bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced Antitumor Immunity via Endocrine Therapy Prevents Mammary Tumor Relapse and Increases Immune Checkpoint Blockade Sensitivity
Authors: Sequeira Gonzalo R. , Sahores Ana , Dalotto-Moreno Tomás , Perrotta Ramiro M. , Pataccini Gabriela , Vanzulli Silvia I. , Polo María L. , Radisky Derek C. , Sartorius Carol A. , Novaro Virginia , Lamb Caroline A. , Rabinovich Gabriel A. , Salatino Mariana , Lanari Claudia 
Published: December 2020

Abstract

The role of active antitumor immunity in hormone receptor–positive (HR+) breast cancer has been historically underlooked. The aim of this study was to determine the contribution of the immune system to antiprogestin-induced tumor growth inhibition using a hormone-dependent breast cancer model. BALB/c-GFP+ bone marrow (BM) cells were transplanted into immunodeficient NSG mice to generate an immunocompetent NSG/BM-GFP+ (NSG-R) mouse model. Treatment with the antiprogestin mifepristone (MFP) inhibited growth of 59–2-HI tumors with similar kinetics in both animal models. Interestingly, MFP treatment reshaped the tumor microenvironment, enhancing the production of proinflammatory cytokines and chemokines. Tumors in MFP-treated immunocompetent mice showed increased infiltration of F4/80+ macrophages, natural killer, and CD8 T cells, displaying a central memory phenotype. Mechanistically, MFP induced immunogenic cell death (ICD) in vivo and in vitro, as depicted by the expression and subcellular localization of the alarmins calreticulin and HMGB-1 and the induction of an ICD gene program. Moreover, MFP-treated tumor cells efficiently activated immature dendritic cells, evidenced by enhanced expression of MHC-II and CD86, and induced a memory T-cell response, attenuating tumor onset and growth after re-challenge. Finally, MFP treatment increased the sensitivity of HR+ 59–2-HI tumor to PD-L1 blockade, suggesting that antiprogestins may improve immunotherapy response rates. These results contribute to a better understanding of the mechanisms underlying the antitumor effect of hormonal treatment and the rational design of therapeutic combinations based on endocrine and immunomodulatory agents in HR+ breast cancer.

Significance:
Antiprogestin therapy induces immunogenic tumor cell death in PRA-overexpressing tumors, eliciting an adaptive immune memory response that protects mice from future tumor recurrence and increases sensitivity to PD-L1 blockade.
Cyclophosphamide and Vinorelbine Activate Stem-Like CD8+ T Cells and Improve Anti-PD-1 Efficacy in Triple-Negative Breast Cancer
Authors: Falvo Paolo , Orecchioni Stefania , Hillje Roman , Raveane Alessandro , Mancuso Patrizia , Camisaschi Chiara , Luzi Lucilla , Pelicci PierGiuseppe , Bertolini Francesco 
Published: December 2020

Abstract

Checkpoint inhibitors (CI) instigate anticancer immunity in many neoplastic diseases, albeit only in a fraction of patients. The clinical success of cyclophosphamide (C)-based haploidentical stem-cell transplants indicates that this drug may re-orchestrate the immune system. Using models of triple-negative breast cancer (TNBC) with different intratumoral immune contexture, we demonstrate that a combinatorial therapy of intermittent C, CI, and vinorelbine activates antigen-presenting cells (APC), and abrogates local and metastatic tumor growth by a T-cell–related effect. Single-cell transcriptome analysis of &gt;50,000 intratumoral immune cells after therapy treatment showed a gene signature suggestive of a change resulting from exposure to a mitogen, ligand, or antigen for which it is specific, as well as APC-to-T-cell adhesion. This transcriptional program also increased intratumoral Tcf1+ stem-like CD8+ T cells and altered the balance between terminally and progenitor-exhausted T cells favoring the latter. Overall, our data support the clinical investigation of this therapy in TNBC.

Significance:
A combinatorial therapy in mouse models of breast cancer increases checkpoint inhibition by activating antigen-presenting cells, enhancing intratumoral Tcf1+ stem-like CD8+ T cells, and increasing progenitor exhausted CD8+ T cells.
Balancing and Differentiating p53 Activities toward Longevity and No Cancer?
Authors: Horikawa Izumi 
Published: December 2020

