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This review describes the scientific basis of a research and breeding pathway designed to boost genetic gains in wheat under drought and heat stress., Despite being the world’s most widely grown crop, research investments in wheat (Triticum aestivum and Triticum durum) fall behind those in other staple crops. Current yield gains will not meet 2050 needs, and climate stresses compound this challenge. However, there is good evidence that heat and drought resilience can be boosted through translating promising ideas into novel breeding technologies using powerful new tools in genetics and remote sensing, for example. Such technologies can also be applied to identify climate resilience traits from among the vast and largely untapped reserve of wheat genetic resources in collections worldwide. This review describes multi-pronged research opportunities at the focus of the Heat and Drought Wheat Improvement Consortium (coordinated by CIMMYT), which together create a pipeline to boost heat and drought resilience, specifically: improving crop design targets using big data approaches; developing phenomic tools for field-based screening and research; applying genomic technologies to elucidate the bases of climate resilience traits; and applying these outputs in developing next-generation breeding methods. The global impact of these outputs will be validated through the International Wheat Improvement Network, a global germplasm development and testing system that contributes key productivity traits to approximately half of the global wheat-growing area.

In enhancing the resilience of our crops to the impacts of climate change, selection objectives need to address increased variability in the production environment. This encompasses the effects of more variable rainfall and temperatures than currently experienced, including extreme weather events, and changes in pest and pathogens distribution with the increased likelihood of major pest and disease outbreaks as well as occurrence of novel pathogens. Farmers manage the inevitable risks associated with cropping by planting varieties that deliver high yields and good quality under optimal conditions but minimise losses when the seasons are bad. Breeders and agronomists work to support farmers in specific target environments, but increased climate variability has meant that they need to broaden the adaptability of varieties grown and increase the yield stability to help minimise climate-induced risks and build resilience.

To contain the COVID-19 pandemic, India imposed a national lockdown at the end of March 2020, a decision that resulted in a massive reverse migration as many workers across economic sectors returned to their home regions. Migrants provide the foundations of the agricultural workforce in the ‘breadbasket’ states of Punjab and Haryana in Northwest India.There are mounting concerns that near and potentially longer-term reductions in labor availability may jeopardize agricultural production and consequently national food security. The timing of rice transplanting at the beginning of the summer monsoon season has a cascading influence on productivity of the entire rice-wheat cropping system. To assess the potential for COVID-related reductions in the agriculture workforce to disrupt production of the dominant rice-wheat cropping pattern in these states, we use a spatial ex ante modelling framework to evaluate four scenarios representing a range of plausible labor constraints on the timing of rice transplanting. Averaged over both states, results suggest that rice productivity losses under all delay scenarios would be low as compare to those for wheat, with total system productivity loss estimates ranging from 9%, to 21%, equivalent to economic losses of USD $674 m to $1.48 billion. Late rice transplanting and harvesting can also aggravate winter air pollution with concomitant health risks. Technological options such as direct seeded rice, staggered nursery transplanting, and crop diversification away from rice can help address these challenges but require new approaches to policy and incentives for change., Graphical abstract Unlabelled Image, Highlights • An ex-ante analysis was done using geospatial tools on potential effect of labour shortage on rice-wheat system. • Food grain production loss due to labor shortage can be 23% from current levels of production. • Residue burning will exacerbate air pollution in winter and could coincide with an anticipated COVID resurgence in the fall. • India needs new strategies to use available technological and management innovations to address emerging constraints.

Meeting the growing demand for food over the next 20–30 years will be challenging, mainly because the fastest population growth is occurring in already highly populated developing countries and because producing cereal crops (the main source of nutrients in these countries) requires that serious production constraints, due mainly to the effects of climate change, be overcome. Wheat supplies the most calories and proteins to the global population in the form of diverse wheat-based foods. Wheat-based foods are staples that are major sources of micronutrients that are fundamental for normal development, as well as metabolic and cognitive functioning, from childhood to adulthood. Furthermore, whole grain, wheat-based foods have potential additional health benefits because they contribute fiber and bioactive compounds that can help reduce the risk of chronic conditions, such as cardiovascular disease, type 2 diabetes, and other chronic conditions. In this article, we describe common wheat-based foods consumed ...

Claims made in the popular press allege that grain-based foods, and the carbohydrates (CHOs) they contain, cause or worsen various neurological disorders, including headache, attention deficit hyperactivity disorder (ADHD), and depression. This article reviews the scientific literature to assess the role of these foods in nutrition and their impact on headache, ADHD, and depression. The bulk of the scientific literature shows that nearly all grain-based products are listed as nonoffending foods and are not thought to increase the risk of most types of headaches. When grain-based foods, and their CHOs, are consumed as part of balanced dietary patterns emphasizing an optimal mix of whole and refined grains, such as DASH (Dietary Approaches to Stop Hypertension) or Mediterranean Diets, they are associated with reduced headache risk. Although there are a number of food triggers for headache, grain-based foods are not listed as likely triggers. Evidence linking specific grain-based foods to headache is either ...

Incidence of mild cognitive impairment (MCI), Alzheimer's disease, and Parkinson's disease is increasing as the mean age of Western populations rises. This article, the second article of a two-part review, assesses the existing scientific literature addressing the role of minerals, phytochemicals, specific grain-based foods, and dietary patterns, with and without grains, to determine whether these foods and their constituents affect the onset or course of these common dementias, as has been alleged in various books, blogs, and other media. Intakes and serum markers of mineral and phytonutrient intakes in many cases have been documented as low or below recommended levels in elderly individuals and patients with MCI, Alzheimer's disease, or Parkinson's disease. However, it is not clear whether adequate intake of these minerals and phytonutrients from all sources, including grains, can impact the onset or course of these dementias. There are few published studies on specific grain-based foods and their relat...

Grain-based foods are alleged in the popular media to cause various neurodegenerative conditions, such as mild cognitive impairment (MCI), Alzheimer's disease, and Parkinson's disease. The scientific literature shows that diets containing the right balance of foods, including grain-based foods with an optimal mix of whole and enriched (or fortified) grains, are associated with lower risk for developing a number of neurological conditions. This article, the first of a two-part review, examines the literature on the role of macronutrients, particularly carbohydrates (CHOs), dietary fiber, and vitamins provided by grain-based foods, in the development of various dementias. Studies suggest that grain-based foods and their CHOs and vitamins when incorporated in diets that meet calorie and nutrient needs are important for maintaining brain health and reducing the risk for various dementias. In contrast, excess CHO, fat, or calorie intake from any source, including grain-based foods, may lead to impairment of gl...

