bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
Authors: Ahmed Kazi Mokim , Veeramachaneni Ratna , Deng Defeng , Putluri Nagireddy , Putluri Vasanta , Cardenas Maria F , Wheeler David A , Decker William K , Frederick Andy I , Kazi Sawad , Sikora Andrew G , Sandulache Vlad C , Frederick Mitchell J 
Published: August 2022

BackgroundThe existence of immunologically ‘cold tumors’ frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden.MethodsUsing a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer.ResultsElevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism—a well-established inflammatory pathway—and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice.ConclusionGPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.
Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small-cell lung cancer
Authors: Moutafi Myrto K , Molero Magdalena , Martinez Morilla Sandra , Baena Javier , Vathiotis Ioannis A , Gavrielatou Niki , Castro-Labrador Laura , de Garibay Gorka Ruiz , Adradas Vera , Orive Daniel , Valencia Karmele , Calvo Alfonso , Montuenga Luis M , Ponce Aix S , Schalper Kurt A , Herbst Roy S , Paz-Ares Luis , Rimm David L , Zugazagoitia Jon 
Published: August 2022

BackgroundMost patients with advanced non-small-cell lung cancer (NSCLC) fail to derive significant benefit from programmed cell death protein-1 (PD-1) axis blockade, and new biomarkers of response are needed. In this study, we aimed to discover and validate spatially resolved protein markers associated with sensitivity to PD-1 axis inhibition in NSCLC.MethodsWe initially assessed a discovery cohort of 56 patients with NSCLC treated with PD-1 axis inhibitors at Yale Cancer Center. Using the GeoMx Digital Spatial Profiling (DSP) system, 71 proteins were measured in spatial context on each spot in a tissue microarray. We used the AQUA method of quantitative immunofluorescence (QIF) to orthogonally validate candidate biomarkers. For external independent validation, we assessed whole tissue sections derived from 128 patients with NSCLC treated with single-agent PD-1 axis inhibitors at the 12 de Octubre Hospital (Madrid) using DSP. We further analyzed two immunotherapy untreated cohorts to address prognostic significance (n=252 from Yale Cancer Center; n=124 from University Clinic of Navarra) using QIF and DSP, respectively.ResultsUsing continuous log-scaled data, we identified CD44 expression in the tumor compartment (pan-cytokeratin (CK)+) as a novel predictor of prolonged progression-free survival (PFS) (multivariate HR=0.68, p=0.043) in the discovery set. We validated by QIF that tumor CD44 levels assessed as continuous QIF scores were associated with longer PFS (multivariate HR=0.31, p=0.022) and overall survival (multivariate HR=0.29, p=0.038). Using DSP in an independent immunotherapy treated cohort, we validated that CD44 levels in the tumor compartment, but not in the immune compartment (panCK–/CD45+), were associated with clinical benefit (OR=1.22, p=0.018) and extended PFS under PD-1 axis inhibition using the highest tertile cutpoint (multivariate HR=0.62, p=0.03). The effect of tumor cell CD44 in predicting PFS remained significant after correcting for programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) in both cohorts. High tumor cell CD44 was not prognostic in the absence of immunotherapy. Using DSP data, intratumoral regions with elevated tumor cell CD44 expression showed prominent (fold change>1.5, adjusted p<0.05) upregulation of PD-L1, TIM-3, ICOS, and CD40 in two independent cohorts.ConclusionsThis work highlights CD44 as a novel indicative biomarker of sensitivity to PD-1 axis blockade that might help to improve immunotherapy strategies for NSCLC.
Visceral adiposity and systemic inflammation in the obesity paradox in patients with unresectable or metastatic melanoma undergoing immune checkpoint inhibitor therapy: a retrospective cohort study
Authors: Lee Ji Hyun , Hyung Sujin , Lee Jeeyun , Choi Sang-Hee 
Published: August 2022

