bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Phenotype and Response to Neoadjuvant Therapy in Triple-Negative Breast Cancer
Authors: Yam Clinton , Yen Er-Yen , Chang Jeffrey T. , Bassett Roland L. , Alatrash Gheath , Garber Haven , Huo Lei , Yang Fei , Philips Anne V. , Ding Qing-Qing , Lim Bora , Ueno Naoto T. , Kannan Kasthuri , Sun Xiangjie , Sun Baohua , Parra Cuentas Edwin Roger , Symmans William Fraser , White Jason B. , Ravenberg Elizabeth , Seth Sahil , Guerriero Jennifer L. , Rauch Gaiane M. , Damodaran Senthil , Litton Jennifer K. , Wargo Jennifer A. , Hortobagyi Gabriel N. , Futreal Andrew , Wistuba Ignacio I. , Sun Ryan , Moulder Stacy L. , Mittendorf Elizabeth A. 
Published: July 2021

AbstractPurpose:Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR.Experimental Design:We obtained pretreatment core-needle biopsies from 105 patients with stage I–III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT.Results:The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage.Conclusions:In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
Valency of HER2 Targeting Antibodies Influences Tumor Cell Internalization and Penetration
Authors: Ramos Madeleine K. , Mandikian Danielle , Sermeño Lauren N. , King Anna , Dent Alecia T. , Ho Jason , Ulufatu Sheila , Lombana T. Noelle , Spiess Christoph , Go Mary Ann T. , Yu Shang-Fan , Kamath Amrita V. , Ferl Gregory Z. , Boswell C. Andrew 
Published: July 2021

Abstract
T-cell–dependent bispecific antibodies (TDB) have been a major advancement in the treatment of cancer, allowing for improved targeting and efficacy for large molecule therapeutics. TDBs are comprised of one arm targeting a surface antigen on a cancer cell and another targeting an engaging surface antigen on a cytotoxic T cell. To impart this function, the antibody must be in a bispecific format as opposed to the more conventional bivalent format. Through in vitro and in vivo studies, we sought to determine the impact of changing antibody valency on solid tumor distribution and catabolism. A bivalent anti-HER2 antibody exhibited higher catabolism than its full-length monovalent binding counterpart in vivo by both invasive tissue harvesting and noninvasive single photon emission computed tomography/X-ray computed tomography imaging despite similar systemic exposures for the two molecules. To determine what molecular factors drove in vivo distribution and uptake, we developed a mechanistic model for binding and catabolism of monovalent and bivalent HER2 antibodies in KPL4 cells. This model suggests that observed differences in cellular uptake of monovalent and bivalent antibodies are caused by the change in apparent affinity conferred by avidity as well as differences in internalization and degradation rates of receptor bound antibodies. To our knowledge, this is the first study to directly compare the targeting abilities of monovalent and bivalent full-length antibodies. These findings may inform diverse antibody therapeutic modalities, including T-cell–redirecting therapies and drug delivery strategies relying upon receptor internalization.
PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus
Authors: Mpilla Gabriel B. , Uddin Md. Hafiz , Al-Hallak Mohammed N. , Aboukameel Amro , Li Yiwei , Kim Steve H. , Beydoun Rafic , Dyson Gregory , Baloglu Erkan , Senapedis William T. , Landesman Yosef , Wagner Kay-Uwe , Viola Nerissa T. , El-Rayes Bassel F. , Philip Philip A. , Mohammad Ramzi M. , Azmi Asfar S. 
Published: July 2021

Abstract
Metastatic pancreatic neuroendocrine tumors (PNET) remain an unmet clinical problem. Chronologic treatment in PNETs includes observation (watchful protocol), surgery, targeted therapy, and chemotherapy. However, increasing evidence illustrates that the outcomes of targeted therapeutic options for the treatment of advanced PNETs show minimal response. The FDA-approved mTOR inhibitor everolimus does not shrink these tumors. It only delays disease progression in a subset of patients, while a significant fraction acquires resistance and shows disease progression. Thus, there is a need for more effective targeted approaches to sensitize PNETs to everolimus for better treatment outcomes. Previously, we showed that mTOR regulator p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyl transferase (NAMPT) were aberrantly expressed in PNET tissue and promoted everolimus resistance. In this report, we demonstrate that PAK4-NAMPT dual inhibitor KPT-9274 can synergize with everolimus (growth inhibition, colony suppression, and glucose uptake assays). KPT-9274-everolimus disrupted spheroid formation in multiple PNET models. Molecular analysis showed alteration of mTORC2 through downregulation of RICTOR as a mechanism supporting synergy with everolimus in vitro. KPT-9274 suppressed β-catenin activity via inhibition of PAK4, highlighting the cross-talk between Rho GTPases and Wnt signaling in PNETs. KPT-9274, given at 150 mg/kg in combination with sub-MTD everolimus (2.5 mg/kg), significantly suppressed two PNET-derived xenografts. These studies bring forward a well-grounded strategy for advanced PNETs that fail to respond to single-agent everolimus.
Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor ResponsesIn Vivo
Authors: Montes de Oca Rocio , Alavi Alireza S. , Vitali Nick , Bhattacharya Sabyasachi , Blackwell Christina , Patel Krupa , Seestaller-Wehr Laura , Kaczynski Heather , Shi Hong , Dobrzynski Eric , Obert Leslie , Tsvetkov Lyuben , Cooper David C. , Jackson Heather , Bojczuk Paul , Forveille Sabrina , Kepp Oliver , Sauvat Allan , Kroemer Guido , Creighton-Gutteridge Mark , Yang Jingsong , Hopson Chris , Yanamandra Niranjan , Shelton Christopher , Mayes Patrick , Opalinska Joanna , Barnette Mary , Srinivasan Roopa , Smothers James , Hoos Axel 
Published: July 2021

AbstractB-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody–drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell–directed checkpoint modulators.
Lipidomic Profiles of Plasma Exosomes Identify Candidate Biomarkers for Early Detection of Hepatocellular Carcinoma in Patients with Cirrhosis
Authors: Sanchez Jessica I. , Jiao Jingjing , Kwan Suet-Ying , Veillon Lucas , Warmoes Marc O. , Tan Lin , Odewole Mobolaji , Rich Nicole E. , Wei Peng , Lorenzi Philip L. , Singal Amit G. , Beretta Laura 
Published: July 2021

AbstractNovel biomarkers for HCC surveillance in cirrhotic patients are urgently needed. Exosomes and their lipid content in particular represent potentially valuable noninvasive diagnostic biomarkers. We isolated exosomes from plasma of 72 cirrhotic patients, including 31 with HCC. Exosomes and unfractionated plasma were processed for untargeted lipidomics using ultra–high-resolution mass spectrometry. A total of 2,864 lipid species, belonging to 52 classes, were identified. Both exosome fractionation and HCC diagnosis had significant impact on the lipid profiles. Ten lipid classes were enriched in HCC exosomes compared with non-HCC exosomes. Dilysocardiolipins were detected in 35% of the HCC exosomes but in none of the non-HCC exosomes (P &lt; 0.001). Cardiolipins and sphingosines had the highest differential effects (fold change of 133.08, q = 0.001 and 38.57, q &lt; 0.001, respectively). In logistic regression analysis, high abundances of exosomal sphingosines, dilysocardiolipins, lysophosphatidylserines, and (O-acyl)-1-hydroxy fatty acids were strongly associated with HCC [OR (95% confidence interval (CI)), 271.1 (14.0–5,251.9), P &lt; 0.001; 46.5 (2.3–939.9), P = 0.012; 14.9 (4.3–51.2), P &lt; 0.001; 10.3 (3.2–33.1), P &lt; 0.001]. Four lipid classes were depleted in HCC exosomes compared with non-HCC exosomes. In logistic regression analysis, lack of detection of sulfatides and acylGlcSitosterol esters was strongly associated with HCC [OR (95% CI): 215.5 (11.5–4,035.9), P &lt; 0.001; 26.7 (1.4–528.4), P = 0.031]. These HCC-associated changes in lipid composition of exosomes reflected alterations in glycerophospholipid metabolism, retrograde endocannabinoid signaling, and ferroptosis. In conclusion, this study identified candidate biomarkers for early detection of HCC as well as altered pathways in exosomes that may contribute to tumor development and progression.Prevention Relevance:This study identifies lipids in circulating exosomes, that could serve as biomarkers for the early detection of hepatocellular carcinoma as well as altered pathways in exosomes that may contribute to tumor development and progression.
ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy
Authors: Feyen Eline , Ricke-Hoch Melanie , Van fraeyenhove Jens , Vermeulen Zarha , Scherr Michaela , Dugaucquier Lindsey , Viereck Janika , Bruyns Tine , Thum Thomas , Segers Vincent F.M. , Hilfiker-Kleiner Denise , De Keulenaer Gilles W. 
Published: July 2021

Background:

Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene
Erbb4
is a common driving factor of PPCM.

