O receptor do peptídeo liberador de gastrina como novo alvo terapêutico para o tratamento da disfunção cognitiva associada à Doença de Alzheimer

Increasing evidence indicates that bombesin (BB)-like peptides (BLPs), such as the gastrin-releasing peptide (GRP) and its receptor (GRPR), might play a role in neurological and psychiatric disorders. The present study reviews fi ndings from animal and human studies suggesting that the GRPR should be considered a target for the treatment of cognitive dysfunction in patients with Alzheimer’s disease (AD). Abnormalities in GRPR-triggered signaling have been described in both fi broblasts from patients with AD, and in transgenic mouse models of AD. Pharmacological and genetic preclinical studies have indicated that BLPs and the GRPR are importantly involved in regulating cognitive function. Moreover, drugs acting at the GRPR have been shown to enhance memory and ameliorate cognitive dysfunction in experimental models of amnesia associated with AD. Taken together, these fi ndings support the view that the GRPR is a novel therapeutic target for the treatment of memory defi cits associated with AD.Estudos recentes indicam que os peptídeos da família da bombesina (BB), como o peptídeo liberador de gastrina (GRP) e seu receptor (GRPR), podem estar envolvidos em doenças neurológicas e psiquiátricas. Este artigo apresenta uma revisão de estudos tanto em humanos como em modelos animais que sugerem que o GRPR deve ser considerado um alvo molecular para o desenvolvimento de novas terapias para o tratamento de défi cits cognitivos em pacientes com doença de Alzheimer (DA). Anormalidades na sinalização celular dependente do GRPR têm sido descritas tanto em fi broblastos de pacientes com DA como em modelos de DA em camundongos transgênicos. Além disso, estudos pré-clínicos utilizando estratégias farmacológicas e genéticas indicam que os peptídeos da família da BB e o GRPR estão envolvidos de forma importante na regulação da função cognitiva. Finalmente, resultados recentes mostram que drogas que agem como ligantes do GRPR podem melhorar a memória e prevenir disfunções cognitivas em modelos experimentais de amnésia asssociada à DA. Em conjunto, os dados indicam que o GRPR é um novo alvo terapêutico para o tratamento de défi cits de memória associadas à DA. Palavras-chave: bombesina, peptídeo liberador de gastrina, receptor do peptídeo liberador de gastrina, facilitadores cognitivos, disfunções de memória, doença de Alzheimer

Survival with nal-IRI (liposomal irinotecan) plus 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in per-protocol and non-per-protocol populations of NAPOLI-1 : expanded analysis of a global phase 3 trial

Background: In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population. Materials and methods: The PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed. Results: For PP patients, median OS was 8.9 (95% confidence interval: 6.4–10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0–7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3–5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7–3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648). Conclusion: A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population

Inovação em saúde: conquistas e desafios

Desde que a palavra inovação foi introduzida por Joseph Schumpeter na teoria do desenvolvimento econômico, ampliou-se muito nossa compreensão sobre sua importância para estruturas produtivas. No Brasil, o crescente interesse em inovação é fruto não apenas da necessidade de produzir tecnologia de alto valor agregado e impacto social, mas também da capacidade dos pesquisadores brasileiros de gerar inovação. O Brasil e o HCPA já possuem comprovada competência num amplo espectro de atividades em inovação em saúde e têm potencial de ampliar ainda mais sua atuaçã

RNA expression of the molecular signature genes for metastasis in colorectal cancer

Colorectal cancer is an endemic disease in the Western world. Search for molecular signatures present in primary tumors that predict tumor metastasis potential has been proposed and in particular, a 17-gene molecular signature is associated with poor survival in breast cancer, prostate cancer, meduloblastoma and lymphoma in a recent study. Using quantitative real-time PCR assay (qPCR), our study observed tumor-normal differential RNA expression in 15 of these 17 genes in a cohort of 52 stage III colorectal cancer patients (all P0.05), two distinct groups among these genes were observed with Spearman correlation scores >0.6 (P0.05), but the recurrence group had more patients with mucinous tumors (9/12 vs. 7/25, P<0.05) and more lymph node involvement (median 7.2 vs. 2.5, P<0.05) compared to the non-recurrence group. Moreover, survival analysis revealed a significant difference in patient overall survival time between low and high tumor RNA levels for 1 of the 17 genes (PTTG1, P=0.024). Our qPCR validation study confirms the importance of most 17-gene molecular signature genes with differential RNA expression and suggests the relevance of PTTG1 for survival in colorectal cancers

De-mystifying the epigenetic free for all : pharmacophore modeling for epigenetic cancer therapy