Research-based dietary guidelines suggest that consumers “make half their grains whole.” Yet some advocate ingesting only whole-grain foods (WGFs) and avoiding all refined-grain foods (RGFs). Some even recommend avoiding all grain-based foods (GBFs). This article will provide arguments to counter negative deductions about GBFs and RGFs, especially staple ones, and to support dietary guidance recommending a balance of GBFs—achieved through the right mix, type, and quantity of WGFs and RGFs. Studies looking at early mortality, body weight, and glucose tolerance and diabetes will be used as examples to characterize the literature about GBFs. The following issues are highlighted: 1) inconsistent findings between epidemiological and interventional studies and impacts of GBFs on health outcomes, and the underreporting of findings showing RGFs neither raise nor lower health risks; 2) multiple confounding and potential interactions make adequate statistical adjustment difficult; 3) nonuniform WGF definitions among studies make comparison of results challenging, especially because some WGFs may contain 49–74% refined grain (RG); 4) binary categorization of GBFs creates bias because nearly all categories of WGFs are recommended, but nearly half the RGF categories are not; 5) ingestion of >5 (30-g) servings RGFs/d and

To address current claims that discourage ingestion of carbohydrates (CHOs), wheat, and cereal grains, as well as to celebrate the versatility, nutritional and health benefits, and contribution of these foods to the world food supply, we felt compelled to defend their role in the diet and write a series of reviews. The eighth review in this series examines scientific research findings on the impact of whole and refined grains and the CHOs they contain on three common cancers: lung, prostate, and stomach. The totality of the data indicates total CHO intake is not related in most cohorts to risk for these cancers. The few studies conducted on the role of dietary fiber in lung cancer show that low CHO and dietary fiber intakes may increase risk. For prostate and stomach cancers, cereal fiber intake specifically has been associated with reduced risk. The effects of refined grains or specific grain-based foods on lung cancer are unclear. For prostate cancer there may be a weak association between increased ris...

To address many current claims that discourage the ingestion of carbohydrates (CHOs), wheat, and cereal grains, as well as to celebrate the versatility, nutritional and health benefits, and contribution of these foods to the world food supply, we felt compelled to defend their role in the diet and write a series of reviews. The seventh review in this series assesses the scientific literature with respect to the impact of whole, refined, and enriched grains and the CHOs they contain, including starch, dietary fiber, and resistant starch, on two of the most common cancers worldwide: breast and colon/rectal cancers. Included in this review is an overview on the relationship between cancer risk and diet. The totality of the data from most large prospective cohorts indicates that total CHO intake is not related to breast or colorectal cancers. Dietary fiber intake appears to be inversely related to colon cancer and to have either no or an inverse association with breast cancer. Most studies show only a slight ...

Recent claims suggesting whole and refined grain-based foods should be omitted from the diet because the carbohydrates (CHOs) they contain negatively impact the brain's long-term health and functioning need to be evaluated in light of the scientific literature. This review reveals that grain-based foods are important sources of glucose for the brain, which preferentially uses glucose as a source of energy. The lipid-rich brain is very metabolically active and, therefore, requires a lot of energy. Further, CHO-rich foods such as whole grains contain a variety of antioxidant and bioactive compounds that counter oxidative stress and inflammation, helping to prevent damage to brain tissue and maintain optimal cognitive functioning. Such compounds become more important with aging because the brain becomes more susceptible to oxidative stress and inflammation—conditions that promote the development of neurological diseases and disorders. An overview of studies on the relationship between CHO-rich, grain-based f...

To address many current claims that discourage the ingestion of carbohydrates (CHOs), wheat, and cereal grains, as well as to celebrate the versatility, nutritional and health benefits, and contribution of these foods to the world food supply, we felt compelled to defend their role in the diet and write a series of reviews. The fifth review in the series assesses the health effects of consumption and overconsumption of CHOs, grains, and wheat and focuses on their roles in blood pressure, stroke, glucose tolerance, metabolic syndrome (MetS), and diabetes. In terms of blood pressure and MetS, CHOs and grain-based foods included as part of a balanced diet do not appear to elevate blood pressure or increase the risk of MetS, even though grain-based foods are major contributors of dietary sodium. Both the DASH (Dietary Approaches to Stop Hypertension) diet, which emphasizes consumption of whole grain breads and cereals as part of its healthy dietary pattern, and dietary fibers, especially viscous ones, have be...

To address many current claims that discourage the ingestion of carbohydrates (CHOs), wheat, and cereal grains, as well as to celebrate the versatility, nutritional and health benefits, and contribution of these foods to the world food supply, we felt compelled to defend their role in the diet and write a series of reviews. The fourth review in the series assesses the health effects of consumption and overconsumption of CHOs, grains, and wheat and focuses on body weight maintenance and loss. In terms of weight gain, no one macronutrient is responsible. Overconsumption of any macronutrient can contribute to overweight by contributing to the intake of more calories than are expended. In addition, several prominent organizations have stated that the charge that diets higher in total CHO cause weight gain is not supported by the scientific evidence. A review of the literature discussing the findings from numerous epidemiological and intervention studies shows that grains and grain-based foods, when consumed a...

Wheat blast caused by Magnaporthe oryzae pathotype Triticum (MoT) is a threat to wheat production especially in the warmer-humid environments. In Zambia, wheat blast symptoms were observed for the first time on wheat (Triticum aestivum L.) grown in experimental plots and five farmers' fields in Mpika district of Muchinga Province during the 2017-18 rainy season. Infected plants showed the typical wheat blast symptoms with the spike becoming partially or completely bleached with the blackening of the rachis in a short span of time. Incidence of blast symptoms on nearly all wheat heads was high and ranged from 50 to 100%. Examination of diseased plant leaves showed the presence of elliptical, grayish to tan necrotic lesions with dark borders on the leaf often mixed with other foliar diseases. A study was conducted to isolate and identify the causal pathogen(s) using classical and molecular methods and determine the pathogenicity of the detected disease causal agent. Morphobiometrical determination of causal pathogen revealed conidia with characteristic pear shaped 2-septate hyaline spores associated with M. oryzae species. Preliminary polymerase chain reaction screening of six isolates obtained from wheat blast infected samples with diagnostic primers (MoT3F/R) was conducted at ZARI, Zambia, and subsequent analysis of two isolates with MoT3F/R and C17F/R was performed at USDA-ARS, USA. Both experiments confirmed that MoT is the causal agent of wheat blast in Zambia. Further, pathogenicity tests performed with pure culture isolates from samples WS4 and WS5 produced typical blast symptoms on all the six inoculated wheat genotypes. Results of this study indicate that MoT is causing wheat blast in rain-fed wheat grown in Zambia, thus making it the first report of MoT in Zambia and Africa. This inter-continental movement of the pathogen (disease) has serious implication for wheat production and trade that needs to be urgently addressed.

Grain yield progress over 50 years of spring wheat breeding at the International Maize and Wheat Improvement Center (CIMMYT) was determined in field trials conducted during five crop seasons (2013–2017) at Norman E. Borlaug research station near Ciudad Obregon, Mexico. The trials included 30 varieties (24 bread wheat and 6 durum wheat) released between 1965–2014 and were sown under managed optimum, drought, and heat stress conditions. The optimum irrigated environment had 3 management systems, flat sowing with weekly drip irrigation (FDI), bed sowing with flood irrigation (BFI), and flat sowing with flood irrigation (FFI). The drought environment had 2 management systems, flat sowing with reduced irrigation (FRI) and flat sowing under severe drought stress (FSD). The heat stress environment was sown in beds (HFI) three months later than the normally sown irrigated and drought environments. The rate of grain yield progress was estimated relative to Sonalika released in 1965 and Mexicali C75 released in 1975 for bread and durum wheat, respectively. Grain yield progress per year for bread wheat was, 31.2 kg ha−1, 35.3 kg ha−1, and 24.7 kg ha−1 in irrigated environments FDI, BFI, and FFI, respectively. In the stress environments, bread wheat grain yield progress was estimated as 25.6 kg ha−1, 17.7 kg ha−1, and 18.1 kg ha−1 per year in FRI, FSD, and HFI, respectively. For durum wheat, the grain yield progress was estimated as 29.6 kg ha−1, 48.1 kg ha−1, 18.8 kg ha−1, and 29.8 kg ha−1, per year in FDI, BFI, FFI, and HFI, respectively. Trait linkage graph analysis using LASSO regularized graphical model estimated that biomass, harvest index, and grains per meter square (GNM) were linked to grain yield progress in all environments. Thousand kernel weight was associated with grain yield progress under optimum and heat stress conditions, whereas grain weight per tiller (GWT) associated with progress under drought. Results also show that the highest yielding varieties in each environment however, had different trait attributes, with some varieties having higher GNM and tillers per meter square compensating for low GWT, while others had high GWT to compensate for reduced GNM. In conclusion, CIMMYT’s wheat breeding program has continued to show progress in grain yield in different environments/management systems, and while certain traits have consistently improved over the years, the varieties developed have employed different trait strategies to achieve final grain yield.

Investment in scientific research is generally asymmetrical: it depends on precedents, current trends in science and technology, and economic, political and social agendas. However, asymmetry occasionally leads to bottlenecks that limit delivery of valuable technologies. This review considers the case of translating plant research to crop genetic improvement. Considerable progress has been made in basic plant science in recent decades fueled largely by the revolution in genetics. Meanwhile, human population has continued to grow exponentially, the natural resource base upon which agriculture depends has diminished significantly, and the climate is becoming less conducive to agriculture in general, especially in already food insecure regions. However, although basic research has delivered promising outputs using model crop species, relatively few new ideas have been tested in a mainstream breeding context. Past successful translational research projects—including enhancing the vitamin A content of maize, increasing the ability of rice to tolerate flooding, approaches for improving the yield potential of spring wheat, and traits for increasing the climate resilience of maize and sorghum—required interdisciplinary and often international collaboration to deliver adequate proofs of concept. They were also driven by a visionary approach and the necessary time commitment from the research institutions and funding bodies involved. These attributes are prerequisite for capitalizing on basic plant research and harnessing it to food security.

Highlights • Linear and consistent grain yield genetic gains in the HRWYT has been observed. • Several best performing lines were common in both high and low rainfall environments. • The genetic gains were explained by paralleled increases in grain weight, day to maturity and grain filling period. • These results indicate continuous genetic progress and yield stability in the HRWYT germplasm developed by CIMMYT., The effects of climate change together with the projected future demand represents a huge challenge for wheat production systems worldwide. Wheat breeding can contribute to global food security through the creation of genotypes exhibiting stress tolerance and higher yield potential. The objectives of our study were to (i) estimate the annual grain yield (GY) genetic gain of High Rainfall Wheat Yield Trials (HRWYT) grown from 2007 (15th HRWYT) to 2016 (24th HRWYT) across international environments, and (ii) determine the changes in physiological traits associated with GY genetic improvement. The GY genetic gains were estimated as genetic progress per se (GYP) and in terms of local checks (GYLC). In total, 239 international locations were classified into two groups: high- and low-rainfall environments based on climate variables and trial management practices. In the high-rainfall environment, the annual genetic gains for GYP and GYLC were 3.8 and 1.17 % (160 and 65.1 kg ha−1 yr−1), respectively. In the low-rainfall environment, the genetic gains were 0.93 and 0.73 % (40 and 33.1 kg ha−1 yr−1), for GYP and GYLC respectively. The GY of the lines included in each nursery showed a significant phenotypic correlation between high- and low-rainfall environments in all the examined years and several of the five best performing lines were common in both environments. The GY progress was mainly associated with increased grain weight (R2 = 0.35 p < 0.001), days to maturity (R2 = 0.20, p < 0.001) and grain filling period (R2 = 0.06, p < 0.05). These results indicate continuous GY genetic progress and yield stability in the HRWYT germplasm developed and distributed by CIMMYT.

A comprehensive analysis of genetic gains in winter wheat, spanning 50 years of breeding and conducted under a wide range of cropping systems, validates the inherent efficiency of breeding for optimal environments.

To address many current claims that disparage and discourage the ingestion of carbohydrates (CHOs), wheat, and cereal grains, as well as to celebrate the versatility, nutritional and health benefits, and contribution of these foods to the world food supply, we felt compelled to defend their role in the diet and write a series of reviews. This third review of CHOs, grains, and whole grains looks at their digestion and absorption, their impact on the microbiome, and how they influence gut function and health and gut-related diseases such as irritable bowel syndrome. Their impact on glycemic response, insulin resistance and inflammation, and the immune system is discussed, and wheat, gluten and grain allergies, and gluten-related disorders, including celiac disease, are addressed. Much of the information on inflammation, glycemic response, and immunity provides a basis for assessing the relationship between CHOs, including starch, dietary fiber, and resistant starch, provided by grains and whole grains and l...

To address many current claims that disparage and discourage the ingestion of carbohydrates (CHOs), wheat, and cereal grains, as well as to celebrate the versatility, nutritional and health benefits, and contribution of these foods to the world food supply, we felt compelled to defend their role in the diet and write a series of reviews. Where data exist, cereal grains and wheat as a source of CHOs and other important nutrients are the focus. In this second review, grain- and wheat-based staples are shown to be important contributors of CHOs (including cereal fiber), as well as necessary proteins, vitamins, and minerals, as part of a balanced diet for most healthy individuals. The terminology associated with grains and whole grains and their processing also is discussed and defined. Dietary fiber and resistant starch are defined, and a whole grain food characterization is provided. Clear delineation of terms is critical because they differ from country to country and are a source of consumer confusion in ...

To address many current claims that disparage and discourage the ingestion of carbohydrates (CHOs), wheat, and cereal grains, even whole grains, as well as to celebrate the versatility, nutritional and health benefits, and contribution of these foods to the world food supply, we felt compelled to defend their role in the diet and write this series of reviews. Where data exist, cereal grains and wheat as a source of CHOs and other important nutrients will be the focus. CHO-rich staple foods, including those from a wide array of whole and refined grains, are inexpensive sources of energy, protein, and other nutrients. Grain-based staple ingredients have been incorporated into an enormous variety of foods, becoming cultural icons and national dishes that are accepted by populations around the world and adapted to specific agricultural necessities and cultural preferences. Dietary guidance by health promotion bodies around the world recommends that 45–65% of total calories be from CHOs and reinforces the mess...

