bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cache Abstraction for Data Race Detection in Heterogeneous Systems with Non-coherent Accelerators
Authors: Young May , Hu Alan J. , Lemieux Guy G. F. 
Published: May 2022

Embedded systems are becoming increasingly complex and heterogeneous, featuring multiple processor cores (which might themselves be heterogeneous) as well as specialized hardware accelerators, all accessing shared memory. Many accelerators are non-coherent (i.e., do not support hardware cache coherence) because it reduces hardware complexity, cost, and power consumption, while potentially offering superior performance. However, the disadvantage of non-coherence is that the software must explicitly synchronize between accelerators and processors, and this synchronization is notoriously error-prone.
We propose an analysis technique to find data races in software for heterogeneous systems that include non-coherent accelerators. Our approach builds on classical results for data race detection, but the challenge turns out to be analyzing cache behavior rather than the behavior of the non-coherent accelerators. Accordingly, our central contribution is a novel, sound (data-race-preserving) abstraction of cache behavior. We prove our abstraction sound, and then to demonstrate the precision of our abstraction, we implement it in a simple dynamic race detector for a system with a processor and a massively parallel accelerator provided by a commercial FPGA-based accelerator vendor. On eleven software examples provided by the vendor, the tool had zero false positives and was able to detect previously unknown data races in two of the 11 examples.
Bimodal Gene Expression in Patients with Cancer Provides Interpretable Biomarkers for Drug Sensitivity
Authors: Ba-Alawi Wail , Nair Sisira Kadambat , Li Bo , Mammoliti Anthony , Smirnov Petr , Mer Arvind Singh , Penn Linda Z. , Haibe-Kains Benjamin 
Published: May 2022

Abstract

Identifying biomarkers predictive of cancer cell response to drug treatment constitutes one of the main challenges in precision oncology. Recent large-scale cancer pharmacogenomic studies have opened new avenues of research to develop predictive biomarkers by profiling thousands of human cancer cell lines at the molecular level and screening them with hundreds of approved drugs and experimental chemical compounds. Many studies have leveraged these data to build predictive models of response using various statistical and machine learning methods. However, a common pitfall to these methods is the lack of interpretability as to how they make predictions, hindering the clinical translation of these models. To alleviate this issue, we used the recent logic modeling approach to develop a new machine learning pipeline that explores the space of bimodally expressed genes in multiple large in vitro pharmacogenomic studies and builds multivariate, nonlinear, yet interpretable logic-based models predictive of drug response. The performance of this approach was showcased in a compendium of the three largest in vitro pharmacogenomic datasets to build robust and interpretable models for 101 drugs that span 17 drug classes with high validation rates in independent datasets. These results along with in vivo and clinical validation support a better translation of gene expression biomarkers between model systems using bimodal gene expression.

Significance:
A new machine learning pipeline exploits the bimodality of gene expression to provide a reliable set of candidate predictive biomarkers with a high potential for clinical translatability.
TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling
Authors: Zhang Xinchao , Li Shuyan , He Jing , Jin Yunjie , Zhang Ruonan , Dong Wenjing , Lin Mingen , Yang Yajing , Tian Tongguan , Zhou Yuefan , Xu Yixin , Lei Qun-Ying , Zhang Jing , Zhang Qing , Xu Yanping , Lv Lei 
Published: May 2022

Abstract

Inactivating mutations of von Hippel–Lindau (VHL) are highly prevalent in clear cell renal cell carcinoma (ccRCC). Improved understanding of the vulnerabilities of VHL-deficient ccRCC could lead to improved treatment strategies. The activity of DNA dioxygenase ten-eleven translocation (TET)2 is significantly reduced in multiple cancers by different mechanisms, but its role in ccRCC progression remains unclear. Here, we report that increased expression of TET2, but not TET1 and TET3, is negatively associated with tumor metastasis and advanced tumor stage and is positively associated with good prognosis uniquely in ccRCC among all 33 types of cancer in The Cancer Genome Atlas datasets. TET2 restrained glycolysis and pentose phosphate pathway metabolism in a VHL deficiency–dependent manner, thereby suppressing ccRCC progression. Notably, TET2 and VHL mutations tended to cooccur in ccRCC, providing genetic evidence that they cooperate to inhibit the progression of ccRCC. Mechanistically, TET2 was recruited by transcription factor HNF4α to activate FBP1 expression, which antagonized the function of hypoxia-inducible factor-1/2α (HIF1/2α) in metabolic reprogramming to impede ccRCC growth. Stimulating the TET2-FBP1 axis with vitamin C repressed the growth of VHL-deficient ccRCC with wild-type TET2 and increased the sensitivity to glycolysis inhibitors. Moreover, combined expression levels of the HNF4α–TET2-FBP1 axis served as a biomarker of prognosis in patients with ccRCC. This study reveals a unique function of TET2 in the suppression of tumor metabolism and HIF signaling, and it also provides therapeutic targets, potential drugs, and prognostic markers for the management of ccRCC.

