bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-31 Displays Subtype Specificity in Lung Cancer
Authors: Davenport Mackenzie L. , Echols John B. , Silva Austin D. , Anderson Joshua C. , Owens Philip , Yates Clayton , Wei Qing , Harada Shuko , Hurst Douglas R. , Edmonds Mick D. 
Published: February 2021

Abstract

miRNA rarely possess pan-oncogenic or tumor-suppressive properties. Most miRNAs function under tissue-specific contexts, acting as either tumor suppressors in one tissue, promoting oncogenesis in another, or having no apparent role in the regulation of processes associated with the hallmarks of cancer. What has been less clear is the role of miRNAs within cell types of the same tissue and the ability within each cell type to contribute to oncogenesis. In this study, we characterize the role of one such tissue-specific miRNA, miR-31, recently identified as the most oncogenic miRNA in lung adenocarcinoma, across the histologic spectrum of human lung cancer. Compared with normal lung tissue, miR-31 was overexpressed in patient lung adenocarcinoma, squamous cell carcinoma, and large-cell neuroendocrine carcinoma, but not small-cell carcinoma or carcinoids. miR-31 promoted tumor growth in mice of xenografted human adenocarcinoma and squamous cell carcinoma cell lines, but not in large- or small-cell carcinoma lines. While miR-31 did not promote primary tumor growth of large- and small-cell carcinoma, it did promote spontaneous metastasis. Mechanistically, miR-31 altered distinct cellular signaling programs within each histologic subtype, resulting in distinct phenotypic differences. This is the first report distinguishing diverse functional roles for this miRNA across the spectrum of lung cancers and suggests that miR-31 has broad clinical value in human lung malignancy.

Significance:
These findings demonstrate the oncogenic properties of miR-31 in specific subtypes of lung cancer and highlight it as a potential therapeutic target in these subtypes.
“3G” Trial: An RNA Editing Signature to Guide Gastric Cancer Chemotherapy
Authors: An Omer , Song Yangyang , Ke Xinyu , So Jimmy Bok-Yan , Sundar Raghav , Yang Henry , Rha Sun Young , Lee Ming Hui , Tay Su Ting , Ong Xuewen , Tan Angie Lay Keng , Ng Matthew Chau Hsien , Tantoso Erwin , Chen Leilei , Tan Patrick , Yong Wei Peng 
Published: February 2021

AbstractGastric cancer cases are often diagnosed at an advanced stage with poor prognosis. Platinum-based chemotherapy has been internationally accepted as first-line therapy for inoperable or metastatic gastric cancer. To achieve greater benefits, selection of patients eligible for this treatment is critical. Although gene expression profiling has been widely used as a genomic classifier to identify molecular subtypes of gastric cancer and to stratify patients for different chemotherapy regimens, its prediction accuracy can be improved. Adenosine-to-inosine (A-to-I) RNA editing has emerged as a new player contributing to gastric cancer development and progression, offering potential clinical utility for diagnosis and treatment. Using a systematic computational approach followed by both in vitro validations and in silico validations in The Cancer Genome Atlas (TCGA), we conducted a transcriptome-wide RNA editing analysis of a cohort of 104 patients with advanced gastric cancer and identified an RNA editing (GCRE) signature to guide gastric cancer chemotherapy. RNA editing events stood as a prognostic and predictive biomarker in advanced gastric cancer. A GCRE score based on the GCRE signature consisted of 50 editing sites associated with 29 genes, predicting response to chemotherapy with a high accuracy (84%). Of note, patients demonstrating higher editing levels of this panel of sites presented a better overall response. Consistently, gastric cancer cell lines with higher editing levels showed higher chemosensitivity. Applying the GCRE score on TCGA dataset confirmed that responders had significantly higher levels of editing in advanced gastric cancer. Overall, this newly defined GCRE signature reliably stratifies patients with advanced gastric cancer and predicts response from chemotherapy.Significance:This study describes a novel A-to-I RNA editing signature as a prognostic and predictive biomarker in advanced gastric cancer, providing a new tool to improve patient stratification and response to therapy.
Acute Kidney Injury Instigates Malignant Renal Cell Carcinoma via CXCR2 in Mice with Inactivated Trp53 and Pten in Proximal Tubular Kidney Epithelial Cells
Authors: Zhou Xunian , Xiao Fei , Sugimoto Hikaru , Li Bingrui , McAndrews Kathleen M. , Kalluri Raghu 
Published: February 2021

