Grant Eilers

Background: Tumor invasion and malignant transformation are spatiotemporally coordinated processes that shape clinical behavior, diagnostic classification, and treatment response. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors that can arise sporadically or in people with neurofibromatosis type 1 (NF-1), yet how distinct spatial niches underlie MPNST intratumor heterogeneity, local invasion, or malignant transformation from benign precursors is not fully understood. Methods: We integrate spatial analysis of 50,896 transcriptomes from 15 human MPNSTs with deep learning image analysis to define the interplay between genetic alterations, the immune microenvironment, and epigenetic cell fate regulation in MPNST invasion and transformation. Results: Spatial transcriptomics reveal distinct infiltrating immune cells and immunomodulatory spatial clusters in sporadic compared to NF-1–associated MPNSTs. Local invasion is marked by spatially defined immunomodulatory and dedifferentiation programs. Analysis of 2 NF-1–associated MPNSTs with contiguous morphologically defined neurofibroma and MPNST components demonstrates that NF-1–associated tumors exhibit a similar malignant transformation process associated with dynamic immune infiltration, chromosome 9p loss, and dedifferentiation concomitant with increased cell proliferation. Finally, deep learning morphology encoders were trained on spatial transcriptomic data to predict spatial transcriptomic cluster identity and chromosome 9p loss from hematoxylin and eosin–stained images although the generalizability of such encoders remains a challenge. Conclusions: Our data provide a spatial framework for peripheral nerve sheath tumor transformation although the limited sample size of the present cohort will require additional validation of the proposed model.

Pathologic studies of Myhre syndrome (OMIM 139201) have provided modest insights into this ultra‐rare multisystem disorder, with postmortem examinations being scarce. Morbidity is related to severe congenital heart defects, aortic hypoplasia, airway stenosis, constrictive pericarditis, and restrictive cardiomyopathy. We report two detailed autopsies: the first of an 8‐year‐old female who succumbed to congenital mitral valve disease and restrictive cardiopulmonary complications. Autopsy documented chronic pericarditis and fibrosing pleuritis, diffuse interstitial pulmonary fibrosis, extensive submucosal interstitial fibrosis of the bladder, and nodular medial hypertrophy of the aorta. The second patient was a 20‐year‐old female with progressive laryngo‐tracheal stenosis, interstitial lung disease, pericardial and peritoneal adhesions, and dermal fibrosis. Both patients had ovarian fibrosis with reduced oocytes. Neuropathologic examination revealed brains below expected weight with hypoxic–ischemic injury. The first patient also had scattered intraparenchymal microcalcifications and a known Chiari I malformation, and the second had a thickened calvarium and dura mater and rounded cerebrum (shortened frontal and occipital lobes). These two patients demonstrate the value of postmortem examination to confirm suspected pathology and elucidate new features. The pleiotropy of Myhre syndrome was demonstrated by complex comorbidities and the devastating impact of indiscriminate fibrosis. Counseling regarding the role of postmortem examination should be considered in the palliative care of Myhre syndrome patients and their families.

Paget disease is an intraepithelial neoplastic proliferation, commonly occurring in the breast and apocrine‐rich areas, often associated with an underlying internal malignancy. Extramammary Paget disease (EMPD) of the oral cavity is exceedingly rare, with only eight reported cases, four of which were associated with an underlying internal malignancy. Here, we report a case of oral EMPD involving the buccal mucosa and gingiva of an 81‐year‐old male with no known underlying internal malignancy. The Paget cells were positive for CK7, CK20, CAM5.2, and androgen receptor, but negative for SOX10 and p63. The immunophenotype, association with internal malignancies, and treatment approaches for oral EMPD are reviewed.

Background: Antiretroviral therapy (ART) can mitigate the morbidity and mortality caused by the human immunodeficiency virus (HIV). Successful development of ART can be accelerated by accurate structural and biochemical data on targets and their responses to inhibitors. One important ART target, HIV integrase (IN), has historically been studied in vitro in a modified form adapted to bacterial overexpression, with a methionine or a longer fusion protein sequence at the N-terminus. In contrast, IN present in viral particles is produced by proteolytic cleavage of the Pol polyprotein, which leaves a phenylalanine at the N-terminus (IN 1F). Inspection of available structures suggested that added residues on the N-terminus might disrupt proper protein folding and formation of multimeric complexes. Results: We purified HIV-1 IN 1F^1–212 and solved its structure at 2.4 Å resolution, which showed extension of an N-terminal helix compared to the published structure of IN^1–212. Full-length IN 1F showed increased in vitro catalytic activity in assays of coupled joining of the two viral DNA ends compared to two IN variants containing additional N-terminal residues. IN 1F was also altered in its sensitivity to inhibitors, showing decreased sensitivity to the strand-transfer inhibitor raltegravir and increased sensitivity to allosteric integrase inhibitors. In solution, IN 1F exists as monomers and dimers, in contrast to other IN preparations which exist as higher-order oligomers. Conclusions: The structural, biochemical, and biophysical characterization of IN 1F reveals the conformation of the native HIV-1 IN N-terminus and accompanying unique biochemical and biophysical properties. IN 1F thus represents an improved reagent for use in integration reactions in vitro and the development of antiretroviral agents.