bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of IFN-Mediated Responses and Tumor Immunogenicity in Patients with Cervical Cancer Receiving Concurrent Chemoradiotherapy
Authors: Chen Jianzhou , Chen Chuangzhen , Zhan Yizhou , Zhou Li , Chen Jie , Cai Qingxin , Wu Yanxuan , Sui Zhihan , Zeng Chengbing , Wei Xiaolong , Muschel Ruth 
Published: March 2021

Abstract

Purpose:
To ask whether the expression of immune markers and IFN signaling in tumor biopsies changes during concurrent chemoradiotherapy (CCRT).

Experimental Design:
Tumor biopsies and peripheral mononuclear blood cells (PMBC) before and immediately after 20 Gy/10 fractions (F) of radiation treatment (RT) from 30 patients with cervical cancer receiving CCRT were evaluated by IHC and qRT-PCR for immune markers and correlated with the short-term response.

Results:
Tumor immune response to radiation before and after 10F RT as reflected by CD8+ T-cell infiltration had substantial heterogeneity with increases, decreases, and no change all evident. Increases in CD8+ T cells during CCRT correlated with the presence of nuclear IRF1 in tumor cells (r = 0.68, P &lt; 0.0001) and the patient short-term response (P &lt; 0.01). Similarly, in a subset of patients (∼40%) PD-L1 positivity in tumor cells increased, which also correlated with nuclear IRF1 staining (r = 0.48, P &lt; 0.01). Patients with augmented PMBC IFN signature expression after 10F had a significantly higher probability of PD-L1 induction (83% vs. 7%, P &lt; 0.0001). Most patients exhibited abundant expression of SERPINB9 and CD47 in tumor cells, and tumor infiltration by CD68+ cells. SERPINB9 expression correlated with STAT1 signaling in tumor cells.

Conclusions:
CCRT leads to differential tumor immunogenicity and IFN signaling in patients with cervical cancer, suggesting radiation induction of immunity is limited to a subset of patients and may reflect the heterogeneity of intratumoral induction of IFNs.
See related commentary by Mondini and Deutsch, p. 3815
A Surgical Window Trial Evaluating Medroxyprogesterone Acetate with or without Entinostat in Patients with Endometrial Cancer and Validation of Biomarkers of Cellular Response
Authors: Duska Linda R. , Filiaci Virginia L. , Walker Joan L. , Holman Laura L. , Hill Emily K. , Moore Richard G. , Ring Kari L. , Pearl Michael L. , Muller Carolyn Y. , Kushnir Christina L. , Lankes Heather A. , Samuelson Megan I. , Carrick Kelley S. , Rajan Anand , Rodgers William H. , Kohn Elise C. , Piekarz Richard , Leslie Kimberly K. 
Published: March 2021

Abstract

Purpose:
This surgical window of opportunity (window) study assessed the short-term effect of medroxyprogesterone acetate (MPA) alone versus MPA plus the histone deacetylase (HDAC) inhibitor entinostat on regulation of progesterone receptor (PR) in women with newly diagnosed endometrioid endometrial adenocarcinoma.

Patients and Methods:
This multisite, randomized, open-label surgical window study treated women intramuscularly on day 1 with 400 mg MPA. Entinostat given 5 mg by mouth on days 1, 8, and 15 was randomly assigned with equal probability. Surgery followed on days 21–24. Pretreatment and posttreatment tissue was assessed for PR H-scores, Ki-67 levels, and histologic response.

Results:
Fifty patients were accrued in 4 months; 22 and 20 participants had PR evaluable pretreatment and posttreatment slides in the MPA and MPA/entinostat arms, respectively. Median posttreatment PR H-scores were significantly lower than pretreatment H-scores in both arms but did not differ significantly (MPA: 247 vs. 27, MPA/entinostat 260 vs. 23, respectively, P = 0.87). Decreased Ki-67 was shown in 90% treated with MPA/entinostat compared with 68% treated with MPA alone (P = 0.13). Median PR H-score decreases were larger when Ki-67 was decreased (208) versus not decreased (45). The decrease in PR pretreatment versus posttreatment was associated with loss of Ki-67 nuclear staining, consistent with reduced cellular proliferation (P &lt; 0.008).

