Histopathologic and immunohistochemical distinction of condyloma and seborrheic keratosis in the genitofemoral area

BackgroundMaking a clinical and histological distinction between condyloma and seborrheic keratosis in the genitofemoral area can be difficult. This study aimed to find reliable histological and immunohistological criteria to diagnose these entities.MethodsWe retrospectively studied genitofemoral skin biopsy specimens obtained between January 2004 and December 2007 that had been diagnosed as showing condyloma or seborrheic keratosis. The histological findings were assessed and immunohistochemical stains were performed for human papillomavirus, Ki-67, and p21. DNA was extracted from paraffin sections and amplified by polymerase chain reaction to detect the presence and type of human papillomavirus.ResultsDNA extraction was successfully performed for 58 lesions. The final diagnoses were condyloma in 41 and seborrheic keratosis in 17. The diagnosis of condyloma rather than seborrheic keratosis was likely in the presence of broad, evenly distributed reticulated acanthosis (p < 0.0001), koilocytosis (p < 0.001), a fascicular arrangement of keratinocytes (p < 0.01), and an absence of horn cysts (p < 0.01). Immunohistochemical staining supported the diagnosis of condyloma when positive for human papillomavirus (p < 0.0001), Ki-67 (p < 0.0001), and p21 (p < 0.0001).ConclusionA combination of histological and immunohistochemical findings is useful to distinguish condyloma from seborrheic keratosis in the genitofemoral area.     

Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: results of the ADVANCE phase 3 multicenter international trial.

BACKGROUND: Earlier phase 1 and 2 studies have shown that regadenoson has desirable features as a stress agent for myocardial perfusion imaging. METHODS AND RESULTS: This multicenter, double-blinded phase 3 trial involved 784 patients at 54 sites. Each patient underwent 2 sets of gated single photon emission computed tomography myocardial perfusion imaging studies: an initial qualifying study with adenosine and a subsequent randomized study with either regadenoson (2/3 of patients) or adenosine. Regadenoson was administered as a rapid bolus (<10 seconds) of 400 mug. The primary endpoint was to demonstrate noninferiority by showing that the difference in the strength of agreement in detecting reversible defects, based on blinded reading, between sequential adenosine-regadenoson images and adenosine-adenosine images, lay above a prespecified noninferiority margin. Other prospectively defined safety and tolerability comparisons and supporting analyses were also performed. The average agreement rate based on the median of 3 independent blinded readers was 0.63 +/- 0.03 for regadenoson-adenosine and 0.64 +/- 0.04 for adenosine-adenosine-a 1% absolute difference with the lower limit of the 95% confidence interval lying above the prespecified noninferiority margin. Side-by-side interpretation of regadenoson and adenosine images provided comparable results for detecting reversible defects. The peak increase in heart rate was greater with regadenoson than adenosine, but the blood pressure nadir was similar. A summed symptom score of flushing, chest pain, and dyspnea was less with regadenoson than adenosine (P = .013). CONCLUSIONS: This phase 3 trial shows that regadenoson provides diagnostic information comparable to a standard adenosine infusion. There were no serious drug-related side effects, and regadenoson was better tolerated than adenosine.     

Parenteral nutrition with fish oil-based lipid emulsion reduces the risk of cholestasis in preterm infants

ObjectivePreterm infants receive long-term parenteral nutrition (PN) for gastrointestinal immaturity. This study aimed to determine if mixed lipid emulsions containing fish oil decrease the incidence of PN-associated cholestasis by reducing oxidative stress and providing an anti-inflammatory effect.MethodsThis retrospective cohort study enrolled 399 very low birth weight premature infants (gestational age ≤32 weeks) between January 2009 and November 2017 at a single neonatal intensive care unit. Preterm infants received total PN with either mixed lipid emulsion including fish oil (SMOFlipid®, n = 195) or soybean oil-based lipid emulsion (Lipovenoes®, n = 204) for at least 7 days. We compared the outcomes of PN-associated cholestasis, comorbidities, and mortality between the groups.ResultsThe incidence of PN-associated cholestasis was significantly lower in the SMOFlipid group than in the Lipovenoes group. The duration to full feeding days was significantly shorter in the SMOFlipid group compared with the Lipovenoes group. Relevant complications, such as severe retinopathy of prematurity and bronchopulmonary dysplasia, were also significantly reduced in the SMOFlipid group compared with the Lipovenoes group.ConclusionIn premature infants, PN with fish oil-based lipid emulsions is associated with a lower incidence of PN-associated cholestasis compared with soybean oil-based lipid emulsions.     

