bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploiting Canonical TGFβ Signaling in Cancer Treatment
Authors: Liu Qi , Chen Genwen , Moore Jade , Guix Ines , Placantonakis Dimitris , Barcellos-Hoff Mary Helen 
Published: October 2021

Abstract
TGFβ is a pleiotropic cytokine that plays critical roles to define cancer cell phenotypes, construct the tumor microenvironment, and suppress antitumor immune responses. As such, TGFβ is a lynchpin for integrating cancer cell intrinsic pathways and communication among host cells in the tumor and beyond that together affect responses to genotoxic, targeted, and immune therapy. Despite decades of preclinical and clinical studies, evidence of clinical benefit from targeting TGFβ in cancer remains elusive. Here, we review the mechanisms by which TGFβ acts to oppose successful cancer therapy, the reported prognostic and predictive value of TGFβ biomarkers, and the potential impact of inhibiting TGFβ in precision oncology. Paradoxically, the diverse mechanisms by which TGFβ impedes therapeutic response are a principal barrier to implementing TGFβ inhibitors because it is unclear which TGFβ mechanism is functional in which patient. Companion diagnostic tools and specific biomarkers of TGFβ targeted biology will be the key to exploiting TGFβ biology for patient benefit.
GAS6/AXL Inhibition Enhances Ovarian Cancer Sensitivity to Chemotherapy and PARP Inhibition through Increased DNA Damage and Enhanced Replication Stress
Authors: Mullen Mary M. , Lomonosova Elena , Toboni Michael D. , Oplt Alyssa , Cybulla Emily , Blachut Barbara , Zhao Peinan , Noia Hollie , Wilke Daniel , Rankin Erinn B. , Kuroki Lindsay M. , Hagemann Andrea R. , Hagemann Ian S. , McCourt Carolyn K. , Thaker Premal H. , Mutch David G. , Powell Matthew A. , Mosammaparast Nima , Vindigni Alessandro , Fuh Katherine C. 
Published: October 2021

AbstractOver 80% of women with high-grade serous ovarian cancer (HGSOC) develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to PARP inhibitors. Here, we tested the hypothesis that expression of growth arrest–specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6–500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared with chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer-cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination (HR). Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer-cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in HR-proficient and HR-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, HR-proficient HGSOC.Implications:GAS6/AXL is a novel target to sensitize ovarian cancers to carboplatin and olaparib. Additionally, GAS6 levels can be associated with response to carboplatin treatment.
The E3 Ligase MIB1 Promotes Proteasomal Degradation of NRF2 and Sensitizes Lung Cancer Cells to Ferroptosis
Authors: Wang Haiyun , Huang Qiuling , Xia Jianhong , Cheng Shan , Pei Duanqing , Zhang Xiaofei , Shu Xiaodong 
Published: October 2021

Abstract

Dysregulation of Notch signaling has been implicated in cellular transformation and tumorigenesis in a variety of cancers while potential roles of MIB1, an E3 ubiquitin ligase required for efficient Notch activation, remains to be investigated. We analyzed MIB1 expression levels in tumor samples and performed gain-of-function and loss-of-function studies in cell lines to investigate potential roles of MIB1 in epithelial-to-mesenchymal transition (EMT), cell migration, and cell survival. We found that overexpression of MIB1 is detected in a subset of lung squamous carcinoma and adenocarcinoma samples and negative correlation is observed between MIB1 expression and overall patient survival. Ectopic expression of MIB1 in A549 cells induces EMT and stimulates cell migration via a Notch-dependent pathway. Meanwhile, MIB1 stimulates the degradation of nuclear factor erythroid 2-related factor 2 (NRF2) in a Notch-independent manner and disrupts the antioxidant capacity of cells, rendering them more sensitive to inducers of ferroptosis. On the other hand, MIB1 knockout induces accumulation of NRF2 and resistance to ferroptosis. Collectively, these results indicate that MIB1 may function as a positive regulator of ferroptosis through targeted degradation of the master antioxidant transcription factor NRF2.

Implications:
This study identifies a MIB1-induced proteasomal degradation pathway for NRF2 and reveals elevated ferroptosis sensitivity in MIB1-overexpressing cells which may provide novel insights into the treatment of MIB1-overexpressing cancers.
Ecdysoneless Protein Regulates Viral and Cellular mRNA Splicing to Promote Cervical Oncogenesis
Authors: Mirza Sameer , Kalluchi Achyuth , Raza Mohsin , Saleem Irfana , Mohapatra Bhopal , Pal Dhananjaya , Ouellette Michel M. , Qiu Fang , Yu Lulu , Lobanov Alexei , Zheng Zhi-Ming , Zhang Ying , Alsaleem Mansour A. , Rakha Emad A. , Band Hamid , Rowley M. Jordan , Band Vimla 
Published: October 2021

