A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics.

Crohn's disease (CD) is a complex and heterogeneous condition with no perfect preclinical model or cure. To address this, we explore adult stem cell-derived organoids that retain their tissue identity and disease-driving traits. We prospectively create a biobank of CD patient-derived organoid cultures (PDOs) from colonic biopsies of 53 subjects across all clinical subtypes and healthy subjects.

A Living Organoid Biobank of Crohn's Disease Patients Reveals Molecular Subtypes for Personalized Therapeutics.

Unlabelled: Crohn's disease (CD) is a complex, clinically heterogeneous disease of multifactorial origin; there is no perfect pre-clinical model, little insight into the basis for such heterogeneity, and still no cure. To address these unmet needs, we sought to explore the translational potential of adult stem cell-derived organoids that not only retain their tissue identity, but also their genetic and epigenetic disease-driving traits. We prospectively created a biobank of CD patient-derived organoid cultures (PDOs) using biopsied tissues from colons of 34 consecutive subjects representing all clinical subtypes (Montreal Classification B1-B3 and perianal disease).

SPT6 loss permits the transdifferentiation of keratinocytes into an intestinal fate that resembles Barrett's metaplasia.

Transient depletion of the transcription elongation factor SPT6 in the keratinocyte has been recently shown to inhibit epidermal differentiation and stratification; instead, they transdifferentiate into a gut-like lineage. We show here that this phenomenon of transdifferentiation recapitulates Barrett's metaplasia, the only human pathophysiologic condition in which a stratified squamous epithelium that is injured due to chronic acid reflux is trans-committed into an intestinal fate. The evidence we present here not only lend support to the notion that the keratinocytes are potentially the cell of origin of Barrett's metaplasia but also provide mechanistic insights linking transient acid exposure, downregulation of SPT6, stalled transcription of the master regulator of epidermal fate TP63, loss of epidermal fate, and metaplastic progression.

Artificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease.

Modeling human diseases as networks simplify complex multi-cellular processes, helps understand patterns in noisy data that humans cannot find, and thereby improves precision in prediction. Using Inflammatory Bowel Disease (IBD) as an example, here we outline an unbiased AI-assisted approach for target identification and validation. A network was built in which clusters of genes are connected by directed edges that highlight asymmetric Boolean relationships.

AI-guided discovery of the invariant host response to viral pandemics.

Background: Coronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions.

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells.

SPT6 promotes epidermal differentiation and blockade of an intestinal-like phenotype through control of transcriptional elongation.

In adult tissue, stem and progenitor cells must tightly regulate the balance between proliferation and differentiation to sustain homeostasis. How this exquisite balance is achieved is an area of active investigation. Here, we show that epidermal genes, including ~30% of induced differentiation genes already contain stalled Pol II at the promoters in epidermal stem and progenitor cells which is then released into productive transcription elongation upon differentiation.

Adult Stem Cell-derived Complete Lung Organoid Models Emulate Lung Disease in COVID-19.

SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type-II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19.

AI-guided discovery of the invariant host response to viral pandemics.

Unlabelled: We sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach.

Maternal veterinary occupation and adverse birth outcomes in Washington State, 1992-2014: a population-based retrospective cohort study.

Objective: Women in veterinary occupations are routinely exposed to potential reproductive hazards, yet research into their birth outcomes is limited. We conducted a population-based retrospective cohort study of the association between maternal veterinary occupation and adverse birth outcomes.

Methods: Using Washington State birth certificate, fetal death certificate and hospital discharge data from 1992 to 2014, we compared birth outcomes of mothers in veterinary professions (n=2662) with those in mothers in dental professions (n=10 653) and other employed mothers (n=8082).

Breast cancer screening: an evidence-based update.

Routine screening mammography is recommended by most groups issuing breast cancer screening guidelines, especially for women 50 years of age and older. However, both the potential benefits and risks of screening should be discussed with individual patients to allow for shared decision making regarding their participation in screening, age of commencement and conclusion, and interval of mammography screening.