bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Survey on Parallelism and Determinism
Authors: Gonnord Laure , Henrio Ludovic , Morel Lionel , Radanne Gabriel 
Published: September 2022

Parallelism is often required for performance. In these situations an excess of non-determinism is harmful as it means the program can have several different behaviours or even different results. Even in domains such as high-performance computing where parallelism is crucial for performance, the computed value should be deterministic. Unfortunately, non-determinism in programs also allows dynamic scheduling of tasks, reacting to the first task that succeeds, cancelling tasks that cannot lead to a result, and so on. Non-determinism is thus both a desired asset or an undesired property depending on the situation. In practice, it is often necessary to limit non-determinism and to identify precisely the sources of non-determinism to control what parts of a program are deterministic or not.
This survey takes the perspective of programming languages, and studies how programming models can ensure the determinism of parallel programs. This survey studies not only deterministic languages but also programming models that prevent one particularly demanding source of non-determinism: data races.
Our objective is to compare existing solutions to the following questions: How programming languages can help programmers write programs that run in a parallel manner without visible non-determinism? What programming paradigms ensure this kind of properties? We study these questions and discuss the merits and limitations of different approaches.
Clinical Curative Effects and Influencing Factors of Uterine Artery Chemoembolization Combined with Uterine Curettage Treating with Cesarean Scar Pregnancy Patients
Authors: Yu Kewen , Zhou Haifeng 
Published: September 2022

Objective. To explore the clinical curative effects of uterine arterial chemoembolization (UACE) combined with uterine curettage treating with cesarean scar pregnancy (CSP) patients, and analyze the influencing factors of postoperative efficacy. Methods. A total of 86 patients with CSP from January 2019 to December 2021 in the Gynecology ward of our hospital were selected and divided into the control group (n = 43) and the observation group (n = 43) according to the random number method. The control group was treated with an injection of methotrexate (MTX) combined with uterine curettage, and the observation group was treated with UACE combined with uterine curettage. Two months after the operation, the therapeutic effect, cesarean scar mass, and β-human chorionic gonadotropin (β-HCG) level were observed and compared between the two groups. The general conditions of patients in two groups were recorded, and the influencing factors of surgical efficacy in patients were analyzed using univariate analysis and a multivariate logistic regression model. Results. After treatment, the total effective rate of the observation group was significantly higher than that of the control group (

P

< 0.05). The volume of intraoperative blood loss, hospitalization period, menstrual recovery time, mass disappearance time, and β-HCG recovery time of the observation group were lower than those of the control group (

P

< 0.05). Single factor analysis showed that the number of cesarean sections, gestational age, the largest diameter of the gestational sac, the thinnest muscular layer, and the type of CSP can all affect postoperative efficacy (

P

< 0.05). Multivariate logistic analysis showed that the gestational age, a maximum diameter of a gestational sac, the thinnest muscular layer, and the type of CSP were independent factors influencing the postoperative efficacy of the patients (

P

< 0.05). Conclusion. UACE combined with uterine curettage for CSP can significantly improve the curative effect, reduce intraoperative bleeding, and improve the recovery time of postoperative-related symptoms. The gestational age of the patient, the maximum diameter of the gestational sac, the thinnest muscular layer, and the type of CSP can independently affect the therapeutic effect of CSP patients. Fully understanding the high-risk factors that affect the efficacy of treatment of CSP, timely preventive measures, and targeted care can effectively improve the prognosis and reduce the risk of CSP.
HOXA5-Mediated Stabilization of IκBα Inhibits the NF-κB Pathway and Suppresses Malignant Transformation of Breast Epithelial Cells
Authors: Pai Priya , Wang Guannan , Teo Wei Wen , Raez-Rodriguez Diana , Gabrielson Kathleen L. , Győrffy Balázs , Downs Bradley M. , Aggarwal Akanksha , Sukumar Saraswati 
Published: September 2022

Abstract

HOXA5 is a transcription factor and tumor suppressor that promotes differentiation of breast epithelial cells and is frequently lost during malignant transformation. HOXA5 loss alone, however, does not confer tumorigenicity. To determine which molecular alterations combined with loss of HOXA5 expression can transform cells, we examined isogenic derivatives of a nonmalignant breast epithelial cell line containing knock-in or knockout mutations in key breast cancer genes. Knockdown (KD) of HOXA5 in cells harboring double knock-in (DKI) of mutated PIK3CA (E545K) and HER2 (V777L) induced epithelial–mesenchymal transition and migration and promoted invasive tumor outgrowth within mouse mammary ducts. The NF-κB pathway was significantly upregulated in DKI cells following HOXA5 KD. HOXA5 KD upregulated multiple NF-κB target genes, including IL6. IκBα protein, but not RNA, expression was reduced in HOXA5-KD cells. HOXA5 bound and stabilized IκBα, forming a nuclear HOXA5-IκBα complex. Chromatin immunoprecipitation sequencing database queries revealed that HOXA5 and IκBα are co-enriched at 528 genomic loci. In patients with breast cancer, high coexpression of HOXA5 and IκBα conferred a significantly better overall and progression-free survival. Collectively, these data suggest that HOXA5 suppresses malignancy in breast epithelial cells by blunting NF-κB action via stabilization of its inhibitor IκBα.

