bluuebunny/crossref_metadata_2025_split huggingface dataset:
HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development
Authors: de Bock Charles E. , Demeyer Sofie , Degryse Sandrine , Verbeke Delphine , Sweron Bram , Gielen Olga , Vandepoel Roel , Vicente Carmen , Vanden Bempt Marlies , Dagklis Antonis , Geerdens Ellen , Bornschein Simon , Gijsbers Rik , Soulier Jean , Meijerink Jules P. , Heinäniemi Merja , Teppo Susanna , Bouvy-Liivrand Maria , Lohi Olli , Radaelli Enrico , Cools Jan 
Published: March 2018

Abstract
Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.
Significance: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases. Cancer Discov; 8(5); 616–31. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 517
A Preexisting Rare PIK3CAE545K Subpopulation Confers Clinical Resistance to MEK plus CDK4/6 Inhibition in NRAS Melanoma and Is Dependent on S6K1 Signaling
Authors: Romano Gabriele , Chen Pei-Ling , Song Ping , McQuade Jennifer L. , Liang Roger J. , Liu Mingguang , Roh Whijae , Duose Dzifa Y. , Carapeto Fernando C.L. , Li Jun , Teh Jessica L.F. , Aplin Andrew E. , Chen Merry , Zhang Jianhua , Lazar Alexander J. , Davies Michael A. , Futreal P. Andrew , Amaria Rodabe N. , Zhang David Y. , Wargo Jennifer A. , Kwong Lawrence N. 
Published: March 2018

Abstract
Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CAE545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.
Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CAE545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CAE545K-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556–67. ©2018 AACR.
See related commentary by Sullivan, p. 532.
See related article by Teh et al., p. 568.
This article is highlighted in the In This Issue feature, p. 517
Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role?
Authors: Noguera-Ortega Estela , Amaravadi Ravi K. 
Published: March 2018

Abstract
Summary: Autophagy has been identified as a potential therapeutic target in pancreatic ductal adenocarcinoma, one of the most lethal cancers, with few therapeutic options. Yang and colleagues successfully created a genetically engineered mouse model focused on the autophagy gene Atg4b that allows the study of therapeutic autophagy inhibition in fully formed tumors. Using this tool, they demonstrated that selective autophagy inhibition in either the tumor cells, normal host cells, or both suppresses tumor growth. Cancer Discov; 8(3); 266–8. ©2018 AACR
See related article by Yang et al., p. 276.
Systematic Review and Meta-Analysis of Liver Resection for Colorectal Metastases in Elderly Patients
Authors: van Tuil Tim , Dhaif Ali A. , te Riele Wouter W. , van Ramshorst Bert , van Santvoort Hjalmar C. 
Published: March 2018

<b><i>Background:</i></b> This systematic review and meta-analysis evaluated the short- and long-term outcomes of liver resection for colorectal liver metastases (CRLM) in elderly patients. <b><i>Methods:</i></b> A PubMed, EMBASE, and Cochrane Library search was performed from January 1995 to April 2017, for studies comparing both short- and long-term outcomes in younger and elderly patients undergoing liver resection for CRLM. <b><i>Results:</i></b> Eleven studies comparing patients aged &#x3c;70 years with patients aged &#x3e;70 years and 4 studies comparing patients aged &#x3c;75 years with patients aged &#x3e;75 years were included. Postoperative morbidity was similar in patients aged &#x3e;70 years (27 vs. 30%; <i>p</i> = 0.35) but higher in patients aged &#x3e;75 years (21 vs. 32%; <i>p</i> = 0.001). Postoperative mortality was higher in both patients aged &#x3e;70 years (2 vs. 4%; <i>p</i> = 0.01) and in patients aged &#x3e;75 years (1 vs. 6%; <i>p</i> = 0.02). Mean 5-year overall survival was lower in patients aged &#x3e;70 years (40 vs. 32%; <i>p</i> &#x3c; 0.001) but equal in patients aged &#x3e;75 years (42 vs. 32%; <i>p</i> = 0.06). <b><i>Conclusion:</i></b> Although postoperative morbidity and mortality were increased with higher age, liver resection for CRLM seems justified in selected elderly patients.
Whose Rights? Freedom-of-Expression Critiques of Ecuadorian Media Democratization
Authors: Tym Christian 
Published: March 2018

