Sustaining aquifers hydrologically, economically, and institutionally: Policy analysis of the Ogallala in New Mexico.

Groundwater discharge exceeding recharge threatens sustainable aquifer water use internationally. Interest remains high in discovering more hydrologically sustainable and economically affordable measures to protect these aquifers. Previous research has conducted various aquifer assessments. Some work has investigated costs and benefits of various plans that would limit aquifer pumping. Despite notable advances in this kind of analysis, little published work to date has unified these elements into a science-based integrated framework to inform more sustainable aquifer policy design. This work's novel contribution is to integrate analysis of hydrology, economics, institutions, and policy into a unified scientific framework to inform choices on more sustainable pumping strategies while protecting economic activity for agricultural and urban water-using sectors. It does so by conceptualizing, formulating, designing, and applying a mathematical programming framework to replicate historically observed pumping patterns in parts of the Southern and Central High Plains Ogallala Aquifer region in New Mexico, USA. We first calibrated the optimization framework to replicate the historically observed data. We then go on to identify least cost pumping caps that would have partly restored the aquifer to its 2014 level by 2020, while comparing the performance of four other partial aquifer protection policy measures. Findings indicate a surprisingly low cost that could have been incurred to partially protect the aquifer over that period. However, these low costs are complicated by (1) decreasing water quality outside of the irrigated regions and (2) focusing of lateral inputs to a narrower zone of depression around the irrigated regions. These findings carry important implications for identifying more sustainable aquifer management plans internationally. The work's importance comes from its capacity to inform policy debates over a range of water shortage sharing plans, while respecting institutional constraints governing equitable burden sharing.

Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity.

CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumor control. Antibodies targeting CTLA-4 have been promising treatments for numerous cancers, but the mechanistic basis of their anti-tumoral immune-boosting effects is poorly understood. Although the ctla4 gene also encodes an alternatively spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in a murine cancer model. We show that expression of sCTLA-4 by tumor cells suppresses CD8+ T cells in vitro and accelerates growth and experimental metastasis of murine tumors in vivo. These effects were accompanied by modification of the immune infiltrate, notably restraining CD8+ T cells in a non-cytotoxic state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoral CD8+ T cell activation and cytolytic potential, correlating with therapeutic efficacy and tumor control. This previously unappreciated role of sCTLA-4 suggests that the biology and function of multi-gene products of immune checkpoint receptors need to be fully elucidated for improved mechanistic understanding of cancer immunotherapies.

A Novel Role for the Soluble Isoform of CTLA-4 in Normal, Dysplastic and Neoplastic Oral and Oropharyngeal Epithelia.

Background: Head and neck cancer (HNC) has a high mortality rate, with late diagnosis remaining the most important factor affecting patient survival. Therefore, it is imperative to identify markers that aid in early detection and prediction of disease progression. HNCs evade the immune system by different mechanisms, including immune checkpoints. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is an immune checkpoint receptor that downregulates anti-tumour immune responses, with evidence of involvement in HNC. The less studied, alternatively spliced, soluble isoform (sCTLA-4) also plays an immunosuppressive role that contributes to immune escape. We quantified sCTLA-4 in normal, potentially malignant, and malignant oral and oropharyngeal tissues to elucidate any role in tumourigenesis and identify its potential as a biomarker for diagnosis and patient stratification. Methods: Normal, low- and high-grade epithelial dysplasia, and squamous cell carcinoma oral and oropharyngeal biopsies were selectively stained for sCTLA-4 and quantified using the image analysis software QuPath. Results: Distinct sCTLA-4 staining patterns were observed, in which normal epithelial sCTLA-4 expression correlated with keratinocyte differentiation, while disrupted expression, both in intensity and localisation, was observed in dysplastic and neoplastic tissues. Conclusions: Our data indicate an additional, previously unknown role for sCTLA-4 in epithelial cell differentiation and proliferation. Furthermore, our findings suggest the potential of sCTLA-4 as a biomarker for predicting disease progression and patient stratification for targeted HNC therapies.

Pain, obesity, and physical function in Mexican American older adults during 20 years of follow-up.

