The Slit protein is a major midline repellent for central nervous system (CNS) axons. In vivo, Slit is proteolytically cleaved into N- and C-terminal fragments, but the biological significance of this is unknown. Analysis in the Drosophila ventral nerve cord of a slit allele (slit-UC) that cannot be cleaved revealed that midline repulsion is still present but longitudinal axon guidance is disrupted, particularly across segment boundaries. Double mutants for the Slit receptors Dscam1 and robo1 strongly resemble the slit-UC phenotype, suggesting they cooperate in longitudinal axon guidance, and through biochemical approaches, we found that Dscam1 and Robo1 form a complex dependent on Slit-N. In contrast, Robo1 binding alone shows a preference for full-length Slit, whereas Dscam1 only binds Slit-N. Using a variety of transgenes, we demonstrated that Dscam1 appears to modify the output of Robo/Slit complexes so that signaling is no longer repulsive. Our data suggest that the complex is promoting longitudinal axon growth across the segment boundary. The ability of Dscam1 to modify the output of other receptors in a ligand-dependent fashion may be a general principle for Dscam proteins.

Testosterone exerts profound effects on reproduction and energy homeostasis. Like other orexigenic hormones, it increases endocannabinoid tone within the hypothalamic feeding circuitry. Therefore, we tested the hypothesis that testosterone upregulates the expression of diacylglycerol lipase (DAGL)α in the hypothalamic arcuate nucleus (ARC) to increase energy intake via enhanced endocannabinoid-mediated retrograde inhibition of anorexigenic proopiomelanocortin (POMC) neurons. Energy intake, meal patterns, and energy expenditure were evaluated in orchidectomized, male guinea pigs treated subcutaneously with testosterone propionate (TP; 400 μg) or its sesame oil vehicle (0.1 mL). TP rapidly increased energy intake, meal size, O₂ consumption, CO₂ production, and metabolic heat production, all of which were antagonized by prior administration of the DAGL inhibitor orlistat (3 μg) into the third ventricle. These orlistat-sensitive, TP-induced increases in energy intake and expenditure were temporally associated with a significant elevation in ARC DAGLα expression. Electrophysiological recordings in hypothalamic slices revealed that TP potentiated depolarization-induced suppression of excitatory glutamatergic input onto identified ARC POMC neurons, which was also abolished by orlistat (3 μM), the CB₁ receptor antagonist AM251 (1 μM), and the AMP-activated protein kinase inhibitor compound C (30 μM) and simulated by transient bath application of the dihydrotestosterone mimetic Cl-4AS-1 (100 nM) and testosterone-conjugated bovine serum albumin (100 nM). Thus, testosterone boosts DAGLα expression to augment retrograde, presynaptic inhibition of glutamate release onto ARC POMC neurons that, in turn, increases energy intake and expenditure. These studies advance our understanding of how androgens work within the hypothalamic feeding circuitry to affect changes in energy balance.

Context.— The World Health Organization Classification of Tumors: Digestive System Tumors, 5th edition, was published in 2019 and shows several impactful changes as compared with the 4th edition published in 2010. Changes include a revised nomenclature of serrated lesions and revamping the classification of neuroendocrine neoplasms. Appendiceal goblet cell adenocarcinoma is heavily revised, and intrahepatic cholangiocarcinoma is split into 2 subtypes. New subtypes of colorectal carcinoma and hepatocellular carcinoma are described. Precursor lesions are emphasized with their own entries, and both dysplastic and invasive lesions are generally recommended to be graded using a 2-tier system. Hematolymphoid tumors, mesenchymal tumors, and genetic tumor syndromes each have their own sections in the 5th edition. New hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma; duodenal-type follicular lymphoma; intestinal T-cell lymphoma, not otherwise specified; and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. This paper will provide an in-depth look at the changes in the 5th edition as compared with the 4th edition. Objective.— To provide a comprehensive, in-depth update on the World Health Organization classification of digestive tumors, including changes to nomenclature, updated diagnostic criteria, and newly described entities. Data Sources.— The 5th edition of the World Health Organization Classification of Tumours: Digestive System Tumours, as well as the 4th edition. Conclusions.— The World Health Organization has made many key changes in its newest update on tumors of the digestive system. Pathologists should be aware of these changes and incorporate them into their practice as able or necessary.

Prostate cancer is the most common visceral malignancy diagnosed in males. Surveillance for post-treatment neoplasms is very crucial. Here we report the first case of recurrent metastatic prostate cancer presenting as acute appendicitis in a background of a high-grade appendiceal mucinous neoplasm. In addition, this case also includes an unusually early presentation of a secondary primary malignancy after radiation therapy. A 70-year-old male with a history of prostate adenocarcinoma status post-proton radiation therapy presented with recurrent poorly differentiated prostate adenocarcinoma with disease progression and extra-prostatic extension. He underwent salvage proton therapy and testosterone replacement therapy. Two years later, the patient presented with right lower quadrant pain. A computed tomography scan showed perforated acute appendicitis with intra-abdominal abscess, which was treated with interval appendectomy. Upon histologic analysis, metastatic prostatic adenocarcinoma was noted in the appendiceal wall and mesoappendix. In addition, an incidental background of high-grade appendiceal mucinous neoplasm was found. Four months later, he presented with persistent abdominal pain, rapid weight loss, fatigue, and fever for 3 months. An abdominal CT scan revealed a 6.1 cm rectal mass. Pathologic analysis diagnosed an aggressive post-radiation spindle cell sarcoma, intermediate to high grade. The patient opted for palliative care. This case shows that a clinical presentation of acute appendicitis in an older patient may sometimes portend a neoplastic rather than infectious etiology. Clinical history and patient epidemiology should always be considered when evaluating an older patient with clinical signs and symptoms of acute appendicitis.

Sarcina species are anaerobic gram-positive cocci rarely seen in the upper gastrointestinal tract and associated with delayed gastric emptying. We present 3 cases of Sarcina infection with varying clinical presentations including the first reported case of Sarcina in a patient with eosinophilic esophagitis. Although the pathogenesis of Sarcina is unclear, awareness of the bacteria is important as they can usually only be detected on histopathologic examination of upper gastrointestinal biopsies. Treatment in symptomatic patients may prevent severe complications such as emphysematous gastritis and gastric perforation.