Significance:
The identification of TET2-mediated inhibition of HIF signaling and tumor metabolic reprogramming provides insights for new therapeutic strategies for VHL-deficient ccRCC.
An Autologous Dendritic Cell Vaccine Promotes Anticancer Immunity in Patients with Ovarian Cancer with Low Mutational Burden and Cold Tumors
Authors: Fucikova Jitka , Hensler Michal , Kasikova Lenka , Lanickova Tereza , Pasulka Josef , Rakova Jana , Drozenova Jana , Fredriksen Tessa , Hraska Marek , Hrnciarova Tereza , Sochorova Klara , Rozkova Daniela , Sojka Ludek , Dundr Pavel , Laco Jan , Brtnicky Tomas , Praznovec Ivan , Halaska Michael J. , Rob Lukas , Ryska Ales , Coosemans An , Vergote Ignace , Cibula David , Bartunkova Jirina , Galon Jérôme , Galluzzi Lorenzo , Spisek Radek 
Published: May 2022

Abstract

Purpose:
The successful implementation of immune checkpoint inhibitors (ICI) in the clinical management of various solid tumors has raised considerable expectations for patients with epithelial ovarian carcinoma (EOC). However, EOC is poorly responsive to ICIs due to immunologic features including limited tumor mutational burden (TMB) and poor lymphocytic infiltration. An autologous dendritic cell (DC)-based vaccine (DCVAC) has recently been shown to be safe and to significantly improve progression-free survival (PFS) in a randomized phase II clinical trial enrolling patients with EOC (SOV01, NCT02107937).

Patients and Methods:
We harnessed sequencing, flow cytometry, multispectral immunofluorescence microscopy, and IHC to analyze (pretreatment) tumor and (pretreatment and posttreatment) peripheral blood samples from 82 patients enrolled in SOV01, with the aim of identifying immunologic biomarkers that would improve the clinical management of patients with EOC treated with DCVAC.

Results:
Although higher-than-median TMB and abundant CD8+ T-cell infiltration were associated with superior clinical benefits in patients with EOC receiving standard-of-care chemotherapy, the same did not hold true in women receiving DCVAC. Conversely, superior clinical responses to DCVAC were observed in patients with lower-than-median TMB and scarce CD8+ T-cell infiltration. Such responses were accompanied by signs of improved effector functions and tumor-specific cytotoxicity in the peripheral blood.

Conclusions:
Our findings suggest that while patients with highly infiltrated, “hot” EOCs benefit from chemotherapy, women with “cold” EOCs may instead require DC-based vaccination to jumpstart clinically relevant anticancer immune responses.
Overcoming Resistance to Anti–Nectin-4 Antibody-Drug Conjugate
Authors: Cabaud Olivier , Berger Ludovic , Crompot Emerence , Adélaide José , Finetti Pascal , Garnier Sèverine , Guille Arnaud , Carbuccia Nadine , Farina Anne , Agavnian Emilie , Chaffanet Max , Gonçalves Anthony , Charafe-Jauffret Emmanuelle , Mamessier Emilie , Birnbaum Daniel , Bertucci François , Lopez Marc 
Published: May 2022

Abstract
Antibody–drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4 as a new therapeutic target in breast cancer and produced an efficient EV-like ADC comprising a human anti–nectin-4 mAb conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical breast cancer model in mice, and report a mechanism of resistance to N41mab-vcMMAE after 9-month treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacologic inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. In contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance.
Synthetic Essentiality of Tryptophan 2,3-Dioxygenase 2 in APC-Mutated Colorectal Cancer
Authors: Lee Rumi , Li Jiexi , Li Jun , Wu Chang-Jiun , Jiang Shan , Hsu Wen-Hao , Chakravarti Deepavali , Chen Peiwen , LaBella Kyle A. , Li Jing , Spring Denise J. , Zhao Di , Wang Y. Alan , DePinho Ronald A. 
Published: May 2022

Abstract

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin–mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn–AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit macrophages into the tumor microenvironment. Therapeutically, APC-deficient colorectal cancer models were susceptible to TDO2 depletion or pharmacologic inhibition, which impaired cancer cell proliferation and enhanced antitumor immune profiles. Thus, APC deficiency activates a TCF4–TDO2–AhR–CXCL5 circuit that affects multiple cancer hallmarks via autonomous and nonautonomous mechanisms and illuminates a genotype-specific vulnerability in colorectal cancer.