INTRODUCTION: Pain remains largely undertreated in older adults irrespective of health care setting. Mexican American adults in the United States have a high age-adjusted prevalence of obesity. However, the association of pain and obesity with physical function is understudied in this population. OBJECTIVE: To examine the association of co-occurring pain and obesity with physical function over 20 years of follow-up in a cohort of older Mexican Americans who scored ≥7 (moderate to high) in the Short Physical Performance Battery (SPPB) test and were nondisabled at baseline. DESIGN: Longitudinal population-based study. SETTING: Community-dwelling older adults from Southwestern United States. PARTICIPANTS: Mexican American adults age 65 years and older. INTERVENTIONS: Not Applicable. MAIN OUTCOME MEASURES: Physical function was assessed with the SPPB test (standing balance, timed 8-ft walk, and five repeated timed chair stands). Participants at baseline were divided into four groups: no pain-no obesity (n = 869), obesity only (n = 282), pain only (n = 216), and pain-obesity (n = 159). Generalized Estimating Equation models were used to estimate the odds ratio (OR) and 95% confidence interval (CI) of lower performance in physical function over 20 years as a function of pain-obesity grouping. RESULTS: Participants with pain only (OR = 1.61, 95% CI = 1.34-1.95) and with co-occurring pain and obesity (OR = 2.32, 95% CI = 1.83-2.95) had significantly greater odds of physical function impairment over those with no pain-no obesity or obesity only, after controlling for all covariates. CONCLUSION: Older Mexican American adults were at high risk for physical function impairment over time if they had pain or co-occurring pain and obesity. Early assessment and proper pain management as well as maintaining a healthy weight may reduce declines in physical function in older Mexican American adults.

Integrating water science, economics, and policy for future climate adaptation.

Water science, water economics, and water policy issues continue to rise in importance internationally as elevated population, income growth, and climate change magnify scarcity, shortages, and injustices in water access. Based on the unique physical, institutional, and economic characteristics of water, this work's first contribution is to characterize a road forward for research innovations that enable better integration of water science, water economics, and water policy. Meeting water's sustainable development and justice goals calls for several research innovations that humanity awaits. The advances called for in this work include deep uncertainty management, red team reviews, innovative water rights design, accelerating SDG achievement, valuing water infrastructure, valuing natural water retention, incentivizing water conservation, improving financial performance of rural water systems, water network modularization, non-price scarcity signals, optimization model calibration, remote sensing, transboundary benefit sharing, optimal growth, and water valuation. The work's second contribution is to present a prototype scalable basin scale hydroeconomic analysis (HEA) as a framework for integrating these above innovations when they occur. Results of the HEA show that losses from a 50% shortage in the basin's surface water supply can continue to protect 93% of total economic benefits across economic sectors if an efficient water trading system is established to move water from lower to higher valued uses when shortages occur. The work concludes by noting that great advances remain needed for better and longer lives.

Outcome reporting bias in nephrology randomized clinical trials: Examining outcomes represented by graphical illustrations.

Background: Outcome reporting bias (ORB) is widely reported in the medical literature, but the contribution from published graphical illustrations is unknown. The aim of this study was to investigate the occurrence of ORB in contemporary nephrology clinical trials relating to the choice of outcomes reported through graphical illustrations. Methods: An observational study was conducted using nephrology clinical trials searched from five high-impact medical journals from 2015 to 2020. Eligible trials reported a phase 2, 3 or 4 trial, contained at least one published outcome graphical illustration and were registered on a clinical trial registry. The primary outcome was the occurrence of ORB based on the choice of graphical illustrations in published trial manuscripts, deemed to be present if a graphical illustration displayed a secondary or unregistered outcome ahead of a trial's primary outcome, or if any unregistered trial outcome was presented as a graphical illustration. Results: In 75 eligible clinical trials, the primary outcome for ORB was present in 60% of the trials (n = 45). Occurrence of the primary outcome did not differ significantly based on trial sample size, funding model, trial phase, individual medical journal or publication year. An unregistered trial outcome was graphically illustrated in 93% (n = 42) of those clinical trials with ORB present. Conclusion: Outcome reporting bias based on the choice of graphical illustration is common, driven primarily by graphical illustration of unregistered trial outcomes. More appropriate choice of outcomes for graphical illustrations by authors, coupled with both increased enforcement of CONSORT guidelines by medical journals and specific guidelines for graphical illustrations choice, are desirable to address these findings.

Climate adaptation guidance: New roles for hydroeconomic analysis.

