Trypanosoma brucei Glycogen Synthase Kinase-3, A Target for Anti-Trypanosomal Drug Development: A Public-Private Partnership to Identify Novel Leads

Over 60 million people in sub-Saharan Africa are at risk of infection with the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT), also known as sleeping sickness. The disease results in systemic and neurological disability to its victims. At present, only four drugs are available for treatment of HAT. However, these drugs are expensive, limited in efficacy and are severely toxic, hence the need to develop new therapies. Previously, the short TbruGSK-3 short has been validated as a potential target for developing new drugs against HAT. Because this enzyme has also been pursued as a drug target for other diseases, several inhibitors are available for screening against the parasite enzyme. Here we present the results of screening over 16,000 inhibitors of human GSK-3β (HsGSK-3) from the Pfizer compound collection against TbruGSK-3 short. The resulting active compounds were tested for selectivity versus HsGSK-3β and a panel of human kinases, as well as their ability to inhibit proliferation of the parasite in vitro. We have identified attractive compounds that now form potential starting points for drug discovery against HAT. This is an example of how a tripartite partnership involving pharmaceutical industries, academic institutions and non-government organisations such as WHO TDR, can stimulate research for neglected diseases

Telomeric DNA induces apoptosis and senescence of human breast carcinoma cells

INTRODUCTION: Cancer is a leading cause of death in Americans. We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways. METHODS: The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos). SCID mice received intravenous injections of MCF-7 cells followed by intravenous administration of T-oligos. RESULTS: Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent. In MCF-7 cells, experimental telomere loop disruption caused identical responses, consistent with the hypothesis that T-oligos act by mimicking telomere overhang exposure. In vivo, T-oligos greatly prolonged survival of SCID mice following intravenous injection of human breast carcinoma cells. CONCLUSION: By inducing DNA damage-like responses in MCF-7 cells, T-oligos provide insight into innate cancer avoidance mechanisms and may offer a novel approach to treatment of breast cancer and other malignancies

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Envelhecimento vocal em idosos instucionalizados Vocal aging of institutionalized elderly people

OBJETIVOS: avaliar de forma perceptivo-auditiva as características vocais de idosos institucionalizados, identificar se essas características interferem no processo de comunicação e correlacioná-las com a avaliação das estruturas do sistema estomatognático e do padrão de fala. MÉTODOS: estudo clínico do tipo transversal, no qual foram realizadas anamneses e avaliações fonoaudiológicas em uma amostra aleatória de 48 indivíduos idosos, residentes na Casa do Ancião Francisco Azevedo - Belo Horizonte/MG, que não apresentavam nenhum tipo de alteração neurológica, uma vez que, buscou-se traçar as manifestações fonoaudiológicas de idosos em processo de envelhecimento sadio. Utilizou-se protocolos específicos, desenvolvidos pelas autoras, de acordo com os aspectos pertinentes aos objetivos do presente estudo. RESULTADOS: na avaliação perceptivo-auditiva da qualidade vocal, constatou-se predominantemente qualidade vocal rouca (70,8%), em grau moderado (33,3%), loudness reduzida (56,2%), pitch grave (62,5%) e tempos máximos de fonação reduzidos (81,2%). Dos 48 participantes, 85,4% relataram que a voz não interfere no processo de comunicação. Em relação aos padrões de fala, predominaram inteligibilidade preservada (83,3%), articulação preservada (72,9%) e precisão articulatória preservada (83,3%). CONCLUSÕES: existem alterações nos parâmetros referentes à voz decorrentes da idade, sendo que elas não interferem na comunicação e mantêm relação diversa com outras mudanças nas estruturas do sistema estomatognático. Este estudo veio complementar as pesquisas na área de voz envolvendo indivíduos da terceira idade, sob processo de envelhecimento sadio e residentes em instituições de longa permanência.<br>PURPOSES: to investigate vocal aspects related to healthy aging in the institutionalized elderly people, and to identify if these aspects interfer with communication and correlate vocal changes with motor oral system evaluation and speech patterns. METHODS: transversal clinic research in which the methods used were interview and phonoaudiological examination of a randomized sample of 48 aged patients, resident in Casa do Ancião Francisco Azevedo - Belo Horizonte/MG, who did not show neurological disabilities. Specific protocols were used, developed by the authors, according to aspects related to the purposes of this study RESULTS: vocal parameters were analyzed and the following conditions were observed: hoarse voice (70,8%), in moderate degree (33,3%), reduced loudness (56,2%), bass pitch (62,5%) and short maximum phonation periods (81,2%). About 41 (85,4%) patients reported that vocal problems do not interfer with their communication process. Normal aging did not result directly in alterations in speech patterns, but changes in motor oral system due to health aging showed different associations with those patterns. CONCLUSIONS: this study showed the presence of alterations in the aspects related to voice but they do not interfer with the communication process. There were not alterations in speech patterns due to health aging but changes in motor oral system showed different association with those patterns. This study has contributed to improve knowledge about voice and elderly that suffer changes due to health aging and live in old people's homes

A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment