tbuckley/cabot-search huggingface dataset:
Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Is Associated with Indigenous American Ancestry in Latin American Women
Authors: Katie M. Marker, Valentina A. Zavala, Tatiana Vidaurre, Paul C. Lott, Jeannie Navarro Vásquez, Sandro Casavilca-Zambrano, Mónica Calderón, Julio E. Abugattas, Henry L. Gómez, Hugo A. Fuentes, Ruddy Liendo Picoaga, Jose M. Cotrina, Silvia P. Neciosup, Carlos A. Castañeda, Zaida Morante, Fernando Valencia, Javier Torres, Magdalena Echeverry, Mabel E. Bohórquez, Guadalupe Polanco-Echeverry, Ana P. Estrada-Florez, Silvia J. Serrano-Gómez, Jenny A. Carmona-Valencia, Isabel Alvarado-Cabrero, María Carolina Sanabria-Salas, Alejandro Velez, Jorge Donado, Sikai Song, Daniel Cherry, Lizeth I. Tamayo, Scott Huntsman, Donglei Hu, Roberto Ruiz-Cordero, Ronald Balassanian, Elad Ziv, Jovanny Zabaleta, Luis Carvajal-Carmona, Laura Fejerman
Journal: Cancer Research (2020)

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2
Partnering to promote public health across the Mediterranean
Authors: Miloud Kaddar, Belgacem Sabri, Yves Charpak, Djamel Zoughailech
Journal: The Lancet Public Health (2020)

The geostrategic position of north African countries in the Mediterranean has played an important role throughout history in developing relationships with Europe through movement of people, goods, and services. Additionally, historical ties are important as former European colonies (France, Italy, and the UK) have shaped health systems after independence in terms of management, service provision, and essential public health functions. However, when assessing the challenges presented today, new ties are needed across the Mediterranean in areas of common interest including strengthening public health, health and social services for refugees and migrants, and migration of human resources for health from countries of the south to Europe and to other developed countries. Forced migrants from Africa and Asia escaping political conflicts, lack of development, and consequences of climate change are trying to cross the oceans to reach Europe and other continents and they are suffering many health and social risks. Migrants either granted asylum or leaving in undocumented status in Europe are living under vulnerable conditions and are lacking basic social and economic rights. In view of an ageing population and barriers to access to medical professions raised by professional associations, most European countries are relying on migrant health professionals from Africa and Asia. Migration of health professionals from northern African countries, encouraged by low civil servants’ salaries and bad working conditions and facilitated by similarity in health personnel education and languages represents a serious challenge to Maghreban and northern African health systems. In addition to strategies aimed at addressing root causes of brain drain of their health professionals, Maghreban countries are in need of a negotiation in which the WHO code of ethical recruitment of health professionals could be implemented and in which other win–win cooperation mechanisms regarding the health workforce could be discussed. Additionally, such negotiations could streamline collaboration in the field of investment in health development in Maghreban countries, in line with national and well planned strategies focusing on health promotion, strengthening health security, supporting population based research, generating and disseminating evidence to support public health, protecting the environment, and targeting cost effective interventions. For all the aforementioned reasons, strengthening the links between northern African countries and Europe with regards to public health professionals, training and research institutions, and civil society organisations is incredibly important. We declare no competing interests.
Efficacy and safety of landiolol, an ultra-short-acting β1-selective antagonist, for treatment of sepsis-related tachyarrhythmia (J-Land 3S): a multicentre, open-label, randomised controlled trial
Authors: Yasuyuki Kakihana, Osamu Nishida, Takumi Taniguchi, Masaki Okajima, Hiroshi Morimatsu, Hiroshi Ogura, Yoshitsugu Yamada, Tetsuji Nagano, Eiichiro Morishima, Naoyuki Matsuda
Journal: The Lancet Respiratory Medicine (2020)
CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target
Authors: Wen Zhang, Huishan Wang, Mingyang Sun, Xueting Deng, Xueru Wu, Yilan Ma, Mengjing Li, Said Maisam Shuoa, Qiang You, Lin Miao
Journal: Cancer Communications (2020)

Abstract The components of the tumor microenvironment (TME) in solid tumors, especially chemokines, are currently attracting much attention from scientists. C‐X‐C motif chemokine ligand 5 (CXCL5) is one of the important chemokines in TME. Overexpression of CXCL5 is closely related to the survival time, recurrence and metastasis of cancer patients. In TME, CXCL5 binds to its receptors, such as C‐X‐C motif chemokine receptor 2 (CXCR2), to participate in the recruitment of immune cells and promote angiogenesis, tumor growth, and metastasis. The CXCL5/CXCR2 axis can act as a bridge between tumor cells and host cells in TME. Blocking the transmission of CXCL5/CXCR2 signals can increase the sensitivity and effectiveness of immunotherapy and slow down tumor progression. CXCL5 and CXCR2 are also regarded as biomarkers for predicting prognosis and molecular targets for customizing the treatment. In this review, we summarized the current literature regarding the biological functions and clinical significance of CXCL5/CXCR2 axis in TME. The possibility to use CXCL5 and CXCR2 as potential prognostic biomarkers and therapeutic targets in cancer is also discussed
An Invited Commentary on “Comparative analysis of weight loss and resolution of comorbidities between laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass: A systematic review and meta-analysis based on 18 studies” (Int J Surg 2020;76:101–110) - Time for shared decision making
Authors: Jared Gallaher, Anthony Charles
Journal: International Journal of Surgery (2020)
Abstract 16207: Cardiovascular Effects of Chimeric Antigen Receptor T-Cell (CART Cell) Therapy in Adults
Authors: Benedicte Lefebvre, Yu Kang, Noelle Frey, Joseph R Carver, Marielle Scherrer-Crosbie
Journal: Circulation (2019)

Purpose: Chimeric antigen receptor T-cell (CART), a therapy in which a patient’s own T cells are engineered to target tumor cells, has demonstrated remarkable response in patients with otherwise un...
Low level of cross-resistance to cytidine analogs in a 9-β-D-arabinofuranosyl-2-fluoroadenine-resistant variant of L1210 mouse leukemia cells
Authors: Yasukazu Kawai, Nobuyuki Yoshio, Takahiro Yamauchi, Takanori Ueda
Journal: Cancer Research (2005)

4101   The mechanisms of resistance to 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), a DNA-directed purine nucleoside analog, have not been fully demonstrated even in cell lines. A variant of mouse leukemia L1210 cells that is more than 54-fold resistant to F-ara-A has been newly established by a stepwise selection in the presence of F-ara-A, and named L1210/F cells. The cross-resistance for 2-chloro-2′-deoxyadenosine, 1-β-D-arabinofuranosylcytosine (ara-C), and 2′, 2′-difluorodeoxycytidine was 16-, 8.4-, and 3.3-fold, respectively, indicating a relatively low degree of cross-resistance to cytidine analogs among those requiring deoxycytidine kinase for cellular anabolism of analogs. To elucidate the mechanisms underlying different pattern of cross-resistance to cytidine and purine analogs, the characteristics of this resistant variant was analyzed by putting a principal objective in comparison between the intracellular pharmacology of F-ara-A and ara-C. The activity of deoxycytidine kinase was 45% of that in the parental cells, when deoxycytidine was used as a substrate. The initial and maximal velocities of F-ara-A triphosphate (F-ara-ATP) and ara-C triphosphate accumulation in L1210/F cells decreased to 24% and 37% compared with the parental cells, respectively. The time-course experiment indicated that the self-potentiating effect of F-ara-A incorporation into DNA was observed in L1210 cells but not in L1210/F cells. The incorporation of F-ara-A and ara-C into DNA decreased to 11% and 57% of the parental cells, respectively, indicating that there was marked impairment of F-ara-A incorporation into DNA in L1210/F cells. The pool size of all deoxyribonucleotide triphosphates was increased, although the expression level of each subunit of ribonucleotide reductase was not different, suggesting the dysregulation of the enzymatic activity. Importantly, the intracellular dATP pool size was increased 4.9-fold, in contrast to that of dCTP, which was increased only 1.9-fold in the L1210/F cells. Simultaneous treatment with hydroxyurea significantly reduced the dATP pool, and substantially enhanced the cytotoxic action of F-ara-A in L1210/F cells. The role of F-ara-ATP in the activating caspase-3/-7 pathway was of no importance in both the parental and resistant cells. Our results indicate that the high level of dATP competes with F-ara-ATP for incorporation into DNA and confers a high level of resistance to F-ara-A compared to cytidine analogues in L1210/F cells. Cytidine analogs may be useful to circumvent this type of resistance to F-ara-A.
Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside
Authors: James J. Beaudoin, Kim L.R. Brouwer, Melina M. Malinen
Journal: Pharmacology & Therapeutics (2020)

Organic solute transporter alpha/beta (OSTα/β) is a heteromeric solute carrier protein that transports bile acids, steroid metabolites and drugs into and out of cells. OSTα/β protein is expressed in various tissues, but its expression is highest in the gastrointestinal tract where it facilitates the recirculation of bile acids from the gut to the liver. Previous studies established that OSTα/β is upregulated in liver tissue of patients with extrahepatic cholestasis, obstructive cholestasis, and primary biliary cholangitis (PBC), conditions that are characterized by elevated bile acid concentrations in the liver and/or systemic circulation. The discovery that OSTα/β is highly upregulated in the liver of patients with nonalcoholic steatohepatitis (NASH) further highlights the clinical relevance of this transporter because the incidence of NASH is increasing at an alarming rate with the obesity epidemic. Since OSTα/β is closely linked to the homeostasis of bile acids, and tightly regulated by the nuclear receptor farnesoid X receptor, OSTα/β is a potential drug target for treatment of cholestatic liver disease, and other bile acid-related metabolic disorders such as obesity and diabetes. Obeticholic acid, a semi-synthetic bile acid used to treat PBC, under review for the treatment of NASH, and in development for the treatment of other metabolic disorders, induces OSTα/β. Some drugs associated with hepatotoxicity inhibit OSTα/β, suggesting a possible role for OSTα/β in drug-induced liver injury (DILI). Furthermore, clinical cases of homozygous genetic defects in both OSTα/β subunits resulting in diarrhea and features of cholestasis have been reported. This review article has been compiled to comprehensively summarize the recent data emerging on OSTα/β, recapitulating the available literature on the structure-function and expression-function relationships of OSTα/β, the regulation of this important transporter, the interaction of drugs and other compounds with OSTα/β, and the comparison of OSTα/β with other solute carrier transporters as well as adenosine triphosphate-binding cassette transporters. Findings from basic to more clinically focused research efforts are described and discussed.
State of the art in CAR T cell therapy for CD19+ B cell malignancies
Authors: Matthew J. Frigault, Marcela V. Maus
Journal: Journal of Clinical Investigation (2020)

Cellular therapy for hematologic malignancies is a rapidly evolving field, with new iterations of novel constructs being developed at a rapid pace. Since the initial reports of chimeric antigen receptor T cell (CAR T cell)success in CD19+ B cell malignancies, multiple clinical trials of CAR T cell therapy directed to CD19 have led to the approval of this therapy by the FDA and the European Medicines Agency for specific indications. Despite strikingly similar efficacy, investigators at multiple centers participating in these studies have observed the nuances of each CAR T cell product, including variability in manufacturing, availability, and toxicity profiles. Here we review state-of-the-art clinical data on CD19-directed CAR T cell therapies in B cell hematologic malignancies, advances made in understanding and modeling associated toxicities, and several exciting advances and creative solutions for overcoming challenges with this therapeutic modality.
Correlation between NK function and response to trastuzumab in metastatic breast cancer
Authors: A. Beano, E. Signorino, M. A. Polimeni, M. Mistrangelo, M. Ardine, R. Spadi, M. Donadio, L. Ciuffreda, L. Matera
Journal: Journal of Clinical Oncology (2007)

3036 Background: Trastuzumab is a monoclonal antibody selectively directed against Her2 approved for the treatment of Her2 overexpressing breast cancer patients. Its proposed mechanisms of action include also a role in mediating antibody-dependent cellular cytotoxicity (ADCC), through the triggering of the FcγRIII on natural killer (NK) cells. This study addressed the correlation between overall NK function and clinical trastuzumab activity. Methods: Between March and September 2006 22 metastatic patients in treatment with trastuzumab alone (8 mg/kg load and then 6 mg/kg every 3 weeks until disease progression) as maintaining therapy after chemotherapy were analyzed for clinical and immunological responses. According to RECIST criteria, 14 patients obtained a response to trastuzumab, while 8 patients had a disease progression. Patient’s peripheral blood mononuclear cells were tested for cytotoxic activity against standard NK target (the MHC class I-negative K562 cell line) and trastuzumab-coated MCF7 (Her2-negative) and SKBR3 (Her2-positive) human cell lines in a 4-h 51 Cr-release cytotoxicity assay in the presence of grading concentrations of effector cells. Results: NK activity was significantly (p&lt;0.05) higher in responder compared to non responder patients at all the four effector:target (50:1 to 6:1) ratios tested. NK activity of non responder patients was significantly lower than that of 25 sex and age matched controls (p&lt;0.02) and this was not merely due to chemotherapy- or tumor-associated immunosuppression, since the values of responder patients did not significantly differ from those of controls. ADCC activity against Her2-positive SKBR3 cells was also significantly higher in responder compared to non responder patients (p&lt;0.05) and markedly so when compared to controls (p&lt;0.001). Conclusions: The fact that, as shown here, normal levels of FcγR- independent and higher than normal levels of FcγR-dependent cytotoxicity are required for trastuzumab response, lends support to a paramount role of NK cells in the mechanism of action of this drug. No significant financial relationships to disclose.
Omission of Heart Transplant Recipients From the Appropriate Use Criteria for Revascularization and the Ramifications on Heart Transplant Centers
Authors: Joe X. Xie, Jon A. Kobashigawa, Kevin F. Kennedy, Timothy D. Henry, Steven W. Tabak, Robert Krebbs, Leslee Shaw, J. Dawn Abbott, Wendy Book, S. Tanveer Rab, John A. Spertus, Abhinav Goyal
Journal: JAMA Cardiology (2020)