Despite its media reforms designed to democratize the country’s media landscape, the Ecuadorian government has been subject to constant condemnation from major U.S.-based human rights organizations on freedom-of-expression grounds. A close examination of these critiques and the Ecuadorian media reforms to which they correspond and a comparison of the Ecuadorian government’s and critical human rights organizations’ positions with liberal scholarship on the right to freedom of expression leads to the conclusion that Ecuadorian media reform is consistent with liberal social-democratic principles and, by contrast, human rights organizations uphold an early-modern interpretation of liberalism that is marginal within scholarship on freedom of expression. A pesar de su programa de reformas para democratizar el campo de los medios de difusión, el gobierno ecuatoriano ha sido objeto de una condena permanente por parte de las principales organizaciones de los derechos humanos de los Estados Unidos por motivos de la libertad de expresión. Un examen minucioso de estas críticas y de las reformas del gobierno ecuatoriano, así como una comparación de las posiciones del gobierno ecuatoriano y las de las organizaciones de derechos humanos con los estudios liberales sobre el derecho a la libertad de expression, revelan que estas reformas son consistentes con los principios liberales y socialdemócratas y que, en cambio, las organizaciones de derechos humanos defienden una interpretación del liberalismo correspondiente al principio de la era moderna temprana que queda marginal dentro de los estudios sobre la libertad de expresión.
Digital Storytelling and the Dispute over Representation in the Ayotzinapa Case
Authors: Meneses María Elena , Castillo-González María Concepción 
Published: March 2018

Comparison of the narratives of civil society and the federal government on YouTube and Twitter in the case of the disappearance of 43 students in Ayotzinapa, Mexico, allows the identification of the codes of representation being disputed in this emblematic case of violation of fundamental rights. Digital storytelling that goes viral and across media offers the possibility of organizing protest in the offline world. Its reflective attributes favor the visibility of injustice and permanence on the local and global agenda and in some cases exert pressure on social actors and authorities to establish mechanisms to resolve the conflict. La comparación de las narrativas sobre la sociedad civil y el gobierno federal en YouTube y en Twitter en el caso de la desaparición de los 43 estudiantes en Ayotzinapa, Mexico, nos permite identificar los códigos de representación en disputa en este caso emblemático de violación de los derechos humanos. Los relatos digitales que se vuelven virales y pasan a otros medios ofrecen la posibilidad de organizar la protesta en el mundo fuera de la Red. Su capacidad de reflejar ayuda a visibilizar la injusticia, manteniéndola como tema importante en las agendas locales y globales, y en algunos casos también ayuda a ejercer presión sobre los agentes sociales y las autoridades para establecer mecanismos que puedan resolver los conflictos.
Dietary Behaviors and Glucose Metabolism in Young Adults at Risk for Type 2 Diabetes
Authors: Cha EunSeok , Paul Sudeshna , Braxter Betty J. , Umpierrez Guillermo , Faulkner Melissa Spezia 
Published: March 2018

Purpose The purpose of the study was to examine the associations between dietary behaviors and glucose metabolism in high-risk young adults to increase the precision of nutrition education to prevent early onset type 2 diabetes (T2D). Method Using a descriptive, cross-sectional study design, 106 overweight or obese sedentary young adults ages 18-29 years from the Atlanta metropolitan area were recruited to screen diabetes risk. Survey questionnaires, anthropometric assessment, blood pressure (BP), and laboratory data were collected in a clinical research unit. The Web-based HOMA2 calculator was used to calculate beta cell function and insulin sensitivity. Results The final sample included 103 participants. There were similar patterns of diet (caloric intake and dietary quality) between African Americans and non-African Americans, whereas African Americans showed hyperinsulinemia compared with non-African Americans. When young adults consumed a good quality diet (appropriate carbohydrate intakes; high fiber, low saturated fat but protein rich diet), their insulin resistance was decreased. There was a marginal interaction effect between insulin sensitivity and beta cell function by race. Systolic BP was higher in African Americans, and total cholesterol, triglycerides, and low-density lipoprotein cholesterol were higher in non-African Americans. Conclusion Findings are useful to develop age-specific nutrition guidelines to prevent early onset T2D in high-risk young adults.
Initial clinical results with a fusion prototype for mammography and three-dimensional ultrasound with a standard mammography system and a standard ultrasound probe
Authors: Emons Julius , Wunderle Marius , Hartmann Arndt , Radicke Marcus , Rauh Claudia , Uder Michael , Gass Paul , Fasching Peter A , Langemann Hanna , Beckmann Matthias W , Schulz-Wendtland Rüdiger , Jud Sebastian M 
Published: March 2018

