bluuebunny/crossref_metadata_2025_split huggingface dataset:
FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence
Authors: Fouillade Charles , Curras-Alonso Sandra , Giuranno Lorena , Quelennec Eddy , Heinrich Sophie , Bonnet-Boissinot Sarah , Beddok Arnaud , Leboucher Sophie , Karakurt Hamza Umut , Bohec Mylène , Baulande Sylvain , Vooijs Marc , Verrelle Pierre , Dutreix Marie , Londoño-Vallejo Arturo , Favaudon Vincent 
Published: December 2019

Abstract

Purpose:
One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. “FLASH” irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity.

Experimental Design:
Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc−/− mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro.

Results:
In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc−/− mice harboring critically short telomeres and lack of telomerase activity.

Conclusions:
The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.
Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression
Authors: Chakraborty Goutam , Armenia Joshua , Mazzu Ying Z. , Nandakumar Subhiksha , Stopsack Konrad H. , Atiq Mohammad O. , Komura Kazumasa , Jehane Lina , Hirani Rahim , Chadalavada Kalyani , Yoshikawa Yuki , Khan Nabeela A. , Chen Yu , Abida Wassim , Mucci Lorelei A. , Lee Gwo-Shu Mary , Nanjangud Gouri J. , Kantoff Philip W. 
Published: December 2019

Abstract

Purpose:
Previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with metastatic castration-resistant prostate cancer (mCRPC). BRCA2, a DDR and cancer susceptibility gene, is frequently deleted (homozygous and heterozygous) in men with aggressive prostate cancer. Here we show that patients with prostate cancer who have lost a copy of BRCA2 frequently lose a copy of tumor suppressor gene RB1; importantly, for the first time, we demonstrate that co-loss of both genes in early prostate cancer is sufficient to induce a distinct biology that is likely associated with worse prognosis.

Experimental Design:
We prospectively investigated underlying molecular mechanisms and genomic consequences of co-loss of BRCA2 and RB1 in prostate cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes in prostate cancer cell lines and subjected them to in vitro studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of BRCA2 and RB1 in prostate cancer cells and patient-derived mCRPC organoids.

Results:
In human prostate cancer cell lines (LNCaP and LAPC4), loss of BRCA2 leads to the castration-resistant phenotype. Co-loss of BRCA2-RB1 in human prostate cancer cells induces an epithelial-to-mesenchymal transition, which is associated with invasiveness and a more aggressive disease phenotype. Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived organoids and human CRPC cells harboring single-copy loss of both genes.

Conclusions:
Our findings suggest that early identification of this aggressive form of prostate cancer offers potential for improved outcomes with early introduction of PARP inhibitor–based therapy.
See related commentary by Mandigo and Knudsen, p. 1784
First-In-Human Study of Cemiplimab Alone or In Combination with Radiotherapy and/or Low-dose Cyclophosphamide in Patients with Advanced Malignancies
Authors: Papadopoulos Kyriakos P. , Johnson Melissa L. , Lockhart Albert C. , Moore Kathleen , Falchook Gerald S. , Formenti Silvia C. , Naing Aung , Carvajal Richard D. , Rosen Lee S. , Weiss Glen J. , Leidner Rom S. , Li Jingjin , Paccaly Anne , Feng Minjie , Stankevich Elizabeth , Lowy Israel , Fury Matthew G. , Crittenden Marka R. 
Published: December 2019

Abstract

Purpose:
This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors.

Patients and Methods:
Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1.

Results:
Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3–84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients.

