bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inorganic arsenic exposure induces sex-disparate effects and exacerbates ischemia-reperfusion injury in the female heart
Authors: Veenema Ryne , Casin Kevin M. , Sinha Prithvi , Kabir Raihan , Mackowski Nathan , Taube Nicole , Bedja Djahida , Chen Rui , Rule Ana , Kohr Mark J. 
Published: March 2019

Arsenic is a common contaminant in drinking water throughout the world, and recent studies support a link between inorganic arsenic (iAS) exposure and ischemic heart disease in men and women. Female hearts exhibit an estrogen-dependent reduction in susceptibility to myocardial ischemic injury compared with males, and as such, female hearts may be more susceptible to the endocrine-disrupting effects of iAS exposure. However, iAS exposure and susceptibility to ischemic heart injury have not been examined in mechanistic studies. Male and female mice (8 wk) were exposed to environmentally relevant concentrations of sodium arsenite (0, 10, 100, and 1,000 parts/billion) via drinking water for 4 wk. Pre- and postexposure echocardiography was performed, and postexposure plasma was collected for 17β-estradiol measurement. Hearts were excised and subjected to ischemia-reperfusion (I/R) injury via Langendorff perfusion. Exposure to 1,000 parts/billion iAS led to sex-disparate effects, such that I/R injury was exacerbated in female hearts but unexpectedly attenuated in males. Assessment of echocardiographic parameters revealed statistically significant structural remodeling in iAS-treated female hearts with no change in function; males showed no change. Plasma 17β-estradiol levels were not significantly altered by iAS in male or female mice versus nontreated controls. Although total eNOS protein levels did not change in whole heart homogenates from iAS-treated male or female mice, eNOS phosphorylation (Ser1177) was significantly elevated in iAS-treated male hearts. These results suggest that iAS exposure can induce sex-disparate effects and modulate susceptibility to ischemic heart injury by targeting distinct sex-dependent pathways. NEW & NOTEWORTHY This is the first mechanistic study examining iAS exposure on myocardial ischemia-reperfusion injury in male and female mice. Following iAS exposure, ischemia-reperfusion injury was exacerbated in female hearts but attenuated in males. iAS treatment induced statistically significant cardiac remodeling in females, with no change in males. iAS treatment also enhanced phosphorylated eNOS levels at Ser1177, but only in male hearts. These results suggest that iAS alters susceptibility to myocardial I/R injury through distinct sex-dependent pathways.
Angiotensin II type 2 receptor stimulation with compound 21 improves neurological function after stroke in female rats: a pilot study
Authors: Eldahshan Wael , Ishrat Tauheed , Pillai Bindu , Sayed Mohammed A. , Alwhaibi Abdulrahman , Fouda Abdelrahman Y. , Ergul Adviye , Fagan Susan C. 
Published: March 2019

The angiotensin II type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.03 mg/kg ip of C21 and followed up for different times (1, 3, and 14 days) after stroke. Behavioral tests were performed (Bederson, paw grasp, beam walk, and rotarod), and animals were euthanized for infarct size analysis and Western blot analysis. In vitro, primary male and female brain microvascular endothelial cells (ECs) were grown in culture, and the expression of the AT2R was compared between males and females. At 1 day, C21 treatment resulted in an improvement in Bederson scores. However, at 3 days and 14 days, the impact of C21 on stroke outcomes was less robust. In vitro, the expression of the AT2R was significantly higher in female ECs compared with male ECs. In conclusion, C21 improves Bederson scores after stroke in female rats when administered early at reperfusion. The ability of C21 to exert its neuroprotective effects might be affected by fluctuating levels of female hormones.NEW & NOTEWORTHY The present study shows the neuroprotective impact of C21 on ischemic stroke in female rats and how the protective effects of C21 can be influenced by the hormonal status of female rodents.
Muscle metaboreflex-induced central blood volume mobilization in heart failure
Authors: O’Leary Donal S. , Senador Danielle , Augustyniak Robert A. 
Published: March 2019

