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By performing stepwise treatment with growth factors and WNT pathway modulators, Crespo et al. (p 878) design a protocol to generate colonic organoids from human induced pluripotent stem cells (iPSCs). They apply this approach to derive organoids from iPSCs from patients with familial adenomatous polyposis (FAP). A drug screen using these organoids indicates that the antibiotic geneticin suppresses abnormal WNT signaling in organoids derived from FAP cells bearing ATM mutations. The cover image depicts a confocal projection of FAP-iPSC-derived colonic organoids, with colon marker CDX2 and proliferation marker CD1 false-colored in green and red, respectively. DAPI, blue. Image credit, Miguel Crespo. Artwork, Erin Dewalt.
Cancer research has made great strides in identifying effective therapies for treating advanced-stage tumors. The next challenge is moving the battle to earlier stages of disease.
Deaths from drug overdose are rising worldwide, in part owing to the growing epidemic of opioid addiction. Efforts to combat opioid addiction will benefit from stronger collaboration between preclinical researchers who are studying addiction and those studying chronic pain.
Enhanced conversion of dietary cholesterol to bile acids through the alternative pathway leads to cold-associated, metabolically beneficial changes in the intestinal microbiome and to elevated bile acid levels that contribute to adaptive thermogenesis.
A mouse model with combined renal epithelium-specific deletion of Vhl, Trp53 and Rb1 that develops clear-cell renal cell carcinoma provides a research tool for investigating the mechanisms that drive this cancer, and for evaluating the efficacy of novel therapeutic agents.
In this Perspective, Michael Czech presents evidence for whether hyperinsulinemia occurs before insulin resistance upon overfeeding or high-fat diet feeding, or whether insulin resistance causes hyperinsulinemia, thus attempting to delineate the relationship between hyperinsulinemia, obesity and insulin resistance.
Bispecific antibodies that connect T cells with tumor cells can be delivered in the form of in vitro–transcribed pharmacologically optimized mRNA; when injected into mice, these mRNA-encoded antibodies reject large established tumors as efficiently as the corresponding recombinant antibody protein.
In a mouse model of spinal cord injury, reactive astrogliosis is found to be context dependent and reversible. Blockade of type I collagen–reactive astrocyte interactions prevents astrocyte scar formation and facilitates functional recovery after injury.
Current mouse models of nonalcoholic steatohepatitis are limited, making identification and preclinical testing of new treatments challenging. Housing mice at thermoneutrality leads to less stress, a stronger immune response and better modeling of this condition.
During cold stimulation, cholesterol is converted to bile acids in an alternative pathway. The bile acids then alter the microbiota, which in turn promotes more heat generation.
Composition of gut bacteria and serum metabolites in young, obese individuals is partially restored following weight loss surgery, including Bacteroides thetaiotaomicron, which decreases serum glutamate levels and fat mass gain in mice.
Through combined deletion of Vhl, Trp53 and Rb1 in renal epithelial cells, the authors develop a new mouse model of renal cell carcinoma that recapitulates the cellular and molecular features of a large proportion of human tumors. This model uncovers a role for primary-cilium-related genes in the development of the disease and provides a reliable platform for preclinical therapeutic studies.
A protocol based on chemical modulation of WNT activity is used to efficiently generate colonic organoids that recapitulate the molecular features of human colon tissue. Colonic organoids generated from induced pluripotent stem cells from patients with familial adenomatous polyposis provide an in vitro platform for disease modeling and preclinical drug testing.
By surgically directing the vascular delivery of decellularization reagents, the in situ decellularization of desired organs or tissues in mice can be achieved, enabling detailed imaging and characterization of the intact extracellular matrix, including in the cancer metastatic niche.