Climate water stress internationally challenges the goal of achieving food, energy, and water security. This challenge is elevated by population and income growth. Increased climate water stress levels reduce water supplies in many river basins and elevate competition for water among sectors. Organized information is needed to guide river basin managers and stakeholders who must plan for a changing climate through innovative water allocation policies, trade-off analysis, vulnerability assessment, capacity adaptation, and infrastructure planning. Several hydroeconomic models have been developed and applied assessing water use in different sectors, counties, cultures, and time periods. However, none to date has presented an optimization framework by which historical water use and economic benefit patterns can be replicated while presenting capacity to adapt to future climate water stresses to inform the design of policies not yet been implemented. This paper's unique contribution is to address this gap by designing and presenting results of a hydroeconomic model for which optimized base conditions exactly match observed data water use and economic welfare for several urban and agricultural uses at several locations in a large European river basin for which water use supports a population of more than 3.2 million. We develop a state-of-the arts empirical dynamic hydroeconomic optimization model to discover land and water use patterns that optimize sustained farm and city income under various levels of climate-water stress. Findings using innovative model calibration methods allow for the discovery of efficient water allocation plans as well as providing insight into marginal behavioral responses to climate water stress and water policies. Results identify that water trade policy under climate water stress provides more economically efficient water use patterns, reallocating water from lower valued uses to higher valued uses such as urban water. The Ebro River Basin in Spain is used as an example to investigate water use adaptation patterns under various levels of climate water stress. That basin's issues and challenges can be of relevance to other river basins internationally.

Enhancing climate resilience of irrigated agriculture: A review.

Emerging evidence showing trends in climate change with a strong likelihood those changes will continue elevates the importance of finding affordable adaptations by irrigated agriculture. Successful climate adaptation measures are needed to affordably sustain irrigated agriculture in the face of elevated carbon emissions affecting the reliability of water supplies. Numerous potential adaptation options are available for adjusting irrigated agricultural systems to implement climate risk adaptation. This work focuses on addressing the gap in the literature defined by a scarcity of reviews on measures to elevate the capacity of irrigated agriculture to enhance its climate change resilience. Accordingly, the original contribution of this work is to review the literature describing measures for enhancing climate resilience by irrigated agriculture. In addition, it describes the role of economic analysis to discover affordable measures to enhance resilience by irrigated agriculture. It achieves those aims by posing the question "What principles, practices, and recent developments are available to guide discovery of measures to improve resilience by irrigated agriculture to adapt to ongoing evidence of climate change?" It addresses that question by reviewing several risk reduction measures to control the economic cost of losses to irrigators in the face of growing water supply unreliability. Following this review, a role for optimizing a portfolio of climate adaptation measures is described, followed by a discussion of potential contributions that can be made by the use of hydroeconomic analysis. Results provide a framework for economic analysis to discover economically attractive methods to elevate resilience of irrigated agriculture.

Sustaining aquifers economically in the face of hydrologic, institutional, and climate constraints.

Aquifers supply water to millions of farms, thousands of cities, and billions of people worldwide. Water use and economic activity in aquifer-dependent regions cannot be sustained if groundwater levels are not stabilized. This article addresses a question relevant to these regions internationally: how can water scarce areas reduce aquifer depletion while supporting the many economically and institutionally important uses of groundwater, which serve as a critical source of supply in many parts of the world with limited or seasonal precipitation which could become more pronounced in the face of future climate stress. Facing that challenge, this work presents a framework for discovering measures to hydrologically stabilize aquifers that control economic losses while respecting local institutional constraints. It advances our capacity to discover measures to efficiently, equitably, and sustainably allocate burden sharing that protects aquifers while adapting to hydrologic, economic, and institutional characteristics of an affected community. Results of this work show that for the aquifers investigated, present practices of groundwater use are unsustainable and finds that alternative practices are possible. It provides scenarios describing such practices and also determines their hydrological and economic consequences. Finally, it shows how these results can feed into policy debates over the several water-sharing arrangements. This work makes several incremental contributions: calibrating modelled pumping patterns to the historical baseline, controlling economic costs of achieving hydrologic sustainability, respecting institutional constraints governing equitable burden sharing, presenting an approach with powers of generalizability, and using routinely collected data. While the approach and findings are illustrated for two aquifers in Africa, its approach carries some generalizability. All data, variables, equations, constraints, and results are included as appendices.

Economic optimization to guide climate water stress adaptation.

Allocation of water over its six dimensions of quantity, quality, timing, location, price, and cost remains an ongoing challenge facing water resource planning worldwide. This challenge is magnified with growing evidence of climate change and related water supply stressors. This stress will challenge food, energy, and water systems as climate adaptation policy measures see continued debate. Despite numerous achievements made many by previous works, few attempts have scanned the literature on economic optimization analysis for water resources planning to discover affordable climate adaptation measures. This paper aims to fill that gap by reviewing the literature on water resource optimization analysis at the basin scale to guide discovery of affordable climate adaptation measures. It does so by posing the question "What principles, practices, and recent developments are available to guide discovery of policy measures to improve water resource system adaptions to growing evidence of climate water stress?" It describes past achievements and identifies improvements needed for optimization analysis to inform policy debates for crafting plans to improve climate resilience. It describes an economic conceptual framework as well as identifying data needs for conducting economic optimization exercises to support river basin planning faced by the challenge of managing the six water dimensions described above. It presents an example from an ongoing issue facing water planners in the Middle East. Conclusions find considerable utility in the use of economic optimization exercises to guide climate water stressadaptation. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government.

Targeting the PI3K/Akt/mTOR pathway: A therapeutic strategy in COVID-19 patients.

Some COVID-19 patients suffer complications from anti-viral immune responses which can lead to both a dangerous cytokine storm and development of blood-borne factors that render severe thrombotic events more likely. The precise immune response profile is likely, therefore, to determine and predict patient outcomes and also represents a target for intervention. Anti-viral T cell exhaustion in the early stages is associated with disease progression. Dysregulation of T cell functions, which precedes cytokine storm development and neutrophil expansion in alveolar tissues heralds damaging pathology.T cell function, cytokine production and factors that attract neutrophils to the lung can be modified through targeting molecules that can modulate T cell responses. Manipulating T cell responses by targeting the PI3K/Akt/mTOR pathway could provide the means to control the immune response in COVID-19 patients. During the initial anti-viral response, T cell effector function can be enhanced by delaying anti-viral exhaustion through inhibiting PI3K and Akt. Additionally, immune dysregulation can be addressed by enhancing immune suppressor functions by targeting downstream mTOR, an important intracellular modulator of cellular metabolism. Targeting this signalling pathway also has potential to prevent formation of thrombi due to its role in platelet activation. Furthermore, this signalling pathway is essential for SARS-cov-2 virus replication in host cells and its inhibition could, therefore, reduce viral load. The ultimate goal is to identify targets that can quickly control the immune response in COVID-19 patients to improve patient outcome. Targeting different levels of the PI3K/Akt/mTOR signalling pathway could potentially achieve this during each stage of the disease.

Managing food-ecosystem synergies to sustain water resource systems.

Measures implemented to restore ecosystem services are widely believed to conflict with food production in the world's irrigated regions because of their competition for scarce water. However, little integrated analysis has been conducted to test this hypothesis. This work tests that hypothesis by presenting results of a basin-scale hydroeconomic analysis linking biophysical, hydrologic, agronomic, ecological, economic, policy, and institutional dimensions of the partially-restored Mesopotamian Marshes of Western Asia. Results serve to partly reject the hypothesis: Here we find that an economically-optimized ecosystem restoration trajectory can be achieved with a minimal loss in food production or farm income where restored wetlands complement important dimensions of food production. Moreover, we find that where water shortage sharing rules can be made more flexible, ecosystem restoration more nearly complements improved food security. Our results point to previously unexplored synergies among food production, ecosystem restoration, and water laws in arid and semi-arid regions internationally.

TGFß2 Induces the Soluble Isoform of CTLA-4 - Implications for CTLA-4 Based Checkpoint Inhibitor Antibodies in Malignant Melanoma.

Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on in vitro immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFß2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFß2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.

Economics of irrigation water conservation: Dynamic optimization for consumption and investment.

