Inositol transporters AtINT2 and AtINT4 regulate arsenic accumulation in Arabidopsis seeds

Arsenic is a global environmental contaminant that threatens tens of millions people world-wide via food and water. Understanding how arsenic is accumulated in crop seeds is of critical importance. To date, membrane transport proteins catalyzing arsenic uptake by roots and translocation through xylem to shoots have been characterized. However, no transporters responsible for loading arsenic from xylem into phloem and further unloading into plant seeds have been identified. In this study we demonstrate that expressing the gene for either Arabidopsis thaliana inositol transporter AtINT2 or AtINT4 in Saccharomyces cerevisiae leads to increased arsenic accumulation and elevated sensitivity to arsenite [As(III)], and Xenopus laevis oocytes expressing AtINT2 import As(III). When A. thaliana plants with disruptions in either AtINT2 or AtINT4 were supplemented with As(III) through roots, there was a substantial decrease in both the arsenic content in the phloem extrude and in total arsenic accumulation in siliques and seeds. Similarly, when As(III) is fed through the leaves, there was a very large decrease in arsenic accumulation in siliques and seeds compared with wild-type plants. These results clearly demonstrate that inositol transporters are responsible for As(III) loading into phloem, the key step regulating arsenic accumulation in seeds

Diversity among Equals: Educational Opportunity and the State of Affirmative Admissions in New England

This report reviews the practice of Affirmative Admissions as a strategy for achieving diversity within New England colleges and universities. It shows how educational leaders perceive Affirmative Admissions, the nature of regional Affirmative Admissions policies, and the numbers of student affected by current enrollment strategies. This report is part of a larger series on educational access and opportunity in New England. Research was organized into five components: (1) analysis of pertinent legal issues related to postsecondary access and equity; (2) interviews with postsecondary campus and state leaders (n=104); (3) interviews with K-12 leaders and educators at state, district, and school levels (n=45); (4) a survey of 221 postsecondary education institutions in New England; and (5) econometric analyses of student data. The focus was on groups of institutions, 18 groups clustered by admissions policies and restrictions. The most compelling conclusion is that there is no significant evidence that colleges have reduced standards to admit greater numbers of minority students. By increasing educational access to a broader segment of the population, the regions higher education institutions have taken crucial steps toward assuring the vitality and vibrancy of New Englands future economy and civic life. The study also indicates that the pool of qualified minority students is much too small, highlighting the need to improve the preparation of minority students. Three appendixes contain details about survey methodology, participating institutions, and regression coefficients. Prepared by the Center for Education Policy (CEP) and Massachusetts Institute for Social and Economic Research (MISER), University of Massachusetts at Amherst. Sponsored by the Nellie Mae Education Foundation

Leg strength in peripheral arterial disease: associations with disease severity and lower-extremity performance

AbstractObjectiveThe purpose of this study was to determine relationships between lower-extremity arterial obstruction, leg strength, and lower-extremity functioning.DesignThe study design was cross-sectional. A total of 514 outpatients (269 with ankle-brachial index [ABI] <0.90), aged 55 and older, were identified from three Chicago-area hospitals. Individuals with history of lower-extremity revascularization were excluded.Main outcome measuresStrength in each leg, 6-minute walk, 4-meter walking velocity, accelerometer-measured physical activity, and a summary performance score were measured. The summary performance score is a composite measure of lower-extremity functioning, ranging from 0 to 12 (12 = best). The leg with the lower ABI was defined as the “index” leg, and the leg with higher ABI was defined as the “contralateral” leg.ResultsIndex leg ABI levels were associated linearly and significantly with strength for hip extension (P < .001), hip flexion (P < .001), knee extension (P = .066), and knee flexion (P = .003), adjusting for known and potential confounders. In adjusted analyses, the index ABI was also associated linearly and significantly with strength in the contralateral leg. Adjusting for confounders, including ABI, knee extension strength, was associated independently with functional measures.ConclusionAmong patients without prior leg revascularization, strength in each leg is highly correlated with the lower-leg ABI. Leg strength is associated independently with functional performance. Further study is needed to determine whether lower-extremity resistance training improves functioning in patients with peripheral arterial disease

Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition

Abstract Background Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored. Methods Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIMSM database. Patient characteristics, toxicity and efficacy were analyzed. Results A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy. Conclusion In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.https://deepblue.lib.umich.edu/bitstream/2027.42/148134/1/40425_2019_Article_522.pd

High-Dose Ipilimumab and High-Dose Interleukin-2 for Patients With Advanced Melanoma.

