antifungal fosmanogepix. At 6 weeks post-HCT, the patient underwent cholecystectomy and completed a course of fosmanogepix, leading to resolution of her infection. Here we review the published literature on non- Candida fungal cholecystitis, underlying risk factors and treatment.

Marker genes used for annotating major cell types in single cell RNA sequencing analysis.

Antibody panel used in co-detection by indexing (CODEX) multiplexed immunofluorescence tissue imaging.

Patient demographics, genetic, and histopathology characteristics.

Additional SRC-enriched markers from single cell RNA sequencing analysis.

Leading edge analysis following GSEA demonstrating enriched pathways associated with ECM remodeling between SRC and EP.

Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multiomic analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of extracellular matrix remodeling in SRC lesions compared with unaffected adjacent gastric epithelium. Single-cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, and KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin reexpression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared with SRC lesions. Implications: The marked differences in the genomic and transcriptomic profiles of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.

Despite extensive investigation into the molecular basis of tumor development, colorectal cancer (CRC) remains a major contributor to cancer-related mortality. LIN28A and LIN28B are highly related RNA-binding proteins that influence development, tissue regeneration and oncogenesis. Here we demonstrate that overexpression of LIN28 drives invasive intestinal adenocarcinoma and cooperates with the Wnt pathway to promote tumor initiation and progression in murine models. Importantly, conditional withdrawal of LIN28 reduced tumor volume and increased tumor differentiation, indicating that LIN28 contributes to tumor maintenance. Furthermore, co-expression of a LIN28-resistant form of the let-7 microRNA reduced tumor burden. We detected aberrant expression of LIN28 in 38% of a large series of tumor samples from human CRC, and LIN28 expression levels were associated with invasive tumor growth pattern. Our robust late-stage CRC murine model demonstrates strong roles for LIN28 in promoting CRC initiation, growth and progression, and suggests the therapeutic potential in targeting the LIN28/let-7 pathway. Citation Format: Ho-Chou Tu, Sarah Schwitalla, Zhirong Qian, Grace LaPier, Alena Yermalovich, Yuan-Chieh Ku, Shann-Ching Chen, Srinivas R. Viswanathan, Hao Zhu, Reiko Nishihara, Kentaro Inamura, Sun A. Kim, Reppi Morikawa, Kosuke Mima, Yasutaka sukawa, Juhong Yang, Gavin Meredith, Charles S. Fuchs, Shuji Ogino, George Q. Daley. LIN28 cooperates with Wnt signaling to drive invasive intestinal and colorectal adenocarcinoma in mouse and human. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2300. doi:10.1158/1538-7445.AM2015-2300

Background: Chronic inflammation is involved in the development of colorectal cancer (CRC) and microsatellite instability (MSI), a distinct phenotype of CRC. Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine ω-3 polyunsaturated fatty acids (PUFAs). However, epidemiologic data remain inconclusive. Methods: We investigated whether the association between marine ω-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses’ Health Study and Health Professionals Follow-up Study. We collected updated data on marine ω-3 PUFA intake and documented 1,125 CRC cases during 24-26 years of follow-up. We determined the MSI status of tumors using 10 microsatellite markers, and classified cases into MSI-high tumors in which ≥30% of the microsatellite markers demonstrated instability, and microsatellite stable (MSS) tumors in which Citation Format: Mingyang Song, Reiko Nishihara, Kana Wu, Zhi Rong Qian, Sun A. Kim, Yasutaka Sukawa, Kosuke Mima, Kentaro Inamura, Atsuhiro Masuda, Juhong Yang, Charles S. Fuchs, Edward L. Giovannucci, Shuji Ogino, Andrew T. Chan. Prospective study of marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1879. doi:10.1158/1538-7445.AM2015-1879