Molecular progression to cervical precancer, epigenetic switch or sequential model?

The evolution of precancerous cervical lesions is poorly understood. A widely held model of cervical intraepithelial neoplasia grade 3 (CIN3) development is sequential progression from normal through CIN1 and CIN2 to CIN3. Another hypothesis, the "molecular switch" model, postulates that CIN3 can evolve directly from human papillomavirus (HPV)-infected normal epithelium without progressing through CIN1 and CIN2. To shed light on this process, we compared DNA methylation of selected human biomarkers and HPV types in two groups of CIN1: CIN1 that were near or adjacent to CIN3 (adjacent-CIN1) and CIN1 that were the principal lesions with no CIN3 detected (principal-CIN1). 354 CIN (CIN1 and CIN3) and normal tissue areas were dissected and typed for HPV from 127 women who underwent loop electrosurgical excision procedures (LEEP). Methylation of genes EPB41L3 and the viral regions of HPV16-L1/L2, HPV18-L2, HPV31-L1, and HPV33-L2 were determined by a highly accurate quantitative pyrosequencing of bisulfite converted DNA. There was a significant trend of increased methylation with disease grade comparing normal to CIN1 and CIN3 (p < 0.0001). Adjacent-CIN1 predominantly shared the same HPV types as the CIN3, however, methylation differed substantially between adjacent-CIN1 and CIN3 (p = 0.008). In contrast diagnostically principal-CIN1 had an indistinguishable methylation distribution compared to adjacent-CIN1 (EPB41L3: p = 0.49; HPVme-All: p = 0.11). Our results suggest that progression from normal epithelium to CIN1 or CIN3 is usually promoted by the same HPV type but occurs via distinct DNA epigenotypes, thus favoring the "molecular switch" model.

Clinical and Pathologic Features of Primary Angiosarcoma of the Kidney.

PURPOSE OF REVIEW: Primary angiosarcoma of the kidney is extremely rare; hence, relatively little is known regarding its clinicopathologic features and prognosis. Herein, we review the literature on primary renal angiosarcoma with emphasis on the clinical and pathologic features. RECENT FINDINGS: Approximately 64 cases have been reported in the literature, and most cases occur in the 6th-7th decade with a strong male predominance. The aetiology is unknown. Patients present with flank pain, haematuria, abdominal mass and weight loss. A considerable number of patients develop metastatic disease at diagnosis or shortly afterwards. Grossly, the tumour comprises ill-defined haemorrhagic spongy masses often with necrosis. Microscopically, the tumour is composed of anastomosing capillary-sized vessels which are lined by malignant endothelial cells. The mainstay of treatment is surgery followed by radiation therapy with or without chemotherapy. Renal angiosarcomas are highly aggressive tumours with dismal outcome, and they must be distinguished from morphologically similar lesions of the kidney.

Role of quantitative p16INK4A mRNA assay and digital reading of p16INK4A immunostained sections in diagnosis of cervical intraepithelial neoplasia.

Visual interpretation of cervical biopsies is subjective and variable, generally showing fair to moderate inter-reader agreement in distinguishing high from low grade cervical intraepithelial neoplasia (CIN). We investigated the performance of two objective p16 quantitative tests in comparison with visual assessment: (i) p16-mRNA assay and (ii) digital analysis of sections stained for p16 protein. The primary analysis considered 232 high-risk human papilloma virus positive (HPV+) samples from diagnostic cervical specimens. A p16 RT-qPCR (p16-mRNA assay) was run on mRNA extracted from formalin-fixed paraffin-embedded sections. Two p16 immunohistochemistry (IHC) readings, a visual read by a histopathologist (Visual IHC) and a digital read of a high-resolution scan (Digital IHC), were done on adjacent sections. The worst reviewed CIN grade (agreed by at least two histopathologists) from up to two biopsies and a loop excision was taken, with CIN2/3 as the primary endpoint. Visual IHC attained a specificity of 70% (95%CI 61-77) for 85% (95%CI 77-91%) sensitivity. The four-point Visual IHC staining area under the curve (AUC) was 0.77 (95%CI 0.71-0.82), compared with 0.71 (95%CI 0.64-0.77) for p16-mRNA and 0.67 (95%CI 0.60-0.74) for Digital IHC. Spearman rank-order correlations were: visual to p16-mRNA 0.41, visual to digital 0.49 and p16-mRNA to digital: 0.22. The addition of p16-mRNA assay to visual reading of p16 IHC improved the AUC from 0.77 to 0.84 (p = 0.0049). p16-mRNA testing may be complementary to visual IHC p16 staining for a more accurate diagnosis of CIN, or perhaps a substitute in locations with a lack of skilled pathologists.

Lipedematous Scalp Occurring in Two Female Siblings: Further Evidence for a Genetic Role.

Introduction: Lipedematous scalp (LS) is a rare disorder characterized by thickening of the adipose subcutaneous scalp layer without associated hair loss. To date, there have been fewer than 100 reported cases of LS. LS occurring in siblings has not been previously reported. Case Presentation: We present a 58-year-old and 63-year-old pair of black Caribbean female siblings with LS. Scalp thickness on ultrasound of the vertex in each case was 12 mm and 11 mm from skin to periosteum, respectively (normal range: 5-6 mm). Histopathological analysis in the younger sibling demonstrated prominent fat, high in the dermis around hair follicles, with follicular distortion and focal perifollicular fibrosis. Co-morbidities in the younger sibling were obesity (body mass index [BMI] 39.0), paranoid schizophrenia, and bipolar disorder; the older sibling was overweight (BMI 26.0) with co-morbidities of hypercholesterolemia, type 2 diabetes mellitus, hypomania, and migraines; both siblings were taking psychiatric medication. Conclusion: We present an unusual case of LS in a pair of female siblings, adding to the limited existing evidence that there may be a genetic role in the pathogenesis of LS. Furthermore, both siblings in this case had psychiatric co-morbidities and were taking psychiatric medication, which have not been previously identified as associations of LS.

