bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB361: Li-Fraumeni syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Tong David R. , Obradovic Aleksandar Z. , Low-Calle Ana M. , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol L. 
Published: April 2023

Abstract
Mutations that occur within the oligomerization domain (OD) of the tumor suppressor p53 generally abolish p53 tetramerization and are associated with increased cancer susceptibility in Li-Fraumeni syndrome (LFS). Despite their prevalence, the impact of OD-mutant p53 proteins in cancer, especially beyond a loss of canonical p53 activity, has not been well elucidated. We sought to delineate the gain-of-function (GOF) vs. loss-of-function (LOF) activities of OD-mutant p53, specifically focusing on the LFS tumor-derived p53(A347D) variant. We obtained LFS patient-derived dermal fibroblasts heterozygous for the mutation and generated an allelic series of U2OS cancer cell lines expressing wild-type p53, heterozygous (p53+/AD) or homozygous (p53AD/AD) mutant p53 or no p53 (p53 KO). In contrast to wild-type p53, mutant p53(A347D) exclusively forms dimers in both fibroblasts and cancer cells and has lost the ability to bind and transactivate the majority of canonical p53 target genes, which yields comparable tumorigenic properties between mutant p53 and p53 KO cells. Mutant p53(A347D), however, displays neomorphic activities. Glycolysis and oxidative phosphorylation pathways are enriched in cells bearing p53(A347D) relative to both wild-type p53 and p53 KO cells. Furthermore, dimeric mutant p53 induces striking mitochondrial network aberration and preferentially associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Ultimately, we describe dimeric mutant p53 as wielding a double-edged sword: driving tumorigenesis through LOF while gaining enhanced apoptogenic activity, thereby providing a potential basis for select therapeutic approaches.
Citation Format: Joshua H. Choe, Tatsuya Kawase, An Xu, Asja Guzman, David R. Tong, Aleksandar Z. Obradovic, Ana M. Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M. Hwang, Joshua D. Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol L. Prives. Li-Fraumeni syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB361.
Data from IOA-244 is a Non–ATP-competitive, Highly Selective, Tolerable PI3K Delta Inhibitor That Targets Solid Tumors and Breaks Immune Tolerance
Authors: Johnson Zoë , Tarantelli Chiara , Civanelli Elisa , Cascione Luciano , Spriano Filippo , Fraser Amy , Shah Pritom , Nomanbhoy Tyzoon , Napoli Sara , Rinaldi Andrea , Niewola-Staszkowska Karolina , Lahn Michael , Perrin Dominique , Wenes Mathias , Migliorini Denis , Bertoni Francesco , van der Veen Lars , Di Conza Giusy 
Published: April 2023

<div><p>PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ inhibition in solid tumors has recently emerged as a potential novel anticancer therapy through the modulation of T-cell responses and direct antitumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non–ATP-competitive PI3Kδ inhibitor, for the treatment of solid tumors. We confirm IOA-244’s selectivity as tested against a large set of kinases, enzymes, and receptors. IOA-244 inhibits the <i>in vitro</i> growth of lymphoma cells and its activity correlates with the expression levels of <i>PIK3CD</i>, suggesting cancer cell–intrinsic effects of IOA-244. Importantly, IOA-244 inhibits regulatory T cell proliferation while having limited antiproliferative effects on conventional CD4<sup>+</sup> T cells and no effect on CD8<sup>+</sup> T cells. Instead, treatment of CD8 T cells with IOA-244 during activation, favors the differentiation of memory-like, long-lived CD8, known to have increased antitumor capacity. These data highlight immune-modulatory properties that can be exploited in solid tumors. In CT26 colorectal and Lewis lung carcinoma lung cancer models, IOA-244 sensitized the tumors to anti-PD-1 (programmed cell death protein 1) treatment, with similar activity in the Pan-02 pancreatic and A20 lymphoma syngeneic mouse models. IOA-244 reshaped the balance of tumor-infiltrating cells, favoring infiltration of CD8 and natural killer cells, while decreasing suppressive immune cells. IOA-244 presented no detectable safety concerns in animal studies and is currently in clinical phase Ib/II investigation in solid and hematologic tumors.</p>Significance:<p>IOA-244 is a first-in-class non–ATP-competitive, PI3Kδ inhibitor with direct antitumor <i>in vitro</i> activity correlated with PI3Kδ expression. The ability to modulate T cells, <i>in vivo</i> antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.</p></div>
Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling
Authors: Nichtová Zuzana , Fernandez-Sanz Celia , De La Fuente Sergio , Yuan Yuexing , Hurst Stephen , Lanvermann Sebastian , Tsai Hui-Ying , Weaver David , Baggett Ariele , Thompson Christopher , Bouchet-Marquis Cedric , Várnai Péter , Seifert Erin L. , Dorn Gerald W. , Sheu Shey-Shing , Csordás György 
Published: April 2023

Background:

Cardiac contractile function requires high energy from mitochondria, and Ca
2+
from the sarcoplasmic reticulum (SR). Via local Ca
2+
transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca
2+
overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering.