Conclusions:
The safety profile of cemiplimab was comparable with other anti–PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.
Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer
Authors: Hong David S. , Concin Nicole , Vergote Ignace , de Bono Johann S. , Slomovitz Brian M. , Drew Yvette , Arkenau Hendrik-Tobias , Machiels Jean-Pascal , Spicer James F. , Jones Robert , Forster Martin D. , Cornez Nathalie , Gennigens Christine , Johnson Melissa L. , Thistlethwaite Fiona C. , Rangwala Reshma A. , Ghatta Srinivas , Windfeld Kristian , Harris Jeffrey R. , Lassen Ulrik Niels , Coleman Robert L. 
Published: December 2019

AbstractPurpose:Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody–drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).Patients and Methods:Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.Results:Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%−37%]. Median duration of response (DOR) was 4.2 months (range: 1.0+−9.7); four patients responded for &gt;8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%−43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%−35%), median DOR of 6.0 months (range: 1.0+−9.7), and 6-month PFS rate of 40% (95% CI: 24%−55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.Conclusions:Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.
Chemoprevention of Colorectal Cancer by Anthocyanidins and Mitigation of Metabolic Shifts Induced by Dysbiosis of the Gut Microbiome
Authors: Mudd Ashley M. , Gu Tao , Munagala Radha , Jeyabalan Jeyaprakash , Egilmez Nejat K. , Gupta Ramesh C. 
Published: December 2019

AbstractDiets rich in fat, smoking, as well as exposure to environmental pollutants and dysbiosis of gut microbiota, increase the risk of developing colorectal cancer. Much progress has been made in combating colorectal cancer. However, options for chemoprevention from environmental insult and dysbiosis of gut microbiota remain elusive. We investigated the influence of berry-derived anthocyanidins (Anthos), with and without encapsulating them in bovine milk–derived exosomes (ExoAnthos), on the chemoprevention of bacteria-driven colon tumor development. Anthos and ExoAnthos treatment of colon cancer cells showed dose-dependent decreases in cell viability. Calculated selectivity index (SI) values for Anthos and ExoAnthos suggest that both treatments selectively targeted cancer over normal colon cells. In addition, ExoAnthos treatment yielded higher SI values than Anthos. Anthos and ExoAnthos treatment of ApcMin/+ mice inoculated with enterotoxigenic Bacteriodes fragilis (ETBF) bacteria led to significant decreases in colon tumor numbers over mice receiving vehicle treatments. Western blot analysis of normal colon, colon tumor, and liver tissue lysates showed that mice inoculated with ETBF featured increased expression of phase I enzymes in normal colon tissue and decreased expression of phase II enzymes in liver tissue. Treatment with the Anthos and ExoAnthos reverted the modulation of phase I and phase II enzymes, respectively; no significant changes in phase II enzyme expression occurred in colon tumor tissue. Treatment of HCT-116 cells with the ubiquitous carcinogen, benzo[a]pyrene (B[a]P) led to similar modulation of phase I and II enzymes, which was partially mitigated by treatment with Anthos. These results provide a promising outlook on the impact of berry Anthos for prevention and treatment of bacteria- and B[a]P-driven colorectal cancer.
Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis
Authors: Erkes Dan A. , Cai Weijia , Sanchez Ileine M. , Purwin Timothy J. , Rogers Corey , Field Conroy O. , Berger Adam C. , Hartsough Edward J. , Rodeck Ulrich , Alnemri Emad S. , Aplin Andrew E. 
Published: December 2019

Abstract

Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat BRAFV600E/K-mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal. Importantly, BRAFi + MEKi–resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi–induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma.

Significance:
Targeted inhibitors and immune checkpoint agents have advanced the care of patients with melanoma; however, detailed knowledge of the intersection between these two research areas is lacking. We describe a molecular mechanism of targeted inhibitor regulation of an immune-stimulatory form of cell death and provide a proof-of-principle salvage therapy concept for inhibitor-resistant melanoma.
See related commentary by Smalley, p. 176.
This article is highlighted in the In This Issue feature, p. 161
Reply to “What Is the Maximum Entropy Principle? Comments on ‘Statistical Theory on the Functional Form of Cloud Particle Size Distributions’”
Authors: Wu Wei , McFarquhar Greg M. 
Published: December 2019