Abstract
Aging and death of cells (cellular senescence and apoptosis, respectively), triggered by or associated with cellular stress and DNA damage, impair organ function and homeostasis, leading to organismal aging and death. On the other hand, defects in physiologic regulations of cellular aging and death (escape from cellular senescence and failed apoptosis of severely damaged cells) contribute to uncontrolled cell division and genetic instability in cancer. In an oversimplified scenario, p53, an inducer of cellular senescence and apoptosis, may thus unfavorably contribute to aging and favorably suppress tumorigenesis. However, physiologic mechanisms should exist and therapeutic approaches may be developed to balance between aging and tumor suppression, for example, by differentially regulating cellular senescence, apoptosis, and other p53-mediated biological processes, such as DNA repair, autophagy, and energy metabolism. Possible mechanisms for such differential regulation of different subsets of p53 target genes may involve posttranslational modifications (e.g., phosphorylation and acetylation) and DNA binding cooperativity of p53. In this issue of Cancer Research, Timofeev and colleagues show that a previously uncharacterized phosphorylation in the p53 core DNA-binding domain regulates the DNA binding cooperativity and transcriptional activity of p53. Their mice deficient for this p53 phosphorylation were resistant to spontaneous and induced tumorigenesis, while they had shortened lifespan, but did not show progeria-like phenotypes. Prompted by this study, research on p53, aging, and cancer will explore balancing and differentiating different p53 activities toward a challenging goal of achieving longevity with no cancer.
See related article by Timofeev et al., p. 5231
Dissemination and Implementation Research at the National Cancer Institute: A Review of Funded Studies (2006–2019) and Opportunities to Advance the Field
Authors: Neta Gila , Clyne Mindy , Chambers David A. 
Published: December 2020

Abstract

Background:
To ensure investment in cancer research reaches populations who can benefit, the NCI has funded implementation science grants since the Dissemination and Implementation Research in Health (DIRH) funding opportunities launched in 2006. We analyzed NCI-funded DIRH grants to provide a snapshot of implementation science conducted across the cancer care continuum and highlight areas ripe for exploration.

Methods:
NCI-funded DIRH grants between fiscal years 2006 and 2019 were identified using the iSearch database. Two coders classified each grant by topic, populations studied, intervention and setting characteristics, strategies tested, study designs and methods used, and outcomes measured.

Results:
Seventy-one grants were awarded addressing cancer prevention (n = 33), screening (n = 33), diagnosis (n = 4), treatment (n = 9), and/or survivorship (n = 11). Colorectal (n = 20), breast (n = 15), and cervical (n = 11) were the most studied cancers. Most grants focused on delivery of guidelines (n = 36) or behavioral change interventions (n = 18) in health care settings (n = 47), studying implementation processes (n = 37) and/or testing implementation strategies (n = 43) using experimental (n = 35) and quasi-experimental (n = 6) designs. Few studied sustainability (n = 7), scale-up (n = 2), deimplementation (n = 4), measure development (n = 6), or policy-level implementation (n = 6).

Conclusions:
Current funding suggests researchers are studying implementation of cancer control interventions across the care continuum. However, research gaps remain in strategies for sustainability, scale-up, and deimplementation. More emphasis is needed on cancer treatment and survivorship. Additional focus on policy implementation and measure development is warranted.

Impact:
Understanding the breadth of NCI-funded implementation science can inform future efforts to build the knowledge base on how to improve dissemination and implementation of evidence in cancer control.
Obstructive Sleep Apnea and Incident Cancer: A Large Retrospective Multicenter Clinical Cohort Study
Authors: Kendzerska Tetyana , Povitz Marcus , Leung Richard S. , Boulos Mark I. , McIsaac Daniel I. , Murray Brian J. , Bryson Gregory L. , Talarico Robert , Hilton John F. , Malhotra Atul , Gershon Andrea S. 
Published: December 2020

Abstract

Background:
To examine the association between the severity of obstructive sleep apnea (OSA) and nocturnal hypoxemia with incident cancer.

Methods:
This was a multicenter retrospective clinical cohort study using linked clinical and provincial health administrative data on consecutive adults who underwent a diagnostic sleep study between 1994 and 2017 in four academic hospitals (Canada) who were free of cancer at baseline. Cancer status was derived from the Ontario Cancer Registry. Cox cause–specific regressions were utilized to address the objective and to calculate the 10-year absolute risk difference (ARD) in the marginal probability of incident cancer and the number needed to harm (NNH).

Results:
Of 33,997 individuals considered, 33,711 with no missing OSA severity were included: median age, 50 years; 58% male; and 23% with severe OSA (apnea-hypopnea index &gt;30). Of the 18,458 individuals with information on sleep time spent with oxygen saturation (SaO2) &lt;90%, 5% spent &gt;30% of sleep with SaO2 &lt;90% (severe nocturnal hypoxemia). Over a median of 7 years, 2,498 of 33,711 (7%) individuals developed cancer, with an incidence rate of 10.3 (10.0–10.8) per 1,000 person-years. Controlling for confounders, severe OSA was associated with a 15% increased hazard of developing cancer compared with no OSA (HR = 1.15, 1.02–1.30; ARD = 1.28%, 0.20–2.37; and NNH = 78). Severe hypoxemia was associated with about 30% increased hazard (HR = 1.32, 1.08–1.61; ARD = 2.38%, 0.47–4.31; and NNH = 42).

