Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor-Negative Breast Cancer

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. Cancer Prev Res; 5(9); 1144-54. ?2012 AACR.     

Rising Metals Concentration in the Environment: A Response to Effluents of Leather Industries in Sialkot

Bulletin of Environmental Contamination and Toxicology - Many leather processing industries in Sialkot, Pakistan, discharge their wastes freely into the environment which then enters nearby water...     

GC-MS profile of antimicrobial and antioxidant fractions from Cordia rothii roots

Context: An ethnobotanical survey of Cordia rothii Roem. & Schult. (Boraginaceae) reveals it as a medicinal plant.

Objective: Antimicrobial and antioxidant potential evaluation and identification of chemical constituents via GC-MS of C. rothii roots fractions. To the best of our knowledge, this is the first systematic investigation of the roots exploiting GC-MS.

Materials and methods: Extraction and fractionation of C. rothii roots furnished various fractions using solvents of varying polarity, i.e., n-hexane, chloroform, ethyl acetate, acetone and methanol. In vitro antimicrobial and antioxidant screening was performed using disk diffusion and DPPH methods, respectively. MIC of active fractions was also determined using disk diffusion method. GC-MS was used to identify constituents which may be responsible for these activities.

Results: Among various fractions from C. rothii roots, fraction KA-C showed strong antibacterial activity against 17 microorganisms tested, with MIC ranging from 250–31.25?μg/mL. Fractions KA-A, KM and KM-A exhibited significant antioxidant potential with EC₅₀ 46.875?μg/mL, while fractions KEA-PE, KM-PE and KM-M were good with EC₅₀ 93.750?μg/mL. Forty-five phytochemicals were identified in GC-MS studies including eight hydrocarbons, six free fatty acids, 11 fatty acids esters, two phenylpropanoids, four aromatics, four terpenoid quinones/hydroquinones, three triterpenes, four phytosterols, two hexose metabolites and a DNA base. Of these, 32 constituents have been reported for the first time from C. rothii, 24 from genus Cordia and 15 from Boraginaceae.

Discussion and conclusion: Strong antibacterial and antioxidant potential of C. rothii roots may be due to the contribution of phytoconstituents identified through GC-MS studies.     

Persistent hyperinsulinemic hypoglycemia of infancy - nesidioblastosis

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or nesidioblastosis is a rare condition presenting with severe hypoglycemia. Prompt diagnosis and early pancreatectomy can save many of them, in spite of the magnitude of surgery. We present two cases in which near total pancreatectomy was performed with favourable outcome. Both patients are normoglycemic, with one requiring pancreatic enzyme supplements.     

Rectal prolapse: an unusual presentation of malakoplakia in a child

A case of a young girl is presented. The main concern was recurrent rectal prolapse not responding to conservative and sclerotherapy. Colonoscopy showed diffuse colitis with superficial ulcerations and pseudopolyps. Colon biopsies finally showed classical features of malakoplakia confirmed by histopathological test. Conservative treatment failed and ultimately proctocolectomy was performed with ileoanal endorectal anastomosis.     

Gene expression profiling of the peripheral blood mononuclear cells of offspring of one type 2 diabetic parent

Several lines of evidence from studies of both twins and offspring of people with type 2 diabetes have shown the importance of genetics in its pathogenesis. Impaired glucose tolerance (IGT) may reflect these genetic changes during the prediabetic stage. Thus, we performed a comprehensive analysis of the gene expression profiles of the peripheral blood mononuclear cells among offspring of one type 2 diabetic parent with normal glucose tolerance and impaired glucose tolerance in comparison to newly diagnosed diabetics and normal controls. Data were analysed from offspring of one type 2 diabetic parent. Gene expression profiles of 84 genes related to insulin-responsive genes were analysed using human insulin signalling pathway array. Of the 84 genes, 42 diabetic genes had at least a twofold change in expression for at least one comparison between the diabetic subjects, offspring with NGT and offspring with IGT as compared with controls. The most significant findings were that FOXP3 and SNAP25 were highly expressed in the offspring with IGT as compared with the controls, with a sixfold change in expression. The differential expression of the 42 genes among the offspring with IGT mainly demonstrates a defect in insulin secretion which suggests β cell dysfunction. The preponderance of experimental evidence favours the presence of impaired rather than excessive insulin secretion in the offspring before the development of IGT and thus supports the concept that the initial lesion in type 2 diabetes may involve impaired insulin secretion rather than insulin resistance. The results from our study suggest that β cell dysfunction starts early in the pathologic process and does not necessarily follow the stage of insulin resistance.     

The cancer testis antigens CABYR-a/b and CABYR-c are expressed in a subset of colorectal cancers and hold promise as targets for specific immunotherapy

Introduction: Calcium-binding tyrosine phosphorylation-regulated protein (CABYR) is expressed in the human germ line but not in adult human tissues, thus, it is considered a cancer testis protein. The aim of this study is to evaluate the CABYR isoforms: a/b and c mRNA expression in colorectal cancer (CRC) and to determine if these proteins hold promise as vaccine targets.Materials and Methods: CABYR mRNA expression in a set of normal human tissues, including the testis, were determined and compared using semi-quantitative PCR. As regards the tumor and normal mucosal samples from study patients, RNA was extracted and cDNA generated after which quantitative PCR was carried out. Analysis of CABYR protein expressions by immunohistochemistry in tumor and normal colon tissues was also performed.Results: A total of 47 paired CRC and normal tissue specimens were studied. The percent of patients with a relative expression ratio of malignant to normal (M/N) tissues over 1 was 70% for CABYR a/b and 72% for CABYR c. The percent with both a M/N ratio over 1 and expression levels over 0.1% of testis was 23.4% for CABYR-a/b and 25.5% for CABYR c. CABYR expression in tumors was further confirmed by immunohistochemistry.Conclusions: CABYR a/b and c hold promise as specific immunotherapy targets, however, a larger and more diverse group of tumors (Stage 1-4) needs to be assessed and evaluation of blood for anti-CABYR antibodies is needed to pursue this concept.     

Exploring synthetic and therapeutic prospects of new thiazoline derivatives as aldose reductase (ALR2) inhibitors

Inhibition of aldose reductase (ALR2) by using small heterocyclic compounds provides a viable approach for the development of new antidiabetic agents. With our ongoing interest towards aldose reductase (ALR2) inhibition, we have synthesized and screened a series of thiazoline derivatives (5a–k, 6a–f, 7a–1 & 8a–j) to find a lead as a potential new antidiabetic agent. The bioactivity results showed the thiazoline-based compound 7b having a benzyl substituent and nitrophenyl substituent-bearing compound 8e were identified as the most potent molecules with IC₅₀ values of 1.39 ± 2.21 μM and 1.52 ± 0.78 μM respectively compared with the reference sorbinil with an IC₅₀ value of 3.14 ± 0.02 μM. Compound 7b with only 23.4% inhibition for ALR1 showed excellent selectivity for the targeted ALR2 to act as a potential lead for the development of new therapeutic agents for diabetic complications.

Inhibition of aldose reductase (ALR2) by using small heterocyclic compounds provides a viable approach for the development of new antidiabetic agents.