Integrative transcriptome analysis of triple negative breast cancer profiles for identification of druggable targets.

As triple negative breast cancer (TNBC) lacks a specific target, exploration of abnormally expressed genes during the progression of TNBC is important for a better understanding of tumorigenesis and to find a specific target. We intended to figure out genes associated with TNBC, which can provide unique insights into gene dysregulation in TNBC while also pointing to new possible therapeutic targets for TNBC. A meta-analysis of multiple TNBC mRNA profiles was performed to identify consistently differentially expressed genes (CDGs). The pathways involved in modulating these genes were analyzed by MsigDB, and the interaction map was constructed. These CDGs were evaluated for their expression in cell lines, and drugs that could modulate the expression of CDGs were obtained using the connectivity map. CDGs were docked with doxorubicin and anethole, which is a phytocompound. The expression of selected CDGs was analyzed in MDA-MB-231 cells after treatment with doxorubicin and anethole. We found 45 CDGs, out of which 36 were upregulated and 9 were downregulated. MDA-MB-231 cell line was found to have high expression of CDGs, and drug that could modulate the expression of CDGs was doxorubicin. Docking results revealed that anethole and doxorubicin had good interaction with the CDGs especially with the genes AURKA, CDC6, DEPDC1, KIF23, KPNA2, MELK, CTNNB1, FLI1 and E2F1. Gene expression studies of the selected CDGs showed that the synergistic effect of anethole and doxorubicin effectively downregulated the expression. The CDGs identified from multiple cohorts have clinical significance and may be effectively exploited in the targeted therapy for TNBC.Communicated by Ramaswamy H. Sarma.

Expression pattern of ALDH1, E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer.

Aim: To evaluate the expression pattern of ALDH1 (aldehyde dehydrogenase 1), E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer (CRC) and to study association of their expression with the occurrence of CRC at a young age. Materials & methods: Immunohistochemistry of ALDH1, E-cadherin, Vimentin and Twist was performed on 103 pretreated CRC biopsy samples. Results: ALDH1 expression was found to have strong correlation with early onset CRC (p < 0.0001). Conclusion: High ALDH1 expression correlates with the early onset of CRC. ALDH1 over-expression correlates with poor overall survival in colon cancer.

Induction of Apoptosis by Pierisin-6 in HPV Positive HeLa and HepG2 Cancer Cells is Mediated by the Caspase-3 Dependent Mitochondrial Pathway.

BACKGROUND: To explore the cytotoxic and apoptotic activity of the pierisin-6 protein in HPV HeLa and HepG2 cell lines. METHODS: In this study, isolation, and purification of cytotoxic Prierisin-6 from the larvae of Pieris napi by affinity column chromatography techniques. Characterization of full-length mRNA of pierisin-6 gene was performed using 3'/5' RACE PCR. The quantitative RT-PCR used to study the developmental stage-specific expression of pierisin-6 mRNA. The most effective concentration of Pierisin-6 protein was determined by measuring cell proliferation. Apoptosis was assessed using AO/Et-Br, Propidium Iodide, and Rhodamine 123 assays, whereas protein levels of caspase 3, cytochrome C were evaluated by ELISA method. Pierisin-6 induced cell cycle arrest was determined using Propidium iodide by FACS. RESULTS: In this study, Pierisin-6, a novel apoptotic protein was found to have cytotoxicity against HeLa, HepG2 human cancer cell lines and L-132 human lung epithelial cell line. Among the target cells, HeLa was the most sensitive to Pierisin-6. Flow cytometry analysis confirms an increased percentage of apoptotic cells in sub G1 phase and cell cycle arrest at S phase. Alteration in the transmembrane potential of mitochondria, Cytochrome c released from the mitochondrial membrane, and caspase substrate assay demonstrated the cleavage of Ac- DEVD-pNA signifying the activation of Caspase-3. These findings suggested that Pierisin-6 significantly induce apoptosis in HeLa and HepG2 cells and is attributed mainly through a mitochondrial pathway by activation of caspases. The developmental and stage-specific expression of pierisin-6 mRNA was one thousand-fold increased from second to third instar larvae and gradually declined before pupation. CONCLUSION: Pierisin-6 represents a promising therapeutic approach for liver cancer patients.

Enterobius vermicularis infestation of the appendix and management at the time of laparoscopic appendectomy: case series and literature review.

