Abernethy malformation associated with Caroli’s syndrome in a patient with a PKHD1 mutation: a case report

Abernethy malformation is a rare congenital anomaly characterised by the partial or complete absence of the portal vein and the subsequent development of an extrahepatic portosystemic shunt. Caroli’s disease i…

http://ift.tt/2w3qpoB

Alterations in SCAI Expression during Cell Plasticity, Fibrosis and Cancer

Abstract

              <p>Suppressor of cancer cell invasion (SCAI) has been originally characterized as a tumor suppressor inhibiting metastasis in different human cancer cells, and it has been suggested that SCAI expression declines in tumors. The expression patterns and role of SCAI during physiological and pathophysiological processes is still poorly understood. Earlier we demonstrated that SCAI is regulating the epithelial-mesenchymal transition of proximal tubular epithelial cells, it is downregulated during renal fibrosis and it is overexpressed in Wilms’ tumors. Here we bring further evidence for the involvement of SCAI during cell plasticity and we examine the prognostic value and expression patterns of SCAI in various tumors. SCAI prevented the activation of the SMA promoter induced by angiotensin II. SCAI expression decreased in a model of endothelial-mesenchymal transition and increased during iPS reprogramming of fibroblasts. During renal fibrosis SCAI expression declined, as evidenced in a rat model of renal transplant rejection and in TGF-β1 overexpressing transgenic mice. High expression of SCAI correlated with better survival in patients with breast and lung cancers. Intriguingly, in the case of other cancers (gastric, prostate, colorectal) high SCAI expression correlated with poor survival of patients. Finally, we bring evidence for SCAI overexpression in colorectal cancer patients, irrespective of stage or metastatic status of the disease, suggesting a diverse role of SCAI in various diseases and cancer.</p><br /><br />

http://ift.tt/2x5WZDo

Rapidly progressive intravascular primary effusion lymphoma in an HIV-positive renal transplant recipient

Summary

We describe the clinical and post-mortem findings of a case of rapidly progressive, ultimately fatal primary effusion lymphoma (PEL) arising in an HIV-positive man two years after renal transplantation. Disseminated multi-organ involvement associated with a peculiar intravascular pattern of growth, as seen in this case, has only been reported once previously. This is also, to our knowledge, the first detailed description of a lymphoma arising post-transplant in an HIV-positive patient.

This article is protected by copyright. All rights reserved.

http://ift.tt/2uQ2FRd

A 3D tri-culture system reveals that activin receptor-like kinase 5 and connective tissue growth factor drive human glomerulosclerosis

Abstract

Glomerular scarring, known as glomerulosclerosis, occurs in many chronic kidney diseases and involves interaction between glomerular endothelial cells (GEC), podocytes and mesangial cells (MCs), leading to signals that promote extracellular matrix deposition and endothelial cell dysfunction and loss. We describe a 3D tri-culture system to model human glomerulosclerosis. In 3D monoculture, each cell type alters its phenotype in response to TGFβ, which has been implicated as an important mediator of glomerulosclerosis. GECs form a lumenized vascular network, which regresses in response to TGFβ. MCs respond to TGFβ by forming glomerulosclerotic-like nodules with matrix deposition. TGFβ treatment of podocytes does not alter cell morphology, but increases connective tissue growth factor (CTGF) expression. BMP7 prevents TGFβ-induced GEC network regression, whereas TGFβ-induced MC nodule formation is prevented by SMAD3 siRNA knock down or ALK5 inhibitors, but not BMP7, and increased phospho-SMAD3 was observed in human glomerulosclerosis. In 3D tri-culture, GECs, podocytes and MCs form a vascular network in which GECs and podocytes interact intimately within a matrix containing MCs. TGFβ treatment induces formation of nodules, but combined inhibition of ALK5 and CTGF is required to prevent TGFβ-induced nodule formation in tri-cellular cultures. Identification of therapeutic targets for glomerulosclerosis depends on the 3D culture of all three glomerular cells.

http://ift.tt/2vIzYH5

Aligning Digital CD8+ Scoring and Targeted Next-Generation Sequencing with PD-L1 Expression: A Pragmatic Approach in Early-Stage Squamous Cell Lung Carcinoma

Abstract

Aims

To study PD-L1 expression, tumour-infiltrating T lymphocytes (TILs) and the molecular context in patients with early-stage squamous cell lung carcinomas (SCCs).

