Evaluation of chalcones as new glycogen phosphorylase inhibitors - an in-vitro and in-silico approach.

Diabetes mellitus (DM) remains one of the pivotal diseases that have drawn the attention of researchers recently and during the last few decades. Due to its devastating symptoms, attempts to develop new drugs with mild side effects have resulted in a number of drugs that are functioning through various mechanisms. Among these, Glycogen phosphorylase (GP) inhibitors emerged as a new strategy for combating DM. GP is an enzyme that regulates blood glucose levels; it catalyses the breakdown of glycogen to glucose-1-phosphate in the liver and tissues with high and fluctuating energy demands. In the present research, we evaluate the possibility of type 2 diabetes therapy with the help of chalcones which are known to have antidiabetic activities. For this purpose, 29 chalcones were modelled, synthesised and investigated for their inhibitory activity against GP using in-vitro methods. Compounds 1, 2, and 3 were found to be the most potent compounds with IC50 values 26.6, 57.1 and 75.6 µM respectively. The observed results were further validated using in-silico methods. Molecular docking simulation revealed interaction patterns that explain the structure-activity relationships of the compounds with GP. Molecular dynamic (MD) simulation demonstrated a stable complex formation between compound 1 and GP through lower value and uniformity in root mean square deviation (RMSD) of the complex and root mean square fluctuation (RMSF) of the protein Cα.

Risk management recommendations and patient acceptance vary with high-risk breast lesions.

INTRODUCTION: Lobular carcinoma in situ (LCIS), atypical ductal and lobular hyperplasia (AH) increase breast cancer risk. We examined risk management recommendations (RMR) and acceptance in AH/LCIS. METHODS: All patients with AH/LCIS on core needle biopsy from 2013 to 2016 at our institution were identified; cancer patients were excluded. Univariate and multivariate analysis examined factors associated with management. RESULTS: 98 % of patients were evaluated by breast surgeons and 53 % underwent risk model calculation (RC). 77 % had new RMR. RMR of MRI screening (MRI), genetic counselling (GC) and medical oncology (MO) referral were 41 %, 18 %, 77 %, respectively. MRI screening was more likely recommended in those with strong family history (p = 0.01), and high RC (p < 0.001). Uptake of at least one RMR did not occur in 84 % of patients. Use of RC correlated with MO acceptance (p = 0.049). CONCLUSIONS: Diagnosis of atypia has the potential to change risk management for most, however only 16 % of patients accepted all RMR.

Directed movement toward, translocation along, penetration into and exit from vascular networks by breast cancer cells in 3D.

We developed a computer-assisted platform using laser scanning confocal microscopy to 3D reconstruct in real-time interactions between metastatic breast cancer cells and human umbilical vein endothelial cells (HUVECs). We demonstrate that MB-231 cancer cells migrate toward HUVEC networks, facilitated by filopodia, migrate along the network surfaces, penetrate into and migrate within the HUVEC networks, exit and continue migrating along network surfaces. The system is highly amenable to 3D reconstruction and computational analyses, and assessments of the effects of potential anti-metastasis monoclonal antibodies and other drugs. We demonstrate that an anti-RHAMM antibody blocks filopodium formation and all of the behaviors that we found take place between MB-231 cells and HUVEC networks.

A Pilot Study of Preoperative Vandetanib on Markers of Proliferation and Apoptosis in Breast Cancer.

