bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance
Authors: Beltran Himisha , Hruszkewycz Andrew , Scher Howard I. , Hildesheim Jeffrey , Isaacs Jennifer , Yu Evan Y. , Kelly Kathleen , Lin Daniel , Dicker Adam , Arnold Julia , Hecht Toby , Wicha Max , Sears Rosalie , Rowley David , White Richard , Gulley James L. , Lee John , Diaz Meco Maria , Small Eric J. , Shen Michael , Knudsen Karen , Goodrich David W. , Lotan Tamara , Zoubeidi Amina , Sawyers Charles L. , Rudin Charles M. , Loda Massimo , Thompson Timothy , Rubin Mark A. , Tawab-Amiri Abdul , Dahut William , Nelson Peter S. 
Published: July 2019

Abstract
Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell–like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.
Natural Killer Cell Recruitment and Activation Are Regulated by CD47 Expression in the Tumor Microenvironment
Authors: Nath Pulak Ranjan , Pal-Nath Dipasmita , Mandal Ajeet , Cam Margaret C. , Schwartz Anthony L. , Roberts David D. 
Published: July 2019

Abstract
Elevated CD47 expression in some cancers is associated with decreased survival and limited clearance by phagocytes expressing the CD47 counterreceptor SIRPα. In contrast, elevated CD47 mRNA expression in human melanomas was associated with improved survival. Gene-expression data were analyzed to determine a potential mechanism for this apparent protective function and suggested that high CD47 expression increases recruitment of natural killer (NK) cells into the tumor microenvironment. The CD47 ligand thrombospondin-1 inhibited NK cell proliferation and CD69 expression in vitro. Cd47−/− NK cells correspondingly displayed augmented effector phenotypes, indicating an inhibitory function of CD47 on NK cells. Treating human NK cells with a CD47 antibody that blocks thrombospondin-1 binding abrogated its inhibitory effect on NK cell proliferation. Similarly, treating wild-type mice with a CD47 antibody that blocks thrombospondin-1 binding delayed B16 melanoma growth, associating with increased NK cell recruitment and increased granzyme B and interferon-γ levels in intratumoral NK but not CD8+ T cells. However, B16 melanomas grew faster in Cd47−/− than in wild-type mice. Melanoma-bearing Cd47−/− mice exhibited decreased splenic NK cell numbers, with impaired effector protein expression and elevated exhaustion markers. Proapoptotic gene expression in Cd47−/− NK cells was associated with stress-mediated increases in mitochondrial proton leak, reactive oxygen species, and apoptosis. Global gene-expression profiling in NK cells from tumor-bearing mice identified CD47-dependent transcriptional responses that regulate systemic NK activation and exhaustion. Therefore, CD47 positively and negatively regulates NK cell function, and therapeutic antibodies that block inhibitory CD47 signaling can enhance NK immune surveillance of melanomas.
Senster: Reactivation of a Cybernetic Sculpture
Authors: Olszewska Anna , Długosz Marek 
Published: July 2019

Abstract
The turbulent history of Senster, a large cybernetic sculpture designed by Edward Ihnatowicz c. 1970, is divided in two periods: its creation and prematurely canceled display (1968–1974) and its recent reactivation (2017–2018). This article presents a comprehensive narrative of Senster's reactivation. It explains how the formulation of the conservation philosophy and methodology employed in the process was instrumental in delivering the solutions. Based on these observations, the authors propose a detailed strategy for the maintenance and reactivation of interactive embodied systems.
A Geometric Interpretation of Southern Ocean Eddy Form Stress
Authors: Poulsen Mads B. , Jochum Markus , Maddison James R. , Marshall David P. , Nuterman Roman 
Published: July 2019