Abstract

Renal cell carcinoma (RCC) is one of the most common urologic malignancies with the highest mortality rates worldwide. However, relevant mouse models that recapitulated the genetic alterations found in RCC have been lacking. In this study, we crossed Trp53 and Pten conditional knockout mice with Ggt1-Cre mice to generate a Ggt1-Cre; Trp53LoxP/LoxP; PtenLoxP/LoxP; YFPLoxP/LoxP (GPPY) mouse model, which resulted in the formation of dysplastic lesions involving kidney tubular epithelial cells (TEC), with only approximately 25% of mice developing RCC at an advanced age. Combining CRISPR/Cas9-mediated Vhl knockout in these mice increased the frequency of dysplasia, but failed to increase the incidence of RCC. Assessments of whether ischemic injury of TECs in the GPPY kidney without Vhl knockout influences the emergence of RCC revealed that advanced RCC predominantly emerged in the contralateral, noninjured kidney with 100% penetrance at a younger age, but rarely in the injured kidney due to severely damaged ischemic TEC. Injured TEC released CXCL1 into the microenvironment that traveled systemically to activate fibroblasts and recruit neutrophils to enable emergence of RCC in the contralateral kidney. Fibroblasts responded to CXCL1 via CXCR2 and recruited tumor-associated neutrophils, which in turn mediated tumor-promoting inflammation and angiogenesis. Treatment with anti-CXCR2 antibodies abolished the emergence of malignant RCC. Collectively, these results demonstrate a defining functional role of systemic inflammation and microenvironment in the emergence of malignant cancer from preestablished dysplastic precursor lesions.

Significance:
These results identify a role for CXCL1/CXCR2 and the tumor microenvironment in the development of RCC.
Treatment Outcomes and Clinical Characteristics of Patients with KRAS-G12C–Mutant Non–Small Cell Lung Cancer
Authors: Arbour Kathryn C. , Rizvi Hira , Plodkowski Andrew J. , Hellmann Matthew D. , Knezevic Andrea , Heller Glenn , Yu Helena A. , Ladanyi Marc , Kris Mark G. , Arcila Maria E. , Rudin Charles M. , Lito Piro , Riely Gregory J. 
Published: February 2021

Abstract

Purpose:
KRAS mutations are identified in approximately 30% of patients with non–small cell lung cancer (NSCLC). Novel direct inhibitors of KRAS G12C have shown activity in early-phase clinical trials. We hypothesized that patients with KRAS G12C mutations may have distinct clinical characteristics and responses to therapies.

Experimental Design:
Through routine next-generation sequencing, we identified patients with KRAS-mutant NSCLC treated at Memorial Sloan Kettering Cancer Center (New York, NY) from 2014 to 2018 and reviewed tumor characteristics, overall survival, and treatment outcomes.

Results:
We identified 1,194 patients with KRAS-mutant NSCLC, including 770 with recurrent or metastatic disease. KRAS G12C mutations were present in 46% and KRAS non-G12C mutations in 54%. Patients with KRAS G12C had a higher tumor mutation burden (median, 8.8 vs. 7 mut/Mb; P = 0.006) and higher median PD-L1 expression (5% vs. 1%). The comutation patterns of STK11 (28% vs. 29%) and KEAP1 (23% vs. 24%) were similar. The median overall survivals from diagnosis were similar for KRAS G12C (13.4 months) and KRAS non-G12C mutations (13.1 months; P = 0.96). In patients with PD-L1 ≥50%, there was not a significant difference in response rate with single-agent immune checkpoint inhibitor for patients with KRAS G12C mutations (40% vs. 58%; P = 0.07).

