bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquired RAD51C Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma
Authors: Nesic Ksenija , Kondrashova Olga , Hurley Rachel M. , McGehee Cordelia D. , Vandenberg Cassandra J. , Ho Gwo-Yaw , Lieschke Elizabeth , Dall Genevieve , Bound Nirashaa , Shield-Artin Kristy , Radke Marc , Musafer Ashan , Chai Zi Qing , Ghamsari Mohammad Reza Eftekhariyan , Harrell Maria I. , Kee Damien , Olesen Inger , McNally Orla , Traficante Nadia , Study Australian Ovarian Cancer , DeFazio Anna , Bowtell David D.L. , Swisher Elizabeth M. , Weroha S. John , Nones Katia , Waddell Nicola , Kaufmann Scott H. , Dobrovic Alexander , Wakefield Matthew J. , Scott Clare L. 
Published: July 2021

Abstract

In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.

In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages.

In a cohort of 12 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic “scarring,” indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neoadjuvant chemotherapy.

As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy.

Significance:
Homozygous RAD51C methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.
Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling
Authors: Liu Huijuan , Yang Jiahuan , Zhang Yang , Han Jingxia , Yang Yuyan , Zhao Zihan , Dai Xintong , Wang Hongqi , Ding Xiujuan , Liu Yanrong , Zhong Weilong , Gao Wenqing , Sun Tao 
Published: July 2021

Abstract

Although it is established that the sustained psychologic stress conditions under which patients with tumors often reside accelerates malignant progression of tumors, the molecular mechanism behind this association is unclear. In this work, the effect of psychologic stress on tumor progression was verified using a stress-stimulated tumor-bearing mouse model (Str-tumor). Both D2 dopamine receptor (DRD2) and hypoxia-inducible factor-1α (HIF1α) were highly expressed in the nucleus of Str-tumors. Treatment with trifluoperazine (TFP), a DRD2 inhibitor, elicited better antitumor effects in Str-tumors than the control group. These results indicate that DRD2 may mediate stress-induced malignant tumor progression. DRD2 interacted with von Hippel-Lindau (VHL) in the nucleus, and competitive binding of DRD2 and HIF1α to VHL resulted in reduced ubiquitination-mediated degradation of HIF1α, enhancing the epithelial-mesenchymal transition of tumor cells. TFP acted as an interface inhibitor between DRD2 and VHL to promote the degradation of HIF1α. In conclusion, DRD2 may promote the progression of malignant tumors induced by psychologic stress via activation of the oxygen-independent HIF1α pathway, and TFP may serve as a therapeutic strategy for stress management in patients with cancer.

Significance:
This work identifies DRD2 regulation of HIF1α as a mechanism underlying the progression of malignant tumors stimulated by psychologic stress and suggests that DRD2 inhibition can mitigate these stress conditions in patients.
See related commentary by Bernabé, p. 5144
FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response
Authors: Velalopoulou Anastasia , Karagounis Ilias V. , Cramer Gwendolyn M. , Kim Michele M. , Skoufos Giorgos , Goia Denisa , Hagan Sarah , Verginadis Ioannis I. , Shoniyozov Khayrullo , Chiango June , Cerullo Michelle , Varner Kelley , Yao Lutian , Qin Ling , Hatzigeorgiou Artemis G. , Minn Andy J. , Putt Mary , Lanza Matthew , Assenmacher Charles-Antoine , Radaelli Enrico , Huck Jennifer , Diffenderfer Eric , Dong Lei , Metz James , Koumenis Constantinos , Cengel Keith A. , Maity Amit , Busch Theresa M. 
Published: July 2021

AbstractIn studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (&gt;40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFβ1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues.Significance:These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.
Copy Number Aberration Analysis to Predict Response to Neoadjuvant Anti-HER2 Therapy: Results from the NeoALTTO Phase III Clinical Trial
Authors: Venet David , Rediti Mattia , Maetens Marion , Fumagalli Debora , Brown David N. , Majjaj Samira , Salgado Roberto , Pusztai Lajos , Harbeck Nadia , El-Abed Sarra , Wang Yingbo , Saura Cristina , Gomez Henry , Semiglazov Vladimir Fedorovich , de Azambuja Evandro , Huober Jens , Nuciforo Paolo , Di Cosimo Serena , Piccart Martine , Loi Sherene , Rothé Françoise , Sotiriou Christos 
Published: July 2021

Abstract

Purpose:
The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial.

Experimental Design:
The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0.

Results:
CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor–positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number.

Conclusions:
Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti–HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation.
A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors
Authors: Manji Gulam A. , Van Tine Brian A. , Lee Shing M. , Raufi Alexander G. , Pellicciotta Ilenia , Hirbe Angela C. , Pradhan Jaya , Chen Andrew , Rabadan Raul , Schwartz Gary K. 
Published: July 2021

Abstract

Purpose:
To evaluate the safety and tolerability in phase I first-in-human combination therapy with pexidartinib, an inhibitor of colony-stimulating factor-1 receptor, and sirolimus, an mTOR inhibitor, to target tumor-associated macrophage (TAM) polarization in soft tissue sarcomas (STS).

Patients and Methods:
This multicenter phase I study used the time-to-event continual reassessment method (TITE-CRM) to study the combination of sirolimus, doses ranging from 2 to 6 mg, with pexidartinib, doses ranging from 600 to 1,000 mg, both provided continuously on a 28-day cycle, in patients with advanced sarcoma. A total of 24 patients [8 malignant peripheral nerve sheath tumor, 3 tenosynovial giant cell tumor (TGCT), 5 leiomyosarcoma, and 8 with other sarcoma subtypes] were enrolled. The median age was 46 years, 56% were male, and 61% had &gt;2 prior lines of therapy.

Results:
The recommended phase II dose was 2 mg of sirolimus combined with 1,000 mg of pexidartinib daily. Of the 18 evaluable subjects, 5 experienced dose-limiting toxicities (2 elevated aspartate aminotransferase/alanine aminotransferase, 2 elevated sirolimus trough levels, and 1 grade 5 dehydration). Most common grade 2 or higher treatment-related adverse events included anemia, fatigue, neutropenia, and lymphopenia. Clinical benefit was observed in 12 of 18 (67%) evaluable subjects with 3 partial responses (all in TGCT) and 9 stable disease. Tissue staining indicated a decreased proportion of activated M2 macrophages within tumor samples with treatment.

Conclusions:
Pexidartinib can be safely administered with sirolimus. These findings support further investigation of this combination to determine clinical efficacy. Clinicaltrials.gov identifier NCT02584647.
Intoxicated Donors and Heart Transplant Outcomes: Long-Term Safety
Authors: Baran David A. , Lansinger Justin , Long Ashleigh , Herre John M. , Yehya Amin , Sawey Edward J. , Badiye Amit P. , Old Wayne , Copeland Jack , Stelling Kelly , Copeland Hannah 
Published: July 2021

Background:
The opioid crisis has led to an increase in available donor hearts, although questions remain about the long-term outcomes associated with the use of these organs. Prior studies have relied on historical information without examining the toxicology results at the time of organ offer. The objectives of this study were to examine the long-term survival of heart transplants in the recent era, stratified by results of toxicological testing at the time of organ offer as well as comparing the toxicology at the time of donation with variables based on reported history.

Methods:
The United Network for Organ Sharing database was requested as well as the donor toxicology field. Between 2007 and 2017, 23 748 adult heart transplants were performed. United Network for Organ Sharing historical variables formed a United Network for Organ Sharing Toxicology Score and the measured toxicology results formed a Measured Toxicology Score. Survival was examined by the United Network for Organ Sharing Toxicology Score and Measured Toxicology Score, as well as Cox proportional hazards models incorporating a variety of risk factors.

Results:

The number and percent of donors with drug use has significantly increased over the study period (
P
<0.0001). Cox proportional hazards modeling of survival including toxicological and historical data did not demonstrate differences in post-transplant mortality. Combinations of drugs identified by toxicology were not associated with differences in survival. Lower donor age and ischemic time were significantly positively associated with survival (
P
<0.0001).

Conclusions:
Among donors accepted for transplantation, neither history nor toxicological evidence of drug use was associated with significant differences in survival. Increasing use of such donors may help alleviate the chronic donor shortage.
Patient‐Reported Outcomes and Patient‐Reported Experience of Patients With Atrial Fibrillation in the IMPACT‐AF Clinical Trial
Authors: Humphries Brittany , Cox Jafna L. , Parkash Ratika , Thabane Lehana , Foster Gary A. , MacKillop James , Nemis‐White Joanna , Hamilton Laura , Ciaccia Antonio , Choudhri Shurjeel H. , Xie Feng ,   IMPACT‐AF Investigators
Published: July 2021

Background
The IMPACT‐AF (Integrated Management Program Advancing Community Treatment of Atrial Fibrillation) trial is a prospective, randomized, cluster design trial comparing atrial fibrillation management with a computerized clinical decision support system with usual care (control) in the primary care setting of Nova Scotia, Canada. The objective of this analysis was to assess and compare patient‐reported health‐related quality of life and patient‐reported experience with atrial fibrillation care between clinical decision support and control groups.