AbstractAn interpretation of eddy form stress via the geometry described by the Eliassen–Palm flux tensor is explored. Complimentary to previous works on eddy Reynolds stress geometry, this study shows that eddy form stress is fully described by a vertical ellipse, whose size, shape, and orientation with respect to the mean flow shear determine the strength and direction of vertical momentum transfers. Following a recent proposal, this geometric framework is here used to form a Gent–McWilliams eddy transfer coefficient that depends on eddy energy and a nondimensional geometric parameter α, bounded in magnitude by unity. The parameter α expresses the efficiency by which eddies exchange energy with baroclinic mean flow via along-gradient eddy buoyancy flux—a flux equivalent to eddy form stress along mean buoyancy contours. An eddy-resolving ocean general circulation model is used to estimate the spatial structure of α in the Southern Ocean and assess its potential to form a basis for parameterization. The eddy efficiency α averages to a low but positive value of 0.043 within the Antarctic Circumpolar Current, consistent with an inefficient eddy field extracting energy from the mean flow. It is found that the low eddy efficiency is mainly the result of that eddy buoyancy fluxes are weakly anisotropic on average. The eddy efficiency is subject to pronounced vertical structure and is maximum at ~3-km depth, where eddy buoyancy fluxes tend to be directed most downgradient. Since α partly sets the eddy form stress in the Southern Ocean, a parameterization for α must reproduce its vertical structure to provide a faithful representation of vertical stress divergence and eddy forcing.
Clinical Traits Characterizing an Exacerbation‐Prone Phenotype in Chronic Rhinosinusitis
Authors: Phillips Katie M. , Barbarite Eric , Hoehle Lloyd P. , Caradonna David S. , Gray Stacey T. , Sedaghat Ahmad R. 
Published: July 2019

ObjectiveAcute exacerbation of chronic rhinosinusitis (AECRS) is associated with significant quality‐of‐life decreases. We sought to determine characteristics associated with an exacerbation‐prone phenotype in chronic rhinosinusitis (CRS).Study DesignCross‐sectional.SettingTertiary care rhinology clinic.SubjectsPatients with CRS (N = 209).MethodsPatient‐reported number of sinus infections, CRS‐related antibiotics, and CRS‐related oral corticosteroids taken in the last 12 months were used as metrics for AECRS frequency. Sinonasal symptom burden was assessed with the 22‐item Sinonasal Outcome Test (SNOT‐22). Ninety patients reporting 0 for all AECRS metrics were considered to have had no AECRS in the prior 12 months. A total of 119 patients reported >3 on at least 1 AECRS metric and were considered as having an exacerbation‐prone phenotype. Characteristics associated with patients with an exacerbation‐prone phenotype were identified with exploratory regression analysis.ResultsAn exacerbation‐prone phenotype was positively associated with comorbid asthma (adjusted odds ratio [ORadj] = 3.68, 95% CI: 1.42‐9.50, P =. 007) and SNOT‐22 (ORadj = 1.06, 95% CI: 1.04‐1.09, P <. 001). Polyps were negatively associated (ORadj = 0.27, 95% CI: 0.11‐0.68, P =. 005) with an exacerbation‐prone phenotype. SNOT‐22 score ≥24 identified patients with an exacerbation‐prone phenotype with a sensitivity of 93.3% and a specificity of 57.8%. Having either a SNOT‐22 score ≥24 with a nasal subdomain score ≥12 or a SNOT‐22 score ≥24 with an ear/facial discomfort subdomain score ≥3 provided >80% sensitivity and specificity for detecting patients prone to exacerbation.ConclusionsIn total, these results point to a CRS exacerbation‐prone phenotype characterized by high sinonasal disease burden with comorbid asthma but interestingly without polyps.
Pattern of Intraoperative Parathyroid Hormone and Calcium in the Treatment of Tertiary Hyperparathyroidism
Authors: Casarim André Luís Maion , Arcadipane Fernando Antonio Maria Claret , Martins Antonio Santos , Del Negro André , Rodrigues André Afonso Nimtz , Tincani Alfio Jose , Marchi Evaldo 
Published: July 2019

