bluuebunny/crossref_metadata_2025_split huggingface dataset:
FS222, a CD137/PD-L1 Tetravalent Bispecific Antibody, Exhibits Low Toxicity and Antitumor Activity in Colorectal Cancer Models
Authors: Lakins Matthew A. , Koers Alexander , Giambalvo Raffaella , Munoz-Olaya Jose , Hughes Robert , Goodman Emma , Marshall Sylwia , Wollerton Francisca , Batey Sarah , Gliddon Daniel , Tuna Mihriban , Brewis Neil 
Published: April 2020

Abstract

Purpose:
With the increased prevalence in checkpoint therapy resistance, there remains a significant unmet need for additional therapies for patients with relapsing or refractory cancer. We have developed FS222, a bispecific tetravalent antibody targeting CD137 and PD-L1, to induce T-cell activation to eradicate tumors without the current toxicity and efficacy limitations seen in the clinic.

Experimental Design:
A bispecific antibody (FS222) was developed by engineering CD137 antigen–binding sites into the Fc region of a PD-L1 IgG1 mAb. T-cell activation by FS222 was investigated using multiple in vitro assays. The antitumor efficacy, survival benefit, pharmacodynamics, and liver pharmacology of a murine surrogate molecule were assessed in syngeneic mouse tumor models. Toxicology and the pharmacokinetic/pharmacodynamic profile of FS222 were investigated in a non-human primate dose-range finding study.

Results:
We demonstrated simultaneous binding of CD137 and PD-L1 and showed potent T-cell activation across CD8+ T-cell activation assays in a PD-L1–dependent manner with a CD137/PD-L1 bispecific antibody, FS222. FS222 also activated T cells in a human primary mixed lymphocyte reaction assay, with greater potency than the monospecific mAb combination. FS222 showed no signs of liver toxicity up to 30 mg/kg in a non-human primate dose-range finding study. A surrogate molecule caused significant tumor growth inhibition and survival benefit, concomitant with CD8+ T-cell activation, in CT26 and MC38 syngeneic mouse tumor models.

Conclusions:
By targeting CD137 agonism to areas of PD-L1 expression, predominantly found in the tumor microenvironment, FS222 has the potential to leverage a focused, potent, and safe immune response augmenting the PD-(L)1 axis blockade.
Tumor CD155 Expression Is Associated with Resistance to Anti-PD1 Immunotherapy in Metastatic Melanoma
Authors: Lepletier Ailin , Madore Jason , O'Donnell Jake S. , Johnston Rebecca L. , Li Xian-Yang , McDonald Elizabeth , Ahern Elizabeth , Kuchel Anna , Eastgate Melissa , Pearson Sally-Ann , Mallardo Domenico , Ascierto Paolo A. , Massi Daniela , Merelli Barbara , Mandala Mario , Wilmott James S. , Menzies Alexander M. , Leduc Charles , Stagg John , Routy Bertrand , Long Georgina V. , Scolyer Richard A. , Bald Tobias , Waddell Nicola , Dougall William C. , Teng Michele W.L. , Smyth Mark J. 
Published: April 2020

Abstract

Purpose:
Resistance to anti-PD1–based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB.

Experimental Design:
Pretreatment tumor specimens, from 155 patients with metastatic melanoma treated with ICB and from 50 patients treated with BRAF/MEK-directed targeted therapy, were assessed for CD155 expression by IHC. Intratumor T-cell features were analyzed using multiplex-immunohistofluorescence for CD8, PD1, and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA sequencing results, as well as clinical RECIST response and progression-free survival.

Results:
High pretreatment CD155 tumor levels correlated with high parenchymal PD1+CD8+/CD8+ T-cell ratios (PD1tR) and poor response to anti-PD1 therapy. In PDL1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/CTLA4 therapy.

Conclusions:
Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1+CD8+ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for patients with metastatic melanoma.
Cardiovascular Risk and Resilience Among Black Adults: Rationale and Design of the MECA Study
Authors: Islam Shabatun J. , Kim Jeong Hwan , Topel Matthew , Liu Chang , Ko Yi‐An , Mujahid Mahasin S. , Sims Mario , Mubasher Mohamed , Ejaz Kiran , Morgan‐Billingslea Jan , Jones Kia , Waller Edmund K. , Jones Dean , Uppal Karan , Dunbar Sandra B. , Pemu Priscilla , Vaccarino Viola , Searles Charles D. , Baltrus Peter , Lewis Tené T. , Quyyumi Arshed A. , Taylor Herman 
Published: April 2020

Background
Cardiovascular disease incidence, prevalence, morbidity, and mortality have declined in the past several decades; however, disparities persist among subsets of the population. Notably, blacks have not experienced the same improvements on the whole as whites. Furthermore, frequent reports of relatively poorer health statistics among the black population have led to a broad assumption that black race reliably predicts relatively poorer health outcomes. However, substantial intraethnic and intraracial heterogeneity exists; moreover, individuals with similar risk factors and environmental exposures are often known to experience vastly different cardiovascular health outcomes. Thus, some individuals have good outcomes even in the presence of cardiovascular risk factors, a concept known as resilience.

Methods and Results

The MECA (Morehouse‐Emory Center for Health Equity) Study was designed to investigate the multilevel exposures that contribute to “resilience” in the face of risk for poor cardiovascular health among blacks in the greater Atlanta, GA, metropolitan area. We used census tract data to determine “at‐risk” and “resilient” neighborhoods with high or low prevalence of cardiovascular morbidity and mortality, based on cardiovascular death, hospitalization, and emergency department visits for blacks. More than 1400 individuals from these census tracts assented to demographic, health, and psychosocial questionnaires administered through telephone surveys. Afterwards, ≈500 individuals were recruited to enroll in a clinical study, where risk biomarkers, such as oxidative stress, and inflammatory markers, endothelial progenitor cells, metabolomic and micro
RNA
profiles, and subclinical vascular dysfunction were measured. In addition, comprehensive behavioral questionnaires were collected and ideal cardiovascular health metrics were assessed using the American Heart Association's Life Simple 7 measure. Last, 150 individuals with low Life Simple 7 were recruited and randomized to a behavioral mobile health (eHealth) plus health coach or eHealth only intervention and followed up for improvement.

Conclusions

The
MECA
Study is investigating socioenvironmental and individual behavioral measures that promote resilience to cardiovascular disease in blacks by assessing biological, functional, and molecular mechanisms.

REGISTRATION

URL
:
https://www.clini​caltr​ials.gov
. Unique identifier:
NCT
03308812.
Goal‐Striving Stress and Incident Cardiovascular Disease in Blacks: The Jackson Heart Study
Authors: Glover LáShauntá M. , Cain‐Shields Loretta R. , Spruill Tanya M. , O'Brien Emily C. , Barber Sharrelle , Loehr Laura , Sims Mario 
Published: April 2020

Background
Goal‐striving stress (GSS), the stress from striving for goals, is associated with poor health. Less is known about its association with cardiovascular disease (CVD).

Methods and Results
We used data from the JHS (Jackson Heart Study), a study of CVD among blacks (21–95 years old) from 2000 to 2015. Participants free of CVD at baseline (2000–2004) were included in this analysis (n=4648). GSS was examined in categories (low, moderate, high) and in SD units. Incident CVD was defined as fatal or nonfatal stroke, coronary heart disease (CHD), and/or heart failure. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident CVD by levels of GSS, adjusting for demographics, socioeconomic status, health behaviors, risk factors, and perceived stress. The distribution of GSS categories was as follows: 40.77% low, 33.97% moderate, and 25.26% high. Over an average of 12 years, there were 140 incident stroke events, 164 CHD events, and 194 heart failure events. After full adjustment, high (versus low) GSS was associated with a lower risk of stroke (HR, 0.38; 95% CI, 0.17–0.83) and a higher risk of CHD (HR, 1.91; 95% CI, 1.10–3.33) among women. A 1‐standard deviation unit increase in GSS was associated with a 31% increased risk of CHD (HR, 1.31; 95% CI, 1.10–1.56) among women.

Conclusions
Higher GSS may be a risk factor for developing CHD among women; however, it appears to be protective of stroke among women. These analyses should be replicated in other samples of black individuals.
Enhancements in Day-Ahead Forecasts of Solar Irradiation with Machine Learning: A Novel Analysis with the Japanese Mesoscale Model
Authors: Gari da Silva Fonseca Joao , Uno Fumichika , Ohtake Hideaki , Oozeki Takashi , Ogimoto Kazuhiko 
Published: April 2020

AbstractThe objective of this study is to propose and evaluate a set of modifications to enhance a machine-learning-based method for forecasting day-ahead solar irradiation. To assess the proposed modifications, they were implemented in an initial forecast method, and their effectiveness was analyzed using two years of data on a national scale in Japan. In addition, the accuracy of the modified method was compared with one of the forecast methods for solar irradiation used by the Japan Meteorological Agency (JMA), namely, the mesoscale model (MSM). Such forecasts were made publicly available only recently, which makes this study one of the first ones to compare them with machine-learning-based forecasts. The annual root-mean-square error (RMSE) of local forecasts of the JMA-MSM varied from 0.1 to 0.14 kW h m−2; the regional equivalent varied from 0.062 to 0.091 kW h m−2. In comparison with these results, the modified model achieved an average RMSE reduction of 7.5% on the local scale and 16% on the regional scale. The modified model also had a skill score that was 23% higher than that of the JMA model. Furthermore, the performance of the JMA model had strong spatial and seasonal dependencies, which were reduced in the machine-learning-based forecasts. The results show that the proposed modifications are effective in reducing large forecasts errors, but they cannot compensate for situations in which the input data used to make the forecasts are highly inaccurate.
A Methodology for Multiobjective Evaluation of Precipitation Products for Extreme Weather (in a Data-Scarce Environment)
Authors: Lu Sha , Veldhuis Marie-claire ten , van de Giesen Nick 
Published: April 2020

AbstractIn this paper, a methodology is proposed to quantitatively evaluate precipitation products for multiple purposes. Evaluation mainly focuses on rainfall characteristics relevant to hydrological or agricultural applications: spatial distribution pattern, effect of aggregation over time, the capture of small-scale variability and seasonality, detection of dry spells and wet spells, and timing and volume of heavy rainfall events. Verification statistics were modified and metrics were reported for extreme weather performance, such as flood and drought monitoring. The analysis was performed for different rainfall categories, over regions dominated by different weather systems or with different topographical structures. The latest versions of seven commonly available, high-resolution rainfall estimates have been evaluated by the method against daily data from 16 rain gauge stations over Tanzania, during 1998–2006. They were TRMM 3B42, CHIRPS, TAMSAT, CMORPH_RAW, CMORPH_BLD, WFDEI_CRU, and CPCU. All products, except for CMORPH_BLD and CPCU, were poorly correlated to gauge data at daily time scale with correlation coefficients < 0.5. Five-day aggregation was the minimum time scale that can be used for the products to reach an accuracy better than monthly-mean of gauge data. Their performance varied across different climatic or topographical regions and different rainfall seasons. Timing of precipitation was inaccurately estimated by all products, particularly for heavy rains, with less than 40% hits. The results of the evaluation procedure allow discrimination between available products and better selection of the product to be used for a specific application, such as crop insurance or flood early warning, under particular climatic conditions.
A Multiscale Dynamical Model in a Dry-Mass Coordinate for Weather and Climate Modeling: Moist Dynamics and Its Coupling to Physics
Authors: Zhang Yi , Li Jian , Yu Rucong , Liu Zhuang , Zhou Yihui , Li Xiaohan , Huang Xiaomeng 
Published: April 2020

AbstractA multiscale dynamical model for weather forecasting and climate modeling is developed and evaluated in this study. It extends a previously established layer-averaged, unstructured-mesh nonhydrostatic dynamical core (dycore) to moist dynamics and parameterized physics in a dry-mass vertical coordinate. The dycore and tracer transport components are coupled in a mass-consistent manner, with the dycore providing time-averaged horizontal mass fluxes to passive transport, and tracer transport feeding back to the dycore with updated moisture constraints. The vertical mass flux in the tracer transport is obtained by reevaluating the mass continuity equation to ensure compatibility. A general physics–dynamics coupling workflow is established, and a dycore–tracer–physics splitting strategy is designed to couple these components in a flexible and efficient manner. In this context, two major physics–dynamics coupling strategies are examined. Simple-physics packages from the 2016 Dynamical Core Model Intercomparison Project (DCMIP2016) experimental protocols are used to facilitate the investigation of the model behaviors in idealized moist-physics configurations, including cloud-scale modeling, weather forecasting, and climate modeling, and in a real-world test-case setup. Performance evaluation demonstrates that the model is able to produce reasonable sensitivity and variability at various spatiotemporal scales. The consideration and implications of different physics–dynamics coupling options are discussed within this context. The appendix provides discussion on the energetics in the continuous- and discrete-form equations of motion.
Mycosis Fungoides of the True Vocal Folds: A Case Report
Authors: Qualliotine Jesse R. , Ahluwalia Rohan , Tzachanis Dmitrios , Sanghvi Parag , Weissbrod Philip A. 
Published: April 2020

Objectives: To report a case of laryngeal involvement of mycosis fungoides and its symptomatic treatment with laser-assisted surgical ablation. Methods: Case report and literature review. Results: A 76-year-old woman with longstanding MF previously treated with Brentuximab Vedotin who developed persistent cough and dysphonia. The patient’s laryngeal disease burden was treated with KTP-laser ablation and further reduced with doxorubicin and radiotherapy. Conclusions: Although laryngeal, and especially glottic, involvement is a rare finding, suspicion should be maintained in symptomatic patients with cutaneous mycosis fungoides. This the first reported surgical laser treatment of laryngeal symptoms in this context, which can greatly improve a patient’s quality of life.
Prospective study comparing the outcome of a population-specific adjusted calcium equation to ionized calcium
Authors: Jassam N , Hayden K , Dearman R , Allgar V , Barth JH 
Published: April 2020

Background Calcium circulates bound to albumin and changes in albumin concentration will therefore affect total calcium measurements. In order to mitigate this, correction factors are frequently used. The most widely used correction equation was described by Payne and colleagues in 1973. This equation was derived from well-defined hospitalized patients’ data. Current clinical practice is consistent with the general application of the adjusted calcium equation irrespective of clinical setting. This study aims to assess the validity of this approach by the derivation of a community care-specific adjusted calcium equation (‘community equation’) and the comparison of its performance to a hospitalized patient equation and ionized calcium. Method Retrospective data were collected according to Payne’s criteria from an inpatient and community care setting. Data were used to derive the two equations: the in-patient equation and community equation. The outcome of these equations was compared with ionized calcium obtained from 123 healthy participants. Results The community equation correctly identified the calcium status of 92% of the 123 healthy participants, while the inpatient equation identified 46% only. Regression analysis against ionized calcium showed a higher R2 for the community equation than for the inpatient equation. Furthermore, we have shown that mean albumin and calcium concentrations are significantly different between these two populations. Conclusion In this study, we found that the diagnostic accuracy of the adjusted calcium equation in ambulant patients was improved by the derivation of a population-specific equation for the community care setting.
The Sociopolitical Dynamics of Coal Transition in India
Authors: Janardhanan Nandakumar , Tamura Kentaro 
Published: April 2020

Energy transition has been gaining significant policy attention in India, especially in the backdrop of the concerns about growing emissions from fossil fuels and the need for cleaner energy services. However, this has been one of the strategic dilemmas for the country. On the one hand, the increasing demand for fossil fuels is prompting critical policy actions to minimize the energy-related emissions and reduce the dependency on the same. On the other hand, the national economic targets that demand high growth have been pivotal in pushing the energy demand growth and have also been unable to shift away from the conventional energy mix. The global debates on shifting away from environmentally damaging energy sources have always paid greater focus on the coal sector. This is primarily due to the fact that coal-fuelled power generation sector has been responsible for the highest quantity of greenhouse gas emissions in many countries. Shifting away from coal sector can have significant adverse sociopolitical impacts. The workforce depending on the sector for mining and processing, as well as in the other allied sectors can be affected by the falling demand for coal. On the contrary, this article identifies that energy transition has not made any serious dent on the workforce or communities that are traditionally dependent on coal sector. Instead, the fall in employment witnessed is primarily due to the increasing mechanization taking place for the past few decades. The article discusses coal transition in the Indian context to present the arguments in this direction.
The Self-Inflicted Dimensions of Puerto Rico’s Fiscal Crisis
Authors: Quiñones-Pérez Argeo T. , Seda-Irizarry Ian J. 
Published: April 2020

The fiscal crisis in Puerto Rico, which constrains the ways in which the government can try to tackle the economic depression, is in important ways self-inflicted—the product of economic policies undertaken at the local level. When the crisis is approached in this way, the resolution of the island’s colonial situation can be seen as a necessary but not sufficient condition for solving the problems of the depression’s victims. La crisis fiscal en Puerto Rico, que limita las formas en que el gobierno puede potencialmente tratar de hacer frente a la depresión económica, es autoinfligida de manera importante: el producto de las políticas económicas implementadas a nivel local. Cuando se aborda la crisis de esta manera, la resolución de la situación colonial de la isla puede verse como una condición necesaria pero no suficiente para resolver los problemas de las víctimas de la depresión.
Contralateral Tongue Muscle Activation during Hypoglossal Nerve Stimulation
Authors: Sturm Joshua J. , Modik Oleg , Koutsourelakis Ioannis , Suurna Maria V. 
Published: April 2020

ObjectiveThe effectiveness of upper airway stimulation via hypoglossal nerve stimulation for obstructive sleep apnea depends upon the pattern of tongue muscle activation produced. This study investigated the nature of contralateral tongue muscle activation by unilateral hypoglossal nerve stimulation using intraoperative nerve integrity monitoring in conjunction with electromyography and explored the relationship between contralateral tongue muscle activation and polysomnographic measures of obstructive sleep apnea severity.Study DesignProspective case series.SettingTertiary care medical center.Subjects and MethodsFifty‐one patients underwent unilateral (right) hypoglossal nerve stimulator implantation for obstructive sleep apnea. Neurophysiological data included electromyographic responses in ipsilateral (right) and contralateral (left) genioglossus muscles in response to intraoperative bipolar probe stimulation (0.3 mA) of medial hypoglossal nerve branches. Clinical data included pre‐ and postoperative apnea‐hypopnea indices and oxygen desaturation levels.ResultsA subset of patients (20/51, 39%) exhibited electromyographic responses in both the ipsilateral and contralateral genioglossus (bilateral), whereas the remaining patients (31/51, 61%) exhibited electromyographic responses only in the ipsilateral genioglossus (unilateral). The baseline characteristics of bilateral and unilateral responders were similar. Both groups exhibited significant and comparable improvements in apnea‐hypopnea index and oxygen desaturations after hypoglossal nerve stimulation. Neither the amplitude nor the latency of contralateral genioglossus responses was predictive of clinical outcomes.ConclusionA subset of patients undergoing unilateral hypoglossal nerve stimulation exhibits activation of contralateral genioglossus muscles. Patients with unilateral and bilateral genioglossus responses exhibit comparable, robust improvements in apnea‐hypopnea index and oxygen desaturation levels.