Underperfusion of active skeletal muscle causes metabolites to accumulate and stimulate group III and IV skeletal muscle afferents, which triggers a powerful pressor response termed the muscle metaboreflex. Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in healthy individuals increases arterial pressure mainly via substantial increases in cardiac output (CO). The increases in CO occur via the combination of tachycardia and increased ventricular contractility. Importantly, MMA also elicits substantial central blood volume mobilization, which allows the ventricular responses to sustain the increases in CO. Otherwise preload would fall and the increases in CO could not be maintained. In subjects with systolic heart failure (HF), the ability to increase CO during exercise and MMA is markedly reduced, which has been attributed to impaired ventricular contractility. Whether the ability to maintain preload during MMA in HF is preserved is unknown. Using a conscious chronically instrumented canine model, we observed that MMA in HF is able to raise central blood volume similarly as in normal subjects. Therefore, the loss of the ability to raise CO during MMA in HF is not because of the loss of the ability to mobilize blood volume centrally. NEW & NOTEWORTHY In normal subjects during dynamic exercise muscle metaboreflex activation elicits large increases in cardiac output that occur via increases in heart rate, ventricular contractility, and, importantly, marked central blood volume mobilization that acts to maintain ventricular preload, thereby allowing the changes in cardiac function to maintain the increases in cardiac output. In subjects with heart failure, the ability to raise cardiac output during muscle metaboreflex activation is impaired. We investigated whether this is because of the inability to maintain ventricular preload. We found that this reflex is still able to elicit large increases in central blood volume, and therefore the limited ability to raise cardiac output likely stems from ventricular dysfunction and not the ability to maintain preload.
The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect
Authors: ten Broeke Sanne W. , Rodríguez-Girondo Mar , Suerink Manon , Aretz Stefan , Bernstein Inge , Capellá Gabriel , Engel Christoph , Gomez-Garcia Encarna B. , van Hest Liselot P. , von Knebel Doeberitz Magnus , Lagerstedt-Robinson Kristina , Letteboer Tom G.W. , Moller Pal , van Os Theo A. , Pineda Marta , Rahner Nils , Olderode-Berends Maran J.W. , von Salomé Jenny , Schackert Hans K. , Spruijt Liesbeth , Steinke-Lange Verena , Wagner Anja , Tops Carli M.J. , Nielsen Maartje 
Published: March 2019

Abstract

Background:
PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families.

Methods:
The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias.

Results:
Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162–4.328] for the second generation and 2.644 (95% CI, 1.082–6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648–2.619) and HR = 1.074 (95% CI, 0.406–2.842) for second and third generations, respectively].

Conclusions:
Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome.

Impact:
This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.
Immunotherapy in Non–Small Cell Lung Cancer: Facts and Hopes
Authors: Doroshow Deborah B. , Sanmamed Miguel F. , Hastings Katherine , Politi Katerina , Rimm David L. , Chen Lieping , Melero Ignacio , Schalper Kurt A. , Herbst Roy S. 
Published: March 2019

AbstractImmune-checkpoint inhibitors (ICI), particularly inhibitors of the PD-1 axis, have altered the management of non–small cell lung cancer (NSCLC) over the last 10 years. First demonstrated to improve outcomes in second-line or later therapy of advanced disease, ICIs were shown to improve overall survival compared with chemotherapy in first-line therapy for patients whose tumors express PD-L1 on at least 50% of cells. More recently, combining ICIs with chemotherapy has been shown to improve survival in patients with both squamous and nonsquamous NSCLC, regardless of PD-L1 expression. However, PD-L1 and, more recently, tumor mutational burden have not proven to be straightforward indicative biomarkers. We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents.
Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth
Authors: Lamano Jonathan B. , Lamano Jason Balquidera , Li Yuping D. , DiDomenico Joseph D. , Choy Winward , Veliceasa Dorina , Oyon Daniel E. , Fakurnejad Shayan , Ampie Leonel , Kesavabhotla Kartik , Kaur Rajwant , Kaur Gurvinder , Biyashev Dauren , Unruh Dusten J. , Horbinski Craig M. , James C. David , Parsa Andrew T. , Bloch Orin 
Published: March 2019

AbstractPurpose:Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.Experimental Design:Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.Results:GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8+ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.Conclusions:Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.
Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis
Authors: Karginova Olga , Weekley Claire M. , Raoul Akila , Alsayed Alhareth , Wu Tong , Lee Steve Seung-Young , He Chuan , Olopade Olufunmilayo I. 
Published: March 2019