Significance:
Loss of HOXA5 reduces IκBα stability and increases NF-κB signaling to exacerbate breast cancer aggressiveness, providing new insights into the tumor suppressor functions of HOXA5.
Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy
Authors: Ykema Berbel L.M. , Gini Andrea , Rigter Lisanne S. , Spaander Manon C.W. , Moons Leon M.G. , Bisseling Tanya M. , de Boer Jan Paul , Verbeek Wieke H.M. , Lugtenburg Pieternella J. , Janus Cecile P.M. , Petersen Eefke J. , Roesink Judith M. , van der Maazen Richard W.M. ,   for the DICHOS study group, Aleman Berthe M.P. , Meijer Gerrit A. , van Leeuwen Flora E. , Snaebjornsson Petur , Carvalho Beatriz , van Leerdam Monique E. , Lansdorp-Vogelaar Iris 
Published: September 2022

Abstract

Background:
Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups.

Methods:
The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 μg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG).

Results:
Overall, the optimal surveillance strategy was annual FIT (47 μg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 μg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 μg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG).

Conclusions:
Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy.

Impact:
Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors.
NASH and Hepatocellular Carcinoma: Immunology and Immunotherapy
Authors: Pinter Matthias , Pinato David J. , Ramadori Pierluigi , Heikenwalder Mathias 
Published: September 2022

Abstract
The last 10 years have revolutionized our basic understanding of nonalcoholic fatty liver disease and consequent liver cancer. It has become clear that several innate and adaptive immune cells play an important role in initiating, maintaining, or exacerbating nonalcoholic steatohepatitis (NASH)—a disease that has been recently defined as autoaggressive. Despite improved disease management aimed at reducing the progression of fibrosis, NASH is set to become a leading cause for hepatocellular carcinoma (HCC). Preliminary data from preclinical studies suggest that immunotherapy efficacy may be reduced in NASH-related HCC compared with viral HCC; however, conclusive evidence supporting clinical translation of these findings is lacking. Comprehensive clinical and immunologic phenotyping of mechanisms linking NASH progression with carcinogenesis and therapeutic resistance is key to prevent progression to cirrhosis, improve monitoring and stratification of NASH according to predicted cancer risk, and ultimately increase survival of patients with NASH-HCC. In this review, we summarize the state of the art in the field of NASH and NASH-HCC with focus on immunobiology. We discuss preclinical and clinical findings underpinning NASH as an immunologically distinct pro-tumorigenic disease entity, and explore areas of potential therapeutic vulnerabilities in NASH-associated HCC.
Novel Lymphocyte-Independent Antitumor Activity by PD-1 Blocking Antibody against PD-1+ Chemoresistant Lung Cancer Cells
Authors: Rotolo Ramona , Leuci Valeria , Donini Chiara , Galvagno Federica , Massa Annamaria , De Santis Maria Chiara , Peirone Serena , Medico Giovanni , Sanlorenzo Martina , Vujic Igor , Gammaitoni Loretta , Basiricò Marco , Righi Luisella , Riganti Chiara , Salaroglio Iris Chiara , Napoli Francesca , Tabbò Fabrizio , Mariniello Annapaola , Vigna Elisa , Modica Chiara , D’Ambrosio Lorenzo , Grignani Giovanni , Taulli Riccardo , Hirsch Emilio , Cereda Matteo , Aglietta Massimo , Scagliotti Giorgio Vittorio , Novello Silvia , Bironzo Paolo , Sangiolo Dario 
Published: September 2022

Abstract

Purpose:
Antibodies against the lymphocyte PD-1 (aPD-1) receptor are cornerstone agents for advanced non–small cell lung cancer (NSCLC), based on their ability to restore the exhausted antitumor immune response. Our study reports a novel, lymphocyte-independent, therapeutic activity of aPD-1 against NSCLC, blocking the tumor-intrinsic PD-1 receptors on chemoresistant cells.