Novel MIR143‐NOTCH fusions in benign and malignant glomus tumors

Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired‐end RNA‐seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT‐PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino‐nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1‐related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1–3 rearrangements in benign and malignant, visceral, and soft tissue GTs. © 2013 Wiley Periodicals, Inc.     

Anti-inflammatory effects of peptides from a marine algicolous fungus Acremonium sp. NTU492 in BV-2 microglial cells

Located in tropical and subtropical region, Taiwan is an island with high algal species diversity. In this study, a number of fungal strains were isolated from marine macroalgae collected from northeastern intertidal zone of Taiwan. Preliminary anti-inflammatory screening has shown that the methanolic extracts of solid fermented products of the red alga Mastophora rosea-derived fungal strain Acremonium sp. NTU492 exhibited significant bioactivity. In an attempt to disclose the active principles from this fungal strain, a series of separation and purification was thus undertaken, which has led to the isolation and characterization of seven compounds including four new peptides, namely acrepeptins A–D (1–4), along with previously reported destruxin B (5), guangomide A (6), and guangomide B (7). Their structures were elucidated by spectroscopic analysis and compared with literatures. Of these, acrepeptins A (1) and C (3) showed markedly inhibitory activities on nitric oxide production in lipopolysaccharide-activated microglial BV-2 cells with IC₅₀ values of 12.0 ± 2.3 and 10.6 ± 4.0 μM, respectively. Furthermore, acrepeptins A (1) and C (3) significantly attenuated the expression of inducible nitric oxide synthase in a concentration-dependent manner (5–40 μM).     

Massive Lower Gastrointestinal Hemorrhage Caused by a Large Extraluminal Leiomyoma of the Colon: Report of a Case

The occurrence of leiomyoma of the colon is uncommon. Most of these lesions are clinically silent and are found incidentally during laparotomy or endoscopic procedures for unrelated conditions. Symptomatic leiomyomas of the colon are encountered less frequently, with only sporadic reports in the literatures. We describe a heretofore unreported case of a large extraluminal leiomyoma of the sigmoid colon presenting as massive lower gastrointestinal hemorrhage. Because it was extraluminal in position, it was difficult to make an accurate diagnosis endoscopically and the condition was easily misdiagnosed as angiodysplasia of the colon until CT scan results were seen. Although rare and benign in nature, leiomyoma of the colon may cause life-threatening complications that require emergency surgery and should be included in the differential diagnosis of lower gastrointestinal hemorrhage.     

Glycolipid GD3 and GD3 synthase are key drivers for glioblastoma stem cells and tumorigenicity

