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Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells. Breast cancers arising in carriers of germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers. We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age- and grade-matched controls, for downregulation of BRCA1. Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P =0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls ( P =0.008). ID4 , a negative regulator of BRCA1 , was expressed at 9.1-fold higher levels in basal-like breast cancer ( P <0.0001), suggesting a potential mechanism of BRCA1 downregulation. BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype. Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls ( P <0.0001). The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer.

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens. Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitises triple negative breast cancer (TNBC) models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer. While CDK4/6 inhibitors (CDK4/6i) have improved outcomes for breast cancer patients, estrogen receptor (ER + ) breast cancers often develop resistance, and triple negative breast cancer (TNBC) show poor sensitivity. Here, the authors identify a vulnerability of CDK4/6i treated ER+ and TNBC on ferroptosis and identify the combination of CDK4/6i and GPX4 inhibition as synergistic.

Breast cancers arising in germline carriers of BRCA1 mutations have a characteristic phenotype that has been shown in many studies to differentiate BRCA1 tumours from sporadic tumours. Recently, it has become clear that the characteristic phenotype of BRCA1 tumours is due to expression of the basal-like phenotype. We review these phenotypes, the evidence for BRCA1 pathway dysfunction in sporadic basal-like cancers, and discuss the clinical significance of the basal-like phenotype for cancer genetics and treatment.

Yields of dryland (rainfed) wheat in Australia have increased steadily over the past century despite rainfall being unchanged, indicating that the rainfall-use efficiency has increased. Analyses suggest that at least half of the increase in rainfall-use efficiency can be attributed to improved agronomic management. Various methods of analysing the factors influencing dryland yields and rainfall-use efficiency, such as simple rules and more complex models, are presented and the agronomic factors influencing water use, water-use efficiency, and harvest index of crops are discussed. The adoption of agronomic procedures such as minimum tillage, appropriate fertilizer use, improved weed/disease/insect control, timely planting, and a range of rotation options, in conjunction with new cultivars, has the potential to increase the yields and rainfall-use efficiency of dryland crops. It is concluded that most of the agronomic options for improving rainfall-use efficiency in rainfed agricultural systems decrease water losses by soil evaporation, runoff, throughflow, deep drainage, and competing weeds, thereby making more water available for increased water use by the crop.

Soil organic carbon (SOC) plays a vital role as both a sink for and source of atmospheric carbon. Revegetation of degraded arable land in China is expected to increase soil carbon sequestration, but the role of perennial legumes on soil carbon stocks in semiarid areas has not been quantified. In this study, we assessed the effect of alfalfa (Medicago sativa L.) and two locally adapted forage legumes, bush clover (Lespedeza davurica S.) and milk vetch (Astragalus adsurgens Pall.) on the SOC concentration and SOC stock accumulated annually over a 2 m soil profile. The results showed that the concentration of SOC in the bare soil decreased slightly over the 7 years, while 7 years of legume growth substantially increased the concentration of SOC over the 0–2.0 m soil depth. Over the 7-year growth period the SOC stocks increased by 24.1, 19.9 and 14.6 Mg C ha−1 under the alfalfa, bush clover and milk vetch stands, respectively, and decreased by 4.2 Mg C ha−1 in the bare soil. The sequestration of SOC in the 1–2 m depth of the soil accounted for 79, 68 and 74 % of the SOC sequestered in the 2 m deep soil profile under alfalfa, bush clover and milk vetch, respectively. Conversion of arable land to perennial legume pasture resulted in a significant increase in SOC, particularly at soil depths below 1 m.

Background: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen. Method: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mg m −2 ), cisplatin (70 mg m −2 ) and streptozocin (1000 mg m −2 ) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival. Results: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3–4 toxicity was neutropaenia (28% patients) but grade 3–4 infection was rare (7%). The most frequent non-haematological grade 3–4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and α -fetoprotein. Conclusions: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response.