Methods:
We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype.

Results:
Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive β-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury.

Conclusions:

We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca
2+
/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca
2+
signaling.
Is Democracy the Answer to Intractable Climate Change?
Authors: Chesler Angela , Javeline Debra , Peh Kimberly , Scogin Shana 
Published: April 2023

Abstract
Climate change is the greatest governance challenge humanity has ever faced. Understanding why some governments successfully reduce greenhouse gas emissions and others fail is thus imperative. While regime type is often hypothesized to be a source of variation in greenhouse gas emissions, empirical findings about the effects of democracy and autocracy on climate action are contradictory. This research note reconciles these inconsistencies and adopts a quasi-experimental approach to investigate the relationship between democratization and greenhouse gas emissions. A fixed effects model with a synthetic control estimator is used to construct appropriate counterfactuals and evaluate the effect of regime type on emissions with data from the World Bank and Varieties of Democracy Project. The analysis shows that movement toward democracy does not have a significant effect on emissions, suggesting that research on the politics of emissions reduction should focus on factors other than regime type.
Beyond Legal Pluralism: Chinese Customs and Customary Laws in Colonial Hong Kong (1841–1997)
Authors: Chiang Cho Kiu 
Published: April 2023

Abstract
This article challenges the label of legal pluralism used in overseas Chinese studies. While legal pluralism has been the long-standing academic tradition of characterizing the law in overseas Chinese societies, the case of colonial Hong Kong, with its experience in rejecting, distorting, and manipulating Chinese customs and customary laws, illustrates that legal pluralism is an untenable position regarding the “plurality” of laws under a colonial regime and the “plurality” of social fields or legal orders with a “plurality” of sources of law. It is further argued that “legal pluralism” as academic jargon, a theory, and a framework, is intertwined with colonialism and therefore not useful as a descriptive category or as a normative ideal. We must go beyond legal pluralism to understand law in overseas Chinese studies.
How Values Are Discussed, Reflected Upon, and Acted On by Patients and Family Caregivers in the Context of Heart Failure: A Scoping Review
Authors: Bechthold Avery C. , Knoepke Christopher E. , Ejem Deborah B. , McIlvennan Colleen K. , Wells Rachel D. , Matlock Daniel D. , Bakitas Marie A. , Dionne-Odom J. Nicholas 
Published: April 2023

Purpose Values are critical to how individuals make decisions and cope, yet the values of heart failure (HF) patients and their family caregivers (FCGs) remain understudied. We sought to report the state of the science on how values are discussed, reflected upon, and acted on by patients with HF, their FCGs, or both related to health-related decision making and coping. Method A scoping review was conducted of empirical studies using the following keywords: “heart failure,” “values,” “decision-making,” and “coping.” PubMed, PsycINFO, and Scopus were searched from inception to June 2022 in English. Included articles reported values as a key finding (outcome/theme) in their abstract. Results Of 448 articles screened for eligibility, 16 met the inclusion criteria. Twelve articles reported findings addressing patient values, 3 addressed patient and FCG values, and 1 addressed FCG values. Values were reported to influence patient self-care behaviors and left ventricular assist device (LVAD) implantation decisions, although their prioritization varied across time and contexts. When prioritized values conflicted with recommended self-care activities, some patients modified their approach to achieving the value. Others modified or abandoned tasks in favor of the value and accompanying goals. Low motivation and alignment between unhealthy behaviors and values often led to nonadherent decisions. Five of 8 articles focusing on cardiac devices reported patient survival as the most prioritized value during implantation decisions. FCG values were rarely reported or evaluated separately from patient values. Patients leveraged several coping strategies, although the processes through which values affected coping was not described. Conclusions Prioritized values influenced HF-related decisions, including self-care and LVAD implantation. While several articles reported on coping and values, none described processes through which values affect coping, which highlights a research gap. Highlights Family caregiver values were rarely reported or evaluated separately from patient values, highlighting a gap in the literature.
On-campus mental health services for Australian university students: A retrospective analysis of service utilisation
Authors: Francis-Taylor Rohan , Lipscomb Rosie , Sanatkar Samineh , Healy Martin , Kefalas Bill 
Published: April 2023