ObjectiveTertiary hyperparathyroidism, an autonomous hyperproduction of parathyroid hormone (PTH), has a challenge in its treatment. This study asked whether the intraoperative PTH and calcium drop can confirm the resection of all parathyroid tissues.Study DesignCase series with planned data collection.SettingTertiary referral medical center.Subjects and MethodsThe study assessed patients with tertiary hyperparathyroidism who were treated at the Hospital of the State University of Campinas from 2007 to 2015. All patients underwent total parathyroidectomy with autotransplantation of parathyroid fragments. PTH and calcium were collected during the preoperative period; at 10, 20, and 240 minutes after resection of the glands; and at 1 year after the procedure. Data were analyzed by analysis of variance and logistic regression analysis with statistical values of P <. 05.ResultsThirty‐five patients were assessed: 17 women (48.57%) and 18 men (51.43%). The percentage of PTH drop was statistically significant at all times, unlike the calcium analysis, but only PTH collected at 20 minutes was able to confirm the removal of all parathyroid tissues (P =. 029). Based on the receiver operating characteristic curve, the 71.2% drop obtained high sensitivity and specificity (P =. 028).ConclusionsTreatment success can be predicted by analyzing the decrease of intraoperative PTH and not by calcium. The 71.2% PTH drop at 20 minutes after parathyroidectomy had high sensitivity and specificity to predict surgical cure.
Brain endothelial specific gene therapy improves experimental Sandhoff disease
Authors: Dogbevia Godwin , Grasshoff Hanna , Othman Alaa , Penno Anke , Schwaninger Markus 
Published: July 2019

In Tay-Sachs and Sandhoff disease, a deficiency of the lysosomal enzyme β-hexosaminidase causes GM2 and other gangliosides to accumulate in neurons and triggers neurodegeneration. Although the pathology centers on neurons, β-hexosaminidase is mainly expressed outside of neurons, suggesting that gene therapy of these diseases should target non-neuronal cells to reconstitute physiological conditions. Here, we tested in Hexb−/− mice, a model of Sandhoff disease, to determine whether endothelial expression of the genes for human β-hexosaminidase subunit A and B ( HEXA, HEXB) is able to reduce disease symptoms and prolong survival of the affected mice. The brain endothelial selective vectors AAV-BR1-CAG- HEXA and AAV-BR1-CAG- HEXB transduced brain endothelial cells, which subsequently released β-hexosaminidase enzyme. In vivo intravenous administration of the gene vectors to adult and neonatal mice prolonged survival. They improved neurological function and reduced accumulation of the ganglioside GM2 and the glycolipid GA2 as well as astrocytic activation. Overall, the data demonstrate that endothelial cells are a suitable target for intravenous gene therapy of GM2 gangliosidoses and possibly other lysosomal storage disorders.
Lupus-like symptoms with anti-RNP/Sm and anti-nuclear antibodies positivity: An extremely rare adverse event of dasatinib
Authors: Maral Senem , Bakanay Sule Mine , Kucuksahin Orhan , Dilek Imdat 
Published: July 2019

Introduction Dasatinib is a potent tyrosine-kinase inhibitor which is used for chronic myeloid leukemia treatment. Pleural effusion is a frequent side effect in patients during dasatinib treatment. Pulmonary arterial hypertension is a rare and life-threatening adverse event of dasatinib. The relationship between dasatinib and autoimmune disorders is unclear, but there are reports of possible mechanisms that have triggered autoimmunity by dasatinib. Case report A 53-year-old male was diagnosed with chronic myeloid leukemia and initiated imatinib mesylate as a treatment. Imatinib was changed to dasatinib as the patient was unresponsive in the first year of treatment. In the fourth year of dasatinib when chronic myeloid leukemia was in both hematological and cytogenetical remission, the patient presented with bilateral massive exudative pleural effusion. Echocardiography was consistent with pericardial effusion with right ventricle enlargement and normal left-side cardiac function. Pulmonary arterial hypertension was diagnosed with high systolic pulmonary arterial pressure. When he had fever and arthralgia, further investigation showed positivity of anti-nuclear antibodies (1/160 titer) and anti-RNP/Sm, which have high specificity for the diagnosis of Systemic Lupus Erythematosus (SLE). Management and outcome Dasatinib was discontinued and nilotinib was initiated. As the pleural effusion persisted despite diuretics and methylprednisolone, mycophenolate mofetil was initiated as a steroid-sparing immune-suppressive agent. The lupus-like symptoms disappeared, and antibodies became undetectable after dasatinib discontinuation. Pericardial effusion improved and pleural effusion did not relapse. Discussion Screening for auto-antibodies may be recommended for patients with a history or symptoms of autoimmune disease before starting dasatinib. All patients who develop pleural effusion while on dasatinib treatment should be investigated for antibodies for lupus.
Patient Attitudes Toward Testicular Prosthesis Placement After Orchiectomy
Authors: Srivatsav Ashwin , Balasubramanian Adithya , Butaney Mohit , Thirumavalavan Nannan , McBride J. Abram , Gondokusumo Jabez , Pastuszak Alexander W. , Lipshultz Larry 
Published: July 2019