A Plaque-Like CD34-Positive Dermal Fibroma Presenting as an Acquired Papule.

CD34-positive dermal fibromas (PDFs) are cutaneous neoplasms that display a characteristic pattern of superficial dermal spindle cell proliferation on histopathology evaluation. They are clinically heterogenous in presentation and thought to follow a benign course. CD34-PDFs have features that overlap with dermatofibrosarcoma protuberans (DFSP), a locally aggressive low-grade superficial sarcoma. Cytogenetic studies are essential to distinguish the two. This report presents the case of a 38-year-old female with a CD34-PDF on the right antecubital fossa.

Intrauterine herpes simplex virus infection presenting with hypopigmented lesions.

Genital herpes simplex virus (HSV) is a sexually transmitted infection that can be transmitted from mother to child in utero, perinatally, or postnatally. Cutaneous infection with HSV commonly presents as vesicles affecting the skin, eyes, or mouth. In our case, we report a well child with cutaneous hypopigmented patches at birth that preceded typical blistering.

GEOS-S2S Version 2: The GMAO High Resolution Coupled Model and Assimilation System for Seasonal Prediction.

The Global Modeling and Assimilation Office (GMAO) has recently released a new version of the Goddard Earth Observing System (GEOS) Sub-seasonal to Seasonal prediction (S2S) system, GEOS-S2S-2, that represents a substantial improvement in performance and infrastructure over the previous system. The system is described here in detail, and results are presented from forecasts, climate equillibrium simulations and data assimilation experiments. The climate or equillibrium state of the atmosphere and ocean showed a substantial reduction in bias relative to GEOS-S2S-1. The GEOS-S2S-2 coupled reanalysis also showed substantial improvements, attributed to the assimilation of along-track Absolute Dynamic Topography. The forecast skill on subseasonal scales showed a much-improved prediction of the Madden-Julian Oscillation in GEOS-S2S-2, and on a seasonal scale the tropical Pacific forecasts show substantial improvement in the east and comparable skill to GEOS-S2S-1 in the central Pacific. GEOS-S2S-2 anomaly correlations of both land surface temperature and precipitation were comparable to GEOS-S2S-1, and showed substantially reduced root mean square error of surface temperature. The remaining issues described here are being addressed in the development of GEOS-S2S Version 3, and with that system GMAO will continue its tradition of maintaining a state of the art seasonal prediction system for use in evaluating the impact on seasonal and decadal forecasts of assimilating newly available satellite observations, as well as to evaluate additional sources of predictability in the earth system through the expanded coupling of the earth system model and assimilation components.

Renal oncocytoma with vascular and perinephric fat invasion.

Renal oncocytoma is a benign epithelial neoplasm typically composed of large cells with granular eosinophilic cytoplasm. Although rare, histologically worrisome features such as vascular and perinephric fat invasion have been reported. Of the 159 renal oncocytomas resected at our institution, 20 (12.6%) had vascular and/or perinephric fat invasion. Microscopically, 10 oncocytomas had perinephric fat invasion, 7 had vascular invasion and 3 had both vascular and perinephric fat invasion. Grossly, perinephric fat invasion was visible in three cases and tumour was identified within the branches of the renal vein in two cases. Tumours occurred in 14 men and 6 women (M:F = 2.3:1). The mean age at diagnosis was 64.5 years (range, 33-88 years). A total of 11 cases had radical nephrectomies while 9 cases had partial nephrectomies. There was no evidence of disease recurrence, metastasis or death due to tumour after a mean follow up of 25.6 months (range, 2-103 months). The presence of vascular and perinephric fat invasion in renal oncocytoma though worrisome, does not alter the benign course of the tumour.

Observational Needs for Improving Ocean and Coupled Reanalysis, S2S Prediction, and Decadal Prediction.

Developments in observing system technologies and ocean data assimilation (DA) are symbiotic. New observation types lead to new DA methods and new DA methods, such as coupled DA, can change the value of existing observations or indicate where new observations can have greater utility for monitoring and prediction. Practitioners of DA are encouraged to make better use of observations that are already available, for example, taking advantage of strongly coupled DA so that ocean observations can be used to improve atmospheric analyses and vice versa. Ocean reanalyses are useful for the analysis of climate as well as the initialization of operational long-range prediction models. There are many remaining challenges for ocean reanalyses due to biases and abrupt changes in the ocean-observing system throughout its history, the presence of biases and drifts in models, and the simplifying assumptions made in DA solution methods. From a governance point of view, more support is needed to bring the ocean-observing and DA communities together. For prediction applications, there is wide agreement that protocols are needed for rapid communication of ocean-observing data on numerical weather prediction (NWP) timescales. There is potential for new observation types to enhance the observing system by supporting prediction on multiple timescales, ranging from the typical timescale of NWP, covering hours to weeks, out to multiple decades. Better communication between DA and observation communities is encouraged in order to allow operational prediction centers the ability to provide guidance for the design of a sustained and adaptive observing network.

Frizzled-8 integrates Wnt-11 and transforming growth factor-ß signaling in prostate cancer.

Wnt-11 promotes cancer cell migration and invasion independently of ß-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-ß signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt-11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt-11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-ß/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-ß-regulated complex with TGF-ß receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-ß signals in prostate cancer.