Experimental Design:
PD-1 in NSCLC cells was explored in vitro at baseline, including stem-like pneumospheres, and following treatment with cisplatin both at transcriptional and protein levels. PD-1 signaling and RNA sequencing were assessed. The lymphocyte-independent antitumor activity of aPD-1 was explored in vitro, by PD-1 blockade and stimulation with soluble ligand (PD-L1s), and in vivo within NSCLC xenograft models.

Results:
We showed the existence of PD-1+ NSCLC cell subsets in cell lines and large in silico datasets (Cancer Cell Line Encyclopedia and The Cancer Genome Atlas). Cisplatin significantly increased PD-1 expression on chemo-surviving NSCLC cells (2.5-fold P = 0.0014), while the sequential treatment with anti–PD-1 Ab impaired their recovery after chemotherapy. PD-1 was found to be associated with tumor stemness features. PD-1 expression was enhanced in NSCLC stem-like pneumospheres (P &lt; 0.0001), significantly promoted by stimulation with soluble PD-L1 (+27% ± 4, P &lt; 0.0001) and inhibited by PD-1 blockade (−30% ± 3, P &lt; 0.0001). The intravenous monotherapy with anti–PD-1 significantly inhibited tumor growth of NSCLC xenografts in immunodeficient mice, without the contribution of the immune system, and delayed the occurrence of chemoresistance when combined with cisplatin.

Conclusions:
We report first evidence of a novel lymphocyte-independent activity of anti–PD-1 antibodies in NSCLC, capable of inhibiting chemo-surviving NSCLC cells and exploitable to contrast disease relapses following chemotherapy.
See related commentary by Augustin et al., p. 505
B-cell Lymphoma 6 (BCL6): From Master Regulator of Humoral Immunity to Oncogenic Driver in Pediatric Cancers
Authors: McLachlan Tabitha , Matthews William C. , Jackson Evangeline R. , Staudt Dilana E. , Douglas Alicia M. , Findlay Izac J. , Persson Mika L. , Duchatel Ryan J. , Mannan Abdul , Germon Zacary P. , Dun Matthew D. 
Published: September 2022

Abstract
B-cell lymphoma 6 (BCL6) is a protooncogene in adult and pediatric cancers, first identified in diffuse large B-cell lymphoma (DLBCL) where it acts as a repressor of the tumor suppressor TP53, conferring survival, protection, and maintenance of lymphoma cells. BCL6 expression in normal B cells is fundamental in the regulation of humoral immunity, via initiation and maintenance of the germinal centers (GC). Its role in B cells during the production of high affinity immunoglobins (that recognize and bind specific antigens) is believed to underpin its function as an oncogene. BCL6 is known to drive the self-renewal capacity of leukemia-initiating cells (LIC), with high BCL6 expression in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and glioblastoma (GBM) associated with disease progression and treatment resistance. The mechanisms underpinning BCL6-driven therapy resistance are yet to be uncovered; however, high activity is considered to confer poor prognosis in the clinical setting. BCL6’s key binding partner, BCL6 corepressor (BCOR), is frequently mutated in pediatric cancers and appears to act in concert with BCL6. Using publicly available data, here we show that BCL6 is ubiquitously overexpressed in pediatric brain tumors, inversely to BCOR, highlighting the potential for targeting BCL6 in these often lethal and untreatable cancers. In this review, we summarize what is known of BCL6 (role, effect, mechanisms) in pediatric cancers, highlighting the two sides of BCL6 function, humoral immunity, and tumorigenesis, as well as to review BCL6 inhibitors and highlight areas of opportunity to improve the outcomes of patients with pediatric cancer.
Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade
Authors: Lander Varintra E. , Belle Jad I. , Kingston Natalie L. , Herndon John M. , Hogg Graham D. , Liu Xiuting , Kang Liang-I , Knolhoff Brett L. , Bogner Savannah J. , Baer John M. , Zuo Chong , Borcherding Nicholas C. , Lander Daniel P. , Mpoy Cedric , Scott Jalen , Zahner Michael , Rogers Buck E. , Schwarz Julie K. , Kim Hyun , DeNardo David G. 
Published: September 2022

Abstract

The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor–stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival.

