Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Consumo e digestibilidade aparente total dos nutrientes e ganho de peso de bovinos de corte alimentados com silagem de Brachiaria brizantha e concentrado em diferentes proporções Intake and apparent digestibility of the nutrients and weight gain of beef cattle fed diets with different proportions of Brachiaria brizantha silage and concentrate

Avaliaram-se o consumo e as digestibilidades aparentes totais dos nutrientes e o ganho de peso de bovinos de corte recebendo dietas contendo concentrado e silagem de Brachiaria brizantha cv. Marandu nas seguintes proporções: 20:80, 35:65, 50:50 e 65:35, com base na matéria seca. Foram utilizados vinte e quatro animais castrados Holandês x Zebu, com peso vivo inicial médio de 364 kg, distribuídos em um delineamento em blocos casualizados. Por ocasião da ensilagem, procedeu-se o tratamento do capim com o inoculante enzimo-bacteriano Nutroeste 50 t. Para o cálculo da matéria seca fecal, utilizou-se a fibra em detergente ácido indigestível (FDAI) como indicador. Os animais foram alojados em baias individuais e alimentados ad libitum. O ensaio teve duração de 84 dias, divididos em três períodos de 28 dias após 15 dias de adaptação. Os consumos médios de matéria seca (MS), matéria orgânica (MO), proteína bruta (PB), extrato etéreo (EE) e carboidratos totais (CHO) e as digestibilidades aparentes totais de MS, MO, CHO e carboidratos não-fibrosos (CNF) elevaram linearmente com o aumento dos níveis de concentrado nas dietas. Comportamento semelhante foi observado para o ganho de peso médio diário, estimando-se incrementos de 0,0184 kg/unidade de concentrado adicionado. Contudo, as digestibilidades aparentes de PB, EE e fibra em detergente neutro (FDN) não foram influenciadas pelas dietas, registrando-se, respectivamente, valores médios de 77, 88 e 60%. Silagem de Brachiaria brizantha não-emurchecida, constituindo 50% da dieta de bovinos H x Z, promoveu ganhos de peso em torno de 1,0 kg/dia.<br>Intake and total apparent digestibilities of the nutrients and average daily gains (ADG) by beef cattle fed diets based on concentrate and Brachiaria brizantha cv. Marandu silage in the following proportions: 20:80, 35:65, 50:50 and 65:35, in dry matter basis were evaluated. Twenty-four crossbred (Holstein x Zebu) steers, with initial live weight of 364 kg were allotted to a randomized blocks design. At the ensiling process, an enzyme-bacterial inoculant Nutroeste 50 t was applied to the forage. For the determination of fecal dry matter, indigestible acid detergent fiber was used as a marker. The animals were housed in individual pens and fed ad libitum. The experiment lasted 84 days, divided in three periods of 28 days after 15 days of adaptation. The dry matter (DM), organic matter (OM), crude protein (CP), ether extract (EE) and total carbohydrates (CHO) average intakes increased linearly with the increment of the concentrate in the diets. The total apparent digestibility of DM, OM, CHO and non fiber carbohydrates also increased linearly with the increment of the concentrate levels in the diets. Similar behavior was observed for ADG, with increments of 0.0184 kg/unit of concentrate added. However, apparent digestibilities of CP, EE and digestibility of neutral detergent fiber were not affected by the diets, showing values of 77, 88 and 60%, respectively. No wilted Brachiaria brizantha silage in the 50:50 concentrate to forage ratio for beef cattle Holstein x Zebu steers, promoted average weight gain close to 1.0 kg/day