Methods and Results
Health‐related quality of life was measured using the EuroQol 5‐dimensional 5‐level scale, whereas patient‐reported experience was assessed using a self‐administered satisfaction questionnaire, both assessed at baseline and 12 months. Health utilities were calculated using the Canadian EuroQol 5‐dimensional 5‐level value set. Descriptive statistics and generalized estimating equations were used to compare between groups. Among 1145 patients enrolled in the trial, 717 had complete EuroQol 5‐dimensional 5‐level data at baseline. The mean age of patients was 73.53 years, and 61.87% were men. Mean utilities at baseline were 0.809 (SD, 0.157) and 0.814 (SD, 0.157) for clinical decision support and control groups, respectively. At baseline, most patients in both groups reported being “very satisfied” with the care received for their atrial fibrillation. There were no statistically significant differences in utility scores or patient satisfaction between groups at 12 months.

Conclusions
Health‐related quality of life of patients remained stable over 12 months, and there was no significant difference in patient satisfaction or utility scores between clinical decision support and control groups.

Registration information
clinicaltrials.gov. Identifier: NCT01927367.
A Conversation with Aliza Shvarts
Authors: Apter Emily 
Published: July 2021

Abstract
Aliza Shvarts first came to widespread attention when her Untitled [Senior Thesis] (2008), consisting of a yearlong performance of self-induced miscarriages, was declared a “fiction” by Yale University and censored from public exhibition. That controversial work was on view for the first time in New York as part of her 2020 exhibition Purported at Art in General. It frames the areas of inquiry she has continued to explore: how the body means and matters and how the subject consents and dissents. In this in-depth conversation, Emily Apter and Aliza Shvarts discuss the exhibition and a wide range of topics relevant to contemporary feminist practice and thought: the genealogy of citation; the uses of theory; speech action; rape kits; nonconsensual collaboration; queer kinship; and memes.
Elephantine Trespasses
Authors: Cornell Collin 
Published: July 2021

Abstract
This article identifies two examples of constructive theological argumentation in recent religion-historical research: specifically, research on the Yahwism of a Persian-period island called Elephantine. These examples are significant because the task of history of religions is to offer critical (re)description of the contents of religion and not to make positive recommendations for current-day god-talk or ethics. In addition to setting out these disciplinary stakes, the article suggests that the location of these trespasses is also of interest: the historical subdiscipline that studies Elephantine, by virtue of its propinquity to the Bible proper, draws theological cachet from the Bible, while its smaller infrastructure relative to academic biblical studies makes room for more editorializing. Lastly, the article answers each theological proposal in kind, with brief theological counterarguments made, not obliquely and paracanonically, but directly from canonical biblical texts. In this way, the article advocates for maintaining the integrity of each discipline: descriptive history of religions and constructive theologizing.
Pictorial Graffiti from the Ghazali Northern Church, Sudan: An Overview
Authors: Obłuski Artur , Maczuga Julia 
Published: July 2021

Abstract
The aim of this paper is to present pictorial graffiti executed on the walls of the Northern Church of the Ghazali Monastery located in what is today the Northern Province of Sudan. The graffiti were recorded during research by the Polish-Sudanese mission at the monastic complex. This paper explores the symbolic meanings of the graffiti as well as possible rationales behind their locations. Some of the depictions have overt religious meanings and may be interpreted as “graphic” prayers. This category of graffiti includes representations of Christ, angels, saints, female figures and horse riders. Other depictions seem to refer to daily life in Nubia – the graffiti abound in motifs such as camels, horses, boats and human beings.
Evaluation of Complications and Weight Outcomes in Pediatric Cerebral Palsy Patients With Gastrostomy Tubes
Authors: Jadi Jihane , Hyder Sudipta , Rodriguez Ormaza Nidia P. , Twer Emma , Phillips Michael , Akinkuotu Adesola , Reid Trista D. 
Published: July 2021