Background The phase II ATX trial aimed at evaluating safety and efficacy of first-line AT or ATX for HER2-negative LR/MBC (NTR1348; BOOG 2006-06). Plasma samples were collected for investigation of circulating proteins involved in angiogenesis and their possible association with therapy outcome. We here report the prognostic value of plasma VEGF-A, soluble (s)VEGFR-2, ANG2, sTIE2, IL6, IL8 and CA9 at baseline (C1D1) and their changes after cycle 1 (C2D1). Methods 312 patients were randomized 1:1 to AT (T 90 mg/m2 d1, 8, 15 & A 10 mg/kg d1, 15 q4w x 6 cycles → A 15 mg/kg d1 q3w for next cycles) or ATX (T 90 mg/m2 d1, 8, A 15 mg/kg d1 & X 825 mg/m2 bid d1–14 q3w x 8 cycles → A & X at same dose q3w for next cycles). Plasma proteins were measured by immunoassays (R&D Systems and MSD). The association of (continuous) protein levels on C1D1 and their changes on C2D1 with response, PFS and OS were evaluated by Mann-Whitney U test and univariate Cox regression analysis. Results The biomarker cohort (n=181) and trial cohort had similar baseline characteristics and clinical outcome. After a median follow-up of 46 months, there were 178 (98%) PFS events and 152 (84%) deaths. On C1D1, levels of ANG2 and sTIE2 were significantly higher in patients with hormone-receptor positive disease compared to those with triple-negative disease (p=.025 and p=.001, respectively). A high level of VEGF-A was noted in patients with visceral metastases (p=.028) and those with an increasing number of metastatic sites (p=.017). High levels of ANG2, IL6, IL8 and CA9 were significantly associated with poor PFS and OS (Table 1). Protein levels were not associated with response. Table 1. Association of circulating proteins at baseline with PFS and OSPFS HR (95%CI)PFS p-valueOS HR (95%CI)OS p-valueANG22.3 (1.0-4.9).043.1 (1.4-7.0).007IL61.6 (1.1-2.3).021.9 (1.3-2.8).001IL81.9 (1.3-2.8).0012.8 (1.8-4.3) On C2D1, levels of all proteins, except for IL6, had significantly changed. Whereas VEGF-A, ANG2, sTIE2 and IL8 decreased significantly, sVEGFR2 and CA9 showed a significant increase. The median relative change of both IL8 and sVEGFR2 was significantly different between patients having CR/PR vs. SD/PD (for IL8: -19.4% vs. 22.3%, p=.001 and for sVEGFR2: 6.5 vs. 2.1%, p=.01). A large relative increase in CA9 level was associated with better PFS (HR = 0.36, 95% CI, 0.19 – 0.68, p=.002) and OS (HR = 0.50, 95% CI, 0.27 – 0.94, p=.03). All patients had very low levels of free VEGF-A on C2D1 (median 8 pg/ml). Conclusions In patients with HER2-negative LR/MBC receiving first-line bevacizumab-containing chemotherapy, high baseline plasma levels of ANG2, IL6, IL8 and CA9 indicate a high risk for poor PFS and OS. These proteins might be useful for stratification according to prognosis. Moreover, relative decrease in IL8 and increase in sVEGFR2 on C2D1 are associated with response, whereas a large relative increase in CA9 is associated with better PFS and OS. Changes in these proteins after one cycle might be early indicators of efficacy of bevacizumab combined with chemotherapy. Financial support from Roche Netherlands. Citation Format: Siu W Lam, Nienke M Nota, Steffen M de Groot, Agnes Jager, Monique MEM Bos, Sabine C Linn, Joan van den Bosch, Hans J Braun, Ankie MT van der Velden, Maartje Los, Johanneke EA Portielje, Judith R Kroep, Aafke H Honkoop, Carolien H Smorenburg, Bea Tanis, Johanna MGH van Riel, Jetske M Meerum Terwogt, Marien O den Boer, Joep Douma, Frank Jeurissen, Johan Berends, Harm van Tinteren, Epie Boven. Plasma biomarker analysis in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC) treated with first-line bevacizumab (A) and paclitaxel (T) without or with capecitabine (X) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-09.

New biotic stresses have emerged around the globe over the last decades threatening food safety and security. In 2016, scientists confirmed the presence of the devastating wheat-blast disease in Bangladesh, South Asia-its first occurrence outside South America. Severely blast-affected wheat fields had their grain yield wiped out. This poses a severe threat to food security in a densely-populated region with millions of poor inhabitants where wheat is a major staple crop and per capita wheat consumption has been increasing. As an ex ante impact assessment, this study examined potential wheat-blast scenarios in Bangladesh, India, and Pakistan. Based on the agro-climatic conditions in the epicenter, where the disease was first identified in Bangladesh in 2016, this study identified the correspondingly vulnerable areas in India, Pakistan and Bangladesh amounting to 7 million ha. Assuming a conservative scenario of 5-10% for blast-induced wheat production loss, this study estimated the annual potential wheat loss across the sampled countries to be 0.89-1.77 million tons, equivalent to USD 132-264 million. Such losses further threaten an already-precarious national food security, putting pressure on wheat imports and wheat prices. The study is a call for action to tackle the real wheat-blast threat in South Asia.

Genotypes produced from plant breeding programs for annual crops are evaluated in multiyear, multilocation field trials where a large number of genotypes grown in a few locations in the first year are progressively reduced by selection and tested in a greater number of locations in successive years. Provided fixed resources are specified, the efficiencies of testing strategies differing in the number of locations and replications used and in the number of genotypes tested in successive years can be evaluated by three statistics (genetic repeatability, acceptance probability, and potential gain) calculated from five variance components applicable to the field trials. The five variance components required are deployed genetic variance, genotype-by-year, genotype-by-location, and genotype-by-year-by-location interaction variances and the residual (error) variance. Strictly, known variance components are required, but the statistics and their standard errors can be calculated using robust estimates of the variance components obtained from a combined analysis over years of a large set of historical data from field trials that are connected by shared genotypes across years, as genotype-by-year and genotype-by-year-by-location variance components are estimable. Single-year analyses are unsuitable, as no estimate of the interactions with year are available, and such analyses produce biased estimates of genetic variance and genotype-by-location interaction variance. These procedures are illustrated using an example from the CIMMYT international wheat breeding program to evaluate 2-yr testing strategies for CIMMYT’s Elite Spring Wheat Yield Trials that has been distributed and evaluated internationally since 1979.

The original article was corrected. Author Muhammad Kundi should instead read: Muhammad Sohail.