Conclusions:
We provide outcome data for a large series of patients with KRAS G12C–mutant NSCLC with available therapies, demonstrating that responses and duration of benefit with available therapies are similar to those seen in patients with KRAS non-G12C mutations. Strategies to incorporate new targeted therapies into the current treatment paradigm will need to consider outcomes specific to patients harboring KRAS G12C mutations.
Diffuse Glioma Heterogeneity and Its Therapeutic Implications
Authors: Nicholson James G. , Fine Howard A. 
Published: February 2021

Abstract

Diffuse gliomas represent a heterogeneous group of universally lethal brain tumors characterized by minimally effective genotype-targeted therapies. Recent advances have revealed that a remarkable level of genetic, epigenetic, and environmental heterogeneity exists within each individual glioma. Together, these interconnected layers of intratumoral heterogeneity result in extreme phenotypic heterogeneity at the cellular level, providing for multiple mechanisms of therapeutic resistance and forming a highly adaptable and resilient disease. In this review, we discuss how glioma intratumoral heterogeneity and malignant cellular state plasticity drive resistance to existing therapies and look to a future in which these challenges may be overcome.

Significance:
Glioma intratumoral heterogeneity and malignant cell state plasticity represent formidable hurdles to the development of novel targeted therapies. However, the convergence of genotypically diverse glioma cells into a limited set of epigenetically encoded transcriptional cell states may present an opportunity for a novel therapeutic strategy we call “State Selective Lethality.” In this approach, cellular states (as opposed to genetic perturbations/mutations) are the subject of therapeutic targeting, and plasticity-mediated resistance is minimized through the design of cell state “trapping agents.”
Metformin Is Associated With a Lower Risk of Atrial Fibrillation and Ventricular Arrhythmias Compared With Sulfonylureas
Authors: Ostropolets Anna , Elias Pierre A. , Reyes Michael V. , Wan Elain Y. , Pajvani Utpal B. , Hripcsak George , Morrow John P. 
Published: February 2021

Background:
Type 2 diabetes is one of the most common chronic disorders worldwide and is an important cause of cardiovascular disease. Studies investigating the risk of atrial and ventricular arrhythmias in diabetic patients taking different oral diabetes medications are sparse.

Methods:
We used IBM MarketScan Medicare Supplemental Database to examine the risk of arrhythmias for patients on different oral diabetes medications by propensity score matching.

Results:
We found that patients on metformin monotherapy had significantly reduced risk of atrial arrhythmias, including atrial fibrillation, compared with monotherapy with DPP4 (dipeptidyl peptidase 4 inhibitor) or thiazolidinedione medications. Patients on metformin monotherapy had significantly reduced risk of atrial arrhythmias, ventricular arrhythmias, and bradycardia compared with monotherapy with sulfonylureas. Combination therapy with sulfonylureas and metformin had an increased risk of atrial arrhythmias compared with some other combinations.

Conclusions:
Different oral diabetes medications have significantly different long-term risk of arrhythmia. Specifically, metformin is associated with reduced risk of atrial fibrillation and ventricular arrhythmias compared with sulfonylureas.
Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure
Authors: Nassif Michael E. , Qintar Mohammed , Windsor Sheryl L. , Jermyn Rita , Shavelle David M. , Tang Fengming , Lamba Sumant , Bhatt Kunjan , Brush John , Civitello Andrew , Gordon Robert , Jonsson Orvar , Lampert Brent , Pelzel Jamie , Kosiborod Mikhail N. 
Published: February 2021

Background:
Sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors) prevent heart failure (HF) hospitalizations in patients with type 2 diabetes and improve outcomes in those with HF and reduced ejection fraction, regardless of type 2 diabetes. Mechanisms of HF benefits remain unclear, and the effects of SGLT2 inhibitor on hemodynamics (filling pressures) are not known. The EMBRACE-HF trial (Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure) was designed to address this knowledge gap.

Methods:
EMBRACE-HF is an investigator-initiated, randomized, multicenter, double-blind, placebo-controlled trial. From July 2017 to November 2019, patients with HF (regardless of ejection fraction, with or without type 2 diabetes) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin 10 mg daily or placebo and treated for 12 weeks. The primary end point was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8–12). Secondary end points included health status (Kansas City Cardiomyopathy Questionnaire score), natriuretic peptides, and 6-min walking distance.