BackgroundThe obesity paradox is a topic of increasing interest in oncology and epidemiology research. Although this phenomenon has been observed in melanoma patients receiving immune checkpoint inhibitors, little is known about its mechanism. We aim to investigate the prognostic value of obesity and its association with adiposity and systemic inflammation.MethodsThis retrospective study evaluates the data of patients who received pembrolizumab or nivolumab for unresectable or metastatic melanoma between June 2015 and April 2021. The skeletal muscle index (SMI) and visceral fat index (VFI) (cm2/m2) were calculated by dividing the cross-sectional areas of skeletal muscle and visceral fat by height squared. The systemic immune-inflammation index (SII) was defined as the total peripheral platelet count×neutrophil/lymphocyte ratio. Cox proportional hazard regression analysis was conducted to determine the association with overall survival.ResultsWe analyzed 266 patients with a median age of 60 years (IQR 51–69 years; 135 men and 131 women). The protective effect of obesity was independent of covariates (HR 0.60; 95% CI 0.37 to 0.99; p=0.048), but disappeared after adjusting for VFI (HR 0.76; 95% CI 0.41 to 1.40; p=0.380) or SII (HR 0.71; 95% CI 0.42 to 1.18; p=0.186). An increase of 10 cm2/m2in VFI was associated with longer overall survival after adjusting for covariates (HR 0.88; 95% CI 0.79 to 0.99; p=0.029). The prognostic value of VFI remained and predicted favorable overall survival after additional adjustment for SMI (HR 0.86; 95% CI 0.76 to 0.98; p=0.025), but disappeared with adjustment for SII (HR 0.92; 95% CI 0.82 to 1.03; p=0.142). An increase of 100×109/L in SII was associated with poor overall survival when adjusted for covariates (HR 1.08; 95% CI 1.05 to 1.11; p<0.001) or when additionally adjusted for VFI (HR 1.07; 95% CI 1.04 to 1.10; p<0.001).ConclusionsVisceral adiposity and systemic inflammation are significant prognostic factors in patients with unresectable or metastatic melanoma receiving immune checkpoint inhibitors. The prognostic impact of visceral adiposity is dependent on systemic inflammation status.
Rubber band ligation versus coagulation for the treatment of haemorrhoids: a meta-analysis of randomised controlled trials
Authors: Ding Zhihao , Xuan Ji , Tang Guoxing , Shi Shaopei , Liang Xuejun , An Qin , Wang Fangyu 
Published: August 2022

Abstract
Non-surgical therapies have the advantage of lower postoperative pain and complication rates compared with surgical therapies. Rubber band ligation and coagulation are two kinds of non-surgical therapies. The aim of this study is to compare the clinical outcomes of rubber band ligation and coagulation. A systematic review was conducted to identify randomised clinical trials that compare rubber band ligation and coagulation treatments for haemorrhoids. PubMed and Web of Science were searched, from inception to April 30th,2022. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Fifty-nine studies were identified. Nine trials met the inclusion criteria. All trials were of moderate methodological quality. No significant difference was found between rubber band ligation and coagulation in terms of efficacy rate, postoperative prolapse rate, recurrence rate and postoperative urine retention rate after treatment. Patients undergoing rubber band ligation had higher postoperative pain rate and lower postoperative bleeding rate than patients undergoing coagulation. The subgroup analysis showed that there was no significant difference between rubber band ligation and infrared coagulation or non-infrared coagulation in terms of efficacy rate, postoperative bleeding and postoperative urine retention rate after treatment. Patients undergoing rubber band ligation had a higher postoperative pain rate than patients undergoing infrared coagulation or non-infrared coagulation. We believe that coagulation for haemorrhoids still has a good future. PROSPERO registration number CRD42022311281.
Impact de la régie sur la productivité et la valeur nutritive de prairies d'alpiste roseau dans le littoral du lac Saint-Pierre
Authors: Seguin Philippe , Smedbol Élise , Gravel Valérie 
Published: August 2022

