bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF
Authors: Shao Wenlin , Mishina Yuji M. , Feng Yun , Caponigro Giordano , Cooke Vesselina G. , Rivera Stacy , Wang Yingyun , Shen Fang , Korn Joshua M. , Mathews Griner Lesley A. , Nishiguchi Gisele , Rico Alice , Tellew John , Haling Jacob R. , Aversa Robert , Polyakov Valery , Zang Richard , Hekmat-Nejad Mohammad , Amiri Payman , Singh Mallika , Keen Nicholas , Dillon Michael P. , Lees Emma , Ramurthy Savithri , Sellers William R. , Stuart Darrin D. 
Published: January 2018

AbstractResistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor–derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors.Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537–48. ©2018 AACR.
Repurposing Tin Mesoporphyrin as an Immune Checkpoint Inhibitor Shows Therapeutic Efficacy in Preclinical Models of Cancer
Authors: Muliaditan Tamara , Opzoomer James W. , Caron Jonathan , Okesola Mary , Kosti Paris , Lall Sharanpreet , Van Hemelrijck Mieke , Dazzi Francesco , Tutt Andrew , Grigoriadis Anita , Gillett Cheryl E. , Madden Stephen F. , Burchell Joy M. , Kordasti Shahram , Diebold Sandra S. , Spicer James F. , Arnold James N. 
Published: January 2018

Abstract
Purpose: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immunosuppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited antitumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinemia, as an immune checkpoint blockade therapy for the treatment of cancer.
Experimental Design: SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (MMTV-PyMT). Single-cell RNA sequencing analysis, tumor microarray, and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations.
Results: We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8+ T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA-sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. In vivo, we therapeutically compare the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably with PD-1 blockade in preclinical models.
Conclusions: SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy. Clin Cancer Res; 24(7); 1617–28. ©2018 AACR.
Оцінка віддалених результатів лікування хворих із ускладненим синдром діабетичної стопи та визначення шляхів надання їм медико-соціальної допомоги
Authors: Tribushnyi O. V. 
Published: January 2018

Мета роботи: проаналізувати структуру віддалених результатів хворих іза ускладненим СДС з визначенням показника фізичного і психологічного компонентів здоров’я, стану їх протезування та корекції взуття в ортопедичній майстерні.Матеріали і методи. Під наглядом перебували 724 хворі з ускладненим СДС віком від 36 до 87 років. У 71 (9,8 %) пацієнта захворювання було обтяжене сепсисом. Померли 36 хворих із ускладненим СДС без сепсису (летальність 5,5 %) та 42 – з сепсисом (летальність 59,1 %). На амбулаторне лікування виписали 617 хворих з ускладненим СДС та 29 пацієнтів, які перенесли сепсис. Терміни проведення контрольного огляду були 6 місяців, 1, 2, 3 та 5 років.Результати досліджень та їх обговорення. Показник фізичного та психологічного компонентів здоров’я через півроку не перевищував (43,2±4,7) ум. од. у хворих, котрим виконані “малі” ампутації та (31,3±3,6) ум. од. (Р < 0,05) у пацієнтів після “високих” ампутацій. Через 2 роки покращення в цьому напрямку не відбувалося. Лише одна пацієнтка протезована, менш ніж 25 % хворих користується ортопедичним взуттям. Серед хворих, які перенесли сепсис та були виписані із стаціонару протягом першого року чи навіть раніше, померли 11 (42,3 %), а впродовж 2 – 3 років 12 (46,2 %) хворих. Через 5 років отримано такі дані: з 364 хворих, яких оперували з приводу гангрени нижньої кінцівки, вижили 23 (6,3 %), а “високу” ампутацію контрлатеральної кінцівки виконано 48 (13,2 %) пацієнтам. З 253 пацієнтів, в анамнезі яких були “малі” ампутації, протягом 5 років були оперовані на передньому відділі стопи цієї ж кінцівки в 14,2 % випадків (36 хворих), на контрлатеральній кінцівці – (12,2 %) 31 хворий. Всього померли 127 (50,2 %) пацієнтів. Дані інших 17 хворих (6,7 %) з’ясувати не вдалося. Віддалені результати у хворих з ускладненим СДС свідчать про відсутність динамічного спостереження за цими хворими на амбулаторному етапі лікування. Оптимально, щоб питання протезування хворих після “високих” ампутацій та підбір ортопедичного взуття пацієнтам після “малих” було б включено до Національної програми допомоги хворим на цукровий діабет.
Pensar la traducción como obra de arte
Authors: Parra Aline Celia Tonon 
Published: January 2018