AbstractHigh-risk human papillomaviruses (HPV), exemplified by HPV16/18, are causally linked to human cancers of the anogenital tract, skin, and upper aerodigestive tract. Previously, we identified Ecdysoneless (ECD) protein, the human homolog of the Drosophila ecdysoneless gene, as a novel HPV16 E6–interacting protein. Here, we show that ECD, through its C-terminal region, selectively binds to high-risk but not to low-risk HPV E6 proteins. We demonstrate that ECD is overexpressed in cervical and head and neck squamous cell carcinoma (HNSCC) cell lines as well as in tumor tissues. Using The Cancer Genome Atlas dataset, we show that ECD mRNA overexpression predicts shorter survival in patients with cervical and HNSCC. We demonstrate that ECD knockdown in cervical cancer cell lines led to impaired oncogenic behavior, and ECD co-overexpression with E7 immortalized primary human keratinocytes. RNA-sequencing analyses of SiHa cells upon ECD knockdown showed to aberrations in E6/E7 RNA splicing, as well as RNA splicing of several HPV oncogenesis–linked cellular genes, including splicing of components of mRNA splicing machinery itself. Taken together, our results support a novel role of ECD in viral and cellular mRNA splicing to support HPV-driven oncogenesis.Implications:This study links ECD overexpression to poor prognosis and shorter survival in HNSCC and cervical cancers and identifies a critical role of ECD in cervical oncogenesis through regulation of viral and cellular mRNA splicing.
Cell‐Free Mitochondrial DNA as a Potential Biomarker for Astronauts' Health
Authors: Bisserier Malik , Shanmughapriya Santhanam , Rai Amit Kumar , Gonzalez Carolina , Brojakowska Agnieszka , Garikipati Venkata Naga Srikanth , Madesh Muniswamy , Mills Paul J. , Walsh Kenneth , Arakelyan Arsen , Kishore Raj , Hadri Lahouaria , Goukassian David A. 
Published: October 2021

Background
Space travel–associated stressors such as microgravity or radiation exposure have been reported in astronauts after short‐ and long‐duration missions aboard the International Space Station. Despite risk mitigation strategies, adverse health effects remain a concern. Thus, there is a need to develop new diagnostic tools to facilitate early detection of physiological stress.

Methods and Results
We measured the levels of circulating cell‐free mitochondrial DNA in blood plasma of 14 astronauts 10 days before launch, the day of landing, and 3 days after return. Our results revealed a significant increase of cell‐free mitochondrial DNA in the plasma on the day of landing and 3 days after return with vast ~2 to 355‐fold interastronaut variability. In addition, gene expression analysis of peripheral blood mononuclear cells revealed a significant increase in markers of inflammation, oxidative stress, and DNA damage.

Conclusions
Our study suggests that cell‐free mitochondrial DNA abundance might be a biomarker of stress or immune response related to microgravity, radiation, and other environmental factors during space flight.
Disability Among Young Adults With Congenital Heart Defects: Congenital Heart Survey to Recognize Outcomes, Needs, and Well‐Being 2016–2019
Authors: Downing Karrie F. , Oster Matthew E. , Klewer Scott E. , Rose Charles E. , Nembhard Wendy N. , Andrews Jennifer G. , Farr Sherry L. 
Published: October 2021

Background
Disabilities have implications for health, well‐being, and health care, yet limited information is available on the percentage of adults with congenital heart defects (CHD) living with disabilities. We evaluated the prevalence of disability and associated characteristics among the 2016–2019 CH STRONG (Congenital Heart Survey to Recognize Outcomes, Needs, and Well‐Being) population‐based sample of 19‐ to 38‐year‐olds with CHD from 3 US locations.

Methods and Results
Prevalence of disability types (hearing, vision, cognition, mobility, self‐care, living independently) were compared with similarly aged adults from the general population as estimated by the American Community Survey and standardized to the CH STRONG eligible population to reduce nonresponse bias and confounding. Health‐related quality of life (HRQOL) was measured via Patient‐Reported Outcomes Measurement Information System Global Health Scale T‐scores standardized to US 18‐ to 34‐year‐olds. Separate multivariable regression models assessed associations between disability and HRQOL. Of 1478 participants, 40% reported disabilities, with cognition most prevalent (29%). Of those reporting disability, 45% ever received disability benefits and 46% were unemployed. Prevalence of disability types were 5 to 8 times higher in adults with CHD than the general population. Those with ≥1 disability had greater odds of being female, and of having non‐Hispanic Black maternal race and ethnicity, severe CHD, recent cardiac care, and noncardiac congenital anomalies. On average, adults with CHD and cognition, mobility, and self‐care disabilities had impaired mental HRQOL and those with any disability type had impaired physical HRQOL.