Conclusions:
This surgical window trial rapidly accrued in a multisite setting and evaluated PR as its primary endpoint and Ki-67 as secondary endpoint. Despite no immediate effect of entinostat on PR in this short-term study, lessons learned can inform future window and treatment trials.
Camrelizumab Combined with Chemotherapy Followed by Camrelizumab plus Apatinib as First-line Therapy for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
Authors: Peng Zhi , Wei Jia , Wang Feng , Ying Jieer , Deng Yanhong , Gu Kangsheng , Cheng Ying , Yuan Xianglin , Xiao Juxiang , Tai Yanfei , Wang Linna , Zou Jianjun , Zhang Yanqiao , Shen Lin 
Published: March 2021

Abstract

Purpose:
Capecitabine plus oxaliplatin (CAPOX) is one of the standard first-line treatments for unresectable, advanced, or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Camrelizumab shows promising antitumor activity in advanced or metastatic G/GEJ adenocarcinoma in a phase I study. We reported the outcomes of cohort 1 in a multicenter, open-label, phase II trial, which assessed camrelizumab in combination with CAPOX followed by camrelizumab plus apatinib as a first-line combination regimen for advanced or metastatic G/GEJ adenocarcinoma.

Patients and Methods:
Systemic treatment-naïve patients with EGFR2-negative advanced or metastatic G/GEJ adenocarcinoma received initial camrelizumab plus CAPOX for 4–6 cycles, and patients without progressive disease were administrated subsequent camrelizumab plus apatinib. Primary endpoint was objective response rate (ORR).

Results:
All 48 enrolled patients comprised the efficacy and safety analysis population. The ORR was 58.3% [95% confidence interval (CI), 43.2–72.4] with this combination regimen. Median duration of response was 5.7 months (95% CI, 4.4–8.3). Median overall survival was 14.9 months (95% CI, 13.0–18.6), and median progression-free survival was 6.8 months (95% CI, 5.6–9.5), respectively. The most common grade ≥3 treatment-related adverse events (&gt;10%) were decreased platelet count (20.8%), decreased neutrophil count (18.8%), and hypertension (14.6%). Treatment-related death occurred in 1 patient (2.1%) due to abnormal hepatic function and interstitial lung disease.

Conclusions:
Camrelizumab combined with CAPOX followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as first-line therapy for patients with advanced or metastatic G/GEJ adenocarcinoma.
Estimated Impact of Achieving Optimal Cardiovascular Health Among US Adults on Cardiovascular Disease Events
Authors: Bundy Joshua D. , Zhu Zhengbao , Ning Hongyan , Zhong Victor W. , Paluch Amanda E. , Wilkins John T. , Lloyd‐Jones Donald M. , Whelton Paul K. , He Jiang , Allen Norrina B. 
Published: March 2021

Background
Better cardiovascular health (CVH) scores are associated with lower risk of cardiovascular disease (CVD). However, estimates of the potential population‐level impact of improving CVH on US CVD event rates are not currently available.

Methods and Results
Using data from the National Health and Nutrition Examination Survey 2011 to 2016 (n=11 696), we estimated the proportions of US adults in CVH groups. Levels of 7 American Heart Association CVH metrics were scored as ideal (2 points), intermediate (1 point), or poor (0 points), and summed to define overall CVH (low, 0–8 points; moderate, 9–11 points; or high, 12–14 points). Using individual‐level data from 7 US community‐based cohort studies (n=30 447), we estimated annual incidence rates of major CVD events by levels of CVH. Using the combined data sources, we estimated population attributable fractions of CVD and the number of CVD events that could be prevented annually if all US adults achieved high CVH. High CVH was identified in 7.3% (95% CI, 6.3%–8.3%) of US adults. We estimated that 70.0% (95% CI, 56.5%–79.9%) of CVD events were attributable to low and moderate CVH. If all US adults attained high CVH, we estimated that 2.0 (95% CI, 1.6–2.3) million CVD events could be prevented annually. If all US adults with low CVH attained moderate CVH, we estimated that 1.2 (95% CI, 1.0–1.4) million CVD events could be prevented annually.