To accelerate genetic gains in breeding, physiological trait (PT) characterization of candidate parents can help make more strategic crosses, increasing the probability of accumulating favorable alleles compared to crossing relatively uncharacterized lines. In this study, crosses were designed to complement “source” with “sink” traits, where at least one parent was selected for favorable expression of biomass and/or radiation use efficiency—source—and the other for sink-related traits like harvest-index, kernel weight and grains per spike. Female parents were selected from among genetic resources—including landraces and products of wide-crossing (i.e. synthetic wheat)—that had been evaluated in Mexico at high yield potential or under heat stress, while elite lines were used as males. Progeny of crosses were advanced to the F4 generation within Mexico, and F4-derived F5 and F6 generations were yield tested to populate four international nurseries, targeted to high yield environments (2nd and 3rd WYCYT) for yield potential, and heat stressed environments (2nd and 4th SATYN) for climate resilience, respectively. Each nursery was grown as multi-location yield trials. Genetic gains were achieved in both temperate and hot environments, with most new PT-derived lines expressing superior yield and biomass compared to local checks at almost all international sites. Furthermore, the tendency across all four nurseries indicated either the superiority of the best new PT lines compared with the CIMMYT elite checks, or the superiority of all new PT lines as a group compared with all checks, and in some cases, both. Results support—in a realistic breeding context—the hypothesis that yield and radiation use efficiency can be increased by improving source:sink balance, and validate the feasibility of incorporating exotic germplasm into mainstream breeding efforts to accelerate genetic gains for yield potential and climate resilience.

Background Newly identified SNPs in genes encoding metabolizing enzymes (CYP2C8, CYP3A4) and drug target (TUBB2A) of paclitaxel have been associated with PNP1-3. A recent GWAS has found novel SNPs in EPHA5 and FGD4 possibly predictive for PNP4. Likewise, SNPs in genes (CDA, CES2) involved in capecitabine activation may play a role in HFS5. Here, we attempted to confirm these SNPs as predictive markers for PNP and HFS in patients (pts) receiving first-line paclitaxel (T) and bevacizumab (A) without or with capecitabine (X). Patients and methods In the phase II ATX trial (NTR1348;BOOG2006-06), 312 pts were randomized 1:1 to AT (T 90 mg/m2 d1, 8, 15 & A 10 mg/kg d1, 15 q4w x 6 cycles → A 15 mg/kg d1 q3w for next cycles) or ATX (T 90 mg/m2 d1, 8, A 15 mg/kg d1 & X 825 mg/m2 bid d1–14 q3w x 8 cycles → the same dose of A & X q3w for next cycles). Toxicity was graded by using NCI CTCAE v3 at each cycle. Germline DNA was isolated for genotyping CYP2C8*3 (1196A>G & 416G>A), CYP3A4*22 (522-191C>T), EPHA5 2895G>A, FGD4 2044-236G>A, CES2 823C>G, TUBB2A 101C>T, TUBB2A 112G>A, CDA 943insC and CDA 451C>T. Results of TUBB2A and CDA SNPs will be presented at the meeting. The association between SNPs and toxicity was analyzed for 1) maximum grade of treatment-related toxicity per patient by Pearson’s X2 or Fisher's exact test; 2) cumulative dose level of drugs until first grade ≥1 toxicity or first dose reduction by Kaplan-Meier curve and Gehan-Breslow test. Results 188 pts had SNPs genotyped; characteristics reflected the trial cohort. Table 1 shows the maximum grade of PNP. When grouped into grades 0–1 and 2–3, no differences in rates of PNP were noted among SNPs. Median cumulative dose of T until grade ≥1 PNP was 1,800 mg/m2 (95% CI 1,534–2,065). Carriers of the CYP2C8 416 A-allele had a significantly lower cumulative dose of T until grade ≥1 PNP compared to those with a homozygous G/G genotype (Gehan-Breslow p=0.011). Carriers of the FGD4 2044-236 A-allele had a significantly higher cumulative dose until first dose reduction of T compared to those with a homozygous G/G genotype (Gehan-Breslow p=0.037). Table 1. toxicity by maximum grade per patient Grade 0123Paclitaxel-treated patients (N=188)PNP, No. (%)62 (33)33 (36)41 (22)17 (9)Capecitabine-treated patients (N=93)HFS, No. (%)17 (18)21 (23)25 (27)30 (32) For ATX-treated pts, rates of HFS are shown in Table 1. With regard to maximum grade of HFS, there was a trend of a lower rate of grade 2–3 HFS for CES 823C/G compared to C/C genotype (33% vs 64%, Fisher’s exact p=0.059). The median cumulative dose of X until grade ≥1 HFS was 98.7 g/m2 (95%CI 82.1–115). CES 823C>G was not associated with the cumulative dose of X until grade ≥1 HFS or dose reduction. Conclusions Our results indicate that CYP2C8 416G>A and FGD4 2044-236G>A might be predictive markers for paclitaxel-induced neurotoxicity, whereas reported associations of other SNPs with toxicity could not be confirmed. 1Hertz et al. Ann Oncol 2013, 2De Graan et al. Clin Cancer Res 2013, 3Leandro-Garcia et al. Clin Cancer Res 2012, 4Baldwin et al. Clin Cancer Res 2012, 5Caronia et al. Clin Cancer Res 2011 Financial support from Roche Netherlands. Citation Format: Siu W Lam, Charlotte N Frederiks, Tahar van der Straaten, Steffen M de Groot, Agnes Jager, Monique MEM Bos, Sabine C Linn, Joan van den Bosch, Hans J Braun, Ankie MT van der Velden, Maartje Los, Jojanneke EA Portielje, Judith R Kroep, Aafke H Honkoop, Carolien H Smorenburg, Bea Tanis, Johanna MGH van Riel, Jetske M Meerum Terwogt, Marien O den Boer, Joep Douma, Frank Jeurissen, Johan Berends, Henk-Jan Guchelaar, Epie Boven. Genetic polymorphisms (SNPs) as predictive markers for paclitaxel-induced peripheral neuropathy (PNP) and capecitabine-induced hand-foot syndrome (HFS) in HER-2 negative metastatic breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-09.

Background The efficacy and feasibility of chemotherapy in elderly metastatic breast cancer (MBC) patients (pts) have been studied in various phase II studies. However, results of prospective randomized studies in elderly MBC pts are scarce. Methods In this phase III multicenter study, MBC pts ≥ 65 years eligible for first-line chemotherapy were randomized between pegylated liposomal doxorubicin (PEGdoxo) (45mg/m2, IV, q 4 wks) or capecitabine (Cape) (1000 mg/m2 PO bid, days 1–14, q 3 wks). Other eligibility criteria were ECOG performance status (PS) ≤ 2 (3 allowed if due to pain or pre existing comorbidity), adequate bone marrow and organ functions. Stratification factors were PS (0–1 vs 2–3), HER2 status, visceral/non-visceral disease, adjuvant hormonal therapy (HTx), and HTx for MBC. Baseline geriatric assessment (GA) included functional status, instrumental activities of daily living, cognition, mood, comorbidity, polypharmacy and nutritional status. Chemotherapy was continued for 24 wks in the absence of progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression-free survival (PFS), secondary endpoints were response rate, overall survival (OS), toxicity (CTC criteria) and compliance. Results Between April 2007 and August 2011, 78 pts were randomized to PEGdoxo (n = 40) or Cape (n = 38). The study was prematurely closed due to slow accrual and supply problems with PEGdoxo. Mean age was 74 years (range 65–86; 75+ 54%; 80+ 13%). Pt characteristics were balanced between the two arms: PS 0–1 77%, ER+ 68%, HER2+ 5%, visceral/non-visceral disease 76%/24%, adjuvant HTx 46%, HTx for MBC 56%, ≥ 3 metastatic sites 50%. Only 22 out of 75 pts with a baseline GA had no geriatric condition (29%), while 32 pts (43%) and 21 pts (28%) had one or ≥ 2 geriatric conditions, respectively. Chemotherapy was given for 6 months in 38%, with a mean dose intensity of 84% in both arms. Reasons for early treatment discontinuation were: PD (31%), toxicity (28%), pt withdrawal (3%). After a median follow up of 32 months, 74 pts had PD and 56 pts had died. The median PFS was 5.7 and 7.7 months with PEGdoxo and Cape (HR 0.68, 95% CI: 0.42–1.11, p = 0.12) and the median OS was 13.8 and 16.8 months, respectively (HR 0.84, 95% CI: 0.49–1.42, p = 0.51). Response was evaluable in 64 pts, with a partial response (PR) in 7 (21%) and 6 pts (19%), and stable disease in 21 (64%) and 17 pts (55%) for PEGdoxo and Cape, respectively. Toxicity was acceptable, mainly being grade 1–2, with for PEGdoxo/Cape grade 1 alopecia in 14/4 pts (grade 2 in 1 PEGdoxo pt), grade 3 fatigue in 5/5 pts, grade 3 HFS in 4/6 pts and grade 3 mucositis in 4/1 pts, respectively. Pts with ≥ 1 geriatric condition more frequently experienced grade 3–4 toxicity, after correcting for type of chemotherapy, age and PS (HR 2.24, 95% CI: 1.21–4.16). Pts aged 75+ had a twofold higher risk of dying, irrespective of treatment arm (HR 2.31, 95% CI: 1.31–4.07). Conclusions First-line chemotherapy with either PEGdoxo or Cape was feasible in elderly MBC pts, with adequate dose intensity and acceptable toxicity, even in non-fit pts or pts aged 75+. Baseline GA correlated with toxicity. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-05.

To ensure future food security, there is an urgent need for improved co-ordination of agricultural research. While advances in biotechnology hold considerable promise, significant technology gaps exist that may reduce their impact. Examples include an incomplete knowledge of target breeding environments, a limited understanding and/or application of optimal crop management practices, and underfunded extension services. A better co-ordinated and more globalized approach to agricultural research through the implementation of Global Crop Improvement Networks (GCIN) is proposed. Such networks could underpin agricultural research and development by providing the following types of services: (i) increased resolution and precision of environmental information, including meteorological data, soil characteristics, hydrological data, and the identification of environmental 'hotspots' for a range of biotic, abiotic, and socio-economic constraints; (ii) augmented research capacity, including network-based variety and crop management trials, faster and more comprehensive diagnosis of emerging constraints, timely sharing of new technologies, opportunities to focus research efforts better by linking groups with similar productivity constraints and complementary skills, and greater control of experimental variables in field-based phenotyping; and (iii) increased communication and impacts via more effective dissemination of new ideas and products, the integration of information globally to elicit well-timed local responses to productivity threats, an increased profile, and the publicity of threats to food security. Such outputs would help target the translation of research from the laboratory into the field while bringing the constraints of rural communities closer to the scientific community. The GCIN could provide a lens which academia, science councils, and development agencies could use to focus in on themes of common interest, and working platforms to integrate novel research approaches on crop adaptation and rural development.

The genetic diversity within wheat breeding programs across Turkey and Kazakhstan was compared with a selection of European cultivars that represented the genetic diversity across eight European countries and six decades of wheat breeding. To focus the measure of genetic diversity on that relevant to disease-resistant phenotypes, nucleotide-binding-site (NBS) profiling was used to detect polymorphisms associated with the NBS motifs found within the NBS – leucine-rich repeat (LRR) class of resistance (R) genes. Cereal-specific NBS primers, designed specifically to the conserved NBS motifs found within cereal R-genes, provided distinct NBS profiles. Although the genetic diversity associated with NBS motifs was only slightly higher within the Eastern wheat genotypes, the NBS profiles produced by Eastern and European wheat lines differed considerably. Structure analysis divided the wheat genotypes into four groups, which compared well with the origin of the wheat genotypes. The highest levels of genetic diversity were seen for the wheat genotypes from the Genetic Resource Collection held in Ankara, Turkey, as wheat genotypes within breeding programs were genetically more similar. The wheat genotypes from Kazakhstan were the most similar to the European cultivars, reflecting the significant number of eastern European cultivars used in the breeding program in Kazakhstan. In general, the NBS profiles suggested that NBS–LRR R-gene usage in winter wheat breeding in Turkey and Kazakhstan differed from that deployed in European cultivars.

The availability of dense molecular markers has made possible the use of genomic selection (GS) for plant breeding. However, the evaluation of models for GS in real plant populations is very limited. This article evaluates the performance of parametric and semiparametric models for GS using wheat (Triticum aestivum L.) and maize (Zea mays) data in which different traits were measured in several environmental conditions. The findings, based on extensive cross-validations, indicate that models including marker information had higher predictive ability than pedigree-based models. In the wheat data set, and relative to a pedigree model, gains in predictive ability due to inclusion of markers ranged from 7.7 to 35.7%. Correlation between observed and predictive values in the maize data set achieved values up to 0.79. Estimates of marker effects were different across environmental conditions, indicating that genotype × environment interaction is an important component of genetic variability. These results indicate that GS in plant breeding can be an effective strategy for selecting among lines whose phenotypes have yet to be observed.