Conclusions
Two of 5 adults with CHD may have disabilities, which are associated with impaired HRQOL. These results may inform healthcare needs and services for this growing population.
Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke
Authors: Leskelä Jaakko , Toppila Iiro , Härma Mari‐Anne , Palviainen Teemu , Salminen Aino , Sandholm Niina , Pietiäinen Milla , Kopra Elisa , Pais de Barros Jean‐Paul ,   FinnGen, Lassenius Mariann I. , Kumar Anmol , Harjutsalo Valma , Roslund Kajsa , Forsblom Carol , Loukola Anu , Havulinna Aki S. , Lagrost Laurent , Salomaa Veikko , Groop Per‐Henrik , Perola Markus , Kaprio Jaakko , Lehto Markku , Pussinen Pirkko J. 
Published: October 2021

Background
Translocation of lipopolysaccharide from gram‐negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity.

Methods and Results

We performed a genome‐wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high‐performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis‐related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome‐wide significant association with 741 single‐nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included
KNG1
,
KLKB1
,
F12
,
SLC34A1
,
YPEL4
,
CLP1
,
ZDHHC5
,
SERPING1
,
CBX5
, and
LIPC
. The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism.

Conclusions
The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.
Limitations of Bin and Bulk Microphysics in Reproducing the Observed Spatial Structure of Light Precipitation
Authors: Witte Mikael K. , Morrison Hugh , Davis Anthony B. , Teixeira Joao 
Published: October 2021

Abstract
Coarse-gridded atmospheric models often account for subgrid-scale variability by specifying probability distribution functions (PDFs) of process rate inputs such as cloud and rainwater mixing ratios (qc and qr, respectively). PDF parameters can be obtained from numerous sources: in situ observations, ground- or space-based remote sensing, or fine-scale modeling such as large-eddy simulation (LES). LES is appealing to constrain PDFs because it generates large sample sizes, can simulate a variety of cloud regimes/case studies, and is not subject to the ambiguities of observations. However, despite the appeal of using model output for parameterization development, it has not been demonstrated that LES satisfactorily reproduces the observed spatial structure of microphysical fields. In this study, the structure of observed and modeled microphysical fields are compared by applying bifractal analysis, an approach that quantifies variability across spatial scales, to simulations of a drizzling stratocumulus field that span a range of domain sizes, drop concentrations (a proxy for mesoscale organization), and microphysics schemes (bulk and bin). Simulated qc closely matches observed estimates of bifractal parameters that measure smoothness and intermittency. There are major discrepancies between observed and simulated qr properties, though, with bulk simulated qr consistently displaying the bifractal properties of observed clouds (smooth, minimally intermittent) rather than rain while bin simulations produce qr that is appropriately intermittent but too smooth. These results suggest fundamental limitations of bulk and bin schemes to realistically represent higher-order statistics of the observed rain structure.
Higher Temperature Enhances Spatiotemporal Concentration of Rainfall
Authors: Long Kaihao , Wang Dagang , Wang Guiling , Zhu Jinxin , Wang Shuo , Xie Shuishi 
Published: October 2021

Abstract
The relationship between extreme precipitation intensity and temperature has been comprehensively studied over different regions worldwide. However, the effect of temperature on the spatiotemporal organization of precipitation, which can have a significant impact on precipitation intensity, has not been adequately studied or understood. In this study, we propose a novel approach to quantifying the spatial and temporal concentration of precipitation at the event level and study how the concentration varies with temperature. The results based on rain gauge data from 843 stations in the Ganzhou county, a humid region in south China, show that rain events tend to be more concentrated both temporally and spatially at higher temperature, and this increase in concentration qualitatively holds for events of different precipitation amounts and durations. The effects of temperature on precipitation organization in space and in time differ at high temperatures. The temporal concentration increases with temperature up to a threshold (approximately 24°C) beyond which it plateaus, whereas the spatial concentration keeps rising with temperature. More concentrated precipitation, in addition to a projected increase of extreme precipitation, would intensify flooding in a warming world, causing more detrimental effects.
Peritumoral portal enhancement during transarterial chemoembolization: a potential prognostic factor for patients with hepatocellular carcinoma
Authors: Nyman Sofi Sennefelt , Creusen Angeliki Dimopoulou , Johnsson Ulf , Rorsman Fredrik , Vessby Johan , Barbier Charlotte Ebeling 
Published: October 2021

