Three pathologic criteria for reproducible diagnosis of colonic sessile serrated lesion versus hyperplastic polyp.

Colonic SSLs are thought to predispose to ∼30% of colonic adenocarcinomas. This increased risk, compared to benign HPs, makes their distinction vitally important. However, no gold standard exists to differentiate them, and wide observer variability is reported. To better distinguish these polyps, we investigated 94 serrated polyps (53 SSLs and 41 HPs) using an easy-to-apply pathologic scoring system that combines, for the first time, three established distinguishing features: polyp morphology, location, and size. As an additional novel approach, polyp size was assessed by serrated biopsy number compared to endoscopic size. RNA expression profiling served as an additional biomarker. The considerable morphologic overlap across serrated polyps was quantitated for the first time. Interobserver variability was assessed by 8 expert gastrointestinal pathologists. By ROC analysis, polyp size by biopsy number performed best, followed by polyp location and morphology (areas under the curves [AUCs] = 85.9%, 81.2%, and 65.9%, respectively). Optimal discrimination combined all 3 features (AUC = 92.9%). For polyp size, the biopsy number proved superior to endoscopic size (AUC = 85.9% versus 55.2%, P = .001). Interobserver variability analysis yielded the highest reported Fleiss and Kappa statistics (0.879) and percent agreement (96.8%), showing great promise toward improved diagnosis. The proposed 3-criteria pathologic system, combining size by biopsy number, location, and morphology, yields an improved, easy-to-use, and highly reproducible diagnostic approach for differentiating SSLs and HPs.

Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy.

BACKGROUND: Identification of target antigens PLA2R, THSD7A, NELL1, or Semaphorin-3B can explain the majority of cases of primary membranous nephropathy (MN). However, target antigens remain unidentified in 15%-20% of patients. METHODS: A multipronged approach, using traditional and modern technologies, converged on a novel target antigen, and capitalized on the temporal variation in autoantibody titer for biomarker discovery. Immunoblotting of human glomerular proteins followed by differential immunoprecipitation and mass spectrometric analysis was complemented by laser-capture microdissection followed by mass spectrometry, elution of immune complexes from renal biopsy specimen tissue, and autoimmune profiling on a protein fragment microarray. RESULTS: These approaches identified serine protease HTRA1 as a novel podocyte antigen in a subset of patients with primary MN. Sera from two patients reacted by immunoblotting with a 51-kD protein within glomerular extract and with recombinant human HTRA1, under reducing and nonreducing conditions. Longitudinal serum samples from these patients seemed to correlate with clinical disease activity. As in PLA2R- and THSD7A- associated MN, anti-HTRA1 antibodies were predominantly IgG4, suggesting a primary etiology. Analysis of sera collected during active disease versus remission on protein fragment microarrays detected significantly higher titers of anti-HTRA1 antibody in active disease. HTRA1 was specifically detected within immune deposits of HTRA1-associated MN in 14 patients identified among three cohorts. Screening of 118 "quadruple-negative" (PLA2R-, THSD7A-, NELL1-, EXT2-negative) patients in a large repository of MN biopsy specimens revealed a prevalence of 4.2%. CONCLUSIONS: Conventional and more modern techniques converged to identify serine protease HTRA1 as a target antigen in MN.

Association of anti-HER2 antibody with graphene oxide for curative treatment of osteosarcoma.

The finding of HER2 overexpression in osteosarcoma (OS) makes HER2 a potential therapeutic target. However, studies indicate OS cells are nonresponsive to anti-HER2 antibody trastuzumab (TRA) therapy. We established stable, non-covalent association of TRA with nanomaterial graphene oxide (GO) to generated multivalent TRA/GO complexes that demonstrated markedly enhanced HER2-binding activity and capacity to rapidly kill OS cells. TRA/GO simultaneously induced oxidative stress and HER2 signaling in the target cells, leading to rapid depletion of the cellular inhibitors of apoptosis protein (cIAP) and caspase-8, formation of RIP1/RIPK3/MLKL necroptosome and necroptosis of the OS cells. Intravenous administration of TRA/GO eradicated established xenograft the OS in immunodeficient mice, resulting in indefinite survival of the animals, whereas TRA in its original form failed to do so. No appreciable side effects were observed with TRA/GO therapy. The results demonstrate a novel, nontoxic, curative therapy for a HER2pos cancer in a preclinical animal model.

Cellular and ultrastructural characterization of the grey-morph phenotype in southern right whales (Eubalaena australis).

Southern right whales (SRWs, Eubalena australis) are polymorphic for an X-linked pigmentation pattern known as grey morphism. Most SRWs have completely black skin with white patches on their bellies and occasionally on their backs; these patches remain white as the whale ages. Grey morphs (previously referred to as partial albinos) appear mostly white at birth, with a splattering of rounded black marks; but as the whales age, the white skin gradually changes to a brownish grey color. The cellular and developmental bases of grey morphism are not understood. Here we describe cellular and ultrastructural features of grey-morph skin in relation to that of normal, wild-type skin. Melanocytes were identified histologically and counted, and melanosomes were measured using transmission electron microscopy. Grey-morph skin had fewer melanocytes when compared to wild-type skin, suggesting reduced melanocyte survival, migration, or proliferation in these whales. Grey-morph melanocytes had smaller melanosomes relative to wild-type skin, normal transport of melanosomes to surrounding keratinocytes, and normal localization of melanin granules above the keratinocyte nuclei. These findings indicate that SRW grey-morph pigmentation patterns are caused by reduced numbers of melanocytes in the skin, as well as by reduced amounts of melanin production and/or reduced sizes of mature melanosomes. Grey morphism is distinct from piebaldism and albinism found in other species, which are genetic pigmentation conditions resulting from the local absence of melanocytes, or the inability to synthesize melanin, respectively.