Background Combinations *Equal contributors. of different imaging techniques in fusion devices appear to be associated with improvements in diagnostic assessment. Purpose The aim of this study was to test the feasibility of using an automated standard three-dimensional (3D) ultrasound (US) device fused with standard mammography for the first time in breast cancer patients. Material and Methods Digital mammograms and 3D automated US images were obtained in 23 patients with highly suspicious breast lesions. A recently developed fusion machine consisting of an ABVS 3D US transducer from an Acuson S2000 machine and a conventional Mammomat Inspiration device (both Siemens Healthcare GmbH, Erlangen, Germany) were used for the purpose. The feasibility of the examinations, imaging coverage, and patients' experience of the procedure were examined. Results In 15 out of 19 patients, the region of interest (ROI) with the tumor marked in the mammogram was visible on US. The examination was experienced positively by the patients, with no unexpected pain or injury. The examination was time-saving and well tolerated. Conclusion In conclusion, we have shown initial clinical feasibility of an US/radiography fusion prototype with good localization and evaluation of the ROIs. The combined examination was well tolerated. The simultaneous evaluation with mammography and US imaging may be able to improve detection and reduce examiner-related variability.
Localization of migraine susceptibility genes in human brain by single-cell RNA sequencing
Authors: Renthal William 
Published: March 2018

Background Migraine is a debilitating disorder characterized by severe headaches and associated neurological symptoms. A key challenge to understanding migraine has been the cellular complexity of the human brain and the multiple cell types implicated in its pathophysiology. The present study leverages recent advances in single-cell transcriptomics to localize the specific human brain cell types in which putative migraine susceptibility genes are expressed. Methods The cell-type specific expression of both familial and common migraine-associated genes was determined bioinformatically using data from 2,039 individual human brain cells across two published single-cell RNA sequencing datasets. Enrichment of migraine-associated genes was determined for each brain cell type. Results Analysis of single-brain cell RNA sequencing data from five major subtypes of cells in the human cortex (neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells) indicates that over 40% of known migraine-associated genes are enriched in the expression profiles of a specific brain cell type. Further analysis of neuronal migraine-associated genes demonstrated that approximately 70% were significantly enriched in inhibitory neurons and 30% in excitatory neurons. Conclusions This study takes the next step in understanding the human brain cell types in which putative migraine susceptibility genes are expressed. Both familial and common migraine may arise from dysfunction of discrete cell types within the neurovascular unit, and localization of the affected cell type(s) in an individual patient may provide insight into to their susceptibility to migraine.
Surgical Treatment of Lateral Epicondylitis: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial
Authors: Kroslak Martin , Murrell George A.C. 
Published: March 2018

Background: A number of surgical techniques for managing tennis elbow have been described. One of the most frequently performed involves excising the affected portion of the extensor carpi radialis brevis (ECRB). The results of this technique, as well as most other described surgical techniques for this condition, have been reported as excellent, yet none have been compared with placebo surgery. Hypothesis: The surgical excision of the degenerative portion of the ECRB offers no additional benefit over and above placebo surgery for the management of chronic tennis elbow. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: This study investigated surgical excision of the macroscopically degenerated portion of the ECRB (surgery; n = 13) as compared with skin incision and exposure of the ECRB alone (sham; n = 13) to treat patients who had tennis elbow for >6 months and had failed at least 2 nonsurgical modalities. The primary outcome measure was defined as patient-rated frequency of elbow pain with activity at 6 months after surgery. Secondary outcome measures included patient-rated pain and functional outcomes, range of motion, epicondyle tenderness, and strength at 6 months and 2.5 years. All outcome measures up to and including the 6-month follow-up were measured in person; the longer-term questionnaire was conducted in person or over the phone. Results: The 2 groups, surgery and sham, were similar for age, sex, hand dominance, and duration of symptoms. Both procedures improved patient-rated pain frequency and severity, elbow stiffness, difficulty with picking up objects, difficulty with twisting motions, and overall elbow rating >6 months and at 2.5 years ( P < .01). Both procedures also improved epicondyle tenderness, pronation-supination range, grip strength, and modified Orthopaedic Research Institute–Tennis Elbow Testing System at 6 months ( P < .05). No significant difference was observed between the groups in any parameter at any stage. No side effects or complications were reported. The study was stopped before the calculated number of patients were enrolled (40 per group); yet, a post hoc futility analysis was conducted that showed, based on the magnitude of the differences between the groups, >6500 patients would need to be recruited per group to see a significant difference between the groups at 26 weeks in the primary outcome (patient-rated frequency of elbow pain with activity). Conclusion: With the number of available participants, this study failed to show additional benefit of the surgical excision of the degenerative portion of the ECRB over placebo surgery for the management of chronic tennis elbow.
Return to Sports and Physical Work After Arthroscopic Superior Capsule Reconstruction Among Patients With Irreparable Rotator Cuff Tears
Authors: Mihata Teruhisa , Lee Thay Q. , Fukunishi Kunimoto , Itami Yasuo , Fujisawa Yukitaka , Kawakami Takeshi , Ohue Mutsumi , Neo Masashi 
Published: March 2018