Conclusions
The potential benefits of achieving high CVH in all US adults are considerable, and even a partial improvement in CVH scores would be highly beneficial.
Pluralism versus Separation: Tension in the Australian Church-State Relationship
Authors: Barker Renae 
Published: March 2021

Abstract
The relationship between the state and religion in Australia exists in a state of tension. On the one hand the “non-establishment” clause in section 116 of the Australian Constitution points to the separation of religion and state. On the other hand there is a high level of cooperation between the state and religion in the public sphere, most visible in the funding of religious schools by the federal government. These two visions of the Australian state-religion relationship are in tension. One requiring the removal of religion from the public sphere while the other calls for a plurality of religions to be accommodated in public spaces. This article seeks to resolve this tension by proposing a new way to understand the Australian state-religion relationship as non-establishment pluralism. Non-establishment in the sense that the Australian Constitution prohibits the establishment of any religion—be that a single state church, multiple state religions, or religion generally. Pluralism in that the state via ordinary legislation, public policy, and government action cooperates with religion in numerous areas of state and religious interest in the public sphere.
Thaqīl (Insufferable) vs. Ẓarīf (Refined)
Authors: Zakeri Mohsen 
Published: March 2021

Abstract
Ẓarf is a well-known concept in classical Arabic adab-literature — it stands for refinement, courtesy, elegance, and wit, among other things. Less known is its counterpart, thiqal, denoting all things heavy. A thaqīl (pl. thuqalāʾ) is a bore whose often boorish conduct is deemed insufferable by anyone whose company he seeks. The oldest extant text on the subject of the insufferable, Ibn al-Marzbān’s Dhamm al-thuqalāʾ, “Censure of the Insufferable,” is studied to shed more light on the characteristics of the thaqīl and on everything a ẓarīf is not.
The Diurnal Cycle of Precipitation according to Multiple Decades of Global Satellite Observations, Three CMIP6 Models, and the ECMWF Reanalysis
Authors: Watters Daniel , Battaglia Alessandro , Allan Richard P. 
Published: March 2021

AbstractNASA Precipitation Measurement Mission observations are used to evaluate the diurnal cycle of precipitation from three CMIP6 models (NCAR-CESM2, CNRM-CM6.1, CNRM-ESM2.1) and the ERA5 reanalysis. NASA’s global-gridded IMERG product, which combines spaceborne microwave radiometer, infrared sensor, and ground-based gauge measurements, provides high-spatiotemporal-resolution (0.1° and half-hourly) estimates that are suitable for evaluating the diurnal cycle in models, as determined against the ground-based radar network over the conterminous United States. IMERG estimates are coarsened to the spatial and hourly resolution of the state-of-the-art CMIP6 and ERA5 products, and their diurnal cycles are compared across multiple decades of June–August in the 60°N–60°S domain (IMERG and ERA5: 2000–19; NCAR and CNRM: 1979–2008). Low-precipitation regions (and weak-amplitude regions when analyzing the diurnal phase) are excluded from analyses so as to assess only robust diurnal signals. Observations identify greater diurnal amplitudes over land (26%–134% of the precipitation mean; 5th–95th percentile) than over ocean (14%–66%). ERA5, NCAR, and CNRM underestimate amplitudes over ocean, and ERA5 overestimates over land. IMERG observes a distinct diurnal cycle only in certain regions, with precipitation peaking broadly between 1400 and 2100 LST over land (2100–0600 LST over mountainous and varying-terrain regions) and 0000 and 1200 LST over ocean. The simulated diurnal cycle is unrealistically early when compared with observations, particularly over land (NCAR-CESM2 AMIP: −1 h; ERA5: −2 h; CNRM-CM6.1 AMIP: −4 h on average) with nocturnal maxima not well represented over mountainous regions. Furthermore, ERA5’s representation of the diurnal cycle is too simplified, with less interannual variability in the time of maximum relative to observations over many regions.
Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery
Authors: Savarirayan Ravi , Irving Melita , Maixner Wirginia , Thompson Dominic , Offiah Amaka C , Connolly Daniel JA , Raghavan Ashok , Powell James , Kronhardt Marcin , Jeha George , Ghani Sajda , Fisheleva Elena , Day Jonathan RS 
Published: March 2021