Conclusions:
In a large cohort of individuals with suspected OSA free of cancer at baseline, the severity of OSA and nocturnal hypoxemia was independently associated with incident cancer.

Impact:
These findings suggest the need for more targeted cancer risk awareness in individuals with OSA.
Provider Discussion about Lifestyle by Cancer History: A Nationally Representative Survey
Authors: Arem Hannah , Duan Xuejing , Ehlers Diane K. , Lyon Maureen E. , Rowland Julia H. , Mama Scherezade K. 
Published: December 2020

Abstract

Background:
Providers are uniquely positioned to encourage health-promoting behaviors, particularly among cancer survivors where patients develop trust in providers.

Methods:
We utilized the National Health Interview Survey to identify adults who reported a visit to a provider in the prior year (44,385 individuals with no cancer history and 4,792 cancer survivors), and reported prevalence of provider discussions on weight loss, physical activity, diet, and smoking. We used generalized linear mixed models to examine predicted prevalence of provider lifestyle discussions by cancer history overall, and among those who do not meet body mass index (BMI), activity, or smoking guidelines.

Results:
Among those with a BMI of 25–&lt;60 kg/m2, 9.2% of those with a cancer history and 11.6% of those without a cancer history reported being told to participate in a weight loss program (P &lt; 0.001). Overall, 31.7% of cancer survivors and 35.3% of those with no cancer history were told to increase their physical activity (P &lt; 0.001). Only 27.6% of cancer survivors and 32.2% of those with no cancer history reported having a general discussion of diet (P &lt; 0.001). Among smokers, 67.3% of cancer survivors and 69.9% of those with no cancer history reported counseling on smoking (P = 0.309).

Conclusions:
Fewer cancer survivors, who are at increased risk for health complications, are reporting provider discussions about critical lifestyle issues than those with no cancer history.

Impact:
Our nationally representative results suggest that providers are missing an opportunity for influencing patient lifestyle factors, which could lead to mitigation of late and long-term effects of treatment.
Combinatorial Efficacy of Olaparib with Radiation and ATR Inhibitor Requires PARP1 Protein in Homologous Recombination–Proficient Pancreatic Cancer
Authors: Parsels Leslie A. , Engelke Carl G. , Parsels Joshua , Flanagan Sheryl A. , Zhang Qiang , Tanska Daria , Wahl Daniel R. , Canman Christine E. , Lawrence Theodore S. , Morgan Meredith A. 
Published: December 2020

Abstract
PARP inhibitor monotherapy (olaparib) was recently FDA approved for the treatment of BRCA1/2-mutant, homologous recombination (HR) repair-deficient pancreatic cancer. Most pancreatic cancers, however, are HR proficient and thus resistant to PARP inhibitor monotherapy. We tested the hypothesis that combined therapy with radiation and ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) would extend the therapeutic indication of olaparib to HR-proficient pancreatic cancers. We show that olaparib combined with AZD6738 significantly reduced radiation survival relative to either agent alone, regardless of HR status. Whereas catalytic inhibition of PARP with low concentrations of olaparib radiosensitized HR-deficient models, maximal sensitization in HR-proficient models required concentrations of olaparib that induce formation of PARP1–DNA complexes. Furthermore, CRISPR-Cas9–mediated PARP1 deletion failed to recapitulate the effects of olaparib on radiosensitivity and negated the combinatorial efficacy of olaparib and AZD6738 on radiosensitization, suggesting that PARP1–DNA complexes, rather than PARP catalytic inhibition, were responsible for radiosensitization. Mechanistically, therapeutic concentrations of olaparib in combination with radiation and AZD6738 increased DNA double-strand breaks. DNA fiber combing revealed that high concentrations of olaparib did not stall replication forks but instead accelerated replication fork progression in association with an ATR-mediated replication stress response that was antagonized by AZD6738. Finally, in HR-proficient tumor xenografts, the combination of olaparib, radiation, and AZD6738 significantly delayed tumor growth compared with all other treatments. These findings suggest that PARP1–DNA complexes are required for the therapeutic activity of olaparib combined with radiation and ATR inhibitor in HR-proficient pancreatic cancer and support the clinical development of this combination for tumors intrinsically resistant to PARP inhibitors.
A Pilot Study of Galunisertib plus Stereotactic Body Radiotherapy in Patients with Advanced Hepatocellular Carcinoma
Authors: Reiss Kim A. , Wattenberg Max M. , Damjanov Nevena , Prechtel Dunphy Elizabeth , Jacobs-Small Mona , Lubas M. Judy , Robinson James , Dicicco Lisa , Garcia-Marcano Luis , Giannone Michael A. , Karasic Thomas B. , Furth Emma E. , Carpenter Erica L. , Wojcieszynski Andrzej P. , Vonderheide Robert H. , Beatty Gregory L. , Ben-Josef Edgar 
Published: December 2020

Abstract
TGFβ is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFβ enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFβ inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (n = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8+PD-1+TIGIT+ T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.
End‐Organ Function and Exercise Performance in Patients With Fontan Circulation: What Characterizes the High Performers?
Authors: Weinreb Scott J. , Dodds Kathryn M. , Burstein Danielle S. , Huang Jing , Rand Elizabeth B. , Mancilla Edna , Heimall Jennifer R. , McBride Michael G. , Paridon Stephen M. , Goldberg David J. , Rychik Jack 
Published: December 2020

Background
The physiologic hallmarks of the Fontan circulation—chronically elevated central venous pressures and low cardiac output—have significant effects not only on cardiovascular status but also impact other organ systems. Exercise capacity is limited in many and declines with age, accelerating in adolescence, but with wide variability. We explore the relationship between exercise performance and end‐organ function in outpatient subjects with a Fontan circulation.

Methods and Results

This is a cross‐sectional analysis of subject end‐organ characterization from our outpatient Fontan circulation clinic with peak oxygen consumption (peak V
o
2
) at cardiopulmonary exercise testing as the primary outcome. We perform linear regression to assess associations between clinical characteristics and peak V
o
2
as well as the magnitude of the association of clinical characteristics with peak V
o
2
. Of 265 subjects age 12.8 (9.5–16.4) years, there is a negative correlation between age and peak V
o
2
(−0.49,
P
<0.001). Of those undergoing ramp cycle exercise testing, 34% perform above 80% predicted peak V
o
2
. Variables positively associated with peak V
o
2
and their effect size include vitamin D sufficiency (+3.00,
P
=0.020) and absolute lymphocyte count (+0.23,
P
=0.005). Status as overweight/obese (−3.91,
P
=0.003) and hemoglobin (−0.77,
P
=0.003) are negatively associated. Neither ventricular morphology, timing of Fontan palliation, nor Fontan circulation type affect peak V
o
2
.

Conclusions

Higher peak V
o
2
in those with a Fontan circulation is associated with younger age, vitamin D sufficiency, absence of overweight/obese, lower hemoglobin, and a healthier hepatic profile. Whether exercise training or other initiatives can modify organ characteristics in those with a Fontan circulation is worthy of exploration.
Does Advanced Placement Economics Exam Participation and Performance Predict Undergraduate Economics Major Completion?
Authors: Ahlstrom Laura J. 
Published: December 2020

Students who take an Advanced Placement (AP) Microeconomics and/or AP Macroeconomics exam may be more interested in economics than their non-AP exam peers and more likely to complete an economics major. Performance on AP exams in economics may also affect students’ economics major completion. This study uses binary probit estimations to assess how participation in and performance on AP exams in economics affects students’ completion of an economics major. The findings suggest students who take both AP exams in economics are significantly more likely to graduate with an economics major compared with non-AP students who complete their introductory economics coursework in college. In addition, strong performance on the AP Microeconomics exam significantly increases a student’s probability of earning an economics major. Receiving high scores on both AP Economics exams is also significantly and positively correlated with economics major completion. JEL Classifications: A21, A22
Impacts of decarbonization on the automotive after sales sector: A review of evidence
Authors: Eslava-Bautista Jorge , Cottrill Caitlin D , Beecroft Mark 
Published: December 2020

Automotive after sales, which include provision of spare parts, customer service, and accessories sales, is one of the most profitable parts of the automotive industry and provides for an ongoing relationship with the customer. In times of recession, performance of after sales remains steady as it is highly independent of macroeconomic behaviors and keeps outstanding margins. Current automotive after sales are predominantly based on fossil fuel power train technologies, involving a significant number of replaceable working parts, lubricants, and supplies, and requiring ongoing manual labor. Current efforts to decarbonize the automotive industry, however, have the potential to disrupt this industry by shifting traditional after sales business models. The objective of this paper is to review the background and development of policies and actions in relation to the decarbonization of transport with a particular focus upon the role of the automotive after sales sector. The review considers the role of a range of stakeholders including multilateral bodies setting targets for participating nations; national governments; and the automotive industry, operating at varying scales. Electrification of vehicles and discouragement of car use and ownership are identified as key decarbonization strategies that could significantly impact upon car manufacturers and the broader automotive industry, which will in turn impact upon the after sales market. The review concludes that there has been limited research about impacts on after sales markets from transport decarbonization strategies. Areas of impact identified include reduction of working parts, fewer additional units, longer service intervals, changes in labor needs, disruption in customer retention, and changes to the repurchase cycle. In order to explore these potential impacts, the development of alternative future scenarios under different power train technologies and regional factors is recommended as an area for further research.