Abstract
Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumulation of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro. Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.
Mouse Strains Influence Clearance and Efficacy of Antibody and Antibody–Drug Conjugate Via Fc–FcγR Interaction
Authors: Li Fu , Ulrich Michelle L. , Shih Vincent Feng-Sheng , Cochran Julia H. , Hunter Joshua H. , Westendorf Lori , Neale Jason , Benjamin Dennis R. 
Published: March 2019

Abstract
To provide a better understanding of the pharmacokinetics–pharmacodynamics relationships of antibody-based drugs, we analyzed several chimeric and humanized monoclonal antibodies or antibody–drug conjugates (ADC) for PK and efficacy among four strains of mice. Notably, antibodies and ADCs displayed a dose-dependent drug disposition profile in the plasma of NSG mice. The increased clearance rate in NSG mice resulted in the reduction of antitumor activity of ADCs. Furthermore, we identified that the abnormal clearance was mediated by Fc–FcγR interaction by comparing antibodies that lack FcγR binding capacity. We also found a high percentage of FcγR-expressing macrophages in the bone marrow, spleen, and liver of NSG mice, which may be responsible for the abnormal distribution of antibodies. Overall, these findings suggest that preclinical evaluation of efficacy and pharmacokinetics of antibodies and ADCs need to consider mouse strain-induced variations.
HDAC3 Inhibition Upregulates PD-L1 Expression in B-Cell Lymphomas and Augments the Efficacy of Anti–PD-L1 Therapy
Authors: Deng Siyu , Hu Qianwen , Zhang Heng , Yang Fang , Peng Cheng , Huang Chuanxin 
Published: March 2019

AbstractProgrammed cell-death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway blockade is a promising therapy for the treatment of advanced cancers, including B-cell lymphoma. The clinical response to PD-1/PD-L1 immunotherapy correlates with PD-L1 levels on tumor cells and other cells in the tumor microenvironment. Hence, it is important to understand the molecular mechanisms that regulate PD-L1 expression. Here, we report that histone deacetylase 3 (HDAC3) is a crucial repressor of PD-L1 transcription in B-cell lymphoma. Pan-HDACs or selective HDAC3 inhibitors could rapidly increase histone acetylation and recruitment of bromodomain protein BRD4 at the promoter region of PD-L1 gene, leading to activation of its transcription. Mechanically, HDAC3 and its putative associated corepressor SMRT were recruited to the PD-L1 promoter by the transcriptional repressor BCL6. In addition, HDAC3 inhibition reduced DNA methyltransferase 1 protein levels to indirectly activate PD-L1 transcription. Finally, HDAC3 inhibition increased PD-L1 expression on dendritic cells in the tumor microenvironment. Combining selective HDAC3 inhibitor with anti–PD-L1 immunotherapy enhanced tumor regression in syngeneic murine lymphoma model. Our findings identify HDAC3 as an important epigenetic regulator of PD-L1 expression and implicate combination of HDAC3 inhibition with PD-1/PD-L1 blockade in the treatment of B-cell lymphomas.
What CAR Will Win the CD19 Race?
Authors: Quintás-Cardama Alfonso 
Published: March 2019

AbstractAdoptive transfer of T cells engineered with synthetic receptors is emerging as a new pillar in the treatment of cancer. The adoptive cell therapy furthest along in clinical development is the engineering of T cells to express chimeric antigen receptors (CAR) against the CD19 antigen. Several platforms have shown remarkable activity in patients with relapsed or refractory B-cell malignancies. In 2017, the FDA approved the first CAR T cell products tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Gilead), and others are expected to follow shortly. Despite their activity, CAR T cell approaches have limitations that will need to be addressed, including excessive toxicity, relapses mediated via antigen escape, difficulties overcoming the suppressive tumor microenvironment, high manufacturing costs and retail prices, and patient access, among others. The CAR T cell product that better addresses those challenges will obtain a critical competitive advantage.
Antibody–Cytokine Fusions: Versatile Products for the Modulation of Anticancer Immunity
Authors: Neri Dario 
Published: March 2019

