Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

From Golden Rice to Golden Diets: How to turn its recent approval into practice.

Following its approval in the Philippines in July 2021, provitamin A-rich "Golden Rice" is set to become the worlds' first commercialized genetically modified crop with direct consumer benefits. Despite supplementation and fortification programs, the burden of micronutrient deficiencies remains high. For Golden Rice to be successful in reducing vitamin A deficiency, it needs to be taken up by food systems and integrated into consumer diets. Despite negative information often being associated with genetic engineering, evidence suggests that consumers react positively to Golden Rice. Thus, it offers policy makers and public health stakeholders a new, powerful option to address micronutrient malnutrition that they can integrate as a cost-effective component in broader nutrition strategies and tailor it to consumers' heterogeneous socio-economic contexts and needs to promote "Golden Diets". For this to happen, the right framing of the pathway from policy to consumption is crucial.

[Biliary tract cancer: on the way to a personalized therapy]. / Gallengangs- und Gallenblasenkarzinome: auf dem Weg zur personalisierten Therapie.

Biliary tract cancer (BTC) is a rare disease with a heterogeneous nomenclature. Carcinomas of the intra- and extrahepatic biliary tract as well as gallbladder cancer are oftentimes combined in clinical research and treatment algorithms. However, these different cancer types vary not only in their anatomical features, but also in the underlying molecular alterations.Surgery remains the only chance of cure. Adjuvant chemotherapy with capecitabine for 6 months should be recommended after curative intended surgery. In the palliative first-line treatment of advanced BTC, the combination chemotherapy gemcitabine and cisplatin remains the only evidence-based standard. For second-line treatment, the combination of 5-FU, folinic acid and oxaliplatin (FOLFOX) is a treatment option based on preliminary data from a randomized phase 3 study. Potential targeted therapies showing efficacy in prospective clinical studies are, for example, IDH-, BRAF-/MEK- and FGFR-inhibitors as well as immunotherapy. Therefore, in the era of personalized medicine, molecular testing should be offered to all patients with advanced disease and indication for systemic treatment.

The social and economic impact of biofortification through genetic modification.

Genetic modification (GM) has been advocated as an alternative or complement to micronutrient interventions such as supplementation, fortification or dietary diversification. While proof-of-concept of various GM biofortified crops looks promising, the decision tree of policy makers is much more complex, and requires insight on their socio-economic impacts: Will it actually work? Is it financially sound? Will people accept it? Can it be implemented in a globalized world? This review shows that GM biofortification could effectively reduce the burden of micronutrient deficiencies, in an economically viable way, and is generally well received by target beneficiaries, despite some resistance and uncertainty. Practically, however, protectionist and/or unscientific regulations in some developed countries raise the (perceived) bar for implementation in target countries.

Soil-type influences human selenium status and underlies widespread selenium deficiency risks in Malawi.

Selenium (Se) is an essential human micronutrient with critical roles in immune functioning and antioxidant defence. Estimates of dietary Se intakes and status are scarce for Africa although crop surveys indicate deficiency is probably widespread in Malawi. Here we show that Se deficiency is likely endemic in Malawi based on the Se status of adults consuming food from contrasting soil types. These data are consistent with food balance sheets and composition tables revealing that >80% of the Malawi population is at risk of dietary Se inadequacy. Risk of dietary Se inadequacy is >60% in seven other countries in Southern Africa, and 22% across Africa as a whole. Given that most Malawi soils cannot supply sufficient Se to crops for adequate human nutrition, the cost and benefits of interventions to alleviate Se deficiency should be determined; for example, Se-enriched nitrogen fertilisers could be adopted as in Finland.

Oxaliplatin: a review of approved uses.

INTRODUCTION: Oxaliplatin, a second-generation platinum analog, has evolved as one of the most important therapeutic agents in colorectal cancer (CRC) treatment. It has had a major impact on the management and outcome of this disease. AREAS COVERED: The pharmacokinetic and pharmacodynamic data of oxaliplatin are reviewed in this paper. It also discusses the current clinical data regarding the use of oxaliplatin in early colon cancer, locally advanced rectal cancer, and in the metastatic setting, with a particular reference to its combination with monoclonal antibodies, and strategies for prevention of cumulative toxicity. EXPERT OPINION: Oxaliplatin has proven beneficial in the treatment of CRC and can currently be regarded as one of the three most important chemotherapeutic drugs used in the treatment of both metastatic disease and adjuvant therapy in stage II/III after resection. With regards to a median overall survival of more than 20 months, and a median progression-free survival for first-line treatment of about 9 - 10 months, the majority of patients will receive all three compounds (oxaliplatin, fluoropyrimidines and irinotecan) during the course of their disease. At the moment there are no drugs in late clinical development which might be able to substitute oxaliplatin in its unique role in CRC.