L'alpiste roseau ( Phalaris arundinacea L.) est une espèce adaptée au littoral du lac Saint-Pierre. Elle peut être utilisée comme source de fourrage et sa biomasse résiduelle en fin de saison peut être utilisée par les poissons pour y déposer leurs œufs lors de la crue printanière. Une régie plus intensive favorise la production fourragère (6974 kg MS/ha), tandis qu'une régie moins intensive produit des rendements en fourrages moindres (2600 kg MS/ha) mais maximise la biomasse résiduelle à l'automne (6271 kg MS/ha). La régie à favoriser dans le littoral devra tenir compte des besoins agricoles et des besoins fauniques.
Establishment and Evaluation of Dual HDAC/BET Inhibitors as Therapeutic Options for Germ Cell Tumors and Other Urological Malignancies
Authors: Burmeister Aaron , Stephan Alexa , Alves Avelar Leandro A. , Müller Melanie R. , Seiwert Andrea , Höfmann Stefan , Fischer Fabian , Torres-Gomez Hector , Hoffmann Michèle J. , Niegisch Guenter , Bremmer Felix , Petzsch Patrick , Köhrer Karl , Albers Peter , Kurz Thomas , Skowron Margaretha A. , Nettersheim Daniel 
Published: August 2022

Abstract
Urological malignancies represent major challenges for clinicians, with annually rising incidences. In addition, cisplatin treatment induced long-term toxicities and the development of therapy resistance emphasize the need for novel therapeutics. In this study, we analyzed the effects of novel histone deacetylase (HDAC) and bromodomain and extraterminal domain-containing (BET) inhibitors to combine them into a potent HDAC-BET-fusion molecule and to understand their molecular mode-of-action. Treatment of (cisplatin-resistant) germ cell tumors (GCT), urothelial, renal, and prostate carcinoma cells with the HDAC, BET, and dual inhibitors decreased cell viability, induced apoptosis, and affected the cell cycle. Furthermore, a dual inhibitor considerably decreased tumor burden in GCT xenograft models. On a molecular level, correlating RNA- to ATAC-sequencing data indicated a considerable induction of gene expression, accompanied by site-specific changes of chromatin accessibility after HDAC inhibitor application. Upregulated genes could be linked to intra- and extra-cellular trafficking, cellular organization, and neuronal processes, including neuroendocrine differentiation. Regarding chromatin accessibility on a global level, an equal distribution of active or repressed DNA accessibility has been detected after HDAC inhibitor treatment, questioning the current understanding of HDAC inhibitor function. In summary, our HDAC, BET, and dual inhibitors represent a new treatment alternative for urological malignancies. Furthermore, we shed light on new molecular and epigenetic mechanisms of the tested epi-drugs, allowing for a better understanding of the underlying modes-of-action and risk assessment for the patient.
Use of Percutaneous Atrioseptotosmy for Left Heart Decompression During Veno‐Arterial Extracorporeal Membrane Oxygenation Support: An Observational Study
Authors: Delmas Clément , Vallee Luigi , Bouisset Frédéric , Porterie Jean , Biendel Caroline , Lairez Olivier , Crognier Laure , Marcheix Bertrand , Conil Jean‐Marie , Maury Philippe , Minville Vincent 
Published: August 2022

Background
Left ventricular overload is frequent under veno‐arterial extracorporeal membrane oxygenation, which is associated with a worsening of the prognosis of these patients. Several left heart decompression (LHD) techniques exist. However, there is no consensus on their timing and type. We aimed to describe characteristics and outcomes of patients undergoing LHD and to compare percutaneous atrioseptostomy (PA) to other LHD techniques.

Methods and Results

Retrospective analysis was conducted of consecutive and prospectively collected patients supported by veno‐arterial extracorporeal membrane oxygenation for refractory cardiac arrest or cardiogenic shock between January 2015 and April 2018, with a 90‐day follow‐up in our tertiary center. Patients were divided according to the presence of LHD, and then according to its type (PA versus others). Thirty‐nine percent (n=63) of our patients (n=163) required an LHD. Patients with LHD had lower left ventricular ejection fraction, more ischemic cardiomyopathy, and no drug intoxication‐associated cardiogenic shock. PA was frequently used for LHD (41% of first‐line and 57% of second‐line LHD). PA appears safe and fast to realize (6.3 [interquartile range, 5.8–10] minutes) under fluoroscopic and echocardiographic guidance, with no acute complications. PA was associated with fewer neurological complications (12% versus 38%,
P
=0.02), no need to insert a second LHD (0% versus 19%,
P
=0.04), and higher 90‐day survival compared with other techniques (42% versus 19%, log‐rank test
P
=0.02), despite more sepsis (96% versus 73%,
P
=0.02) and blood transfusions (13.5% versus 7%,
P
=0.01). Multivariate analysis confirms the association between PA and 90‐day survival (hazard ratio, 2.53 [1.18–5.45],
P
=0.019).