Improved winter wheat (Triticum aes- tivum L.) cultivars are needed for the diverse environ- ments in Central and West Asia to improve rural livelihoods. This study was conducted to determine the performance of elite winter wheat breeding lines developed by the International Winter Wheat Improvement Program (IWWIP), to analyze their stability across diverse environments, and to identify superior genotypes that could be valuable for winter wheat improvement or varietal release. One hundred and one advanced winter wheat breeding lines and four check cultivars were tested over a 5-year period (2004-2008). Grain yield and agronomic traits were analyzed. Stability and genotypic superiority for grain yield were determined using genotype and geno- type 9 environment (GGE) biplot analysis. The experimental genotypes showed high levels of grain yield in each year, with mean values ranging from 3.9 to 6.7 t ha -1 . A set of 25 experimental genotypes was identified. These were either equal or superior to the best check based on their high mean yield and stability across environments as assessed by the GGE biplot analysis. The more stable high yielding genotypes were ID800994.W/Falke, Agri/Nac//Attila, ID8009 94W/Vee//F900K/3/Pony/Opata, AU//YT542/N10B/ 3/II8260/4/JI/Hys/5/Yunnat Esskiy/6/KS82W409/Spn and F130-L-1-12/MV12. The superior genotypes also had acceptable maturity, plant height and 1,000-kernel weight. Among the superior lines, Agri/Nac//Attila and Shark/F4105W2.1 have already been proposed for release in Kyrgyzstan and Georgia, respectively. The findings provide information on wide adaptation of the internationally important winter wheat genotypes, and demonstrate that the IWWIP program is enriching the germplasm base in the region with superior winter wheat genotypes to the benefit of national and international winter wheat improvement programs.

Wheat is grown on 210 million ha throughout the world producing approximately 600 million tonnes of grain (10 year average; FAO 2005) and providing on average one fifth of the total calorific input of the world's population (FAO 2003). For some regions such as North Africa, Turkey and Central Asia, wheat provides half of total dietary energy intake. Of the cultivated wheat area, half is located in less developed countries where there have been steady increases in productivity since the green revolution, associated with genetic improvements in yield potential, resistance to diseases and adaptation to abiotic stresses (Reynolds & Borlaug 2006a, b) as well as better agronomic practices (Derpsch 2005). Nonetheless, challenges to wheat production are still considerable, especially in the developing world, not only because of increased demand but also because of the increased scarcity of water resources (Rosegrant 1997; WMO 1997), ever more unpredictable climates (Fischer et al. 2002), increased urbanization and loss of good quality land away from agriculture (Hobbs 2007), and decreased public sector investment in agriculture and rural affairs (Falcon & Naylor 2005). To meet demand in a sustainable way, more resources are required to breed a new generation of genetically improved cultivars as well as implement resource-conserving agronomic management practices.

Purpose To compare the efficacy and safety of doxorubicin and docetaxel (AT) with fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy for metastatic breast cancer (MBC). Patients and Methods Patients (n = 216) were randomly assigned to either AT (doxorubicin 50 mg/m2 and docetaxel 75 mg/m2) or FAC (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); both regimens were administered on day 1, every 3 weeks. Results A median number of six cycles was delivered in both arms, with a median relative dose-intensity of more than 98%. Median time to progression (TTP) and median overall survival (OS) were significantly longer for patients on AT compared with FAC (TTP: 8.0 v 6.6 months, respectively; P = .004; and OS: 22.6 v 16.2 months, respectively; P = .019). The overall response rate (ORR) was significantly higher in patients on AT compared with FAC (58% v 37%, respectively; P = .003). The ORR on AT was also higher in patients with visceral disease compared with FAC patients with visceral disease (59% v 36%, respectively; P = .003). There were no differences in grade 3 to 4 neutropenia and infections (AT 89% v FAC 84% and AT 12% v FAC 9%, respectively). Neutropenic fever was more common in AT-treated patients than FAC-treated patients (33% v 9%, respectively; P < .001). Grade 3 to 4 nonhematologic toxicity was infrequent in both arms. Congestive heart failure was observed in 3% and 6% of patients on AT and FAC, respectively. Conclusion In this phase II to III study, AT resulted in a significantly longer TTP and OS and a higher objective ORR than FAC. First-line AT is a valid treatment option for patients with MBC.

Fifteen accessions of Aegilops tauschii (DD), 10 of Ae. speltoides (SS) and 8 of the tetraploid Aegilops species sharing the U genome were used to study the influence of varied zinc (Zn) supply on development of Zn-deficiency symptoms, and on shoot dry weight and Zn concentration. Plants were grown in a Zn-deficient calcareous soil under greenhouse conditions with (+Zn = 5 mg kg—1 soil) and without (—Zn) Zn supply. Four accessions of wild tetraploid wheat, Triticum turgidum var. dicoccoides (BBAA), a group known for its high sensitivity to Zn-deficiency, were used in the experiments for comparison. As expected, the accessions of wild T. turgidum var. dicoccoides showed the highest sensitivity to Zn deficiency, and had more severe leaf symptoms of Zn deficiency (whitish-brown necrotic patches). Among the Aegilops species, leaf symptoms of Zn deficiency were, in general, more distinct in Ae. tauschii (DD) and least in Ae. speltoides (SS). Zinc efficiency, expressed as the percentage of shoot dry weight produced under conditions of Zn deficiency compared to Zn supply, averaged, 15% for T. turgidum, 32% for Ae. tauschii, 52% for Ae. speltoides and 61% for the tetraploid Aegilops species carrying the U genome. Differences in Zn efficiency among and within Aegilops species and T. turgidum were significantly correlated with the Zn amount per shoot, but not with the Zn amount per unit dry weight of shoots. The results show that Aegilops species can be exploited as an important genetic source for Zn efficiency genes, particularly Ae. speltoides var. ligustica (SS) and Ae. triuncialis (UUCC). Transfer of these genes to cultivated modern wheat may bring about a greater variation in Zn efficiency in wheat, and facilitate production of Zn-efficient modern wheat cultivars for Zn-deficient soil conditions. Reaktion verschiedener Aegilops-Arten auf Zinkmangel Zinkmangelsymptome, Spross-Trockengewicht und die Zn-Konzentration im Spross wurde an 15 Aegilops tauschii (DD Genom), 10 Ae. speltoides (SS Genom) und 8 tetraploiden Aegilops-Herkunften untersucht. Die Pflanzen wurden in einem kalkhaltigen Boden mit Zn-Mangel im Gewachshaus angezogen. Die Versuchsvarianten waren keine Zn-Dungung (—Zn) und 5 mg Zn kg—1 Boden (+Zn). Als Vergleich wurden 4 tetraploide Wildherkunfte von Triticum turgidum var. dicoccoides (BBAA) berucksichtigt, da sie Zn-Mangel gegenuber sehr anfallig sind. Wie erwartet, erwiesen sich die T. turgidum var. dicoccoides Wildherkunfte als am anfalligsten und ihre Blatter hatten die ausgepragtesten Zn-Mangelsymptome (weiss-braune nekrotische Flecken). Ein Vergleich zwischen den Aegilopsarten zeigte, dass im allgemeinen die Zn-Mangelsymptome auf den Blattern bei Ae. tauschii (DD) am starksten und bei Ae. speltoides (SS) am wenigsten ausgepragt waren. Die Zn-Effizienz, ausgedruckt als Prozentsatz des Spross-Trockengewichts unter Zn-Mangel relativ zum Spross-Trockengewicht unter Zugabe von Zn, war im Durchschnitt 15% fur T. turgidum, 32% fur Ae. tauschii, 52% fur Ae. speltoides und 61% fur die tetraploiden Aegilopsarten mit U Genom. Die Unterschiede in der Zn-Effizienz sowohl zwischen als auch innerhalb der Aegilopsarten waren signifikant mit der Gesamtmenge Zn pro Spross korreliert, nicht jedoch mit der Menge Zn pro Einheit Spross-Trockengewicht. Die Ergebnisse zeigen, das Aegilopsarten eine wichtige Quelle fur Gene zur Verbesserung der Zn-Effizienz in Weizen sein konnen, insbesondere Ae. speltoides var. ligustica (SS) und Ae. triuncialis (UUCC). Die Ubertragung dieser Gene konnte die Zuchtung von Zn-effizienten Sorten fur Zn-Mangelstandorte ermoglichen.

