Aluminum Tolerance in the Model Legume \u3cem\u3eMedicago Truncatula\u3c/em\u3e

Aluminum (Al) is the most abundant metal found in the earth\u27s crust, comprising up to 7% of its mass. At low pH, Al becomes soluble and available to plants, resulting in inhibition of root elongation and reduced plant growth. Aluminum toxicity associated with acid soils has been a major obstacle in alfalfa (Medicago sativa) production. The objective of this study is to identify genes that are differentially expressed under normal and Al stress conditions in the model legume M. truncatula, with the long term goal of using these genes to improve cultivated alfalfa

Aluminum Tolerance QTL in Diploid Alfalfa

Aluminum (Al) toxicity associated with acid soils greatly inhibits alfalfa (Medicago sativa L.) productivity throughout much of the world’s major grassland areas. In this paper, we report the identification of quantitative trait loci (QTL) controlling aluminum tolerance in diploid alfalfa (Medicago sativa L). An in vitro callus growth bioassay was used to select aluminum tolerant and aluminum sensitive parents, and to screen an F2 population for aluminum tolerance. Fifty-eight cDNA probes were mapped to nine linkage groups, and the F2 genotypic classes were contrasted with means from the callus growth bioassay using ANOVA. We also used Mapmaker-QTL to identify markers associated with aluminum tolerance. Four markers, UGAc044, UGAc053, UGAc141, and UGAc782, were found to be associated with aluminum tolerance. UGAc044 had the greatest effect, accounting for 15% (LOD 2.3) of the variation in aluminum tolerance

Impact of primary breast cancer therapy on energetic capacity and body composition

PURPOSE: This observational study was designed to measure baseline energy parameters and body composition in early-stage breast cancer patients, and to follow changes during and after various modalities of treatment. This will provide information to aid in the development of individualized physical activity intervention strategies. METHODS: Patients with newly diagnosed stage 0-III breast cancer were enrolled into three cohorts: A (local therapy alone), B (endocrine therapy), or C (chemotherapy with or without endocrine therapy). At baseline, 6 months, and 12 months, subjects underwent a stationary bicycle protocol to assess power generation and DEXA to assess body composition. RESULTS: Eighty-three patients enrolled. Patients had low and variable levels of power generation at baseline (mean power per kilogram lean mass 1.55 W/kg, SD 0.88). Power normalized to lean body mass (W/kg) decreased significantly, and similarly, by 6 months in cohorts B (1.42-1.04 W/kg, p = 0.008) and C (1.53-1.18 W/kg, p < 0.001). In all cohorts, there was no recovery of power generation by 12 months. Cohort C lost lean body mass (- 1.5 kg, p = 0.007), while cohort B maintained lean body mass (- 0.2 kg, p = 0.68), despite a similar trajectory in loss of power. Seven patients developed sarcopenia during the study period, including four patients who did not receive any chemotherapy (cohort B). CONCLUSIONS: The stationary bike protocol was feasible, easy, and acceptable to patients as a way to measure energetic capacity in a clinical setting. Early-stage breast cancer patients had low and variable levels of power generation, which worsened following primary therapy and did not show evidence of 'spontaneous recovery' by 12 months. Effective physical activity interventions will need to be personalized, accounting for both baseline ability and the effect of treatment

Quantitative trait loci and candidate gene mapping of aluminum tolerance in diploid alfalfa

Aluminum (Al) toxicity in acid soils is a major limitation to the production of alfalfa (Medicago sativa subsp. sativa L.) in the USA. Developing Al-tolerant alfalfa cultivars is one approach to overcome this constraint. Accessions of wild diploid alfalfa (M. sativa subsp. coerulea) have been found to be a source of useful genes for Al tolerance. Previously, two genomic regions associated with Al tolerance were identified in this diploid species using restriction fragment length polymorphism (RFLP) markers and single marker analysis. This study was conducted to identify additional Al-tolerance quantitative trait loci (QTLs); to identify simple sequence repeat (SSR) markers that flank the previously identified QTLs; to map candidate genes associated with Al tolerance from other plant species; and to test for co-localization with mapped QTLs. A genetic linkage map was constructed using EST-SSR markers in a population of 130 BC(1)F(1) plants derived from the cross between Al-sensitive and Al-tolerant genotypes. Three putative QTLs on linkage groups LG I, LG II and LG III, explaining 38, 16 and 27% of the phenotypic variation, respectively, were identified. Six candidate gene markers designed from Medicago truncatula ESTs that showed homology to known Al-tolerance genes identified in other plant species were placed on the QTL map. A marker designed from a candidate gene involved in malic acid release mapped near a marginally significant QTL (LOD 2.83) on LG I. The SSR markers flanking these QTLs will be useful for transferring them to cultivated alfalfa via marker-assisted selection and for pyramiding Al tolerance QTLs

Poly(ADP-Ribose) Polymerase Inhibition: "Targeted" Therapy for Triple-Negative Breast Cancer

In contrast to endocrine-sensitive and HER2-positive breast cancer, novel agents capable of treating advanced triple negative breast cancer (TNBC) are lacking. PARP (Poly-(adenosine diphosphate [ADP]-ribose) polymerase) inhibitors are emerging as one of the most promising ‘targeted’ therapeutics to treat TNBC, with the intended ‘target’ being DNA repair. PARP's are a family of enzymes involved in multiple cellular processes including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized PARP inhibition, in conjunction with the loss of DNA-repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and TNBC. The focus of this review will include an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA-deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, conclude with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer

Case report: Androgen-secreting adrenocortical tumors in eight cats

Urine marking, aggression, and other behavioral concerns are common reasons for cat owners to seek veterinary care. Empiric treatment for lower urinary tract disease or primary behavior disorders are commonly pursued, especially in those cases with normal routine laboratory evaluations. Herein, we report the clinicopathologic findings in eight sexually altered cats that were diagnosed with androgen-secreting adrenocortical tumors. Nearly all cats (n = 7) initially were evaluated for inappropriate urination and pungent urine, with additional behavioral concerns including aggression (n = 3) and excess vocalization (n = 4) commonly reported. Penile barbs (n = 5) were identified in all five male cats, and an enlarged clitoris was observed in one female cat. Testing of serum androgen concentrations revealed abnormally high androstenedione (n = 1) or testosterone (n = 7) concentrations. In the five cases with available adrenal tissue, histopathologic evaluation identified either an adrenocortical adenoma (n = 3) or adrenocortical carcinoma (n = 2). Hormonal abnormalities resolved and clinical signs improved in the four cats that underwent surgical adrenalectomy, with each of these cats surviving &gt;1 year. However, clinical signs were minimally impacted with medical treatments, including one cat in which trilostane treatment failed to improve clinical signs or testosterone concentrations. This collection of cases underscores the importance of a detailed physical examination as well as the consideration of endocrine disturbances in cats undergoing evaluation for inappropriate urination or aggression. Furthermore, this report adds to the growing body of evidence that sex-hormone secreting adrenal tumors in cats may be an under-recognized syndrome

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100

Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. Methods: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3–5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. Results: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10−8OR=3.3) and in the cumulative dose model (P=4.7 × 10−8HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3–5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037OR=2.4). Conclusions: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care