Measures to protect irrigation water supplies for food security continue to receive international attention to address growing water scarcity when faced by increased food demands combined with reduced water supply reliability. Yet, a common problem where water is delivered with earthen canals is delivery inefficiency combined with low economic values per unit of water. In many of the world's arid regions, climate stressed water shortages have raised the importance of discovering measures to improve irrigation delivery efficiency. However, little research grade work to date has presented an integrated analysis of the economic performance of irrigation delivery improvements faced by drought and climate stressed regions. This paper's unique contribution is to investigate the economic performance of water conservation infrastructure combined with dynamically optimized use of saved water. We develop a state-of-the arts empirical dynamic optimization model to discover land and water use patterns that optimize sustained farm income. Results from the upper watershed irrigation region of the Canadian Basin in the southwestern US show that canal and delivery system lining can raise the sustained economic value of water for crop irrigation. The saved water can see immediate use in dry years. It can also be stored in wet years to mitigate the most adverse impacts of future climate water stress. This double dividend is especially important in rain-fed watersheds for which surface water supplies for irrigation are difficult to forecast accurately. Findings light a path for water managers and other stakeholders who bear responsibility of finding economically responsible measures to improve irrigation water productivity in the world's dry regions.

Deciphering the Role of Regulatory CD4 T Cells in Oral and Oropharyngeal Cancer: A Systematic Review.

Background: Recruiting regulatory CD4 T cells (Tregs) into the tumor microenvironment is an important tumor escape mechanism. Diminishing these suppressive cells is therefore one of the targets of cancer immunotherapy. Selective depletion of Tregs has proven successful in enhancing anti-tumor immunity and therapeutic efficacy in multiple tumor types. However, the role of Tregs in oral/oropharyngeal cancers is unclear with conflicting evidence regarding the effect of these suppressive cells on tumor prognosis. In this study, we sought to review the role of Tregs in oral/oropharyngeal cancer with the aim of deciphering the controversy regarding their effect on tumor progression and prognosis. Methods: A systematic review of the literature pertaining to the role of Tregs in oral/oropharyngeal cancer was performed using Scopus, Embase, and PubMed. Forty-five records were deemed eligible and data describing methodology of Treg detection, tumor type, and association with prognosis were extracted. Results: Of the 45 eligible manuscripts accepted for this systematic review, thirty-nine studies reported data from human subjects while the remaining studies focused on animal models. Sixteen studies were carried out using peripheral blood samples, while samples from the tumor site were analyzed in 18 studies and 11 studies assessed both blood and tumor samples. The transcriptional factor, Foxp3, was the most commonly used marker for Treg identification (38/45). The findings of 25 studies suggested that an increase in Tregs in the tumor microenvironment and/or peripheral blood was associated with poorer prognosis. These conclusions were attributed to the suppression of immune responses and the consequent tumor progression. Conversely, nine studies showed an increase in Tregs in peripheral blood and/or tumor microenvironment was related to a favorable prognosis, particularly in the presence of human papilloma virus (HPV), the status of which was only assessed in 11 studies. Conclusions: This review underlines the importance of host immunity in the behavior of oral/oropharyngeal cancer. Furthermore, we report an apparent lack of clarity regarding the true role Tregs play in oral/oropharyngeal cancer progression which could be attributed to inconsistent detection techniques of Tregs. Our results therefore highlight the need for clearer methodologies and more robust phenotyping when defining Tregs.

On the Road to Immunotherapy-Prospects for Treating Head and Neck Cancers With Checkpoint Inhibitor Antibodies.

Head and neck cancers (HNC) represent a heterogeneous cluster of aggressive malignancies that account for 3% of all cancer cases in the UK. HNC is increasing in frequency particularly in the developing world, which is related to changes in risk factors. Unfortunately, the mortality rate is high, which is chiefly attributed to late diagnosis at stages where traditional treatments fail. Cancer immunotherapy has achieved great successes in anti-tumor therapy. Checkpoint inhibitor (CI) antibodies enhance anti-tumor activity by blocking inhibitory receptors to drive tumor-specific T and NK cell effector responses. Since their introduction in 2011, CI antibodies have been approved for many cancer types including HNC. Here, we examine the development of CI therapies and look forward to future developments for treatment of HNC with CI therapies.

Hiding in Plain Sight: Soluble Immunomodulatory Receptors.

Alternatively spliced natural soluble isoforms of immunomodulatory receptors [cytotoxic T lymphocyte antigen-4 (CTLA-4), 4-1BB, and programmed death-1 (PD-1)/PD-L1] have been overlooked in favor of their cell-surface-bound counterparts that have generated blockbuster antibodies for the treatment of cancer. We propose that the soluble variants of these receptors contribute to immune regulation and offer potential as targets for immunotherapy.