Results:

Overall, 93 patients were screened, and 65 were randomized (33 to empagliflozin, 32 to placebo). The mean age was 66 years; 63% were male; 52% had type 2 diabetes; 54% were in New York Heart Association class III/IV; mean ejection fraction was 44%; median NT-proBNP (N-terminal pro B-type natriuretic peptide) was 637 pg/mL; and mean PADP was 22 mm Hg. Empagliflozin significantly reduced PADP, with effects that began at week 1 and amplified over time; average PADP (weeks 8–12) was 1.5 mm Hg lower (95% CI, 0.2–2.8;
P
=0.02); and at week 12, PADP was 1.7 mm Hg lower (95% CI, 0.3–3.2;
P
=0.02) with empagliflozin versus placebo. Results were consistent for PA systolic and PA mean pressures. There was no difference in mean loop diuretic management (daily furosemide equivalents) between treatment groups. No significant differences between treatment groups were observed in Kansas City Cardiomyopathy Questionnaire scores, natriuretic peptide levels, and 6-min walking distance.

Conclusions:
In patients with HF and CardioMEMS PA pressure sensor, empagliflozin produced rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03030222.
The International Criminal Court and the Issue of Intersectionality—A Conceptual and Legal Framework for Analysis
Authors: Maučec Gregor 
Published: February 2021

Abstract
A survey of relevant case law of the International Criminal Court (icc or Court) reveals inconsistencies, as well as conceptual flaws and limitations in the Court’s mainly uni-sectional approach to mass atrocities that involve multiple and intersecting forms discrimination, in particular with regard to the cornerstones of such cases—the identification of the protected groups and their members. This has resulted in discrepancies and low levels of legal protection against intersectional targeting. Such a cautious, selective and inconsistent approach of the icc to this issue is unsurprising given that the application of intersectionality in practice is a radical and transformative project. Espousing a more consistent and intersectional approach of the icc in considering mass atrocities against different protected groups and their members, this article discusses the Court’s legal framework and major conceptual and statutory concerns surrounding the icc prosecutor’s and judges’ enhanced engagement—through more progressive law interpretation—with the phenomena of intersectionality and key concepts related to it. The main purpose of this contribution is thus two-fold: (1) to demonstrate and explain why, in practice, the focus on intersectional dimensions of such situations and cases in their selection, prosecution and adjudication does not interfere with strict adherence to the principle of legality underlying the Rome Statute, and (2) to analyse the legal grounds and avenues for the Court to implement intersectionality when dealing with atrocities involving intersectional discrimination. It is ultimately suggested that Article 21(3) of the Rome Statute offers a proper and solid legal basis for interpreting and applying pertinent international criminal law in light of intersectionality.
Studies on sexual compatibility and or incompatibility among Psidium species and their hybridity confirmation through ssr markers
Authors: Mulagund Jagadeesha , Dinesh M.R. , Vasugi C. , Rekha A. , Ravishankar K.V. 
Published: February 2021

Abstract
The present investigation was carried out with an aim to determine the cross compatibility between Psidium species (P. chinensis, P. guineense, P. cattleianum and P. molle) and commercial guava cultivars (Arka Kiran, Arka Rashmi, Arka Mridula and Allahabad Safed). The results revealed that, P. chinensis and P. guineense were found to be good cross compatible male parents whereas, Allahabad Safeda and Arka Kiran were found to be good cross compatible female parents. However, no fruit set and seed set were obtained when P. cattleianum and P. molle were used as male parent indicating the cross incompatibility of these species with commercial guava cultivars which is reconfirmed using florescence microscopy technique to understand the pollen-pistil interaction between incompatible P. cattleianum and P. molle species with P. guajava cv. Allahabad Safeda. Result indicated that low fluorescence intensity along with poor pollen germination and improper pollen-tube growth could be the reason for incompatibility. In order to break this incompatibility, a modified pollination technique called stigma maceration technique was followed wherein stigma of the male parent macerated with different chemicals viz., carbohydrate source (2% sucrose), growth regulators (50 ppm GA3 and iaa) and micronutrients (50 ppm of each Boric acid, MgSO4, CaNO3 and KNO3) and pollinated twice i.e., on the day of flower opening and the same time of next day resulted in cross compatibility of P. cattleianum and P. molle with commercial guava cultivars. Further hybridity confirmation of interspecific hybrids using ssr markers revealed that, 8 markers were found to be co-dominant and confirmed the hybridity of interspecific hybrid combinations.
The Obesity Paradox in Emergency General Surgery Patients
Authors: Maloney Sean R. , Reinke Caroline E. , Nimeri Abdelrahman A. , Ayuso Sullivan A. , Christmas A. Britton , Hetherington Timothy , Kowalkowski Marc , Sing Ronald F. , May Addison K. , Ross Samuel Wade 
Published: February 2021