Abstract
We welcome the opportunity to correct the misunderstandings and misinterpretations contained in Yano’s comment that led him to incorrectly state that Wu and McFarquhar misunderstood the maximum entropy (MaxEnt) principle. As correctly stated by Yano, the principle itself does not suffer from the problem of a lack of invariance. But, as restated in this reply and in Wu and McFarquhar, the commonly used Shannon–Gibbs entropy does suffer from a lack of invariance for coordinate transform when applied in continuous cases, and this problem is resolved by the use of the relative entropy. Further, it is restated that the Wu and McFarquhar derivation of the PSD form using MaxEnt is more general than the formulation by Yano and allows more constraints with any functional relations to be applied. The derivation of Yano is nothing new but the representation of PSDs in other variables.
A Bayesian Framework for the Multiscale Assessment of Storm Severity and Related Uncertainties
Authors: Blanchet Juliette , Mélèse Victor 
Published: December 2019

AbstractThis article proposes a statistical framework for assessing the multiscale severity of a given storm at a given location. By severity we refer to the rareness of the storm event, as measured by the return period. Rather than focusing on predetermined spatiotemporal scales, we consider a model assessing the return period of a storm event observed across the continuum of durations and areas around a focus location. We develop a Bayesian intensity–duration–area–frequency model based on extreme value distribution and space–time scale invariance hypotheses. The model allows us to derive an analytical expression of the return period for any duration and area, while the Bayesian framework allows us by construction to assess the related uncertainties. We apply this framework to high-resolution radar–rain gauge reanalysis data covering a mountainous region of southern France during the autumns 2008–15 and comprising 50 rain events. We estimate the model at two grid points located a few kilometers apart on either side of the mountain crest, considering spatiotemporal scales ranging over 3–48 h and 1–2025 km2. We show that at all scales and for all significant events, the return period uncertainties are skewed to the right, evidencing the need of considering uncertainty to avoid systematic risk underestimation. We also reveal the large variability of the storm severity both at short distance and across scales, due to both the natural variability of rainfall and the mask effect induced by the mountain crest.
Ensemble-Based Targeted Observation Method Applied to Radar Radial Velocity Observations on Idealized Supercell Low-Level Rotation Forecasts: A Proof of Concept
Authors: Kerr Christopher A. , Wang Xuguang 
Published: December 2019

Abstract
The potential future installation of a multifunction phased-array radar (MPAR) network will provide capabilities of case-specific adaptive scanning. Knowing the impacts adaptive scanning may have on short-term forecasts will influence scanning strategy decision-making in hopes to produce the most optimal ensemble forecast while also benefiting human severe weather warning decision-making. An ensemble-based targeted observation algorithm is applied to an observing system simulation experiment (OSSE) where the impacts of synthetic idealized supercell radial velocity observations are estimated before the observations are “collected” and assimilated. The forecast metric of interest is the low-level rotation forecast metric (0–1-km updraft helicity), a surrogate for tornado prediction. It is found that the ensemble-based targeted observation approach can reasonably estimate the true error variance reduction when an effective method that treats sampling error is applied, the period of model forecast is associated with less degrees of nonlinearity, and the observation information content relative to the background forecast is larger. In some scenarios, a subset of a full-volume scan assimilation produces better forecasts than all observations within the full volume. Assimilating the full-volume scan increases the number of potential spurious correlations arising between the forecast metric and radial velocity observation induced state perturbations, which may degrade the forecast metric accuracy.
Contralateral deep vein thrombosis after stenting across the iliocaval confluence in chronic venous disease – A systematic review
Authors: Duarte-Gamas Luis , Rocha-Neves João P , Pereira-Neves António , Dias-Neto Marina , Baekgaard Niels 
Published: December 2019