Objective To investigate on-campus mental health service utilisation by Australian university students. Method Retrospective analysis of clinical data from two on-campus health services (general practice and psychology and counselling service). Descriptive statistics include total consults, demographic factors, diagnoses, presenting concerns and rates of suicidal ideation. Results Mental health conditions account for the largest proportion of ongoing illness in on-campus health service users, representing 46% of all ongoing health conditions. Depression and anxiety were the most common diagnoses, and stress, anxiety and low mood were the most common presenting concerns. Females utilise mental health services more frequently than males, accounting for 65.3% and 60.1% of patients for the respective services. International students present for specific mental health consults less frequently than domestic students. Rates of suicidal ideation at presentation were high (37%). Conclusions This retrospective analysis provides important information regarding the proportion and distribution of mental health conditions and service utilisation amongst Australian university students. There is clear scope for increased access to specialist care, renewed efforts to decrease stigma and increase rates of presentation (particularly amongst international students and males), greater support for general practitioners and more rigorous routine data collection and reporting, both within and across universities nationally.
Is It Time to Expand Our Definition of “Clinical Utility”?
Authors: Sorscher Steven 
Published: April 2023

Currently, genetic tests that predict cancer risk or risk of recurrence in patients who have had their cancer treated with curative intent must have proven “clinical utility” to be recommended by the organizations responsible for publishing the standard-of-care guidelines for cancer care. Based on the current definition of clinical utility, most patients are denied testing for cancer-predisposing genes or pathogenic germline variants even though germline testing has been proven as highly accurate in identifying pathogenic germline variant carriers, there are measures recommended to prevent and diagnose early cancers associated with particular PGVs, and disparities in patient access to genetic tests are well described. Similarly, despite dozens of studies demonstrating that detected circulating tumor DNA (ctDNA) after curative intention therapy of different cancer types is a highly accurate biomarker that predicts recurrence, the major organizations that publish guidelines for cancer monitoring after curative intention therapy recommend against using ctDNA assays to detect minimal residual disease and thereby predict recurrence for all solid tumor malignancies. Here, the primary reasons that these genetic tests are considered to lack proven clinical utility and the primary evidence suggesting that a broader definition of clinical utility should be considered are discussed. By expanding the definition of clinical utility, many patients will benefit from the information gained from having these genetic tests.
The Iatrogenic Injury Potential of Self-adherent, Elastic Bandages in Finger Injuries
Authors: Yu Henry H. , Nadeau Jason , Powell Jenna , Fox Charles , Lauder Alexander , Ipaktchi Kyros 
Published: April 2023

Background: The use of a self-adherent, elastic bandage is a practical way to dress finger injuries. Multiple reports describe iatrogenic injuries from elastic bandages, ranging from skin necrosis to finger gangrene, necessitating amputations. This study investigated whether elastic bandages can compromise digital perfusion by occluding arterial blood flow in healthy volunteers and evaluated the utility of pulse oximetry as a monitoring tool for digital perfusion. A technique for safe bandage application is proposed. Methods: A commercially available elastic bandage was wrapped around the index finger of 20 healthy volunteers at varying degrees of stretch. Digital perfusion measurements were carried out using photoelectric pulse transduction, laser Doppler flowmetry, and pulse oximetry. Intracompartmental pressure measurements were recorded using a separate in vitro experimental model. Results: Elastic bandages applied at maximum stretch did not change digital brachial index or pulse oximetry values, suggesting arterial blood flow was preserved distal to the bandage. Intracompartmental pressure measurements at maximum stretch remained below the systolic digital pressure. In contrast, superficial dermal perfusion fell to 32% of normal as measured by laser Doppler flow, at 100% bandage stretch. Conclusion: This study suggests a risk for iatrogenic injury when using elastic bandages for finger dressings. While arterial inflow was never compromised, pressures were high enough to occlude superficial venous outflow, which may begin at 20% bandage stretch. Pulse oximetry failed to detect changes distal to applied dressings, and we do not recommend it to detect digital vascular compromise in this setting.
Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the Fondazione Italiana Linfomi MCL0208 trial
Authors: Ferrero Simone , Grimaldi Daniele , Arrigoni Elena , Pironti Mariapia , Zaccaria Gian Maria , Alessandria Beatrice , Genuardi Elisa , De Luca Gabriele , Ghislieri Marco , Tavarozzi Rita , Di Rocco Alice , Re Alessandro , Stefoni Vittorio , Cavallo Federica , Boccomini Carola , Balzarotti Monica , Zilioli Vittorio , Moita Filipa , Arcaini Luca , Lucchini Elisa , Ballerini Filippo , Ferreri Andrés J. M. , Puccini Benedetta , Palumbo Giuseppe A. , Galimberti Sara , Cortelazzo Sergio , Di Paolo Antonello , Ladetto Marco 
Published: April 2023