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality. Trial registrations: ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40
Driving simulator study of the relationship between motion strategy preference and self-reported driving behavior
Authors: Rengifo Carolina , Chardonnet Jean-Rémy , Mohellebi Hakim , Paillot Damien , Kemeny Andras 
Published: March 2021

Faithful motion restitution in driving simulators normally focuses on track monitoring and maximizing the platform workspace by leaving aside the principal component—the driver. Therefore, in this work we investigated the role of the motion perception model on motion cueing algorithms from a user’s viewpoint. We focused on the driving behavior influence regarding motion perception in a driving simulator. Participants drove a driving simulator with two different configurations: (a) using the platform dynamic model and (b) using a supplementary motion perception model. Both strategies were compared and the participants’ data were classified according to the strategy they preferred. To this end, we developed a driving behavior questionnaire aiming at evaluating the self-reported driving behavior influence on participants’ motion cueing preferences. The results showed significant differences between the participants who chose different strategies and the scored driving behavior in the hostile and violations factors. In order to support these findings, we compared participants’ behaviors and actual motion driving simulator indicators such as speed, jerk, and lateral position. The analysis revealed that motion preferences arise from different reasons linked to the realism or smoothness in motion. Also, strong positive correlations were found between hostile and violation behaviors of the group who preferred the strategy with the supplementary motion perception model, and objective measures such as jerk and speed on different road segments. This indicates that motion perception in driving simulators may depend not only on the type of motion cueing strategy, but may also be influenced by users’ self-reported driving behaviors.
Vitamin K and ECMO for neonatal hypoxic respiratory failure
Authors: Lock Nicole E , Sawyer Alexandra A , Wise Linda , Bhatia Jatinder , Stansfield Brian K 
Published: March 2021

Introduction: The objectives of this retrospective cohort study were to examine the effect of vitamin K administration on hemorrhagic and thrombotic complications, blood product utilization, and outcomes in neonatal extracorporeal membrane oxygenation (ECMO). Methods: In the pilot study, complications, blood product use, and outcome data for neonates who received ( n = 21) or did not receive ( n = 18) a single dose of vitamin K (5 mg) immediately after initiation of ECMO for respiratory failure between 2006 and 2010 were compared. In the validation cohort, complications and outcomes were compared for 74 consecutive neonates supported with ECMO for respiratory failure who received ( n = 45) or did not receive ( n = 29) additional vitamin K once daily for prothrombin time (PT) ⩾14 seconds during ECMO from 2014 to 2019. Results: In the pilot study, vitamin K at ECMO initiation was associated with fewer thrombotic complications and similar hemorrhagic complications. The volume of fresh frozen plasma was higher in neonates who received vitamin K, but total blood product and other component volume did not differ between groups. ECMO run time, survival off ECMO, survival to discharge, and length of stay did not differ between cohorts. In the validation cohort, neonates who received additional vitamin K during ECMO had longer ECMO run time and length of stay, but no difference in mortality was observed. Further, thrombotic and hemorrhagic complications as well as blood product exposure were similar between cohorts. Conclusions: These data suggest that routine vitamin K administration may have limited or no benefit during neonatal ECMO.
Immunotherapy associated pain crisis and the haemophagocytic lymphohistiocytosis syndrome in advanced melanoma: Case report and review of the literature
Authors: Krasovitsky Michael , Borbasi Jessica 
Published: March 2021