Objective Stenting of the iliac veins is increasingly considered in the presence of symptomatic obstructive chronic lesions in the iliac vein segment. However, it is often necessary to extend the stented zone into the inferior vena cava, increasing the risk of contralateral iliac vein thrombosis. This study aims to review the current literature concerning the incidence of contralateral deep vein thrombosis after stenting across the iliocaval confluence. Methods A systematic review from potentially relevant published articles reporting contralateral deep vein thrombosis after iliac venous stenting between January 2007 and February 2019 was performed. Results A total of 764 references were retrieved initially. Twelve studies reporting events of contralateral deep vein thrombosis were selected for review, with a total of 1864 patients. Contralateral deep vein thrombosis incidence varied between 0% and 15.6%. The post-interventional and follow-up anticoagulation regimens were heterogeneous between studies. The decision to maintain patients on anticoagulation and the duration of treatment was based on the presence of comorbidities, hypercoagulable states, post-thrombotic syndrome and history of recurrent deep vein thrombosis. Patients with non-thrombotic iliac vein lesions were either anticoagulated for three or six months after stenting or received no anticoagulation. Patients with post-thrombotic syndrome were anticoagulated for longer periods. Most studies (eight studies) used an oral vitamin K antagonist agent. The data on compliance with anticoagulation treatment is scarce and few references present data on whether contralateral deep vein thrombosis occurred during anticoagulation treatment. The use of antiplatelet agents in addition to the anticoagulant treatment in the follow-up period was also variable. Conclusion The incidence of contralateral deep vein thrombosis due to iliac vein jailing is not negligible and reported being as high as 15.6%. Large-scale studies on the ideal antithrombotic treatment and its impact are necessary. It is possible that patients with stent crossing the iliocaval confluence might benefit from long-term antithrombotic treatment.
Migration pattern of a short uncemented stem with or without collar: a randomised RSA-study with 2 years follow-up
Authors: Weber Erik , Flivik Carl , Sundberg Martin , Flivik Gunnar 
Published: December 2019

Background: There is an increasing interest in shorter, proximally loading, uncemented femoral stems. The aim of this study was to evaluate a new short stem type, its design based on a well-proven precursor, but with several new design features to facilitate easier insertion and possible preservation of proximal bone stock. It is available with or without a collar. Methods: The study includes 50 patients with primary osteoarthritis, mean age 59 (range 36–75) years, randomised to receive either the collar-fitted or the collarless stem. The patients underwent repeated radiostereometry (RSA) examinations (0, 0.5, 3, 12, 24 months), conventional radiography and filled out both hip-specific (HOOS) and general health (EQ-5D) questionnaires. Results: There was no statistically significant difference between the collared and collarless stems regarding migration and clinical outcome. Both stem types exhibit a similar pattern of initial subsidence (collared 0.63 mm vs. collarless 0.75 mm [ p = 0.50]) and retroversion (collared 0.71° vs. collarless 0.97° [ p = 0.36]) up to 3 months followed by stabilisation, in similarity with its precursors, suggesting good osseointegration. No stem has been revised or considered loose. Conclusions: The new design features, including shortening the stem, do not compromise migration pattern or osseointegration, regardless collar or not.
Studying biological science does not lead to adoption of a healthy lifestyle
Authors: Bhatti SN , Leidi A , Leake D , Li J-M 
Published: December 2019

Aims: The lifestyle and physical activity (PA) habits of young people play a key role in the prevention of cardiovascular and metabolic diseases at older ages. The current generation of biological science students at university holds promise for better future medicine and medical technology. However, their physical fitness and lifestyle are often ignored. Methods: Lifestyle, PAs and common risk factors for cardiovascular disease before, and at, university were collected from 408 students using self-completed, anonymous surveys between the academic years of 2017 and 2019 from the School of Biological Sciences, University of Reading. Statistical analysis was performed using SAS® 9.4 software. Results: Among the 408 participants, 134 were male and 274 were female with a mean ( SD) age of 19.6 (2.24). Approximately 19% of participants consumed alcohol beyond the safe limit of <14 units/week (112 g/week). Among them, 65% were males. Before university, 47% of students failed to meet the UK National Physical Activity Guidelines (NPAG) which increased to 56% during university with males exhibiting a steeper incline. Compared to their lifestyles before university, more students had insufficient sleep and displayed greater sedentariness during university. Moreover, 16% of students declared no engagement in PA which was greater than the value of 12% before university. Fitness perceptions worsened by 11% during university particularly for females. Statistical analysis revealed that gender, BMI and fitness perceptions were significantly correlated with PA levels. The most prevalent explanation for inadequacy in meeting NPAG was insufficient time. Conclusions: Compared to their pre-university lifestyles, biological science students at university are more likely to adopt unhealthier behaviours with less time for exercise and prolonged sedentary behaviours, which increases the risk for cardiovascular diseases. It is important to raise awareness of their fitness perceptions and to encourage health-promoting programmes at university.