Epigenetic regulators have quickly become one of the most widely studied therapeutic agents for a vast array of diseases, making histone deacetylase inhibitors (HDIs) and DNA methyl-transferase (DNMT) inhibitors commonly used molecules in pre-clinical and clinical anti-cancer studies. Their ability to regulate gene expression and to potentiate the effects of other chemotherapeutic drugs has put HDIs and DNMT inhibitors in the spotlight not only as single agents, but also as combined therapy. The plethora of HDIs and DNMT inhibitors available nowadays has led to promising results in Phase I, II and III clinical oncology studies. While it was first believed that these molecules would all have an additive or synergistic effect when combined with the classical chemotherapeutic drugs available, our group and others have shown that epigenetic regulators potentiate the effects of some, but not all, anti-cancer molecules. Pharmacophore modeling may therefore serve the purpose to optimize pre-clinical research and to develop more efficient and targeted therapies incorporating epigenetic regulators

International scientific collaboration in HIV and HPV: a network analysis.

Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis. Through a systematic review of the literature, we obtained epidemiological data, as well as data on countries and authors involved in co-infection studies. The collaboration network was analysed in respect to the following: centrality, density, modularity, connected components, distance, clustering and spectral clustering. We observed that for many low- and middle-income countries there were no epidemiological estimates of HPV infection of the cervix among HIV-infected individuals. Most studies found only involved researchers from the same country (64%). Studies derived from international collaborations including high-income countries and either low- or middle-income countries had on average three times larger sample sizes than those including only high-income countries or low-income countries. The high global clustering coefficient (0.9) coupled with a short average distance between researchers (4.34) suggests a "small-world phenomenon." Researchers from high-income countries seem to have higher degree centrality and tend to cluster together in densely connected communities. We found a large well-connected community, which encompasses 70% of researchers, and 49 other small isolated communities. Our findings suggest that in the field of HIV and HPV, there seems to be both room and incentives for researchers to engage in collaborations between countries of different income-level. Through international collaboration resources available to researchers in high-income countries can be efficiently used to enroll more participants in low- and middle-income countries

Treatment of Breast Cancer in Countries with Limited Resources

Early and accurate diagnosis of breast cancer is important for optimizing treatment. Local treatment of early stage breast cancer involves either mastectomy or breast-conserving surgery followed by whole-breast irradiation. The pathologic and biologic properties of a woman's breast cancer may be used to estimate her probability for recurrence of and death from breast cancer, as well as the magnitude of benefit she is likely to receive from adjuvant endocrine therapy or cytotoxic chemotherapy. Ovarian ablation or suppression with or without tamoxifen is an effective endocrine therapy in the adjuvant treatment of breast cancer in premenopausal women with estrogen receptor (ER)-positive or ER-unknown breast cancer. In postmenopausal women with ER- and/or progesterone receptor (PR)-positive or PR-unknown breast cancer, the use of tamoxifen or anastrozole is effective adjuvant endocrine therapy. The benefit of tamoxifen is additive to that of chemotherapy. Cytotoxic chemotherapy also improves recurrence rates and survival, with the magnitude of benefit decreasing with increasing age. Substantial support systems are required to optimally and safely use breast-conserving approaches to local therapy or cytotoxic chemotherapy as systemic therapy. Locally advanced breast cancer (LABC) accounts for at least half of all breast cancers in countries with limited resources and has a poor prognosis. Initial treatment of LABC with anthracycline-based chemotherapy is standard and effective. Addition of a sequential, neoadjuvant taxane thereafter increases the rate of pathologic complete responses. Neoadjuvant endocrine therapy may benefit postmenopausal women with hormone receptor-positive LABC. After an initial response to neoadjuvant chemotherapy, the use of local-regional surgery is appropriate. Most women will require a radical or modified radical mastectomy. In those women in whom mastectomy is not possible after neoadjuvant chemotherapy, the use of whole-breast and regional lymph node irradiation alone is appropriate. In those women who cannot receive neoadjuvant chemotherapy because of resource constraints, mastectomy with node dissection, when feasible, may still be considered in an attempt to achieve local-regional control. After local-regional therapy, most women should receive additional systemic chemotherapy. Women with LABC that has a positive or unknown hormone receptor status benefit from endocrine therapy with tamoxifen. The treatment of LABC requires multiple disciplines and is resource intensive. Efforts to reduce the number of breast cancers diagnosed at an advanced stage thus have the potential to improve rates of survival while decreasing the use of limited resources

Efeitos do bloqueio de receptores GRPR sobre o crescimento de gliomas humanos in vitro

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