AbstractIn the Fondazione Italiana Linfomi MCL0208 phase 3 trial, lenalidomide maintenance (LEN) after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single-nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell-surface receptors might predict drug efficacy. Genotypes were obtained via real-time polymerase chain reaction of the peripheral blood germ line DNA. Polymorphisms of ABCB1 and VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type (WT) in the LEN arm was 3-year PFS of 85% vs 70% (P &lt; .05) and 85% vs 60% (P &lt; .01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (76%); in fact, in these patients, LEN did not improve PFS vs OBS (3-year PFS, 44% vs 60%; P = .62). Moreover, the CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, whereas ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL.
Preliminary construct validity of patient-reported outcomes to assess chronic pain in adults with sickle cell disease
Authors: Mucalo Lana , Field Joshua J. , Highland Janelle , Khan Hamda , Hankins Jane S. , Singh Ashima , Brandow Amanda M. 
Published: April 2023

Abstract
Chronic pain affects 30% to 40% of individuals with sickle cell disease (SCD) and impairs patient functioning. Clinically meaningful, practical, and valid assessment tools for investigation, evaluation, and management of chronic pain are limited, representing a barrier for advancing SCD care. We sought to determine whether patient-reported outcomes (PROs) show preliminary construct validity in identifying individuals with SCD who were a priori defined as suggestive of having chronic pain based on previously published criteria. All individuals completed the Patient-Reported Outcomes Measurement Information System (PROMIS) domains: pain interference, pain behavior, pain quality (nociceptive, neuropathic), fatigue, sleep disturbance, depression, and anxiety; the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) domains: pain impact and emotional impact; and the painDETECT questionnaire. Thirty-three adults living with SCD were enrolled, and 42.4% had chronic pain. Pain-related PROs scores distinctly differentiated individuals with chronic pain from those without. Individuals with chronic pain had significantly worse pain-related PROs scores: PROMIS pain interference (64.2 vs 54.3), PROMIS pain behavior (63.2 vs 50), and ASCQ-Me pain impact (42.9 vs 53.2). According to published PROMIS clinical cut scores for the pain-related domains, individuals with chronic pain were categorized as having moderate impairment, whereas those without chronic pain had mild or no impairment. Individuals with chronic pain had PRO pain features consistent with neuropathic pain and worse scores in fatigue, depression, sleep disturbance, and emotional impact. Pain-related PROs show preliminary construct validity in differentiating individuals with and without chronic SCD pain and could be used as valuable tools for research and clinical monitoring of chronic pain.
Repeatability of radiomics studies in colorectal cancer: a systematic review
Authors: Liu Ying , Wei Xiaoqin , Feng Xu , Liu Yan , Feng Guiling , Du Yong 
Published: April 2023

Abstract
Background
Recently, radiomics has been widely used in colorectal cancer, but many variable factors affect the repeatability of radiomics research. This review aims to analyze the repeatability of radiomics studies in colorectal cancer and to evaluate the current status of radiomics in the field of colorectal cancer.

Methods
The included studies in this review by searching from the PubMed and Embase databases. Then each study in our review was evaluated using the Radiomics Quality Score (RQS). We analyzed the factors that may affect the repeatability in the radiomics workflow and discussed the repeatability of the included studies.

Results
A total of 188 studies was included in this review, of which only two (2/188, 1.06%) studies controlled the influence of individual factors. In addition, the median score of RQS was 11 (out of 36), range-1 to 27.

Conclusions
The RQS score was moderately low, and most studies did not consider the repeatability of radiomics features, especially in terms of Intra-individual, scanners, and scanning parameters. To improve the generalization of the radiomics model, it is necessary to further control the variable factors of repeatability.