High-dose ipilimumab (IPI) and high-dose interleukin-2 (IL-2) are approved agents for metastatic melanoma, but the efficacy and safety of the combination are unknown. The objective of this study was to evaluate the feasibility, safety, and efficacy of combination high-dose IPI and high-dose IL-2 in patients with histologically confirmed advanced unresectable stage III and IV melanoma. This Phase II, multicenter, open-label, single-arm trial was conducted in nine patients enrolled between 12/2014 and 12/2015. Subjects were treated with high-dose IPI 10 mg/kg intravenous (IV) every 3 weeks for four doses starting at week 1 and high-dose IL-2 (600,000 IU/kg IV bolus every 8 h for up to 14 doses) concurrently with IPI at weeks 4 and 7. After the first 12 weeks of combination therapy, maintenance IPI (10 mg/kg IV) monotherapy was administered every 12 weeks for up to 1 year. No patient had received prior PD-1 blockade, and only one received prior vemurafenib. Confirmed partial response was achieved in one (11%), stable disease in four (44%), and progressive disease in four (44%) of nine patients. Two patients achieved durable disease control of 44+ and 50+ months at the most recent follow-up without subsequent therapy. The median overall survival was not reached after a minimum 24 months of follow-up time. One-year and 2-year survival rates were 89 and 67%, respectively. Seven patients (78%) experienced grade 3 or 4 adverse events related to the study therapy, three of which were attributed to both agents. One patient discontinued the treatment due to liver and kidney toxicity. While toxicity was significant, all events were reversible, and there was no treatment-related mortality. In peripheral blood of patients with decreasing tumor burden, the ratio of the non-classical MHC-II proteins HLA-DM to HLA-DO increased 2-fold, raising the possibility of the ratio of HLA-DM:HLA-DO as a novel biomarker of response to treatment. Although the sample size was limited, combination therapy with high-dose IPI and high-dose IL-2 was feasible and associated with clinical benefit. IL-2-based compounds in combination with CTLA-4 blockade should be studied in advanced melanoma patients who fail to benefit from first-line PD-1 blockade

Change in Blood Pressure Variability Among Treated Elderly Hypertensive Patients and Its Association With Mortality

Background: Information is scarce regarding effects of antihypertensive medication on blood pressure variability (BPV) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long-term mortality in an elderly hypertensive population. Methods and Results: We used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24-hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow-up). Weighted day-night systolic BPV was calculated for both baseline and follow-up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates as high and low based on the baseline median BPV value and then classified BPV changes into stable: low BPV, stable: high BPV, decline: high to low, and increase: low to high. We observed an annual decline (mean±SD: −0.37±1.95; 95% CI, −0.54 to −0.19; P<0.001) in weighted day-night systolic BPV between baseline and follow-up. Having constant stable: high BPV was associated with an increase in all-cause mortality (hazard ratio: 3.03; 95% CI, 1.67–5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62–8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow-up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group. Conclusions: Our results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow-up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long-term mortality

A Landscape and Climate Data Logistic Model of Tsetse Distribution in Kenya

, biologically transmitted by the tsetse fly in Africa, are a major cause of illness resulting in both high morbidity and mortality among humans, cattle, wild ungulates, and other species. However, tsetse fly distributions change rapidly due to environmental changes, and fine-scale distribution maps are few. Due to data scarcity, most presence/absence estimates in Kenya prior to 2000 are a combination of local reports, entomological knowledge, and topographic information. The availability of tsetse fly abundance data are limited, or at least have not been collected into aggregate, publicly available national datasets. Despite this limitation, other avenues exist for estimating tsetse distributions including remotely sensed data, climate information, and statistical tools.Here we present a logistic regression model of tsetse abundance. The goal of this model is to estimate the distribution of tsetse fly in Kenya in the year 2000, and to provide a method by which to anticipate their future distribution. Multiple predictor variables were tested for significance and for predictive power; ultimately, a parsimonious subset of variables was identified and used to construct the regression model with the 1973 tsetse map. These data were validated against year 2000 Food and Agriculture Organization (FAO) estimates. Mapcurves Goodness-Of-Fit scores were used to evaluate the modeled fly distribution against FAO estimates and against 1973 presence/absence data, each driven by appropriate climate data.Logistic regression can be effectively used to produce a model that projects fly abundance under elevated greenhouse gas scenarios. This model identifies potential areas for tsetse abandonment and expansion

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM

BACKGROUND: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). PATIENTS AND METHODS: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin RESULTS: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. CONCLUSIONS: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients