bluuebunny/crossref_metadata_2025_split huggingface dataset:
DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma
Authors: Fitzgerald Allison A , Wang Shangzi , Agarwal Veena , Marcisak Emily F , Zuo Annie , Jablonski Sandra A , Loth Melanie , Fertig Elana J , MacDougall John , Zhukovsky Eugene , Trivedi Shubhendu , Bhatia Dimple , O'Neill Vince , Weiner Louis M 
Published: November 2021

BackgroundPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because of PDAC’s extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, ‘cold’) tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored.MethodsWe examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy.ResultsIn both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis.ConclusionsThese findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in ‘cold’ tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.
Surface enhanced infrared spectroelectrochemistry using a microband electrode
Authors: Morhart Tyler A. , Tu Kaiyang , Read Stuart T. , Rosendahl Scott M. , Wells Garth , Achenbach Sven , Burgess Ian J. 
Published: November 2021

The successful use of a microband electrode printed on a silicon internal reflection element to perform time resolved infrared spectroscopy is described. Decreasing the critical dimension of the microband electrode to several hundred micrometers provides a sub-microsecond time constant in a Kretschmann configured spectroelectrochemical cell. The high brilliance of synchrotron sourced infrared radiation has been combined with a specially designed horizontal attenuated total reflectance (ATR) microscope to focus the infrared beam on the microband electrode. The first use of a sub-microsecond time constant working electrode for ATR surface enhanced infrared absorption spectroscopy (ATR-SEIRAS) is reported. Measurements show that the advantage afforded by the high brilliance of the synchrotron source is at least partially offset by increased noise from the experimental floor. The test system was the potential induced desorption of an adsorbed monolayer of 4-methoxypyridine (MOP) as measured using step-scan interferometry. Based on diffusion considerations alone, the expected time scale of the process was less than 10 microseconds but was experimentally measured to be three orders of magnitude slower. A defect-mediated dissolution of the condensed film is speculated to be the underlying cause of the unexpected slow kinetics.
Loss of FBXW7 Correlates with Increased IDH1 Expression in Glioma and Enhances IDH1-Mutant Cancer Cell Sensitivity to Radiation
Authors: Yang Zhuo , Hu Nan , Wang Weiwei , Hu Weihua , Zhou Shaolong , Shi Jianxiang , Li Minghe , Jing Zhou , Chen Chao , Zhang Xuyang , Yang Ruyi , Fu Xudong , Wang Xinjun 
Published: November 2021

Abstract

F-box and WD repeat domain containing 7 (FBXW7) is a substrate receptor of the ubiquitin ligase SKP1-Cullin1-F-box complex and a potent tumor suppressor that prevents unregulated cell growth and tumorigenesis. However, little is known about FBXW7-mediated control of cell metabolism and related functions in cancer therapy. Here, we report that FBXW7 expression inversely correlates with the expression levels of the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in patients with glioma and public glioma datasets. Deletion of FBXW7 significantly increased both wild-type (WT) and mutant IDH1 expression, which was mediated by blocking degradation of sterol regulatory element binding protein 1 (SREBP1). The upregulation of neomorphic mutant IDH1 by FBXW7 deletion stimulated production of the oncometabolite 2-hydroxyglutarate at the expense of increasing pentose phosphate pathway activity and NADPH consumption, limiting the buffering ability against radiation-induced oxidative stress. In addition, FBXW7 knockout and IDH1 mutations induced nonhomologous end joining and homologous recombination defects, respectively. In vitro and in vivo, loss of FBXW7 dramatically enhanced the efficacy of radiation treatment in IDH1-mutant cancer cells. Taken together, this work identifies FBXW7 deficiency as a potential biomarker representing both DNA repair and metabolic vulnerabilities that sensitizes IDH1-mutant cancers to radiotherapy.

Significance:
Deficiency of FBXW7 causes defects in DNA repair and disrupts NADPH homeostasis in IDH1-mutant glioma cells, conferring high sensitivity to radiotherapy.
Vertical Inhibition of the RAF–MEK–ERK Cascade Induces Myogenic Differentiation, Apoptosis, and Tumor Regression inH/NRASQ61XMutant Rhabdomyosarcoma
Authors: Garcia Natalia , Del Pozo Vanessa , Yohe Marielle E. , Goodwin Craig M. , Shackleford Terry J. , Wang Long , Baxi Kunal , Chen Yidong , Rogojina Anna T. , Zimmerman Sara M. , Peer Cody J. , Figg William D. , Ignatius Myron S. , Wood Kris C. , Houghton Peter J. , Vaseva Angelina V. 
Published: November 2021

AbstractOncogenic RAS signaling is an attractive target for fusion-negative rhabdomyosarcoma (FN-RMS). Our study validates the role of the ERK MAPK effector pathway in mediating RAS dependency in a panel of H/NRASQ61X mutant RMS cells and correlates in vivo efficacy of the MEK inhibitor trametinib with pharmacodynamics of ERK activity. A screen is used to identify trametinib-sensitizing targets, and combinations are evaluated in cells and tumor xenografts. We find that the ERK MAPK pathway is central to H/NRASQ61X dependency in RMS cells; however, there is poor in vivo response to clinically relevant exposures with trametinib, which correlates with inefficient suppression of ERK activity. CRISPR screening points to vertical inhibition of the RAF–MEK–ERK cascade by cosuppression of MEK and either CRAF or ERK. CRAF is central to rebound pathway activation following MEK or ERK inhibition. Concurrent CRAF suppression and MEK or ERK inhibition, or concurrent pan-RAF and MEK/ERK inhibition (pan-RAFi + MEKi/ERKi), or concurrent MEK and ERK inhibition (MEKi + ERKi) all synergistically block ERK activity and induce myogenic differentiation and apoptosis. In vivo assessment of pan-RAFi + ERKi or MEKi + ERKi potently suppress growth of H/NRASQ61X RMS tumor xenografts, with pan-RAFi + ERKi being more effective and better tolerated. We conclude that CRAF reactivation limits the activity of single-agent MEK/ERK inhibitors in FN-RMS. Vertical targeting of the RAF–MEK–ERK cascade and particularly cotargeting of CRAF and MEK or ERK, or the combination of pan-RAF inhibitors with MEK or ERK inhibitors, have synergistic activity and potently suppress H/NRASQ61X mutant RMS tumor growth.
Assistência técnica em habitação de interesse social para promoção do habitat saudável
Authors: Scotton Josiane Andréia , Miron Luciana Inês Gomes , Lersch Inês Martina 
Published: November 2021

A precariedade das condições de moradia no Brasil tem sérias implicações sobre o habitat saudável. No ano de 2020, o advento da pandemia de Covid-19 acrescentou urgência às discussões acerca da habitação saudável, principalmente nas periferias das cidades; onde se encontram as maiores carências: de habitabilidade, de fornecimento de água, de infraestrutura e saneamento básico. Nesse contexto, a aplicação da Lei 11.888 de 2008, da Assistência Técnica em Habitação de Interesse Social (ATHIS), tem oportunizado o acesso ao trabalho dos profissionais de arquitetura para a população de baixa renda. Além disso, as iniciativas de ATHIS têm buscado a consolidação de projetos de habitação de interesse social que resultem na produção de unidades habitacionais mais saudáveis. O presente artigo apresenta um estudo de caso sobre o processo de desenvolvimento da ATHIS para uma comunidade de 68 famílias da cidade de São Leopoldo, Região Metropolitana de Porto Alegre, estado do Rio Grande do Sul. O objetivo deste estudo é compreender como o processo de ATHIS pôde contribuir para a promoção do habitat saudável naquela comunidade. As técnicas de coleta de dados utilizadas foram: análise de documentos, observação assistemática não-participante e entrevistas semiestruturadas. Os resultados permitiram constatar que: i) a ATHIS envolvendo a população através de processo participativo, apresenta contribuições para a melhoria das condições de habitabilidade das populações envolvidas; ii) a ATHIS pode contribuir para a consolidação de um habitat saudável através da melhoria da qualidade do ambiente urbano e habitacional, destacando-se as condições básicas de saneamento.
High-Definition Hurricanes: Improving Forecasts with Storm-Following Nests
Authors: Alaka Ghassan J. , Zhang Xuejin , Gopalakrishnan Sundararaman G. 
Published: November 2021

Abstract
To forecast tropical cyclone (TC) intensity and structure changes with fidelity, numerical weather prediction models must be “high definition,” i.e., horizontal grid spacing ≤ 3 km, so that they permit clouds and convection and resolve sharp gradients of momentum and moisture in the eyewall and rainbands. Storm-following nests are computationally efficient at fine resolutions, providing a practical approach to improve TC intensity forecasts. Under the Hurricane Forecast Improvement Project, the operational Hurricane Weather Research and Forecasting (HWRF) system was developed to include telescopic, storm-following nests for a single TC per model integration. Subsequently, HWRF evolved into a state-of-the-art tool for TC predictions around the globe, although its single-storm nesting approach does not adequately simulate TC–TC interactions as they are observed. Basin-scale HWRF (HWRF-B) was developed later with a multistorm nesting approach to improve the simulation of TC–TC interactions by producing high-resolution forecasts for multiple TCs simultaneously. In this study, the multistorm nesting approach in HWRF-B was compared with a single-storm nesting approach using an otherwise identical model configuration. The multistorm approach demonstrated TC intensity forecast improvements, including more realistic TC–TC interactions. Storm-following nests developed in HWRF and HWRF-B will be foundational to NOAA’s next-generation hurricane application in the Unified Forecast System.
Energetic constraints on the time-dependent response of the ITCZ to volcanic eruptions
Authors: Erez Moran , Adam Ori 
Published: November 2021

AbstractEnergetic constraints on the time-dependent response of the intertropical convergence zone (ITCZ) to volcanic eruptions are analyzed using the Community Earth System Model Last Millennium Ensemble project. The energetic constraints are found to vary during the first few years, governed by conjoined variations of the energy budgets of the stratosphere, troposphere, and oceans. Specifically, following eruptions, sulfate aerosols heat the stratosphere by long-wave absorption and cool the surface by shortwave reflection, leading to contrasting energy transport anomalies in the stratosphere and troposphere, which are of comparable strength during the first year. Similar contrasting responses are also seen by the mean and eddy components of atmospheric energy transport (AET). Consequently, ocean energy transport (OET) dominates the anomalous total interhemispheric energy transport during the first year. However, wind-driven OET, generally assumed to constrain shifts of the ITCZ, has a negligible role in the transient ocean response. Consistent with theory, anomalous cross-equatorial tropospheric energy transport, dominated by the anomalous Hadley circulation, is strongly negatively correlated with ITCZ shifts. However, due to the strong anomalous stratospheric energy fluxes, the commonly used energy flux equator (derived from net AET) is a poor predictor of transient ITCZ shifts following eruptions. El Niño-like conditions typically appear during the second year after eruptions, and La Niña-like conditions after the third year. These variations modulate ITCZ shifts in a complex manner, via changes in surface conditions and in associated energy transport variations in the atmosphere and oceans.
The Impact of Snowfall on Crashes, Traffic Volume, and Revenue on the New York State Thruway
Authors: Call David A. , Flynt Guy A. 
Published: November 2021

Abstract
Snow has numerous effects on traffic, including reduced traffic volumes, greater crash risk, and increased travel times. This research examines how snow affects crash risk, traffic volume, and toll revenue on the New York State Thruway. Daily data from January for a 10-yr period (2010–19) were analyzed for the Thruway from the Pennsylvania state line in western New York to Syracuse. Anywhere from 35% to 50% of crashes are associated with inclement weather, with smaller impacts, proportionally, in areas with greater traffic volumes. As expected, snow was almost always involved when weather was a factor. “Unsafe speed” was the most common cause of crashes in inclement weather with all other factors (e.g., animals, drowsiness) much less likely to play a role. The percentage of crashes resulting in an injury did not change significantly with inclement conditions when compared with crashes occurring in fair conditions, and there were too few fatal crashes to make any inferences about them. Daily snowfall rates predicted about 30% of the variation in crash numbers, with every 5.1 cm of snowfall resulting in an additional crash, except in Buffalo where 5.1 cm of snow resulted in an additional 2.6 crashes. Confirming earlier results, daily snowfall had a large impact on passenger vehicle counts whereas commercial vehicle counts were less affected. Revenue data showed a similar pattern, with passenger revenue typically decreasing by 3%–5% per 2.5 cm of snow, whereas commercial revenue decreases were 1%–4% per 2.5 cm of snow.

Significance Statement
While it seems obvious that snowfall increases the number of crashes, decreases traffic volume, and reduces toll revenues, research is limited to support these assumptions, especially the latter two. This study involved an analysis of such items for the New York State Thruway. We found that increasing amounts of snow did cause more crashes. While traffic counts decreased, most of the decrease was in the number of passenger vehicles; commercial vehicle traffic was much less affected. Every 2.5 cm of snow costs the New York State Thruway approximately $1300 at each toll barrier and about $331 at each exit. These findings are helpful to law enforcement, emergency responders, and highway managers.
COMPERA 2.0: a refined four-stratum risk assessment model for pulmonary arterial hypertension
Authors: Hoeper Marius M. , Pausch Christine , Olsson Karen M. , Huscher Doerte , Pittrow David , Grünig Ekkehard , Staehler Gerd , Vizza Carmine Dario , Gall Henning , Distler Oliver , Opitz Christian , Gibbs J. Simon R. , Delcroix Marion , Ghofrani H. Ardeschir , Park Da-Hee , Ewert Ralf , Kaemmerer Harald , Kabitz Hans-Joachim , Skowasch Dirk , Behr Juergen , Milger Katrin , Halank Michael , Wilkens Heinrike , Seyfarth Hans-Jürgen , Held Matthias , Dumitrescu Daniel , Tsangaris Iraklis , Vonk-Noordegraaf Anton , Ulrich Silvia , Klose Hans , Claussen Martin , Lange Tobias J. , Rosenkranz Stephan 
Published: November 2021

BackgroundRisk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.MethodsWe analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan–Meier analyses, log-rank testing and Cox proportional hazards models.ResultsData from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.ConclusionsModified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.
Nutritional assessment in idiopathic pulmonary fibrosis: a prospective multicentre study
Authors: Faverio Paola , Fumagalli Alessia , Conti Sara , Madotto Fabiana , Bini Francesco , Harari Sergio , Mondoni Michele , Oggionni Tiberio , Barisione Emanuela , Ceruti Paolo , Papetti Maria Chiara , Bodini Bruno Dino , Caminati Antonella , Valentino Angela , Centanni Stefano , Noè Donatella , Della Zoppa Matteo , Crotti Silvia , Grosso Marco , Sukkar Samir Giuseppe , Modina Denise , Andreoli Marco , Nicali Roberta , Suigo Giulia , De Giacomi Federica , Busnelli Sara , Cattaneo Elena , Mantovani Lorenzo Giovanni , Cesana Giancarlo , Pesci Alberto , Luppi Fabrizio 
Published: November 2021

BackgroundNutritional status impacts quality of life and prognosis of patients with respiratory diseases, including idiopathic pulmonary fibrosis (IPF). However, there is a lack of studies performing an extensive nutritional assessment of IPF patients. This study aimed to investigate the nutritional status and to identify nutritional phenotypes in a cohort of IPF patients at diagnosis.MethodsPatients underwent a thorough pulmonary and nutritional evaluation including questionnaires on nutritional status, and physical activity, anthropometry, body impedance, dynamometry, 4-m gait speed and blood tests.Results90 IPF patients (78.9% males, mean age 72.7 years) were enrolled. The majority of patients were classified as Gender-Age-Physiology Index stage 2 (47, 52.2%) with an inactive lifestyle according to International Physical Activity Questionnaire score (39, 43.3%), and had mean forced vital capacity and diffusing capacity for carbon monoxide 86.5% and 54.2%, respectively. In regards to nutritional phenotypes, the majority of patients were normally nourished (67.8%, 95% CI 58.6–77.7%), followed by non-sarcopenic obese (25.3%, 95% CI 16.1–35.2%), sarcopenic (4.6%, 95% CI 0.0–14.5%) and sarcopenic obese (2.3%, 95% CI 0.0–12.2%). Among the normally nourished, 49.2% showed early signs of nutritional and physical performance alterations, including body mass index ≥30 kg·m−2in 4.3%, history of weight loss ≥5% in 11.9%, and reduction of gait speed and hand grip strength in 11.9% and 35.6%, respectively. Low vitamin D values were observed in 56.3% of cases.ConclusionsIPF patients at diagnosis are mainly normally nourished and obese, but early signs of nutritional and physical performance impairment can already be identified at this stage.
Emergency department point-of-care ultrasound for upper extremity deep venous thrombosis ED POCUS for upper extremity DVT
Authors: Tan Gregory , Ng Mingwei 
Published: November 2021

Abstract
Background
Upper extremity deep vein thrombosis (UEDVT) is an uncommon disease but has to be carefully considered in patients with isolated unilateral upper limb swelling due to its potential to cause devastating complications and sequelae such as pulmonary embolism and septic thrombophlebitis. Given the extreme rarity of this condition, it is not surprising that point-of-care ultrasonographic evaluation of the upper limb for deep venous thrombosis is hardly ever performed in the emergency department. This case report serves to highlight how point-of-care ultrasonographic evaluation of the upper extremity venous system could be incorporated as a tool in the diagnostic armamentarium of the emergency physician.

Case presentation
A 51-year-old Chinese gentleman presented to the emergency department with a 1-day duration of progressive right upper extremity swelling and pain. On examination, his hemodynamic parameters were stable with no tachycardia. He was noted to have a hyperaemic and grossly swollen but non-tender right upper limb. Distal pulses remained strong. Point-of-care ultrasonography of his right upper limb venous system with Doppler colour flow and single-point augmentation with the arm squeeze manoeuvre immediately confirmed the diagnosis of right upper extremity deep venous thrombosis, which in turn permitted anticoagulation to be instituted promptly whilst in the emergency department.

Conclusion
The use of point-of-care ultrasonography of the upper limb venous system can prove invaluable as a rapid, non-invasive technique to facilitate expedient diagnosis of and early intervention for UEDVT in the emergency department.