The neuroblastoma tumour-suppressor trkAI and its oncogenic alternative trkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells

Hsp90 chaperones stabilize many tyrosine kinases including several oncogenes, which are inhibited or induced to degrade by the Hsp90 inhibitor geldanamycin (GA). As a consequence, GA has been developed for future chemotherapeutic use in several tumour types including neuroblastoma (NB). Alternative splicing of the neurotrophin receptor tyrosine kinase TrkA may have a pivotal function in regulating NB behaviour, with reports suggesting that tumour-suppressing signals from TrkA may be converted to oncogenic signals by stress-regulated alternative TrkAIII splicing. Within this context, it is important to know whether Hsp90 interacts with TrkA variants in NB cells and how GA influences this. Here, we report that both TrkAI and TrkAIII are Hsp90 clients in human NB cells. TrkAI exhibits GA-sensitive interaction with Hsp90 required for receptor endoplasmic reticulum export, maturation, cell surface stabilization and ligand-mediated activation, whereas TrkAIII exhibits GA-sensitive interactions with Hsp90 required for spontaneous activity and to a lesser extent stability. We show that GA inhibits proliferation and induces apoptosis of TrkAI expressing NB cells, whereas TrkAIII reduces the sensitivity of NB cells to GA-induced elimination. Our data suggest that GA-sensitive interactions with Hsp90 are critical for both TrkAI tumour suppressor and TrkAIII oncogenic function in NB and that TrkAIII expression exerts a negative impact on GA-induced NB cell eradication, which can be counteracted by a novel TrkAIII-specific peptide nucleic acid inhibitor

Intoxicação natural por Clostridium botulinum tipo “C” em grupo de aves domésticas.

Clostridium botulinum causative oftoxic infections due to toxin ingestion previouslyformed, occur in several ingestion species, mainlybirds. In a poultry farm, located at São Paulo State,more than 3,000 birds have been attacked by thistoxic infections, when the birds showed motionless,loss of weight, accelerated, breathing, resulting indeath of the birds. The blood harvest for attainmentof the serum and later necropsy was carried outthrowgh the following samples: liver, gizzard, crop,feed, water and litter. After that, the toxin wasextracted by gelatin-phosphate buffer and inoculationin mice, isolation of the agent in Blood ágar andReinforced Clostridium ágar and neutralization oftoxin determine its type. The inoculation in miceshowed positive results in samples of liver, gizzad,crop and symptoms like was waist, and death ofthe birds by limp paralysis. The colonies that havebeen isolated, suspected of Clostridium botulinumshowed expected results and further analysisrevealed positive results to botulinical toxin type C.The farms have to pay attention in the routine jobs,choicer, and elimination of carcass because theyare essential to keep this problem away.O Clostridium botulinum, causador detoxinfecção devido à ingestão de toxina previamenteformada, acomete várias espécies com destaquepara as aves. Em uma granja do estado deSão Paulo, mais de 3000 aves foram acometidaspor esta toxinfecção, a qual foi caracterizada poranimais imóveis, dispnéicos, anoréxicos, paralisiaflácida e morte subseqüente. Foi realizada a colheitade sangue para obtenção do soro e posteriornecropsia sendo que as amostras separadas paraanálise foram: fígado, conteúdo da moela e do inglúvio,ração, água e cama. Foram realizadas extraçãode toxina em gelatina tamponada e inoculaçãoem camundongos, isolamento do agente em meioAgar Sangue, “Reinforced Clostridium ágar“ e neutralizaçãoda toxina para especificação de seu tipo.A inoculação em camundongos apresentou positividadepara amostras do fígado, conteúdo da moelae do inglúvio, pela observação de cintura de vespae morte dos animais por paralisia flácida. Colôniasisoladas suspeitas de Clostridium botulinum apresentarambioquímica compatível com a da espéciee a análise com a antitoxina revelou positividadepara toxina botulínica tipo C. A conscientização doprodutor para um bom manejo e eliminação adequadade carcaças são práticas fundamentais para evitar casos como este

Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy

Review article[Abstract] The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy

Bolsa Família: um survey sobre os efeitos do programa de transferência de renda condicionada do Brasil

Revisam-se pesquisas sobre efeitos do Programa Bolsa Família. Há quatro evidências frequentes. A primeira é que o programa tem focalização relativamente boa, mas que pode ainda ser melhorada. A segunda é o efeito positivo sobre a aquisição (consumo) de alimentos – sem conclusões sobre a qualidade da dieta. A terceira diz respeito ao estimulo às crianças a participarem da escola (matrícula, frequência e progressão), embora pouco se saiba sobre os efeitos na aprendizagem. A ausência de efeitos sobre a fecundidade das mulheres caracteriza a quarta conclusão robusta que se pode tirar da literatura, ainda que mais estudos devam ser realizados. Em outras dimensões, as evidências não formam consenso sobre direção dos efeitos.This paper surveys the literature about the effects of Bolsa Familia Program. We found four main results. The first is that the program is relatively well targeted, but it can still be improved.The second is the positive effect on the acquisition (consumption) of food, but there is no conclusions about the quality of the diet. The third is that the program encourages children to attend school (enrollment, attendance and progression). However, little is known about the effects on learning. The absence of effects on the fecundity of the women characterizes the fourth conclusion that can be drawn from the literature, although more studies must be carried out on this topic. In other dimensions, the evidence does not form consensus on the direction of effects

Myeloid cell diversification and complexity: an old concept with new turns in oncology.

Tumour development is accompanied by an enhanced haematopoiesis. This is not a widespread activation since only cells belonging to the myelo-monocytic compartment are expanded and mobilized from primary sites of haematopoiesis to other organs, reaching also the tumour stroma. This process occurs early during tumour formation but becomes more evident in advanced disease. Far from being a simple, unwanted consequence of cancer development, accumulation of myelo-monocytitc cells plays a role in tumour vascularization, local spreading, establishment of metastasis at distant sites, and contribute to create an environment unfavourable for the adoptive immunity against tumour-associated antigens. Myeloid populations involved in these process are likely different but many cells, expanded in primary and secondary lymphoid organs of tumour-bearing mice, share various levels of the CD11b and Gr-1 (Ly6C/G) markers. CD11b(+)Gr-1(+) cells are currently named myeloid-derived suppressor cells for their ability to inhibit T lymphocyte responses in tumour-bearing hosts. In this manuscript, we review the recent literature on tumour-conditioned myeloid subsets that assist tumour growth, both in mice and humans

The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells

Hsp90 chaperones stabilize many tyrosine kinases including several oncogenes, which are inhibited or induced to degrade by the Hsp90 inhibitor geldanamycin (GA). As a consequence, GA has been developed for future chemotherapeutic use in several tumour types including neuroblastoma (NB). Alternative splicing of the neurotrophin receptor tyrosine kinase TrkA may have a pivotal function in regulating NB behaviour, with reports suggesting that tumour-suppressing signals from TrkA may be converted to oncogenic signals by stress-regulated alternative TrkAIII splicing. Within this context, it is important to know whether Hsp90 interacts with TrkA variants in NB cells and how GA influences this. Here, we report that both TrkAI and TrkAIII are Hsp90 clients in human NB cells. TrkAI exhibits GA-sensitive interaction with Hsp90 required for receptor endoplasmic reticulum export, maturation, cell surface stabilization and ligand-mediated activation, whereas TrkAIII exhibits GA-sensitive interactions with Hsp90 required for spontaneous activity and to a lesser extent stability. We show that GA inhibits proliferation and induces apoptosis of TrkAI expressing NB cells, whereas TrkAIII reduces the sensitivity of NB cells to GA-induced elimination. Our data suggest that GA-sensitive interactions with Hsp90 are critical for both TrkAI tumour suppressor and TrkAIII oncogenic function in NB and that TrkAIII expression exerts a negative impact on GA-induced NB cell eradication, which can be counteracted by a novel TrkAIII-specific peptide nucleic acid inhibito