Guidelines endorse routine coronary angiography and percutaneous coronary intervention (PCI) to screen for and treat cardiac allograft vasculopathy in heart transplant recipients. However, the current Appropriate Use Criteria for Revascularization (AUC-R) do not recognize prior heart transplant as a unique PCI indication. Whether this affects rates of rarely appropriate (RA) PCIs is unknown. To assess the rate of RA PCI procedures in heart transplant recipients and how it pertains to hospital PCI appropriateness metrics and pay-for-performance scorecards. This observational study used National Cardiovascular Data Registry CathPCI Registry data on all patients undergoing elective PCIs from 96 Medicare-approved heart transplant centers from quarter 3 of 2009 to quarter 2 of 2017. The data were analyzed in July 2018. Prior heart transplant. Rates of RA elective PCIs in heart transplant recipients compared with nonrecipients and hospital rates of RA PCI before vs after exclusion of heart transplant recipients using paired t tests. In a subset of heart transplant centers participating in the Anthem Blue Cross and Blue Shield's Quality-In-Sights Hospital Incentive Program (Q-HIP), we compared the change in Q-HIP scorecards before vs after excluding heart transplant recipients. Of 168 802 participants, 123 124 (72.9%) were men, 137 457 were white, and the mean (SD) age was 66.3 (11.4) years. Of 168 802 elective PCIs performed in heart transplant centers, 1854 (1.1%) were for heart transplant recipients. Heart transplant recipients were less likely to have ischemic symptoms (14.6% vs 61.4%, P < .001), had lower rates of antecedent stress testing (15.0% vs 58.4%, P < .001), and had higher RA PCI rates (66.0% vs 16.9%, P < .001) compared with nonrecipients. In heart transplant centers, the absolute difference in RA rates (before vs after excluding transplant recipients) was directly associated with the proportion of PCIs performed in heart transplant recipients (r = 0.91; P < .001). In the subset of heart transplant centers participating in Q-HIP during the 2016 and 2017 calendar years, 8 of 20 (40%) and 8 of 16 centers (50%), respectively, could have benefited from a change in their Q-HIP scorecards if their RA PCI rates excluded transplant recipients. Two-thirds of PCIs in heart transplant recipients were deemed RA by the AUC-R. The failure of the AUC-R to consider prior heart transplant as a unique PCI indication may lead to inflated RA PCI rates with the potential for affecting quality reporting and pay-for-performance metrics in heart transplant centers.
m6A-dependent glycolysis enhances colorectal cancer progression
Authors: Chaoqin Shen, Baoqin Xuan, Tingting Yan, Yanru Ma, Pingping Xu, Xianglong Tian, Xinyu Zhang, Yingying Cao, Dan Ma, Xiaoqiang Zhu, Youwei Zhang, Jing-Yuan Fang, Haoyan Chen, Jie Hong
Journal: Molecular Cancer (2020)

Abstract Background Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N 6 -methyladenosine (m 6 A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m 6 A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m 6 A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized. Methods Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m 6 A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC. Results A strong correlation between METTL3 and 18 F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions of HK2 , and the 3’UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M 6 A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m 6 A reader IGF2BP2 or IGF2BP2/3, respectively. Conclusions METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m 6 A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.
No evidence of increased cancer incidence in children using topical tacrolimus for atopic dermatitis
Authors: Amy S. Paller, Regina Fölster-Holst, Suephy C. Chen, Thomas L. Diepgen, Craig Elmets, David J. Margolis, Brad H. Pollock
Journal: Journal of the American Academy of Dermatology (2020)

Long-term safety of topical calcineurin inhibitors is not well understood. APPLES (A Prospective Pediatric Longitudinal Evaluation to Assess the Long-Term Safety of Tacrolimus Ointment for the Treatment of Atopic Dermatitis; NCT00475605) examined incidence of lymphoma and other cancers in a pediatric population with atopic dermatitis.To quantify incident malignancies during 10 years in children with atopic dermatitis who used topical tacrolimus for ≥6 weeks.Standardized incidence ratios for cancer events were analyzed relative to sex-, age-, and race-matched control data from national cancer registries.There were 7954 eligible patients enrolled at 314 sites in 9 countries. During 44,629 person-years, 6 confirmed incident cancers occurred (standardized incidence ratio, 1.01; 95% confidence interval, 0.37-2.20). No lymphomas occurred.Observational prospective cohort study.The cancer incidence was as expected, given matched background data. This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with atopic dermatitis.