Significance:
This study identifies critical effectors in the maintenance of APC-deficient colorectal cancer and demonstrates the relationship between APC/WNT pathway and kynurenine pathway signaling. It further determines the tumor-associated macrophage biology in APC-deficient colorectal cancer, informing genotype-specific therapeutic targets and the use of TDO2 inhibitors.
This article is highlighted in the In This Issue feature, p. 1599
The Arbitrating Effects of Leadership, Equity, and Integrity on Employee’s Organizational Commitment – A study of Hotels in Jharkhand
Authors: Sharma Viveka Nand , Hans Arvind 
Published: May 2022

Research Aims: Improve organizational commitment through leadership, organizational equity, and Integrity. Design/methodology/approach: A survey method with path analysis techniques to test the direct effect and use Sobel test to test the Arbitrating effect of variable variables: Leadership (X1), Equity (X2), and Integrity (X3), on the Organizational Commitment (Y) at Hotels in India. Data were collected using a questionnaire. The number of samples for the study was 123 respondents drawn from a population of 153 people. Research Findings: Leadership, organizational equity, and Integrity have a positive and significant effect on organizational commitment. That the variable that most affects organizational commitment is the Integrity variable. Whereas for testing the Arbitrating effect, the results obtained are Arbitrating effects of leadership on organizational commitment through Integrity, there is an Arbitrating effect of leadership on organizational commitment through equity, and there is an Arbitrating effect of organizational equity on organizational commitment through Integrity, with the number of Arbitrating effects. It was found that the Arbitrating effects of leadership through equity showed greater results than through Integrity. Theoretical Contribution/Originality: The effect of leadership, equity, and Integrity to increase organizational commitment. Managerial Implication in the South East Asian context: A great organizational commitment from human resources in a hotel, management of hotel could improve the business and adapt in response to situation changes.
Research limitation & implications: management of hotels should find a strategic point how to improve organizational commitment of their employees to their company.
Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression
Authors: Zhang Xinbo , Rotllan Noemi , Canfrán-Duque Alberto , Sun Jonathan , Toczek Jakub , Moshnikova Anna , Malik Shipra , Price Nathan L. , Araldi Elisa , Zhong Wen , Sadeghi Mehran M. , Andreev Oleg A. , Bahal Raman , Reshetnyak Yana K. , Suárez Yajaira , Fernández-Hernando Carlos 
Published: May 2022

Background:
miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis.

Methods:
We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics.

Results:

The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes (
Col2a1, Col3a1, Col1a2, Fn1
, etc) and tissue inhibitor of metalloproteinase 3 (
Timp3
) and downregulation of
Mmp12
in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33.

Conclusions:
This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
A Review of Quality Improvement Process Measures for Colorectal Surgery in the United States Using the American College of Surgeons National Surgical Quality Improvement Program Database - Have We Made Progress?
Authors: McAtee Erin E. , Talukder Asif M. , Davenport Daniel L. , Bhakta Avinash S. , Patel Jitesh A. 
Published: May 2022

Numerous guidelines have been published regarding Enhanced Recovery Programs (ERP) following colorectal surgery over the past decade. Participation in these guidelines at a national level is unclear. We hypothesize that the adaptation of ERP for patients undergoing elective colorectal surgery is limited but the use of quality improvement measures has increased and while outcomes have improved over the past several years. A total of 86 402 patients were evaluated undergoing elective colectomy between 2013-2018 using the ACS-NSQIP database. Over a 5-year period, there was a significant increase in the use of quality improvement process measures: mechanical and oral bowel preparation and minimally invasive approach. During this time, there was a significant decrease in overall perioperative morbidities (P <.001). These encouraging results from a large national database suggest that evidence-based, quality improvement guidelines are being embraced and that overall outcomes for patients undergoing elective colectomy are improving.
Evaluation of the optimal duration for retrograde intrarenal stone surgery to prevent postoperative complications
Authors: Yitgin Yasin , Altınkaya Nurullah , Turaliev Nurmanbet , Guven Selcuk , Ergul Rifat Burak , Boyuk Abubekir , Verep Samed , Tefik Tzevat , Karagoz Mehmet Ali , Ibis Muhammed Arif , Gokce Mehmet Ilker , Sarıca Kemal 
Published: May 2022