El siguiente trabajo ha sido presentado para evaluación final del curso realizado en intercambio en la Universidad de Buenos Aires en mayo de 2016. El curso –que se llamó “Filosofía de la Traducción” y cuyo profesor responsable era Horácio Gonzales– incentivaba la discusión de la posibilidad de pensarse un género artístico a partir de los lenguajes de otros géneros y entender cómo se da el proceso de una nueva época o una forma original de sensibilidad antes desconocida a partir de un descubrimiento artístico. Traducción era pensada allí como una práctica de diversas interpretaciones posibles para el hacer y entender artístico y filosófico. ¿Sería posible pensar el propio acto de traducir como una creación artística? A partir de la lectura de diversos autores que permean el tema de manera más teórica –como Benjamin y Haroldo de Campos– y también de autores que lo abordan desde una concepción más poética del tema –como es el caso de Cesar Aira y Jorge Luis Borges–, este ensayo busca abrir nuevas posibilidades para el entendimiento de la traducción como categoría estética.
Probability Distribution for the Visually Observed Fractional Cloud Cover over the Ocean
Authors: Aleksandrova Marina , Gulev Sergey K. , Belyaev Konstantin 
Published: January 2018

Abstract
The authors suggest a three-parameter bounded distribution from the family of mixed gamma distributions for characterizing the probability density distributions of fractional total and low cloud cover over the global oceans. The authors derive both the continuous form of this distribution and its discrete counterpart, which can be directly applied to cloud cover reports. The distribution is applied to the cloud cover characteristics reported by voluntary observing ships (VOS) for the period from 1950 to 2011 after filtering nighttime observations with poor lunar illumination. The suggested distribution demonstrates a high goodness of fit to the data and good skill in capturing probability distributions with different shapes. The authors present seasonal climatologies of the parameters of the derived distribution for the chosen 60-yr period and demonstrate that applying the PDF-based concept to the analysis of cloud cover allows identification of areas where similar mean cloud amounts can be produced by probability distributions with very different shapes. The roles of the different parameters of the distribution in producing the observed cloud conditions in different regions of the World Ocean are discussed. The application of the derived probability distribution allows for accurate estimation of the percentiles of the distribution, which represent the probabilities of specific cloud conditions. These probabilities are presented for both total and low cloud cover, as well as for daytime and nighttime. The authors also discuss the applicability of the suggested distribution for the validation of different cloud cover data products over the globe and the prospects of additional applications.
Temporalis Fascia Transplantation for Sulcus Vocalis and Vocal Fold Scar: Long-Term Outcomes
Authors: Karle William E. , Helman Samuel N. , Cooper Amy , Zhang Yuan , Pitman Michael J. 
Published: January 2018

Objective: Sulcus vocalis and vocal fold scar involve derangement of the superficial lamina propria of the vocal fold, which results in significant dysphonia. Many options exist for treatment, most of which have unsatisfactory and unpredictable outcomes. Autologous transplantation of temporalis fascia into the vocal fold (ATFV) has the potential to be a better treatment option, but long-term outcomes have not been well studied. Methods: Retrospective chart review and patient survey. Twenty-one patients diagnosed with vocal fold scar or sulcus vocalis and treated with ATFV with at least 1-year follow-up were included. Voice Handicap Index 10 (VHI-10) questionnaires were collected preoperatively and 6 months postoperatively. Patients were reached at the time of the study to complete another VHI-10 and a Likert scale survey. Results: The mean decrease in VHI-10 scores between preoperation and 6 months postoperation was 8.35 ( P < .001). From preoperation to the time of the study (average 44 months; range, 12-72 months), the VHI decreased 13.53 ( P < .001). Eighty-eight percent of patients reported they would recommend this surgery to others with the same diagnosis. Only 1 minor self-limited complication occurred. Conclusion: Autologous transplantation of temporalis fascia into the vocal fold for the treatment of vocal fold scar and sulcus vocalis is a safe surgery with good long-term outcomes and high patient satisfaction.
Effects and underlying mechanisms of unstable shoes on chronic low back pain: a randomized controlled trial
Authors: Lisón Juan Francisco , Ortega-Santana Borja , Antón-Nogués Álvaro , González-Requena Palmy , Vera-Hervás Cristina , Doménech-Fernández Julio , Sánchez-Zuriaga Daniel , Salvador-Coloma Pablo 
Published: January 2018

