Leptin signaling is required for bleomycin-induced lung fibrosis. Leptin augments TGF-β(1) signaling in lung fibroblasts by inhibiting PPARγ. These findings provide a mechanism for the observed protection against ARDS observed in diabetic patients.

Background Achalasia has three distinct manometric phenotypes. This study aimed to determine if there were corresponding histopathologic patterns. Methods We retrospectively examined surgical muscularis propria biopsies obtained from 46 patients during laparoscopic esophagomyotomy. Pre-operative (conventional) manometry tracings were reviewed by 2 expert gastroenterologists who categorized patients into Chicago Classification subtypes. Pathology specimens were graded on degree of neuronal loss, inflammation, fibrosis, and muscle changes. Key Results Manometry studies were categorized as follows: type I (n=20), type II (n=20), type III (n=3), and esophagogastric junction outflow obstruction (EGJOO) (n=3). On histopathology, complete ganglion cell loss occurred in 74% of specimens, inflammation in 17%, fibrosis in 11%, and muscle atrophy in 2%. Comparing type I and type II specimens, there was a statistically significant greater proportion of type I specimens with aganglionosis (19/20 vs. 13/20, p=0.044) and a statistically significant greater degree of ganglion cell loss in type I specimens (Wilcoxon Rank-Sum, p=0.016). CD3+/CD8+ cytotoxic T cells represented the predominant inflammatory infiltrate on immunohistochemistry. Three patients had completely normal appearing tissue (1 each in type II, type III, EGJOO). Conclusions and Inferences The greater degree, but similar pattern, of ganglion cell loss observed in type I compared to type II achalasia specimens suggests that type I achalasia represents a progression from type II achalasia. The spectrum of histopathologic findings – from complete neuronal loss to lymphocytic inflammation to apparently normal histopathology – emphasizes that ‘achalasia’ represents a pathogenically heterogeneous patient group with the commonality being EGJ outflow obstruction.

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Context.—Individuals who are immune deficient are at an increased risk for developing lymphoproliferative lesions and lymphomas. Human immunodeficiency virus (HIV) infection is 1 of 4 clinical settings associated with immunodeficiency recognized by the World Health Organization (WHO) in which there is an increased incidence of lymphoma and other lymphoproliferative disorders. Objectives.—To describe the major categories of benign lymphoid proliferations, including progressive HIV-related lymphadenopathy, benign lymphoepithelial cystic lesions, and multicentric Castleman disease, as well as the different types of HIV-related lymphomas as defined by the WHO. The characteristic morphologic, immunophenotypic, and genetic features of the different entities will be discussed in addition to some of the pathogenetic mechanisms. Data Sources.—The WHO classification of tumors of hematopoietic and lymphoid tissues (2001 and 2008), published literature from PubMed (National Library of Medicine), published textbooks, and primary material from the authors' current and previous institutions. Conclusions.—HIV infection represents one of the clinical settings recognized by the WHO in which immunodeficiency-related lymphoproliferative disorders may arise. Although most lymphomas that arise in patients with HIV infection are diffuse, aggressive B-cell lesions, other lesions, which are “benign” lymphoid proliferations, may also be associated with significant clinical consequences. These lymphoproliferations, like many other immunodeficiency-associated lymphoproliferative disorders, are often difficult to classify. Studies of HIV-associated lymphoid proliferations will continue to increase our understanding of both the immune system and lymphomagenesis.

The heterogeneity of colorectal cancer (CRC) contributes to substantial differences in patient response to standard therapies. The consensus molecular subtypes (CMS) of CRC is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signatures, such as RNF43-dependent modulation of the WNT pathway or the PLAU-PLAUR ligand-receptor interaction. Our data show the power of ST to bring the CMS-based classification of CRC to another level and thereby gain useful molecular insights for personalized therapy.