Objective To evaluate retrograde intrarenal surgery (RIRS) outcomes and to determine the effect of operative time on complications of RIRS. Methods Patients undergoing RIRS for renal stones were evaluated. These patients were divided into two groups according to the operation time (Group 1<60 minutes and Group 2>60 minutes). Peroperative outcomes such as fluoroscopy time, stone-free rates, complications and duration of hospitalization were compared. Results Group 1 consisted of 264 patients and Group 2 consisted of 297 patients. SFR rates, duration of hospitalization, and postoperative urinary tract infection rates were similar in both groups. Fluoroscopy time was 7.8±7.3 (0-49) sec in group 1 and 13.1±9.8 (0-81) sec in group 2. Complications according to modified Clavien–Dindo classification system (MCDCS) were 13 and 32 patients (Grade 1), 31 and 63 patients (Grade 2), 1 and 1 patient (Grade 3) in group 1 and 2, respectively. There was statistical difference between the two groups in terms of duration of fluoroscopy time and the MCDCS. Although duration of hospitalization and UTI rates were higher in group 2, no statistical significance was observed among groups. Conclusion Limiting the operation time to 60 minutes in RIRS seems to be important in reducing postoperative complications.
José Carlos Mariátegui and Twenty-first-Century Socialism: Recovery and Renewal
Authors: Munck Ronaldo 
Published: May 2022

As Latin America entered the turn to the left, there was a recovery and renewal of the work of José Carlos Mariátegui. The “practical socialism” that he advocated and led in the course of a short but brilliant political career (basically, the 1920s) has much to teach us today if set in its proper historical context and not reduced to catchphrases. Mariátegui was, arguably, the first Marxist in Latin America, and his open, imaginative, transgressive, and energizing writings may well illuminate our paths in the 2020s. His was not a Marxist catechism but a living Marxism. What we can take from Mariátegui is a grounded Marxism—devoid of all theoreticisms—that, understood in its historical context, may point toward a period of renewal after the seeming collapse of the left project to build a twenty-first-century socialism. A medida que América Latina dio un giro izquierdista se produjo una recuperación y renovación de la obra de José Carlos Mariátegui. El “socialismo práctico” que él defendió y dirigió durante su corta pero brillante carrera política (básicamente, la década de 1920) tiene mucho que enseñarnos hoy si se mira en su contexto histórico adecuado y no se reduce a frases hechas. Mariátegui fue, posiblemente, el primer marxista latinoamericano y sus escritos abiertos, imaginativos, transgresores y llenos de energía bien pueden iluminar nuestro camino en la década de 2020. El suyo no era un catecismo marxista sino un marxismo vivo. Lo que podemos tomar de Mariátegui es un marxismo fundamentado, desprovisto de todo teoricismo que, entendido en su contexto histórico, puede apuntar hacia un período de renovación después del aparente colapso del proyecto de izquierda para construir un socialismo del siglo XXI.
Pulsatile versus non-pulsatile perfusion in coronary artery bypass operation: The comparison of laboratory and clinical outcomes
Authors: Shahandashti Farshad Jalili , Asadian Sanaz , Habibi Neda , Gorjipour Farhad , Jalali Amirhossein , Toloueitabar Yaser 
Published: May 2022

Introduction The superiority of pulsatile or non-pulsatile perfusion in cardiopulmonary bypass (CPB) regarding morbidity and mortality is still debated. Therefore, we aimed to investigate the effect of different pulse rates in pulsatile perfusion in patients undergoing coronary artery bypass graft (CABG) and compared it with non-pulsatile perfusion. Materials and Methods In this randomized clinical trial, 90 patients who were all candidates for CABG under CPB were enrolled. Patients in groups A and B received pulsatile perfusion with 30 and 70 pulses per minute, and group C received non-pulsatile perfusion. The biochemical and clinical parameters in the ICU were evaluated in the study groups. Results There was no statistically significant difference between patients' clinical outcomes and kidney and liver function markers (all Ps> 0.05). Mean serum lactate level increased but did not show a statistically significant difference between the study groups ( p = 0.8). The mean urine volume at 12 and 24 h after surgery was higher in group A, but there was no statistically significant difference between the three groups during the study period ( p = 0.3). No significant difference was found in the length of the ICU stay between the study groups ( p = 0.2). Conclusion Our studied parameters demonstrated no significant difference between pulsatile and non-pulsatile and between 30 and 70 pulse rate pulsatile perfusion methods. Our findings support that pulsatile perfusion with different pulse rates has no advantages over non-pulsatile perfusion in selected CABG cases.