Conclusions
LHD was frequently used for patients supported with veno‐arterial extracorporeal membrane oxygenation, especially in cases of ischemic cardiomyopathy and low left ventricular ejection fraction. PA seems to be a safe and efficient LHD technique associated with greater mid‐term survival justifying the pursuit of research on this topic.
Association of Systemic Vascular Resistance Analog and Cardiovascular Outcomes: The Heart and Soul Study
Authors: Lu Dai‐Yin , Fang Qizhi , Bibby Dwight , Arora Bhaskar , Schiller Nelson B. 
Published: August 2022

Background
Systemic vascular resistance (SVR) is an integral component of the hemodynamic profile. Previous studies have demonstrated a close correlation between an estimated SVR analog (eSVR) based on echocardiographic methods and SVR by direct hemodynamic measurement. However, the prognostic impact of eSVR remains unestablished.

Methods and Results

Study participants with established coronary artery disease from the Heart and Soul Study formed this study cohort. We defined Doppler‐derived eSVR as the ratio of systolic blood pressure to left ventricular outflow tract velocity time integral. Study participants were separated based on baseline eSVR tertile: <5.6, 5.6 to <6.9, and ≧6.9. An elevated eSVR was defined as an eSVR in the third tertile (≧6.9). Follow‐up eSVR was calculated at the fifth year of checkup. Cardiovascular outcomes included heart failure, major cardiovascular events, and all‐cause death. Among the 984 participants (67±11 years old, 82% men), subjects with the highest baseline eSVR tertile were the oldest, with the highest systolic blood pressure and lowest left ventricular outflow tract velocity time integral. A higher eSVR was associated with increased risk of heart failure, major cardiovascular events, and death. The hazard ratio for major cardiovascular events was 1.38 (95% CI, 1.02–1.86,
P
=0.03) for subjects with the highest eSVR tertile compared with the lowest. In addition, those with a persistently elevated eSVR during follow‐up had the most adverse outcomes.

Conclusions
An elevated eSVR, derived by the ratio of systolic blood pressure and left ventricular outflow tract velocity time integral, was more closely correlated with cardiovascular events than systolic blood pressure alone. Repeatedly elevated eSVR was associated with more adverse outcomes.
Gut Microbiota and Coronary Plaque Characteristics
Authors: Nakajima Akihiro , Mitomo Satoru , Yuki Haruhito , Araki Makoto , Seegers Lena Marie , McNulty Iris , Lee Hang , Kuter David , Ishibashi Midori , Kobayashi Kazuna , Dijkstra Jouke , Onishi Hirokazu , Yabushita Hiroto , Matsuoka Satoshi , Kawamoto Hiroyoshi , Watanabe Yusuke , Tanaka Kentaro , Chou Shengpu , Naganuma Toru , Okutsu Masaaki , Tahara Satoko , Kurita Naoyuki , Nakamura Shotaro , Das Suman , Nakamura Sunao , Jang Ik‐Kyung 
Published: August 2022

Background
The relationship between gut microbiota and in vivo coronary plaque characteristics has not been reported. This study was conducted to investigate the relationship between gut microbiota and coronary plaque characteristics in patients with coronary artery disease.