INTRODUCTION: Enterobius vermicularis infestation of the vermiform appendix can mimic appendicitis. In these cases, laparoscopic appendicectomy runs a risk of contamination of the peritoneal cavity with worms. We reviewed our practice to suggest changes that will reduce the release of worms and propose methods to use in case contamination occurs. METHODS: 498 patients underwent appendicectomy over a sixty-three month period. 13 (2.6%) patients had confirmed E. vermicularis on histology of whom 6 (46%) were performed laparoscopically. These patients' case notes were retrospectively reviewed. RESULTS: The worms were noted intra-operatively during the laparoscopic appendectomies. In 2 cases, where peritoneal cavity contamination with worms occurred, they were dealt with careful diathermy or endoscopic suction. In the other cases, contamination was avoided by simple measures including division of the appendix in a staggered manner whilst maintaining traction, removal of worms using endoscopic suction or diathermy and quick transfer to a specimen bag. CONCLUSION: We highlight that the symptoms of appendicitis can be due to Enterobius vermicularis infestation without any histological evidence of acute inflammation. Surgeons need to be aware of this possibility during laparoscopic appendicectomy and simple techniques can minimise the risk of contamination. It also enables early diagnosis and treatment without awaiting histological findings.

Novel agents to manage dyslipidemias and impact atherosclerosis.

Strong epidemiological evidence linked elevated levels of low-density lipoprotein cholesterol (LDL-C) to risk of atherosclerotic heart disease. As a consequence, LDL-C lowering has been the main goal of therapy to reduce cardiovascular risk for the past few decades and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become some of the most commonly prescribed drugs. In spite of the proven efficacy of these drugs, statins reduce cardiovascular events by only 30-40%. Epidemiological analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Furthermore, several quantitative coronary angiography studies showing regression of atherosclerosis and reduction in subsequent events utilized a combination of drugs effective on LDL-C as well as other lipoproteins. Hence, several new drugs are being investigated that affect more than the traditional LDL-C pathways. In this article, we review lipoprotein-modifying agents that have either been recently released, or are still in various phases of development. They include agents that reduce LDL-C levels by mechanisms other than HMG-CoA inhibition (such as cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, sterol-regulating binding protein cleavage activating protein ligands, microsomal triglyceride transfer protein inhibitors, LDL-C receptor activators and farnesoid X receptor antagonists) and agents that raise HDL-C cholesterol or improve cholesterol efflux (such as cholesterol ester transfer protein inhibitors, retinoid X receptor selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and estrogen like compounds).

Impaired vascular reactivity in African-American patients with type 2 diabetes mellitus and microalbuminuria or proteinuria despite angiotensin-converting enzyme inhibitor therapy.

BACKGROUND: Microalbuminuria, an early indicator of diabetic nephropathy that reflects other vascular abnormalities, usually improves or resolves with angiotensin-converting enzyme inhibitor (ACEI) therapy. Persistent microalbuminuria despite ACEI therapy may be associated with poor prognosis for cardiovascular disease and mortality. African-Americans are reported to respond less well to ACEI and are at increased risk of disease progression. METHODS AND RESULTS: We compared flow-mediated dilatation (FMD) and nitroglycerine-dependent dilatation (NDD) in African-American diabetic subjects with persistent microalbuminuria (n = 35) despite ACEI therapy and those in whom microalbuminuria had resolved (n = 15). The two groups were not statistically different in terms of blood pressure, age, sex, lipids, and hemoglobin A1c. FMD was reduced in the microalbuminuria group, compared with subjects without microalbuminuria (4.2 vs. 11.4%; P < 0.0001). Similarly, NDD was reduced in the microalbuminuria group, compared with subjects without microalbuminuria (10.8 vs.16.6%; P = 0.011). The FMD in African-American patients with persistent microalbuminuria was also significantly lower than in clinically similar Caucasian patients whose microalbuminuria had persisted despite ACEI therapy (4.2 vs. 7.5%; P = 0.03). On multiple regression analysis, persistent microalbuminuria is the only predictor of abnormal endothelial function in these patients. CONCLUSIONS: Our study clearly demonstrates that African-American type 2 diabetic subjects with persistent microalbuminuria have severely impaired FMD and NDD, compared with matched patients who had microalbuminuria that was eliminated by ACEI. This may explain the poor prognosis for cardiovascular disease in patients who have persistent microalbuminuria. Alternative strategies for reducing microalbuminuria in high-risk patients who do not respond adequately to ACEI therapy such as African-Americans are needed.

Bacteroides peritonitis associated with colon cancer in a continuous ambulatory peritoneal dialysis patient.

Peritonitis is not an uncommon complication of continuous ambulatory peritoneal dialysis (CAPD). We report a case of Bacteroides fragilis-induced bacterial peritonitis, probably due to clinically occult malignancy, in a 76-year-old woman on CAPD.

Cough in a patient with an infusion port.

In this case report, we describe a patient with a history of fallopian tube adenocarcinoma who had an infusion port in place for the past 4 years. During the course of her stay in the hospital for pneumonia, she developed a cough that became worse with the infusion of fluids through the port. A portogram done to investigate this problem revealed the presence of a portobronchial fistula. This is the first reported case of a portobronchial fistula. Various possibilities to explain the formation of portobronchial fistula are discussed.

Acute hepatocellular and cholestatic injury in a patient taking celecoxib.

A case of acute hepatocellular and cholestatic liver injury that may have been associated with the use of celecoxib is described. This case was reported to US Food and Drug Administration and the manufacturer of celecoxib.