Background Tumor response and survival varies in patients treated with transarterial chemoembolization (TACE) for intermediate stage hepatocellular carcinoma (HCC) and may be associated with several factors. Purpose To evaluate safety and efficacy of TACE in patients with intermediate stage HCC and to identify factors related to tumor response and survival. Material and Methods Consecutive patients with HCC treated with TACE between September 2008 and September 2018 were retrospectively reviewed. Results In 87 patients (71 men; mean age = 68 ± 9 years), 327 TACE treatments were performed (mean = 3/patient; range = 1–12). Mean and median overall survival were 32 and 19 months, respectively. Survival rates at 30 days, one, three, and five years were 99%, 71%, 19%, and 8%, respectively. Objective response (OR) was seen in 84% and disease control (DC) was seen in 92% of the patients. Patients in whom peritumoral portal lipiodol enhancement (PPLE) was seen during TACE had better OR (97 vs. 73%; P = 0.007) and DC (100 vs. 85%; P = 0.024), and a reduced risk of death (hazard ratio [HR] = 0.52; 95% confidence interval = 0.32–0.86) compared to those without PPLE. Severe adverse events were rare (15%) and occurred more often in patients with a larger tumor size. Conclusions TACE was effective and safe in patients with intermediate stage HCC. Patients with PPLE during TACE had better tumor response and longer survival than those without PPLE. Severe adverse events occurred more often in patients with larger tumors.
Regional Differences in Anterior Cruciate Ligament Signal Intensity After Surgical Treatment
Authors: Kiapour Ata M. , Flannery Sean W. , Murray Martha M. , Miller Patricia E. ,   BEAR Trial Team, Proffen Benedikt L. , Sant Nicholas , Portilla Gabriela , Sanborn Ryan , Freiberger Christina , Henderson Rachael , Barnett Samuel , Ecklund Kirsten , Yen Yi-Meng , Kramer Dennis E. , Micheli Lyle J. , Fleming Braden C. 
Published: October 2021

Background: Magnetic resonance–based measurements of signal intensity have been used to track healing of surgically treated anterior cruciate ligaments (ACLs). However, it is unknown how the signal intensity values in different regions of the ligament or graft change during healing. Hypotheses: (1) Normalized signal intensity of the healing graft or repaired ACL is heterogeneous; (2) temporal changes in normalized signal intensity values differ among the tibial, middle, and femoral regions; and (3) there are no differences in regional normalized signal intensity values 2 years postoperatively among grafts, repaired ACLs, and contralateral native ACLs. Study Design: Cohort study; Level of evidence, 2. Methods: Magnetic resonance imaging scans were analyzed from patients in a trial comparing ACL reconstruction (n = 35) with bridge-enhanced ACL repair (n = 65). The ACLs were segmented from images acquired at 6, 12, and 24 months postoperatively and were partitioned into 3 sections along the longitudinal axis (femoral, middle, and tibial). Linear mixed modeling was used to compare location-specific differences in normalized ligament signal intensity among time points (6, 12, and 24 months) and groups (ACL reconstruction, repair, and contralateral native ACL). Results: For grafts, the middle region had a higher mean normalized signal intensity when compared with the femoral region at all time points ( P < .01) but compared with the tibial region only at 6 months ( P < .01). For repaired ACLs, the middle region had a higher mean normalized signal intensity versus the femoral region at all time points ( P < .01) but versus the tibial region only at 6 and 12 months ( P < .04). From 6 to 24 months, the grafts showed the greatest reduction in normalized signal intensity in the femoral and middle regions (vs tibial regions; P < .01), while there were no regional differences in repaired ACLs. At 2 years after surgery, repaired ACLs had a lower normalized signal intensity in the tibial region as compared with reconstructed grafts and contralateral native ACLs ( P < .01). Conclusion: The results suggest that graft remodeling is location specific. Repaired ACLs were more homogeneous, with lower or comparable normalized signal intensity values at 2 years as compared with the contralateral native ACL and reconstructed grafts.
The Environment as a Patient: A Content Analysis of Canadian Nursing Organizations and Regulatory Bodies Policies on Environmental Health
Authors: Mundie Courtney , Donelle Lorie 
Published: October 2021

Background Individual, community, and societal health is impacted by the environment, specifically by air, water and soil pollution, and climate change. Poor environmental conditions have been associated with many illness exacerbations. Although global nursing organizations have increased their environmental health focus, evidence is lacking that Canadian nurse leaders and organizations are similarly invested. Purpose The purpose of this analysis was to explore the policies of Canadian nursing regulatory bodies and associations on nursing practice specific to environmental health. Methods A content analysis of nursing focused position statements and competency documents was conducted to assess Canadian nursing policies in environmental health. Publicly available position statements and competency documents regarding health and the environment were retrieved from Canadian nursing regulatory colleges and nursing associations, the Canadian Nursing Associations, and the International Council of Nurses. All documents were coded inductively and thematically analyzed. Results In total, 22 documents were retrieved which consisted of 11 policy statements from nursing associations and 11 competency documents from nursing regulators and national associations. Four themes were generated: collaboration, language of engagement, nursing actions, and social justice. Conclusion There is a gap between nursing policies and competencies directing nursing action related to the health of the environment across Canada. There is an opportunity to improve eco-literacy within the nursing profession, undergraduate education and to produce nursing research on environmental health.