The first recorded occurrence in Asia of wheat blast caused by Magnaporthe oryzae, pathotype Triticum (synonym Pyricularia oryzae) occurred in Bangladesh in March 2016. Crop losses of up to 90% have been reported, with latesown wheat suffering particularly badly. The emergence of this disease has raised concern in neighboring countries where wheat represents a significant crop, most notably in India and Nepal. The existence of effective genetic resistance is in doubt, so for the moment the sole means of control is via the application of fungicides and adoption of beneficial cultural practices. The disease has been endemic in parts of South America for the last 30 years, so only a coordinated program of research and development has the potential to deliver rapid progress in combating the disease. In addition to evaluating and deploying genetic resistance and applying fungicides on an occasional basis, some control could be made possible by altering current crop rotation practice and/or manipulating the sowing time to promote disease escape.

Background Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach. Methods In a multicenter phase II trial, 101 patients with overexpression of human epidermal growth factor receptor 2 (HER2 + ) MBC were randomized between combination-therapy trastuzumab (Herceptin) plus docetaxel (H+D) and sequential therapy of single-agent trastuzumab followed at disease progression by docetaxel alone (H→D) as first-line chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) after completed sequential or combination therapy. Results For the H+D group the median PFS was 9.4 vs. 9.9 months for the H→D group and 1-year PFS rates were 44% vs. 35%, respectively. However the overall response rates (ORRs) were 79% vs. 53%, respectively ( P = .016), and overall survival was 30.5 vs. 19.7 months, respectively ( P = .11). In the H→D group, response rates to monotherapy trastuzumab and subsequent docetaxel were 34% and 39%, respectively, with a median PFS during single-agent trastuzumab of 3.9 months. The incidence and severity of neuropathy were significantly higher in the H+D group. Retrospective analysis of trastuzumab treatment beyond progression (applied in 46% of patients in the H+D group and 37% in the H→D group) showed a correlation with longer overall survival in both treatment arms (36.0 vs. 18.0 months and 30.3 vs. 18.6 months, respectively). Conclusion First-line treatment in patients with MBC with H→D resulted in a similar PFS compared with H+D, but the response rate was lower and the overall survival nonsignificantly shorter.

Item does not contain fulltext BACKGROUND: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8.5 months in the observation group and 11.7 months in the maintenance group (HR 0.67, 95% CI 0.56-0.81, p

1014 Background: Treatment with trastuzumab and chemotherapy has improved the outcome of HER2-positive MBC. It is unknown what the outcome and toxicity is of monotherapy trastuzumab, followed by chemotherapy at progression, as compared to the combination of chemotherapy/trastuzumab. Methods: HER2-positive MBC pts., being eligible for first line chemotherapy were randomised between combination treatment docetaxel (TAX) (100 mg/m2, q3wks)/trastuzumab (HER) (loading dose 4mg/kg, whereafter weekly 2mg/kg) (arm A) or monotherapy HER, followed upon progression by TAX (similar doses as arm A) (arm B). Further in- /exclusion criteria were adjuvant non-taxoid chemotherapy allowed, previous HER treatment not; normal ejection fraction (EF), adequate liver/renal functions and bone marrow reserve. Primary endpoint was PFS, secondary endpoints: response rate (RR), overall survival (OS) and toxicities. Kaplan-Meier curve was tested by log-rank test, RR by Pearson χ2-test. Results: Of the 101 randomly selected patients, ...

The relationship between the simultaneously observed positions of the maximum omnidirectional flux of the quiet-time ring current positive ions (Λ φ ) and the maximum electron temperature Λ T in the trough is studied in the midnight sector of the topside ionosphere. Λ φ maps to the inner edge of the plasma sheet where ring current fluxes change from nearly isotropic to trapped. At altitudes near 2500 km, the electron temperature at trough latitudes were always sharply peaked. Although Λ φ varied with the level of geomagnetic activity, ( Λ φ − Λ T ) did not. These observations support the hypothesis that the quiet-time ring current is the source of elevated electron temperatures found near the plasmapause. Below 1300 km, peaked electron temperature distributions in the trough were not consistent features of the data. It is shown that ( Λ φ − Λ T ) increased with decreasing altitude. The possible influences of a westward component to the convective electric field and ionospheric refraction of ion cyclotron waves are discussed.

The effect of exogenous hypercortisolism and 1,25-dihydroxyvitamin D-3 on small-intestinal calcium and glucose transport in the rat was studied at the level of brush-border membrane vesicles generated from isolated villous cells by a freeze-thaw procedure. At 5 · 10 −5 M extravesicular calcium, initial uptake rates in vesicles prepared from triamcinolone-treated adult rats were decreased by 30% after 5 days. Since calcium ionophore A23187 virtually abolished the difference in calcium uptake, triamcinolone appeared to affect calcium channel density or activity rather than intravesicular binding capacity. Kinetic analysis showed that a decrease in V max of a saturable calcium transport system could entirely account for the diminished rate of vesicular calcium uptake. Calcium transport rates could be partially restored by in vivo administration of 1,25-dihydroxyvitamin D-3 at a dosage which did not affect vesicular calcium uptake in control animals. Conversely, sodium-driven glucose accumulation in brush-border vesicles from triamcinolone-treated rats was stimulated by 50–70% after 36 h and appeared insensitive to vitamin D. A specific triamcinolone action on the glucose carrier itself rather than on the driving force of the sodium gradient was indicated by (i) a similar stimulation of glucose transport under equilibrium exchange conditions and (ii) an opposite effect of triamcinolone on sodium-driven alanine transport. The triamcinolone-induced changes in calcium and glucose uptake were not accompanied by a gross alteration of membrane integrity in vitro or by major alterations in vesicular protein composition, intravesicular glucose space and sucrase or alkaline phosphatase activity. The modification of vesicular transport properties is discussed in relation to the vitamin D-antagonized inhibition of intestinal calcium uptake and the stimulation of glucose absorption in response to supraphysiologic amounts of glucocorticoids observed in intact epithelium.