Methods:

miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific
Erbb4
mice (

Erbb4
F/+
αMHC-Cre
+

, n=9) with their age-matched nonpregnant CTRLs (n=9–10).

Results:

Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (−29% to −50%;
P
<0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of
Erbb4
during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL;
P
<0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice,
P
<0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (−33±17%,
P
=0.07; −27±20%,
P
<0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL,
P
<0.05) but without signs of myocardial apoptosis and inflammation.

Conclusions:
ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00998556.
Epigenetic Regulation by
Suv4-20h1
in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease
Authors: Qi Hui , Liu Hang , Pullamsetti Soni Savai , Günther Stefan , Kuenne Carsten , Atzberger Ann , Sommer Natascha , Hadzic Stefan , Günther Andreas , Weissmann Norbert , Zhou Yonggang , Yuan Xuejun , Braun Thomas 
Published: July 2021

Background:
The pathogenesis of life-threatening cardiopulmonary diseases such as pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions that is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals.

Methods:

To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human patients with PH and COPD for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of
Suv4-20h1
knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular, and biochemical techniques were applied to analyze the function of Suv4-20h1–dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives.

Results:

We discovered a strong reduction of the histone modifications of H4K20me2/3 in human patients with COPD but not patients with PH that depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of
Suv4-20h1
in cardiopulmonary progenitor cells caused a COPD-like/PH phenotype in mice including the formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyperproliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5′-upstream regulatory element of the superoxide dismutase 3 (
Sod3
) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in
Suv4-20h1
mutants increases hydrogen peroxide concentrations, causing vascular defects and impairing alveolarization.

Conclusions:
Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary codevelopment and uncover the developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD and aid the development of epigenetic drugs for the treatment of cardiopulmonary diseases.
Narratives of Home on the Fringe of Tehran: The Case of Shahriar County
Authors: Dalil Saeed , Wind Barend , Meshkini Abolfazl , Javan Jafar 
Published: July 2021

Abstract
This paper focuses on the notion of home as a narrative of one’s lived experience that clashes with planners’ understanding of housing and housing policies, using as a case study Shahriar County, located on the western fringe of the metropolitan area of Tehran. Following Heidegger, the feeling of home is a fundamental aspect of human existence. From this perspective, housing policies and spatial planning impact the sense of home in a geographical context. The empirical analysis is based on an overview of institutional changes since the Islamic Revolution in 1979, and interviews with inhabitants of Shahriar. The results indicate that Iran has developed a particular form of neoliberal, speculative model of urban development, in which urban segregation and seclusion and uneven regional development are noteworthy. Consequently, the sense of home is structurally undermined on the metropolitan fringe, generating a feeling of living on the edge of the world.
Dynamics of Eddies Generated by Sea Ice Leads
Authors: Cohanim Kaylie , Zhao Ken X. , Stewart Andrew L. 
Published: July 2021

AbstractInteraction between the atmosphere and ocean in sea ice–covered regions is largely concentrated in leads, which are long, narrow openings between sea ice floes. Refreezing and brine rejection in these leads inject salt that plays a key role in maintaining the polar halocline. The injected salt forms dense plumes that subsequently become baroclinically unstable, producing submesoscale eddies that facilitate horizontal spreading of the salt anomalies. However, it remains unclear which properties of the stratification and leads most strongly influence the vertical and horizontal spreading of lead-input salt anomalies. In this study, the spread of lead-injected buoyancy anomalies by mixed layer and eddy processes are investigated using a suite of idealized numerical simulations. The simulations are complemented by dynamical theories that predict the plume convection depth, horizontal eddy transfer coefficient, and eddy kinetic energy as functions of the ambient stratification and lead properties. It is shown that vertical penetration of buoyancy anomalies is accurately predicted by a mixed layer temperature and salinity budget until the onset of baroclinic instability (~3 days). Subsequently, these buoyancy anomalies are spread horizontally by eddies. The horizontal eddy diffusivity is accurately predicted by a mixing-length scaling, with a velocity scale set by the potential energy released by the sinking salt plume and a length scale set by the deformation radius of the ambient stratification. These findings indicate that the intermittent opening of leads can efficiently populate the polar halocline with submesoscale coherent vortices with diameters of ~10 km, and they provide a step toward parameterizing their effect on the horizontal redistribution of salinity anomalies.
Missed Opportunities for Human Papillomavirus Vaccination by Parental Nativity, Minnesota, 2015-2018
Authors: Groene Emily A. , Horvath Keith J. , Yared Nicholas , Mohammed Inari , Muscoplat Miriam , Kuramoto Sydney , Richter Tyler , Kulasingam Shalini 
Published: July 2021