The cancer stem cells (CSCs) of glioblastoma multiforme (GBM), a grade IV astrocytoma, have been enriched by the expressed marker CD133. However, recent studies have shown that CD133⁻ cells also possess tumor-initiating potential. By analysis of gangliosides on various cells, we show that ganglioside D3 (GD3) is overexpressed on eight neurospheres and tumor cells; in combination with CD133, the sorted cells exhibit a higher expression of stemness genes and self-renewal potential; and as few as six cells will form neurospheres and 20–30 cells will grow tumor in mice. Furthermore, GD3 synthase (GD3S) is increased in neurospheres and human GBM tissues, but not in normal brain tissues, and suppression of GD3S results in decreased GBM stem cell (GSC)-associated properties. In addition, a GD3 antibody is shown to induce complement-dependent cytotoxicity against cells expressing GD3 and inhibition of GBM tumor growth in vivo. Our results demonstrate that GD3 and GD3S are highly expressed in GSCs, play a key role in glioblastoma tumorigenicity, and are potential therapeutic targets against GBM.Glioblastoma multiforme (GBM) is extremely infiltrative and difficult to treat, and most patients develop recurrence after therapy. Over the past decade, many studies have suggested that bulk GBM tumors harbor cancer stem cells (CSCs) (1, 2), a distinct subpopulation of cancer cells that are able to initiate new tumors efficiently, have long-term self-renewal capacity, and survive better against chemo- or radiotherapy (2–4). CD133 has become a widely used marker for the enrichment of GBM CSCs (GSCs) and other tumor types (5–10). However, recent studies have shown that CD133 is not specific for GSCs because CD133⁻ cells also possess tumor-initiating potential (11–13), indicating the need to identify more specific and exclusive markers for GSCs to facilitate our understanding of GSCs and therapeutic development against GBM. Several reports have proposed L1CAM, A2B5, integrin α6, MET, and CD15 as markers for GSCs (14–18). However, none of these protein markers could be used specifically to identify GSCs, and no study was reported with respect to glycans as potential markers, although glycan biosynthesis involves multiple genes and it is possible to create different structures in cancer progression. It is noted that ganglioside D2 (GD2) and ganglioside D3 (GD3) were found on the surface of neural stem cells (NSCs) and that stage-specific embryonic antigen 3 (SSEA3) and SSEA4 were found on embryonic stem cells and cancer cells (19–21), but there is no glycan marker found on the surface of GSCs.Gangliosides are sialic acid-containing glycosphingolipids (GSLs) that are most abundant in the nervous system (22). The expression levels and patterns of gangliosides during brain development shift from simple gangliosides, such as GM3 and GD3, to complex gangliosides, such as GM1, GD1a, GD1b, and GT1b (23, 24). Moreover, several unique ganglioside markers, including SSEA3, SSEA4, GD2, and GD3, have been identified in stem cells (19). GD3, a b-series ganglioside containing two sialic acids, is highly expressed in mouse and human embryonic NSCs (20, 25). In cancers, GD3 is highly accumulated in human primary melanoma tissues as well as in established melanoma cell lines (26), whereas human normal melanocytes express no or minimal levels of GD3 (27). Moreover, malignant gliomas contain higher levels of GD3, and its expression correlates with the degree of malignancy (28). GD3 is produced from the precursor GM3 by the activity of GD3 synthase (GD3S), which mediates the properties of CSCs through the c-MET signaling pathway and correlates with poor prognosis in triple-negative human breast tumors (29). These findings suggest that GD3 may play an important role in the transformation of normal cells into tumors, and imply that GD3 could be a cell surface marker for GSCs.This study was designed to identify glycan markers for the enrichment of GBM stem cells and then uses these enriched GBM stem cells to characterize tumorigenicity, their association with clinical GBM specimens, and their regulation in tumor progression. The results showed that GD2 and GD3 were positively stained on GBM neurospheres. We found that cells with high GD3 expression display functional characteristics of GSCs. Suppression of GD3S, a critical enzyme for GD3 synthesis, impeded neurosphere formation and tumor initiation. The expression of GD3S correlated with the grades of astrocytomas and mediated self-renewal through c-Met activation. Furthermore, a GD3 antibody was found to eliminate the GD3⁺ cells through complement-dependent cytotoxicity (CDC) in vitro and to suppress tumor growth in mice. These results suggest that GD3 could be a significant biomarker for GSCs, that CD3 could be combined with CD133 for the enrichment of GSCs, and that both GD3 and GD3S could be targets for the development of new therapies against GBM.     

Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth

A fundamental property of platelets is their ability to transmit cytoskeletal contractile forces to extracellular matrices. While the importance of the platelet contractile mechanism in regulating fibrin clot retraction is well established, its role in regulating the primary hemostatic response, independent of blood coagulation, remains ill defined. Real-time analysis of platelet adhesion and aggregation on a collagen substrate revealed a prominent contractile phase during thrombus development, associated with a 30% to 40% reduction in thrombus volume. Thrombus contraction developed independent of thrombin and fibrin and resulted in the tight packing of aggregated platelets. Inhibition of the platelet contractile mechanism, with the myosin IIA inhibitor blebbistatin or through Rho kinase antagonism, markedly inhibited thrombus contraction, preventing the tight packing of aggregated platelets and undermining thrombus stability in vitro. Using a new intravital hemostatic model, we demonstrate that the platelet contractile mechanism is critical for maintaining the integrity of the primary hemostatic plug, independent of thrombin and fibrin generation. These studies demonstrate an important role for the platelet contractile mechanism in regulating primary hemostasis and thrombus growth. Furthermore, they provide new insight into the underlying bleeding diathesis associated with platelet contractility defects.