Background Feeding difficulties are common in children with cerebral palsy (CP). The goal of this study was to examine pediatric CP patients undergoing gastrostomy tube (G tube) placement and assess the association between patient characteristics and weight after 3 months, 6 months, and 1 year. Methods This was a retrospective study of all pediatric patients with CP who received a G tube placement between April 2014 and December 2017 at a single institution. Bivariate analysis was used to examine association between patient characteristics and the primary outcome of improvement in weight Z score at 3, 6, and 12 months. Results Of 63 patients who received a G tube, 81% had an increase in Z score at 3 months, 44% at 6 months, and 64% at 12 months. By 12 months, factors associated with a positive Z score change included moderate and severe malnutrition, lack of prior G tube, and fewer comorbidities. The majority (69.8%) of patients experienced complications. Seven (11%) patients died, with only 1 death related to G tube placement. Discussion The use of G tubes in CP patients resulted in an increase in an improvement in nutritional status for the majority of patients over the course of a year. Although most complications were minor, patients had a high complication rate and frequently visited the emergency department, highlighting the need for standardized education and follow-up among this patient population.
Relationship between Lp-PLA2 and in-stent restenosis after coronary stenting: a 3-year follow-up study
Authors: Sheng Guohua , Zhou Juan , Zhang Chi , Wu Caijuan , Huang Kairong , Qin Xiaotong , Wu Jie 
Published: July 2021

Background and aims Coronary in-stent restenosis (ISR) is an important complication of percutaneous coronary intervention (PCI). However, the relationship between lipoprotein associated phospholipase A2 (Lp-PLA2) level and ISR after PCI is rarely reported. This study aims to explore the relationship between Lp-PLA2 and the occurrence of ISR at post-PCI and its predictive value for ISR. Methods and results Plasma Lp-PLA2 mass were measured in 847 patients planting 1262 stents and evaluated along with known risk indicators. One-year angiographic follow-up showed that baseline elevated Lp-PLA2 mass was strongly associated with early restenosis (95% CI = 1.062-3.050, P < 0.05). Beyond the first year, the occurrence of late restenosis (95% CI = 1.043-3.214, P < 0.05) was significantly larger in the elevated Lp-PLA2 group. Kaplan-Meier analysis after three-year clinical follow up suggested that Lp-PLA2 mass did add the positive effect on the occurrence of major adverse cardiovascular events (MACEs). Conclusion In conclusion, increased baseline plasma Lp-PLA2 predicts increased risks of re-stenosis and MACEs, which may be a novel biomarker for predicting ISR and MACEs.
Evaluation and Comparison of Artificial Intelligence Vision Aids: Orcam MyEye 1 and Seeing AI
Authors: Granquist Christina , Sun Susan Y. , Montezuma Sandra R. , Tran Tu M. , Gage Rachel , Legge Gordon E. 
Published: July 2021

Introduction: We compared the print-to-speech properties and human performance characteristics of two artificial intelligence vision aids, Orcam MyEye 1 (a portable device) and Seeing AI (an iPhone and iPad application). Methods: There were seven participants with visual impairments who had no experience with the two reading aids. Four participants had no light perception. Two individuals with measurable acuity and one with light perception were tested while blindfolded. We also tested performance with text of varying appearance in varying viewing conditions. To evaluate human performance, we asked the participants to use the devices to attempt 12 reading tasks similar to activities of daily living. We assessed the ranges of text attributes for which reading was possible, such as print size, contrast, and light level. We also assessed if individuals could complete tasks with the devices and measured accuracy and completion time. Participants also completed a survey concerning the two aids. Results: Both aids achieved greater than 95% accuracy in text recognition for flat, plain word documents and ranged from 13 to 57% accuracy for formatted text on curved surfaces. Both aids could read print sizes as small as 0.8M (20/40 Snellen equivalent, 40 cm viewing distance). Individuals successfully completed 71% and 55% ( p = .114) of tasks while using Orcam MyEye 1 and Seeing AI, respectively. There was no significant difference in time to completion of tasks ( p = .775). Individuals believed both aids would be helpful for daily activities. Discussion: Orcam MyEye 1 and Seeing AI had similar text-reading capability and usability. Both aids were useful to users with severe visual impairments in performing reading tasks. Implications for Practitioners: Selection of a reading device or aid should be based on individual preferences and prior familiarity with the platform, since we found no clear superiority of one solution over the other.