Background: Immunotherapy is increasingly used in the management of early and advanced malignancy. There is limited data regarding the associations between immunotherapy, malignancy, pain and haemophagocytic lymphohistiocytosis. Case: A 40-year-old woman was diagnosed with advanced melanoma, with metastases to her brain, liver, lung, adrenal glands and bone. She had moderate opioid requirements prior to the initiation of therapy. Following doublet immunotherapy with nivolumab and ipilimumab, she experienced a severe pain crisis associated with pyrexia and haemophagocytic lymphohistiocytosis. Possible courses of action: Management dilemmas included whether or not to initiate non-steroidal and steroidal anti-inflammatory therapies, how to address the patient’s nociceptive, neuropathic and inflammatory pain, and how to manage the haemophagocytic lymphohistiocytosis. Formulation of management plan: The patient required rapid up-titration of analgesia, including methadone, ketamine, hydromorphone, pregabalin and benzodiazepines. Ketorolac and high dose steroid therapy were administered for pain management and to mitigate treatment associated inflammation and haemophagocytic lymphohistiocytosis. Outcome: The patient’s pain was inadequately managed despite multimodal analgesia, and stigmata of inflammation progressed. She died 14 days following treatment. Lessons: The case demonstrates that severe pain may be a consequence of immunotherapy given for advanced, high volume melanoma. Research avenues: There is laboratory evidence suggesting an association between immunotherapy, malignancy, pain and haemophagocytic lymphohistiocytosis. Further clinical evidence is required in order to understand these intersecting phenomena.
Trends of concerns from diagnosis in patients with advanced lung cancer and their family caregivers: A 2-year longitudinal study
Authors: Sato Takashi , Fujisawa Daisuke , Arai Daisuke , Nakachi Ichiro , Takeuchi Mari , Nukaga Shigenari , Kobayashi Keigo , Ikemura Shinnosuke , Terai Hideki , Yasuda Hiroyuki , Kawada Ichiro , Sato Yasunori , Satomi Ryosuke , Takahashi Saeko , Hashiguchi Mizuha Haraguchi , Nakamura Morio , Oyamada Yoshitaka , Terashima Takeshi , Sayama Koichi , Saito Fumitake , Sakamaki Fumio , Inoue Takashi , Naoki Katsuhiko , Fukunaga Koichi , Soejima Kenzo 
Published: March 2021

Background: Both advanced cancer patients and their family caregivers experience distress and have a range of concerns after cancer diagnosis. However, longitudinal studies on this topic have been lacking. Aim: To investigate concerns in both patients with advanced lung cancer and their family caregivers longitudinally from diagnosis. Design: A multi-center prospective questionnaire-based study. Setting/participants: We recruited patients with newly diagnosed advanced lung cancer and their family caregivers at 16 hospitals in Japan. We prospectively assessed the prevalence of their concerns using the Concerns Checklist and investigated the associations between their concerns and mental status as well as quality of life until 24 months after diagnosis. Results: A total of 248 patients and their 232 family caregivers were enrolled. The prevalence of serious concerns was highest at diagnosis (patients: 68.3%, family caregivers: 65.3%). The most common serious concern was concern about the future in both groups at diagnosis (38.2% and 40.5%, respectively) and this remained high in prevalence over time, while the high prevalence of concern about lack of information improved 3 months after diagnosis in both groups. Approximately one-third of patient-family caregiver dyads had discrepant reports of serious concerns. The presence of serious concerns was significantly associated with anxiety and depression continuously in both groups. Conclusions: The majority of advanced lung cancer patients and their family caregivers have serious concerns from diagnosis, which is associated with their psychological distress. The spectrum of concerns alters over the disease trajectory, warranting efficient tailored care and support for both groups immediately after diagnosis.