Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma

Purpose The purpose of this study was to define the contribution of docetaxel to combination chemotherapy in the outcome of patients with advanced gastric or gastroesophageal adenocarcinoma. We compared the overall response rate (ORR) and safety of docetaxel plus cisplatin (DC) with DC plus fluorouracil (DCF) to select either DC or DCF as the experimental treatment in the ensuing phase III part of trial V-325. Patients and Methods In this phase II randomized study, untreated patients with confirmed advanced gastric or gastroesophageal adenocarcinoma received either DCF (docetaxel 75 mg/m(2), cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2)/d as continuous infusion on days 1 to 5) or DC (docetaxel 85 mg/m(2) and cisplatin 75 mg/m(2) on day 1) every 3 weeks. An independent data monitoring committee (IDMC) was to select one of the two regimens based primarily on ORR and safety profile. Results Of 158 randomly assigned patients, 155 (DCF, n = 79; DC, n = 76) received treatment. The confirmed ORR was 43% for DCF (n = 79) and 26% for DC (n = 76). Median time to progression was 5.9 months for DCF and 5.0 months for DC. Median overall survival time was 9.6 months for DCF and 10.5 months for DC. The most frequent grade 3 and 4 events per patient included neutropenia (DCF = 86%; DC = 87%) and GI (DCF = 56%; DC = 30%). Conclusion Both regimens were active, but DCF produced a higher confirmed ORR than DC. Toxicity profiles of DCF were considered manageable. The IDMC chose DCF for the phase III part of V-325, which compares DCF with cisplatin plus fluorouracil

Relationship between the nucleolar cycle and chromatoid body formation in the spermatogenesis of Phrynops geoffroanus (Reptilia Testudines)

The nucleolus is a distinct nuclear territory involved in the compartmentalization of nuclear functions. There is some evidence of a relationship between nuclear fragmentation during spermatogenesis and chromatoid body (CB) formation. The CB is a typical cytoplasmic organelle of haploid germ cells, and is involved in RNA and protein accumulation for later germ-cell differentiation. The goal of this study was to qualitatively and quantitatively describe the nucleolar cycle during the spermatogenesis of Phrynops geoffroanus (Reptilia Testudines), and compare this nucleolar fragmentation with CB formation in this species through the use of cytochemical and ultrastructural analysis. Qualitative analysis showed a fragmentation of the nuclear material after pachytene of the first meiotic division in the primary spermatocytes. Quantitative analysis of the nucleolar cycle revealed a significant difference in the number of nucleoli and in the size of the nucleolus between spermatogonia and early spermatids. Using ultrastructural analysis, we recorded the beginning of the CB formation process in the cytoplasm of primary spermatocytes at the same time as when nuclear fragmentation occurs. In the cytoplasm of primary spermatocytes, the CB was observed in association with mitochondrial aggregates and the Golgi complex. In the cytoplasm of early spermatids, the CB was observed in association with lipid droplets. In conclusion, our data show that the nucleolus plays a role in the CB formation process. During spermatogenesis of P. geoffroanus, the CB is involved in some important biological processes, including acrosome formation and mitochondrial migration to the spermatozoon tail and middle piece region.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Stability studies of a recombinant cutinase immobilized to dextran and derivatized silica supports

Recombinant cutinase from Fusarium solani pisi was covalently attached to dextran and two derivatized silica supports, Biosil-NH2 and Biosil-Dextran-NH2. Kinetic parameters were determined for all three systems as well as for soluble cutinase. Long-term stability in aqueous media was studied; dextran may have a stabilizing role not only due to the covalent links involved but also in the same way as other polyhydroxides in aqueous media. Differential scanning calorimetry analysis suggests an enhancement of conformational stability of the immobilized forms.http://www.sciencedirect.com/science/article/B6TG1-4165DGC-9/1/b62e6c1431e1ea508958b8675595919

Morphological Changes of the Epididymis and Description of the Excurrent Ducts of Phrynops geoffroanus (Testudines: Chelidae) During the Reproductive Cycle

The seminal ducts (efferent ductule, epididymis, and deferent duct) in adults of Phrynops geoffroanus were examined using light microscopy. A series of tubules (efferent ductules) connect the testes to the epididymides. The efferent ductules are formed by a rete of small tubules of varying diameters, with simple columnar epithelium formed by the ciliated cells, nonciliated cells, and few basal cells. The epididymis is a simple, long and highly convoluted tubule that receives the efferent ductules throughout its extension. It is covered by a pseudostratified columnar epithelium with three cellular types: the principal cells, which are the most abundant, basal cells, and a small narrow cell. The histological differences in the epididymis region (cranial, medial, and caudal), as well as the differences in the epithelium throughout the reproductive cycle, are discussed. The deferent ducts consist of a low pseudostratified epithelium with two cellular types: the principal and basal cells. During the months analyzed, spermatozoa were stored in the epididymis, and deferent ducts were found. Anat Rec, 294:145-155, 2011. (C) 2010 Wiley-Liss, Inc.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Prenatal exposure to finasteride promotes sex-specific changes in gerbil prostate development

Finasteride is a drug that is widely used in the treatment of benign prostatic hyperplasia, hair loss and even as a chemotherapeutic agent in the treatment of prostatic adenocarcinoma. However, its use is known to cause several side effects in adults and it can also cause changes in the embryonic development of the male prostate, which is a cause for concern given the possibility of the accumulation of finasteride in the environment. Nevertheless, no studies have investigated the effects of finasteride on the development of the prostate in females, which occurs in several species of mammals. To evaluate the effects of intrauterine exposure to finasteride (500 mg kg 1 day 1 ) on postnatal prostate development in the Mongolian gerbil in the present study, we used immunohistochemistry, immunofluorescence, serological analysis and three-dimensional reconstruction techniques. Differences were observed in the effects of finasteride on periductal smooth muscle and cell proliferation between the sexes, as well as intersex differences in the presence of the androgen receptor, which was elevated in males, and the oestrogen receptor ERa, which was increased in females. Together, the data indicate that the female prostate has its own hormone dynamics and that there are sex-specific differences in the way in which the female prostate reacts to prenatal exposure to finasteride311117191729CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP305840/2015-0; 442630/ 2014-0305840/2015-0; 442630/ 2014-0The authors are grateful to Luiz Roberto Falleiros Junior for technical assistance, as well as colleagues at the Laboratory of Microscopy and Microanalysis. This paper forms part of the M.Sc. thesis presented by Juliana S. Maldarine to the Institute of Biology, UNICAMP, in partial fulfilment of the requirements for an M.Sc. degree. This study was funded by grants from FAPESP (2013/15939-0 and 2016/16509-8) and CNPq (National Council of Scientific and Technological Development; 305840/2015-0 and 442630/ 2014-0

Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer

Purpose Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer. Patients and Methods Patients were randomly assigned to first-or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS). Results In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand-foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively). Conclusion Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.RocheRocheSOLTI GroupSOLTI GroupOnyx PharmaceuticalsOnyx PharmaceuticalsBayer HealthCare PharmaceuticalsBayer HealthCare Pharmaceutical