Methods and results

The study included samples from 40 patients (discovery cohort) and 29 patients (validation cohort) diagnosed with early-stage SCC. PD-L1 immunohistochemistry (IHC) was performed with three commercially available clones (E1L3N, SP263 and SP142). CD8+ TILs were scored with a digital algorithm. All tumours were analyzed with targeted next-generation sequencing (NGS). Additionally, TP53 mutations were investigated with direct sequencing. In both cohorts, we observed a significant association between CD8+ TILs density and high PD-L1 IHC expression in tumour cells (TCs). Furthermore, high SP142 PD-L1 expression in immune cells (ICs) was also significantly associated with CD8+ TILs density. Therefore, CD8+ TILs density discriminated between patients with high versus low PD-L1 IHC expression with excellent sensitivity and specificity. Interestingly, the highest percentages of PD-L1 positive TCs with the three antibodies were found in samples with CDK6 amplification, with high amplification of CMYC or with CCND1-PIK3CA co-amplification. High SP142 PD-L1 IHC expression in ICs showed a non-significant correlation with TP53 mutations. Conversely, most cases with FGFR1 amplification were negative for all PD-L1 clones.

Conclusions

Our preliminary results support the use of digital CD8+ TILs scoring and targeted NGS alongside PD-L1 expression. The approach presented herein could help define patients with SCCs candidates to immune checkpoints inhibitors.

This article is protected by copyright. All rights reserved.

http://ift.tt/2x4QUqO

Application of the Condensed Protocol for the NIA-AA guidelines for the neuropathologic assessment of Alzheimer’s disease in an academic clinical practice

Abstract

Aims

In response to concerns regarding resource expenditures required to fully implement the 2012 NIA-AA Sponsored Guidelines for the neuropathologic assessment of Alzheimer’s disease (AD), we previously developed a sensitive and cost-reducing Condensed Protocol (CP) at the University of Washington (UW) Alzheimer’s Disease Research Center (ADRC) that consolidated the recommended NIA-AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA-AA protocols, but instead to make the NIA-AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA-AA guidelines.

Methods and Results

In this regard, we developed practical criteria to instigate CP sampling and immunostaining, and applied these criteria in an academic clinical neuropathological practice. Over the course of one year, 73 cases were sampled using the CP; of those, 53 (72.6%) contained histologic features that prompted CP workup. We found that the CP resulted in increased identification of AD and Lewy body disease neuropathologic changes from what was expected using a clinical history-driven workup alone, while saving approximately $900 per case.

Conclusions

This study demonstrates the feasibility and cost-savings of the CP applied to a clinical autopsy practice, and highlights potentially unrecognized neurodegenerative disease processes in the general aging community.

This article is protected by copyright. All rights reserved.

http://ift.tt/2wb2QLh

Cerebrospinal fluid cytology in nonmalignant aseptic meningeal disorders

Cerebrospinal fluid cytology examination is a common and reliable primary and/or complementary procedure for the diagnosis of central nervous system (CNS) disorders. This review provides an update of aseptic meningeal disorders that may be encountered in cytopathology practice. The article covers the cytological findings and helpful ancillary studies needed of nonmalignant aseptic CNS disorders such as viral, bacterial, fungal and parasitic infections, and other noninfectious diseases, such as Mollaret´s meningitis (recurrent benign lymphocytic meningitis), Guillain-Barré syndrome, multiple Sclerosis, subarachnoid haemorrhage, and drug-induced disorders.

http://ift.tt/2uI78td