Background Operative management of emergency general surgery (EGS) diagnoses involves a range of procedures which can carry high morbidity and mortality. Little is known about the impact of obesity on patient outcomes. The aim of this study was to examine the association between body mass index (BMI) >30 kg/m2 and mortality for EGS patients. We hypothesized that obese patients would have increased mortality rates. Methods A regional integrated health system EGS registry derived from The American Association for the Surgery of Trauma EGS ICD-9 codes was analyzed from January 2013 to October 2015. Patients were stratified into BMI categories based on WHO classifications. The primary outcome was 30-day mortality. Longer-term mortality with linkage to the Social Security Death Index was also examined. Univariate and multivariable analyses were performed. Results A total of 60 604 encounters were identified and 7183 (11.9%) underwent operative intervention. Patient characteristics include 53% women, mean age 58.2 ± 18.7 years, 64.2% >BMI 30 kg/m2, 30.2% with chronic obstructive pulmonary disease, 19% with congestive heart failure, and 31.1% with diabetes. The most common procedure was laparoscopic cholecystectomy (36.4%). Overall, 90-day mortality was 10.9%. In multivariable analysis, all classes of obesity were protective against mortality compared to normal BMI. Underweight patients had increased risk of inpatient (OR = 1.9, CI = 1.7-2.3), 30-day (OR = 1.9, CI = 1.7-2.1), 90-day (OR = 1.8, CI 1.6-2.0), 1-year (OR = 1.8, CI = 1.7-2.0), and 3-year mortality (OR = 1.7, CI = 1.6-1.9). Conclusions When stratified by BMI, underweight EGS patients have the highest odds of death. Paradoxically, obesity appears protective against death, even when controlling for potentially confounding factors. Increased rates of nonoperative management in the obese population may impact these findings.
Implementation of Electronic Clinical Decision Support Tools for Antibiotic Stewardship in Pediatric Appendicitis
Authors: Marulanda Kathleen , Willis Zachary , Wilson William , Koonce Robin D. , Lamm Amy , McLean Sean E. , Hayes-Jordan Andrea , Phillips Michael R. 
Published: February 2021

Background The efficacy of clinical decision support (CDS) tools to promote antibiotic stewardship in pediatric appendicitis remains poorly understood. Here, we developed an electronic order panel (OP) to assist with decreased utilization of extended spectrum antibiotics. Methods Retrospective review of patients (≤18 years) at a single institution from May 2018 to October 2019 treated with ≥1 dose of preferred (narrow) or nonpreferred (broad-spectrum) antibiotics was performed, and they were categorized as pre- (PIC) or postimplementation cohorts (PISC). Results Of 234 encounters, 170 (73%) and 107 (46%) received preferred and nonpreferred antibiotics, respectively. Postimplementation cohort encounters had a sustained 50% increase in preferred antibiotic use compared to PIC (92% vs 42%, P = .014). Order panel utilization accounted for 31% of overall encounters and 44% of PISC encounters. Conclusion Despite sustained improvement in antibiotic stewardship, OP utilization remains low. The use of CDS tools may not be a good process measure for quality improvement.
Double Effect Donation
Authors: Camosy Charles C. , Vukov Joseph 
Published: February 2021

Double Effect Donation claims it is permissible for a person meeting brain death criteria to donate vital organs, even though such a person may be alive. The reason this act is permissible is that it does not aim at one’s own death but rather at saving the lives of others and because saving the lives of others constitutes a proportionately serious reason for engaging in a behavior in which one foresees one’s death as the outcome. Double Effect Donation, we argue, opens a novel position in debates surrounding brain death and organ donation and does so without compromising the sacredness and fundamental equality of human life. Summary: Recent cases and discussion have raised questions about whether brain death criteria successfully capture natural death. These questions are especially troubling since vital organs are often retrieved from individuals declared dead by brain death criteria. We therefore seem to be left with a choice: either salvage brain death criteria or else abandon current organ donation practices. In this article, we present a different way forward. In particular, we defend a view we call Double Effect Donation, according to which it is permissible for a person meeting brain death criteria to donate vital organs, even though such a person may be alive. Double Effect Donation, we argue, is not merely compatible with but grows out of a view that acknowledges the sacredness and fundamental equality of human life.