Abstract
The remarkable clinical success of immune-checkpoint inhibitors for the treatment of a growing number of cancer types has sparked interest in the discovery of novel forms of immunotherapy, which may be used alone or in combination. In this context, cytokine-based therapeutics are well poised to play a role in modern cancer therapy. This article focuses on antibody–cytokine fusion proteins (also called “immunocytokines”) as one class of biopharmaceuticals that can substantially improve the therapeutic index and, thus, the applicability of cytokine products. In many preclinical settings, antibodies can be used to preferentially deliver many (but not all) types of cytokines to primary and metastatic tumor lesions. The antibody-based delivery of certain proinflammatory payloads (such as IL2, IL12, and TNF) to the tumor microenvironment can lead to a dramatic potentiation of their anticancer activity. However, although some fusion proteins have advanced to late-stage clinical trials, much work remains to be done in order to fully characterize the mechanism of action and the pharmaceutical potential of immunocytokines in the clinical setting. Various factors contribute to in vivo performance, including the target antigen, the antibody properties, the nature of the payload, the format of the fusion protein, the dose, and schedule, as well as their use in combination with other therapeutic modalities. Protein engineering opportunities and insights in cancer immunology are contributing to the development of next-generation immunocytokine products and of novel therapeutic concepts, with the goal to increase antitumor activity and reduce systemic toxicity (a common problem for cytokine-based biopharmaceuticals).
Weather Radar Network Benefit Model for Tornadoes
Authors: Cho John Y. N. , Kurdzo James M. 
Published: March 2019

AbstractA monetized tornado benefit model is developed for arbitrary weather radar network configurations. Geospatial regression analyses indicate that improvement of two key radar parameters—fraction of vertical space observed and cross-range horizontal resolution—leads to better tornado warning performance as characterized by tornado detection probability and false-alarm ratio. Previous experimental results showing faster volume scan rates yielding greater warning performance are also incorporated into the model. Enhanced tornado warning performance, in turn, reduces casualty rates. In addition, lower false-alarm ratios save costs by cutting down on work and personal time lost while taking shelter. The model is run on the existing contiguous U.S. weather radar network as well as hypothetical future configurations. Results show that the current radars provide a tornado-based benefit of ~$490 million (M) yr−1. The remaining benefit pool is about $260M yr−1, split roughly evenly between coverage- and rapid-scanning-related gaps.
Adjoint Sensitivity of North Pacific Atmospheric River Forecasts
Authors: Reynolds Carolyn A. , Doyle James D. , Ralph F. Martin , Demirdjian Reuben 
Published: March 2019

AbstractThe initial-state sensitivity and optimal perturbation growth for 24- and 36-h forecasts of low-level kinetic energy and precipitation over California during a series of atmospheric river (AR) events that took place in early 2017 are explored using adjoint-based tools from the Coupled Ocean–Atmosphere Mesoscale Prediction System (COAMPS). This time period was part of the record-breaking winter of 2016–17 in which several high-impact ARs made landfall in California. The adjoint sensitivity indicates that both low-level winds and precipitation are most sensitive to mid- to lower-tropospheric perturbations in the initial state in and near the ARs. A case study indicates that the optimal moist perturbations occur most typically along the subsaturated edges of the ARs, in a warm conveyor belt region. The sensitivity to moisture is largest, followed by temperature and winds. A 1 g kg−1 perturbation to moisture may elicit twice as large a response in kinetic energy and precipitation as a 1 m s−1 perturbation to the zonal or meridional wind. In an average sense, the sensitivity and related optimal perturbations are very similar for the kinetic energy and precipitation response functions. However, on a case-by-case basis, differences in the sensitivity magnitude and optimal perturbation structures result in substantially different forecast perturbations, suggesting that optimal adaptive observing strategies should be metric dependent. While the nonlinear evolved perturbations are usually smaller (by about 20%, on average) than the expected linear perturbations, the optimal perturbations are still capable of producing rapid nonlinear perturbation growth. The positive correlation between sensitivity magnitude and wind speed forecast error or precipitation forecast differences supports the relevance of adjoint-based calculations for predictability studies.