Significance:
Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy.
This article is highlighted in the In This Issue feature, p. 2711
Uterine Lavage Identifies Cancer Mutations and IncreasedTP53Somatic Mutation Burden in Individuals with Ovarian Cancer
Authors: Ghezelayagh Talayeh S. , Kohrn Brendan F. , Fredrickson Jeanne , Manhardt Enna , Radke Marc R. , Katz Ronit , Gray Heidi J. , Urban Renata R. , Pennington Kathryn P. , Liao John B. , Doll Kemi M. , Simons Elise J. , Burzawa Jennifer K. , Goff Barbara A. , Speiser Paul , Swisher Elizabeth M. , Norquist Barbara M. , Risques Rosa Ana 
Published: September 2022

Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultradeep sequencing for the detection of disseminated ovarian cancer cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with ovarian cancer [6 non-serous and 14 high-grade serous-like (serous)]. Ultradeep duplex sequencing (∼3,000×) with a panel of common ovarian cancer genes identified the tumor mutation in 33% of non-serous (all early stage) and 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A, and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without ovarian cancer, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with ovarian cancer, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential ovarian cancer risk factor.Significance:Cancer driver mutations are found in uterine lavage DNA in all individuals, but driver TP53 mutations presented as significantly larger clones and with higher frequency in lavages from individuals with ovarian cancer. This suggests that TP53-specific clonal expansion plays a role in tumorigenesis and presents opportunities for early detection.
Effects of Electrode-Tissue Proximity on Cardiac Lesion Formation Using Pulsed Field Ablation
Authors: Howard Brian , Verma Atul , Tzou Wendy S. , Mattison Lars , Kos Bor , Miklavčič Damijan , Onal Birce , Stewart Mark T. , Sigg Daniel C. 
Published: September 2022

Background:
Pulsed field ablation (PFA) is a novel energy modality for treatment of cardiac arrhythmias. The impact of electrode-tissue proximity on lesion formation by PFA has not been conclusively assessed. The objective of this investigation was to evaluate the effects of electrode-tissue proximity on cardiac lesion formation with a biphasic, bipolar PFA system.

Methods:
PFA was delivered on the ventricular epicardial surface in an isolated porcine heart model (n=8) via a 4-electrode prototype catheter. An offset tool was designed to control the distance between electrodes and target tissue; deliveries were placed 0 mm (0 mm offset), 2 mm (2 mm offset), and 4 mm away from the tissue (4 mm offset). Lesions were assessed using tetrazolium chloride staining. Numerical models for the experimental setup with and without the offset tool validated and supported results.

Results:
Cardiac lesion dimensions decreased proportional to the distance between epicardial surface and electrodes. Lesion depth averaged 4.3±0.4 mm, 2.7±0.4 mm, and 1.3±0.4 mm for the 0, 2, and 4 mm and lesion width averaged 9.4±1.1 mm, 7.5±0.8 mm and 5.8±1.4 mm for the 0, 2, and 4 mm offset distances, respectively. Numerical modeling matched ex vivo results well and predicted lesion creation with and without the offset tool.

Conclusions:
Using a biphasic, bipolar PFA system resulted in cardiac lesions even in the 0 mm offset distance case. The relationship between lesion depth and offset distance was linear, and the deepest lesions were created with 0 mm offset distance, that is, with electrodes in contact with tissue. Therefore, close electrode-tissue proximity increases the likelihood of achieving transmural lesions by maximizing the electric field penetration into the target tissue.
Sustained Attention as Measured by Reaction Time Variability Is a Strong Modulator for the P600, but Not the N400
Authors: Contier Friederike , Weymar Mathias , Wartenburger Isabell , Rabovsky Milena 
Published: September 2022

Abstract
The functional significance of the two prominent language-related ERP components N400 and P600 is still under debate. It has recently been suggested that one important dimension along which the two vary is in terms of automaticity versus attentional control, with N400 amplitudes reflecting more automatic and P600 amplitudes reflecting more controlled aspects of sentence comprehension. The availability of executive resources necessary for controlled processes depends on sustained attention, which fluctuates over time. Here, we thus tested whether P600 and N400 amplitudes depend on the level of sustained attention. We reanalyzed EEG and behavioral data from a sentence processing task by Sassenhagen and Bornkessel-Schlesewsky [The P600 as a correlate of ventral attention network reorientation. Cortex, 66, A3–A20, 2015], which included sentences with morphosyntactic and semantic violations. Participants read sentences phrase by phrase and indicated whether a sentence contained any type of anomaly as soon as they had the relevant information. To quantify the varying degrees of sustained attention, we extracted a moving reaction time coefficient of variation over the entire course of the task. We found that the P600 amplitude was significantly larger during periods of low reaction time variability (high sustained attention) than in periods of high reaction time variability (low sustained attention). In contrast, the amplitude of the N400 was not affected by reaction time variability. These results thus suggest that the P600 component is sensitive to sustained attention whereas the N400 component is not, which provides independent evidence for accounts suggesting that P600 amplitudes reflect more controlled and N400 amplitudes reflect more automatic aspects of sentence comprehension.