INTRODUCTION: Preclinical data supports antitumor activity of tyrosine kinase inhibitor vandetanib with Ret as the therapeutic target in breast cancer. We investigated the effect of preoperative vandetanib on markers of proliferation and apoptosis in breast cancer. METHODS: Patients with invasive breast cancer were randomly assigned vandetanib 300 mg or placebo PO daily for 2 weeks before operative resection from January 2014 to June 2017. Pretreatment and posttreatment specimens were analyzed by immunohistochemistry for Ki-67, TUNEL, and p-ERK with stratification by Ret expression by immunohistochemistry. RESULTS: Ten patients were enrolled. There was no statistically significant difference in ERK activation compared with placebo (P=0.45); however, ERK activation was reduced 74% compared with pretreatment biopsy with vandetinib treatment (P=0.005) without a significant reduction in the placebo group (-29%, P=0.55). Mean change in Ki-67 after vandetanib treatment was +0.3% compared with +2.0% in placebo treated patients, P=0.72. Mean change in TUNEL was +0.48 apoptotic nuclei per HPF in the vandetanib arm compared with +1.02 in the placebo arm, P=0.32. In vandetanib treated patients, Ki-67 was reduced 0.3% in RET-positive tumors compared with increased 1.0% in RET-negative tumors, P=0.43 and TUNEL was increased 0.77 in RET-positive tumors and 0.2 in RET-negative tumors, P=0.21. CONCLUSIONS: In this pilot study, no statistically significant differences on prespecified markers were seen with vandetanib compared with placebo. In accordance with the investigational hypothesis, there was a nonsignificant trend with vandetanib treatment of reduction in p-ERK and increased effects in Ret expressing tumors.

Infiltrating Kaposi sarcoma presenting as acute kidney injury: An unexpected consequence of deliberate hepatitis C-positive organ transplantation.

Kaposi sarcoma (KS) following kidney transplantation can result from recipient reactivation of latent human herpesvirus 8 (HHV-8) infection or activation of donor-acquired HHV-8 infection. Post-transplant KS typically manifests with cutaneous pathology, but rare cases of renal allograft involvement have been reported. We describe two cases of donor-derived HHV-8 infection in two hepatitis C (HCV) viremia-negative transplant recipients who each received a kidney from a donor with HCV viremia. One recipient did not develop KS while the other presented with acute kidney injury caused by extensive KS infiltration of the renal parenchyma and metastatic disease. This report reviews the literature for cases of KS involving the renal allograft and highlights an unexpected consequence of deliberate HCV-positive organ transplantation.

BST-2 promotes survival in circulation and pulmonary metastatic seeding of breast cancer cells.

Bone marrow stromal antigen 2 (BST-2) mediates various facets of cancer progression and metastasis. Here, we show that BST-2 is linked to poor survival in invasive breast cancer patients as its expression positively correlates with disease severity. However, the mechanisms that drive the pro-metastatic functions of BST-2 are not fully understood. Correlation of BST-2 expression and tumor aggressiveness was analyzed in human tissue samples. Migration, invasion, and competitive experimental metastasis assays were used to measure the cellular responses after silencing BST-2 expression. Using a mouse model of breast cancer, we show that BST-2 promotes metastasis independent of the primary tumor. Additional experiments show that suppression of BST-2 renders non-adherent cancer cells non-viable by sensitizing cells to anoikis. Embedment of cancer cells in basement membrane matrix reveals that silencing BTS-2 expression inhibits invadopodia formation, extracellular matrix degradation, and subsequent cell invasion. Competitive experimental pulmonary metastasis shows that silencing BST-2 reduces the numbers of viable circulating tumor cells (CTCs) and decreases the efficiency of lung colonization. Our data define a previously unknown function for BST-2 in the i) formation of invadopodia, ii) degradation of extracellular matrix, and iii) protection of CTCs from hemodynamic stress. We believe that physical (tractional forces) and biochemical (ECM type/composition) cues may control BST-2's role in cell survival and invadopodia formation. Collectively, our findings highlight BST-2 as a key factor that allows cancer cells to invade, survive in circulation, and at the metastatic site.

Poorly differentiated neuroendocrine carcinoma of the breast with Merkel cell features.

Neuroendocrine carcinoma of the breast is a rare tumor subtype comprising less than 1% of breast cancers in the United States. Merkel cell features within this rare subtype are even rarer. We report a neuroendocrine breast carcinoma with Merkel cell features. The patient underwent breast conservation therapy and a sentinel lymph node biopsy. Unfortunately, the tumor was extremely aggressive and at 5 weeks postoperatively she presented with widely metastatic disease. Due to the aggressive nature of this tumor, we reviewed the literature and treatment options for this rare variant of a rare subtype.