Synaptic vesicles are constitutively active fusion machines that function independently of Ca2+.

BACKGROUND: In neurons, release of neurotransmitter occurs through the fusion of synaptic vesicles with the plasma membrane. Many proteins required for this process have been identified, with the SNAREs syntaxin 1, SNAP-25, and synaptobrevin thought to constitute the core fusion machinery. However, there is still a large gap between our understanding of individual protein-protein interactions and the functions of these proteins revealed by perturbations in intact synaptic preparations. To bridge this gap, we have used purified synaptic vesicles, together with artificial membranes containing core-constituted SNAREs as reaction partners, in fusion assays. RESULTS: By using complementary experimental approaches, we show that synaptic vesicles fuse constitutively, and with high efficiency, with proteoliposomes containing the plasma membrane proteins syntaxin 1 and SNAP-25. Fusion is inhibited by clostridial neurotoxins and involves the formation of SNARE complexes. Despite the presence of endogenous synaptotagmin, Ca(2+) does not enhance fusion, even if phosphatidylinositol 4,5-bisphosphate is present in the liposome membrane. Rather, fusion kinetics are dominated by the availability of free syntaxin 1/SNAP-25 acceptor sites for synaptobrevin. CONCLUSIONS: Synaptic vesicles are constitutively active fusion machines, needing only synaptobrevin for activity. Apparently, the final step in fusion does not involve the regulatory activities of other vesicle constituents, although these may be involved in regulating earlier processes. This is particularly relevant for the calcium-dependent regulation of exocytosis, which, in addition to synaptotagmin, requires other factors not present in the vesicle membrane. The in vitro system described here provides an ideal starting point for unraveling of the molecular details of such regulatory events.

Potential impacts of iron biofortification in India.

Iron deficiency is a widespread nutrition and health problem in developing countries, causing impairments in physical activity and cognitive development, as well as maternal mortality. Although food fortification and supplementation programmes have been effective in some countries, their overall success remains limited. Biofortification, that is, breeding food crops for higher micronutrient content, is a relatively new approach, which has been gaining international attention recently. We propose a methodology for ex ante impact assessment of iron biofortification, building on a disability-adjusted life years (DALYs) framework. This methodology is applied in an Indian context. Using a large and representative data set of household food consumption, the likely effects of iron-rich rice and wheat varieties are simulated for different target groups and regions. These varieties, which are being developed by an international public research consortium, based on conventional breeding techniques, might be ready for local distribution within the next couple of years. The results indicate sizeable potential health benefits. Depending on the underlying assumptions, the disease burden associated with iron deficiency could be reduced by 19-58%. Due to the relatively low institutional cost to reach the target population, the expected cost-effectiveness of iron biofortification compares favourably with other micronutrient interventions. Nonetheless, biofortification should not be seen as a substitute for other interventions. Each approach has its particular strengths, so they complement one another.

Plant breeding to control zinc deficiency in India: how cost-effective is biofortification?

OBJECTIVE: To estimate the potential impact of zinc biofortification of rice and wheat on public health in India and to evaluate its cost-effectiveness compared with alternative interventions and international standards. DESIGN: The burden of zinc deficiency (ZnD) in India was expressed in disability-adjusted life years (DALYs) lost. Current zinc intakes were derived from a nationally representative household food consumption survey (30-day recall) and attributed to household members based on adult equivalent weights. Using a dose-response function, projected increased zinc intakes from biofortified rice and wheat were translated into potential health improvements for pessimistic and optimistic scenarios. After estimating the costs of developing and disseminating the new varieties, the cost-effectiveness of zinc biofortification was calculated for both scenarios and compared with alternative micronutrient interventions and international reference standards. SETTING: India. SUBJECTS: Representative household survey (n = 119 554). RESULTS: The calculated annual burden of ZnD in India is 2.8 million DALYs lost. Zinc biofortification of rice and wheat may reduce this burden by 20-51% and save 0.6-1.4 million DALYs each year, depending on the scenario. The cost for saving one DALY amounts to $US 0.73-7.31, which is very cost-effective by standards of the World Bank and the World Health Organization, and is lower than that of most other micronutrient interventions. CONCLUSIONS: Not only may zinc biofortification save lives and prevent morbidity among millions of people, it may also help accommodate the need to economise and to allocate resources more efficiently. Further research is needed to corroborate these findings.