Background: Although sports participation and heavy physical work can contribute to rotator cuff tears, many patients expect to return to these activities after surgery; however, irreparable rotator cuff tears can preclude this outcome. A new surgical treatment—arthroscopic superior capsule reconstruction (SCR)—restores shoulder stability and muscle balance in patients with irreparable rotator cuff tears; consequently, it improves shoulder function and relieves pain. Purpose: To evaluate the rates of return to sports and physical work among patients treated with arthroscopic SCR. Study Design: Cohort study; Level of evidence, 3. Methods: From 2007 to 2014, we performed arthroscopic SCR in 105 patients with irreparable rotator cuff tears, 5 of whom were lost to follow-up. Consequently, 100 patients (mean age, 66.9 years; range, 43-82 years) were enrolled in the study. Before surgery, 26 patients had participated in sports (2 competitive, 24 recreational), and 34 patients had physical work. Rates of return to sports and physical work, the American Shoulder and Elbow Surgeons (ASES) score, active shoulder range of motion, and rate of graft tear were evaluated. The mean time to final follow-up was 48 months (range, 24-88 months). Results: All 26 patients who played sports before their injuries returned fully to them. In addition, 32 patients returned fully to their previous physical work, whereas the 2 remaining patients returned with reduced hours and workloads. As compared with the nonsports group, the sports group had significantly higher postoperative active elevation (160° ± 32° vs 146° ± 39°; P = .04) and higher postoperative ASES scores (97 ± 7 vs 91 ± 12; P = .02). The shoulder range of motion and ASES scores before and after surgery did not differ significantly between the physical and nonphysical work groups ( P = .11-.99). The rate of graft tear did not differ between the sports group (4%) and nonsports group (5%) ( P = .75) and between the physical work group (6%) and nonphysical work group (5%) ( P = .77). Conclusion: Arthroscopic SCR restored shoulder function and resulted in high rates of return to recreational sports and physical work.
Voriconazole Autoinduction and Saturable Metabolism After Cessation of Rifampin in a Patient With Invasive Central Nervous System Aspergillus: Importance of Therapeutic Drug Monitoring
Authors: Farrokh Salia , Avdic Edina 
Published: March 2018

Purpose: Optimization of antifungal therapy with voriconazole can be challenging due to inter- and intrapatient variability in voriconazole pharmacokinetics (PK). In this case, we introduce challenges in voriconazole therapy due to drug–drug interactions, autoinduction, and saturable metabolism. Summary: A 32-year-old male on chronic prednisone developed central nervous system (CNS) aspergillosis. He was started on high-dose intravenous (IV) voriconazole 8.5 mg/kg every 12 hours due to concerns for lasting induction effects of recent rifampin therapy. The initial voriconazole trough was 2 μg/mL. Frequent dose adjustments were made to maintain the therapeutic trough goal. On day 24 of voriconazole therapy, his trough was undetectable on IV voriconazole 5.5 mg/kg every 12 hours. His dose was escalated to 8.5 mg/kg every 12 hours to avoid subtherapeutic levels and therapeutic failure. On day 48, his trough level was 1.1 μg/mL on the same dose. His regimen was changed to 6.5 mg/kg every 8 hours at this point. Sixteen days after this regimen on day 74 of voriconazole therapy, his trough was 27.2 μg/mL indicating saturable PK of voriconazole in the absence of interacting drugs. Conclusion: Our findings highlight the unpredictable PK of voriconazole and reinforce the importance of continuous therapeutic drug monitoring in critically ill patients.
External costs from fossil electricity generation: A review of the applied impact pathway approach
Authors: Jorli Mojtaba , Van Passel Steven , Sadeghi Saghdel Hossein 
Published: March 2018

This paper reviews and compares 11 studies that have estimated external costs of fossil electricity generation by benefits transfer. These studies include 13 countries and most of these countries are developing countries. The impact pathway approach is applied to estimate the environmental impact arising from fossil fuel-fired power plant’s air emission and the related damages on human health. The estimated damages are used to value the monetary external costs from fossil fuel electricity generation. The estimated external costs in the 13 countries vary from 0.51 to 213.5 USD (2005) per MW h due to differences in fossil fuel quality, location, technology, and efficiency of power plants and additionally differences in assumptions, monetization values, and impact estimations. Accounting for these externalities can indicate the actual costs of fossil energy. The results can be applied by policy makers to take measures to avoid additional costs and to apply newer and cleaner energy sources. The described methods in the selected studies for estimating the external costs with respect to incomplete local data can be applied as a useful example for other developing countries.