Simultaneous detection of single-nucleotide variant, deletion/insertion, and fusion in lung and thyroid carcinoma using cytology specimen and an RNA-based next-generation sequencing assay.

BACKGROUND: Molecular testing for epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion is routinely performed in patients with stage IV lung adenocarcinoma to assess their eligibility for targeted therapy. Fine-needle aspiration (FNA)-derived material frequently is the only pathologic material available. The identification of genomic aberrations in thyroid nodules from FNA smears may help stratify cancer risk and spare patients from a second surgery. In the current study, the authors tested nucleic acid extracted from the cytology smears of lung and thyroid carcinomas for simultaneous detection of single-nucleotide variant, insertion/deletion, and gene fusion using an RNA-based next-generation sequencing assay. METHODS: A total of 27 cases (17 lung and 10 thyroid carcinomas, the majority of which had known variants) were tested. Areas of interest were scrapped from stained smears using a scalpel. Total nucleic acid was extracted. Gene fusion and mutational analysis was performed using the Comprehensive Thyroid and Lung FusionPlex Assay. Data were analyzed using the analysis pipeline provided by the vendor. Eleven cases with available formalin-fixed, paraffin-embedded (FFPE) tissue were tested in parallel. RESULTS: Gene fusions were detected in 6 cases; common single-nucleotide variants in EGFR, RAS, and BRAF in 14 cases; and in-frame deletions within EGFR in 3 cases. A concordance rate of 100% was observed between FNA and FFPE tissue. CONCLUSIONS: Cytology preparations can be a reliable source for the detection of both DNA and RNA aberrations. The ability to simultaneously detect multiple types of genomic variants is crucial for patients with advanced cancer and maximizes the usefulness of cytology specimens. Cancer Cytopathol 2018;126:158-69. © 2018 American Cancer Society.

IgG4-related disease in an adolescent with radiologic-pathologic correlation.

Immunoglobulin G4-related disease (IgG4RD) is an immune-mediated condition characterized by lymphoplasmacytic infiltrates and fibrosis of affected organs. IgG4RD may affect many different organs either individually or together in a multiorgan condition and, thus, incorporates a wide range of fibroinflammatory phenotypes with shared pathologic features. Although IgG4RD most commonly occurs in late adulthood, it may affect children and adolescents. Only one case of IgG4RD presenting as isolated submandibular gland involvement has been reported in the pediatric population. Radiographic features of IgG4RD are often nonspecific making diagnosis challenging, but it is important for radiologists to be familiar with this diseased as its inclusion the differential for diffuse salivary enlargement may be the first step in making an accurate diagnosis. Here, we report a case of a child presenting with bilateral submandibular gland swelling to increase awareness of this condition in the pediatric population. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Sinonasal adenocarcinoma: immunohistochemical marking and expression of oncoproteins.

BACKGROUND: Relatively little is known concerning the immunohistochemical marking of sinonasal adenocarcinoma (SNA). The most clinically problematic tumors are those that seem histologically identical to colonic adenocarcinoma, a neoplasm that may metastasize to the sinonasal region. To determine whether differentiated immunohistochemical expression of keratins could differentiate primary from metastatic tumors and to understand the biology of these tumors, differentiated keratin and oncoprotein expression was investigated. METHODS: Eleven patients with sinonasal adenocarcinoma were investigated for expression of cytokeratins 7 and 20 (CK7, CK20), AE 1/3, CAM 5.2, smooth muscle-specific actin, muscle-specific actin, desmin, S-100, carcinoembryonic antigen (CEA), p53, and HER-2/neu. RESULTS: All sinonasal adenocarcinomas of intestinal type were cytokeratin 7 positive. None of the tumors showed myoepithelial differentiation. Strong HER-2/neu staining was seen in some tumors. CONCLUSIONS: Strong HER-2/neu staining in some cases suggests this oncogene may be involved in the genesis of SNA. Immunohistochemical staining with cytokeratin 7 may be potentially useful in differentiating primary from metastatic disease in sinonasal adenocarcinomas of the intestinal subtype.