Methods and Results

Patients who underwent both optical coherence tomography and intravascular ultrasound imaging and provided stool and blood specimens were included. The composition of gut microbiota was evaluated using 16S rRNA sequencing. A total of 55 patients were included. At the genus level, 2 bacteria were associated with the presence of thin‐cap fibroatheroma, and 9 bacteria were associated with smaller fibrous cap thickness. Among them, some bacteria had significant associations with inflammatory/prothrombotic biomarkers.
Dysgonomonas
had a positive correlation with interleukin‐6,
Paraprevotella
had a positive correlation with fibrinogen and negative correlation with high‐density lipoprotein cholesterol,
Succinatimonas
had positive correlations with fibrinogen and homocysteine, and
Bacillus
had positive correlations with fibrinogen and high‐sensitivity C‐reactive protein. In addition,
Paraprevotella
,
Succinatimonas
, and
Bacillus
were also associated with greater plaque volume. Ten bacteria were associated with larger fibrous cap thickness. Some were associated with protective biomarker changes;
Anaerostipes
had negative correlations with trimethylamine N‐oxide, tumor necrosis factor α, and interleukin‐6, and
Dielma
had negative correlations with trimethylamine N‐oxide, white blood cells, plasminogen activator inhibitor‐1, and homocysteine, and a positive correlation with high‐density lipoprotein cholesterol.

Conclusions
Bacteria that were associated with vulnerable coronary plaque phenotype and greater plaque burden were identified. These bacteria were also associated with elevated inflammatory or prothrombotic biomarkers.

Registration

URL:
https://www.umin.ac.jp/ctr/
; Unique identifier: UMIN000041692.
Impact of Hospital Volume on Utilization of Minimally Invasive Surgery for Gastric Cancer
Authors: Dougherty Kristen , Zhang Zidong , Montenegro Grace , Hinyard Leslie , Xu Evan , Hsueh Eddy , Luu Carrie 
Published: August 2022

Background Minimally invasive surgery (MIS) for gastric cancer is increasingly performed. The purpose of this study is to evaluate trends in utilization of laparoscopic and robotic techniques compared to open surgery as well as utilization based on hospital volume. Methods We used the National Cancer Database to query patients who underwent gastrectomy from 2010 to 2017 for adenocarcinoma. Regression analyses were used to determine associations between MIS and clinical factors, the trend of MIS over time, and survival. Results A total of 18,380 patients met inclusion criteria. The annual rates of MIS increased for all hospital volumes, though lower volume centers were less likely to undergo MIS. MIS was associated with a shorter length of stay compared to open, and robotic gastrectomy had a higher rate of obtaining at least 15 lymph nodes and lower rate of having a positive margin. Conclusions MIS utilization for resection of gastric cancer increased over time, with robotic surgery increasing at a higher rate than laparoscopic surgery. Importantly, this occurred without increased in mortality or sacrificing adequate oncologic outcomes.
Characteristics Associated With US Adults’ Self-Reported COVID-19 Protective Behaviors When Getting Food From Restaurants, Winter 2021
Authors: Wittry Beth C. , Hoover Edward R. , Pomeroy Mary A. , Dumas Brianna L. , Marshall Katherine E. , Yellman Merissa A. , St. Louis Michael E. , Garcia-Williams Amanda G. , Brown Laura G. 
Published: August 2022

Objectives: Visiting restaurants and bars, particularly when doing so indoors, can increase transmission risk of SARS-CoV-2, the virus that causes COVID-19, among people who are not fully vaccinated. We aimed to understand US adults’ self-reported protective behaviors when getting food from restaurants during the COVID-19 pandemic when vaccines were not widely available. Methods: We used online nationwide survey data from January 2021 to assess self-reported restaurant-related behaviors of respondents (n = 502). We also used multiple logistic regression models to examine associations between respondents’ characteristics and these restaurant-related behaviors. Results: Half (49.7%) of respondents reported eating indoors at a restaurant at least once in the month before the survey. Respondents most likely to report eating inside restaurants were in the youngest age category (18-34 y), had personal COVID-19 experience, or indicated they felt safe eating inside a restaurant. Among respondents who had gotten food from a restaurant, more than 65% considered each of the following factors as important in their restaurant dining decision: whether the restaurant staff were wearing face masks, the restaurant requires face masks, other customers are wearing face masks, seating was spaced at least 6 feet apart, someone in their household was at risk for severe COVID-19 illness, and the restaurant was crowded. The most common protective behavior when eating at a restaurant was wearing a face mask; 44.9% of respondents who had eaten at a restaurant wore a face mask except when actively eating or drinking. Conclusion: The need for practicing prevention strategies, especially for those not up to date with COVID-19 vaccines, will be ongoing. Our findings can inform COVID-19 prevention messaging for public health officials, restaurant operators, and the public.