Objective: To investigate the effects that wearing unstable shoes has on disability, trunk muscle activity, and lumbar spine range of motion (ROM) in patients with chronic lower back pain (CLBP). Design: Randomized controlled trial. Setting: Orthopedic Surgery Service. Participants: We randomized 40 adults with nonspecific CLBP either to an unstable shoes group ( n = 20) or to the control group ( n = 20). Intervention: The participants in the unstable shoes group were advised to wear these shoes for a minimum of six hours a day for four weeks. Control group participants were asked to continue wearing their regular shoes. Outcome measures: Our primary outcome was measurement of back-related dysfunction, assessed using the Roland-Morris Disability Questionnaire. Secondary outcomes included changes in electromyographic (EMG) activity of erector spinae (ES), rectus abdominis (RA), internus obliquus (IO), and externus obliquus (EO) muscles, and changes in lumbar spine ROM. Results: Between-group analysis highlighted a significant decrease in disability in the unstable shoes group compared to the control (−5, 95% confidence interval (CI) = −8.4 to −1.6). Our results revealed a significant increase in the percentage of RA, ES, IO, and EO EMG activity and in lumbar spine ROM in the unstable shoes group compared to the control group. Moreover, our results showed a significant negative correlation between disability and the percentage of ES, RA, and IO muscle activity at the end of the intervention. Conclusion: This study shows that the use of unstable shoes contributes to improvements in disability, which are likely related to increased trunk muscle activity and lumbar spine ROM.
Myocardial strain/stress changes identified by echocardiography may reveal early sepsis-induced myocardial dysfunction
Authors: Wang Xiaoting , Su Longxiang , Yang Rongli , Zhang Hongmin , Liu Dawei 
Published: January 2018

Objective To perform early assessment of sepsis-induced myocardial dysfunction (SIMD) using strain/stress echocardiography. Methods A canine model of SIMD was established using intravenous injection of lipopolysaccharide (LPS, 2 mg/kg). Thirteen dogs were included, comprising an LPS-treated SIMD group ( n = 7) and saline control group ( n = 6). SIMD was assessed at various time-points using cardiac measurements including haemodynamics and echocardiography. Results Systolic and radial ventricular wall stress and circular ventricular wall stress (WSsc) were significantly lower in the sepsis group versus the control group at all time-points. Logistic regression analysis revealed an inverse correlation between stress rate of the front-posterior and bottom wall and left ventricle systolic wall strength. In contrast, a positive correlation was found between the mean velocity of circumferential fibre shortening (mVCF) or heart rate-adjusted mVCF (RVCF) and WSsc. Using regression equations, predicted values for mVCF and RVCF in animals with sepsis were significantly higher than measured values at 4- 5- and 6-h time-points. Conclusions These findings will further the understanding of pathophysiological alterations in SIMD at the early stage of sepsis, and suggest that strain rate may reflect the nature of myocardial contractility.
International Entrepreneurship: The State of the Field
Authors: Giamartino Gary A. , McDougall Patricia P. , Bird Barbara J. 
Published: January 2018

Editor's Note: Periodically, it is helpful to take the pulse of our colleagues and determine what is actually being studied and taught. In 1990, the Academy of Management In the United States formed task forces and charged them with surveying Academy members regarding the Internationalization of various management disciplines. The following article reports the results of the survey of Entrepreneurship Division members of the Academy.
Toward Entrepreneurial Organizations: Meeting Ambiguity with Engagement
Authors: Jelinek Mariann , Litterer Joseph A. 
Published: January 2018

Entrepreneurial activities fit poorly with traditional organizational approaches–-the rules, procedures and structure to delimit members’ response that seek to constrain behavior to a predetermined program. Nevertheless, in response to increasing competition, organizations have emerged to support broad entrepreneurial activity. Three interrelated elements appear necessary to support organizational entrepreneurship: pervasive sharing of managerial tasks and responsibilities, mindful alertness to anomalies, and ambiguity absorption by means of mutual support and information sharing. These elements render organizations more flexible, but also increase ambiguity, requiring further action incompatible with traditional organizational approaches. Entrepreneurship is not only inconsistent with traditional organizations, but with traditional organization theory. To effectively analyze entrepreneurial organizations requires a shift from the static, deterministic paradigm of traditional organization and theory to a cognitive paradigm which focuses on individual sensemaking and collective decision processes, and on the organizational context that shapes and influences them. This article outlines basic elements of an emerging cognitive paradigm to describe organizational entrepreneurship in theoretical and pragmatic terms, contrasting with traditional theory and practice. Benefits and hazards of entrepreneurial approaches are discussed. The Implications for research and management practice are also suggested.
Effect of a group medical clinic for veterans with diabetes on body mass index
Authors: Eisenberg Adva , Crowley Matthew J , Coffman Cynthia , Edelman David 
Published: January 2018