Objectives Human papillomavirus (HPV) vaccination coverage in the United States is far below coverage for other routine adolescent vaccines. We examined whether missed opportunities for HPV vaccination among adolescents differ by parental nativity (country of origin) in Minnesota. Methods We retrospectively analyzed birth record and immunization information data for adolescents in Minnesota born during 2004-2007 using data from January 1, 2015, through December 31, 2018. Using logistic regression, we assessed the association between parental nativity and missed opportunities for HPV vaccine initiation, or receipt of other vaccines without receipt of the HPV vaccine. We adjusted for parent/child demographic and vaccination characteristics. We defined nativity as the number of non–US-born parents and maternal region of birth. Results Adolescents with mothers born in Eastern Europe (adjusted odds ratio [aOR] = 2.33; 95% CI, 2.01-2.73) and Africa (aOR = 1.36; 95% CI, 1.28-1.43) had greater adjusted odds of missed opportunities for HPV vaccination than adolescents with US-born mothers. However, adolescents with mothers from Latin America and the Caribbean had lower odds of missed opportunities than adolescents with US-born mothers (aOR = 0.61; 95% CI, 0.58-0.65). Adolescents with 1 or 2 non–US-born parents had lower odds of missed opportunities for HPV vaccination than adolescents with 2 US-born parents (1 parent: aOR = 0.92; 95% CI, 0.88-0.96; 2 parents: aOR = 0.90; 95% CI, 0.87-0.94). Conclusions Future studies should evaluate outreach to groups with HPV vaccination disparities and identify other drivers of missed opportunities among adolescents with US-born parents, such as multiparity.
Relationship between air pollution levels in Madrid and the natural history of idiopathic pulmonary fibrosis: severity and mortality
Authors: Aguilar Pablo Mariscal , Carrera Luis Gómez , Segura Carlos Carpio , Sánchez María Isabel Torres , Peña María Fernández-Velilla , Hernán Gema Bonilla , Rodríguez Isabel Esteban , Zapata Rita María Regojo , Lucas Ester Zamarrón De , Álvarez Prudencio Díaz-Agero , Bueno Elena Villamañán , Sánchez Concepción Prados , Walther Rodolfo Álvarez-Sala 
Published: July 2021

Objective We aimed to assess the relationship between major air pollutants and the natural history and mortality of idiopathic pulmonary fibrosis (IPF). Methods We conducted a retrospective cohort study from 2013 to 2019 among 52 patients with IPF from the pneumology department of a tertiary hospital. According to their geocoded residential address, each patient was assigned a mean concentration of carbon monoxide (CO), nitrogen dioxide, particulate matter 2.5 and 10, ozone, and sulfur dioxide, as measured at a single surveillance station in central Madrid, Spain. We analyzed forced vital capacity (FVC), CO diffusing capacity, 6-minute walking test, degree of dyspnea, radiologic pattern, and signs of pulmonary hypertension in all patients. Results Patients’ mean age was 66 ± 10 years, and 79% were men. The mean predicted FVC was 78.9 ± 0.5%. Forty-two patients met the criteria for severe disease, and 18 patients died. Mortality was significantly associated with increased CO exposure (for each 0.1 mg/m2 increase: odds ratio 2.45, 95% confidence interval 1.39–4.56). We observed no association between any of the other investigated contaminants and IPF mortality or severity. Conclusions Air pollution, specifically that caused by carbon monoxide, can increase mortality in patients with IPF.