Arguably the most important adaptive criterion in annual crops is appropriate phenology that minimizes exposure to climatic stresses and maximizes productivity in target environments. To date this has been achieved empirically by selecting among diverse genotypes in target locations. This approach is likely to become inadequate with pending climate change because selection is imposed on the outcome (flowering time) rather than the underlying mechanism (i.e. responses to daylength, ambient or vernalizing temperatures). In contrast to the cereals, in legumes the interaction between phenological mechanisms and environmental selection pressure is largely unknown. This paper addresses this shortcoming through photothermal modelling of chickpea germplasm from the world’s key production areas using a meta-analysis of multi-environment trials located from 49° N to 35° S. Germplasm origin had significant effects on temperature and daylength responsiveness, the former strongly correlated to vegetative phase temperatures at the collection or development site ( r  = 0.8). Accordingly, temperature responses increase from winter- to spring-sown Mediterranean and Australian material, and then to north, central & southern India. Germplasm origin also affects the relationship between photoperiod and temperature response. In Eastern Mediterranean material a strong negative relationship ( r  = −0.77) enables temperature insensitive genotypes to compensate through a strong photoperiod response. Clearly, chickpea evolution has selected for different phenological mechanisms across the habitat range. Given that under the anticipated global warming temperature sensitive cultivars will flower relatively earlier than those responding largely to photoperiod, it is important to exploit this diversity in developing better-adapted genotypes for future cropping environments.

Plant roots transfer water between soil layers of different water potential thereby significantly affecting the distribution and availability of water in the soil profile. We used a modification of the heat pulse method to measure sap flow in roots of Grevillea robusta and Eucalyptus camaldulensis and demonstrated a redistribution of soil water from deeper in the profile to dry surface horizons by the root system. This phenomenon, termed \"hydraulic lift\" has been reported previously. However, we also demonstrated that after the surface soils were rewetted at the break of season, water was transported by roots from the surface to deeper soil horizons -- the reverse of the \"hydraulic lift\" behaviour described for other woody species. We suggest that \"hydraulic redistribution\" of water in tree roots is significant in maintaining root viability, facilitating root growth in dry soils and modifying resource availability.

Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. R E Buckingham , K A Al-Barazanji , C D Toseland , M Slaughter , S C Connor , A West , B Bond , N C Turner and J C Clapham SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK. Abstract Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia.

Water-use efficiency (WUE [g grain yield m⁻² mm⁻¹ ET]) and nitrogen-use efficiency (NUE [Δ g grain yield g⁻¹ Nappiied]) are important measures that can affect the productivity of crops in different environmental systems. However, measurement and interpretation of WUE and NUE in the field are often hampered by the high degree of complexity of these systems due to season-to-season variability in rainfall, the variation in crop responses to soil types and to agronomic management. To be able to guide agronomic practice, experimentally-derived measurements of WUE and NUE need to be extrapolated across time and space through appropriate modelling. To illustrate this approach, the Agricultural Production Systems Simulator (APSIM), which has been rigorously tested for wheat (Triticum aestivum L.) in a Mediterranean environment, was used to estimate and analyse the WUE and NUE of wheat crops in the Mediterranean-climatic region of the central Western Australian agricultural zone. The APSIM model was run for three locations (average annual rainfall of 461 mm [high rainfall zone], 386 mm [medium] and 310 mm [low]) and two soil types that had contrasting plant-available water-holding capacities in the rooting zone (sand: 55 mm, clay soil: 109 mm). Simulations were carried out with historical weather records (82-87 years) assuming current crop management and cultivars. The modelling analyses highlighted the inherently high degree of seasonal variability in yield, WUE and NUE of wheat, depending on soil type, N fertiliser input, rainfall amount and, in particular, rainfall distribution. The clay soil tended to be more productive in terms of grain yield, WUE and NUE in the high and medium rainfall zones, but less productive in most years in the low rainfall zone. The sandy soil was less productive in the high rainfall zone due to the high nitrate leaching potential of this soil type, but more productive than the clay in the low rainfall zone due to poorer pre-anthesis growth and less water use, less water loss by soil evaporation and relatively more water use in the post-anthesis phase. When a wheat crop was sown early on clay soil in the low rainfall zone, it yielded as high as in the other rainfall zones in seasons when rainfall was above average or there was a good store of water in the soil prior to sowing. The simulations confirmed findings from a limited number of field experiments and extended these findings both qualitatively and quantitatively across soil types, rainfall regions and crop management options. Furthermore, by using long-term historical weather records, the simulations extended the findings across the wide range of climatic scenarios experienced in mediterranean-climatic regions.