Objective To assess the impact of a group medical clinic designed for patient with type 2 diabetes mellitus and hypertension on body mass index. Methods Using data from a randomized trial of 239 veterans with type 2 diabetes mellitus, we performed a secondary analysis using analysis of covariance mixed models to explore the effect of a 12-month group medical clinic intervention on change in body mass index vs. usual care. In an exploratory subgroup analysis, we compared change in body mass index between treatment arms stratified by whether patients had >0.5% reduction in hemoglobin A1c at 12 months. Results Baseline body mass index was 33.5 kg/m2. At 12 months, there was no significant difference in change in body mass index between treatment arms (estimate=−0.02, 95% CI −0.51 to 5.05; P = 0.94); body mass index increased by approximately 0.20 points in both groups. There was also no significant difference in change in body mass index between treatment arms by whether or not patients had >0.5% reduction in hemoglobin A1c (estimate=−0.14, 95% CI −1.21 to −0.92; P = 0.79). Discussion Improved glycemic control was not associated with improved body mass index in the group medical clinic intervention. Given their positive effects on other outcomes, group medical clinics for patients with type 2 diabetes mellitus may be more beneficial if focus is shifted towards weight loss.
PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke
Authors: Sinha Ranjeet K. , Wang Yaoming , Zhao Zhen , Xu Xiao , Burnier Laurent , Gupta Naveen , Fernández José A. , Martin Greg , Kupriyanov Sergey , Mosnier Laurent O. , Zlokovic Berislav V. , Griffin John H. 
Published: January 2018

Key Points
R41Q and R46Q point mutations in PAR1 in mice enabled studies of APC’s in vivo mechanism of action in lethal sepsis and ischemic stroke. APC-biased, PAR1-dependent signaling due to cleavage at R46 in PAR1 is required for APC’s in vivo benefits in sepsis and ischemic stroke.
Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update
Authors: Anderson Kenneth , Ismaila Nofisat , Flynn Patrick J. , Halabi Susan , Jagannath Sundar , Ogaily Mohammed S. , Omel Jim , Raje Noopur , Roodman G. David , Yee Gary C. , Kyle Robert A. 
Published: January 2018

Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw. Additional information is available at www.asco.org/hematologic-malignancies-guidelines and www.asco.org/guidelineswiki .
Randomized Phase IIA Trial of Gemcitabine Compared With Bleomycin Plus Vincristine for Treatment of Kaposi’s Sarcoma in Patients on Combination Antiretroviral Therapy in Western Kenya
Authors: Busakhala Naftali W. , Waako Paul J. , Strother Matthew Robert , Keter Alfred Kipyegon , Kigen Gabriel Kimutai , Asirwa Fredrick Chite , Loehrer Patrick J. 
Published: January 2018

Purpose Kaposi’s sarcoma (KS) is a spindle cell tumor resulting from growth dysregulation in the setting of infection with human herpes virus-8 (also called KS herpes virus). Advanced KS is characterized by poor responses to antiretroviral therapy and some of the chemotherapy readily accessible to patients in low-resource areas. Gemcitabine induced partial and complete regression of AIDS-associated KS (AIDS-KS) in 11 of 24 patients in a pilot study. The current study compares the antimetabolite gemcitabine with the standard care bleomycin and vincristine (BV) in the treatment of chemotherapy-naïve patients with AIDS-KS in a resource-limited setting. Patients and Methods Patients with persistent or progressive KS despite treatment with combined antiretroviral therapy were randomly assigned to receive gemcitabine 1,000 mg/m2 or bleomycin 15 IU/ m2 and vincristine 1.4 mg/m2 given twice weekly. The main end point was objective response by bidirectional measurement, adverse events, and quality of life after three cycles of chemotherapy. Results Of 70 participants enrolled, 36 received gemcitabine and 34 received BV. Complete response was achieved in 12 patients (33.3%) in the gemcitabine arm and six (17.6%) in the BV arm ( P = .175). The partial response rate was 52.8% (n = 19) in the gemcitabine arm and 58.8% (n = 20) in the BV arm. Both study arms reported similar neurologic and hematologic adverse events; there was statistically significant baseline to post-treatment improvement in health-related quality-of-life scores. Conclusion The results of this randomized, phase IIA trial demonstrate gemcitabine activity in chemotherapy-naïve patients with AIDS-KS, on the basis of response rates, adverse events, and health-related quality-of-life scores.