Orchiectomy is the standard of care for many testicular conditions. Testicular prosthesis placement (TPP) can mitigate psychosocial burden, restore self-image, and improve quality of life for patients requiring orchiectomy. Limited data exist regarding patient attitudes and counseling on TPP in the United States. The objective of this study was to characterize patient experiences after TPP, rationale for pursuing/declining TPP, and satisfaction levels. Patients with a history of urologic conditions warranting orchiectomy were identified and sent an anonymous survey addressing demographics, pre/post counseling, attitudes toward TPP, satisfaction rates, and postoperative complications. Sixteen percent (76/480) of patients completed the survey. Of these, 50.8% (32/63) undergoing orchiectomy were counseled by their surgeon about TPP, and 22.2% (14/63) received a prosthesis. The most common reasons for declining TPP included lack of concern for cosmetic appearance and lack of counseling. Leading reasons for pursuing TPP included improving self-confidence and cosmetic appearance. Although 71% (10/14) of patients were satisfied with TPP, they did highlight areas for improvement. Twenty percent (2/10) felt their implant was too high, 60% (6/10) felt their implant was too firm, 10% (1/10) endorsed discomfort during sex, and 30% (3/10) felt that TPP did not match their size expectations. Despite these findings, 71% (10/14) reported that they would have TPP again and 79% (11/14) would recommend TPP to others. TPP improves body image and quality of life following orchiectomy. Provider counseling plays an important role in influencing a patient’s decision to undergo TPP. Areas of improvement include implant positioning and more effective replication of testicular consistency.
Iloprost treatment on top of infrapopliteal angioplasty accelerates wound healing in critical leg ischemia
Authors: K Ay Nuray , Inan Bekir 
Published: July 2019

Objectives This study aimed to examine the efficacy of the concomitant use of infrapopliteal drug-eluting balloon angioplasty and a medical treatment (iloprost) in the treatment of critical leg ischemia. Methods Eighty-seven patients that underwent infrapopliteal drug-eluting balloon angioplasty for critical leg ischemia were included in this retrospective study. For analyses, patients were allocated into one of the two groups: 55 patients that underwent drug-eluting balloon angioplasty alone (drug-eluting balloon Group), and 32 patients that received intravenous iloprost for one week after drug-eluting balloon (DEB-I Group). Demographic, perioperative and follow-up clinical data were extracted retrospectively and analyzed. Results Duration of hospitalization was significantly longer in the DEB-I group (9.7 vs. 3.1 days, p < 0.001); however, the two groups were similar in terms of other clinical outcomes including early postoperative mortality, and primary patency, wound healing, reintervention, mortality, and amputation rates at one year ( p > 0.05 for all). Primary patency was similar across groups. Wound healing occurred earlier in the DEB-I group when compared to drug-eluting balloon group, in the subgroup of patients with ischemic wound at baseline. Mean time to wound healing was 3.0 ± 0.6 and 4.4 ± 0.6 months in DEB-I and drug-eluting balloon groups, respectively ( p = 0.037). Conclusions Iloprost add-on treatment in patients undergoing drug-eluting balloon angioplasty for critical limb ischemia seems to have additional benefits, at least in terms of accelerated wound healing. Further large prospective studies are warranted.
Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy
Authors: Ballantyne Christie M , Laufs Ulrich , Ray Kausik K , Leiter Lawrence A , Bays Harold E , Goldberg Anne C , Stroes Erik SG , MacDougall Diane , Zhao Xin , Catapano Alberico L 
Published: July 2019

Aims The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy. Methods This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol. Results Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (–36.2%) significantly more than placebo (1.8% (placebo-corrected difference –38.0%); P < 0.001), ezetimibe alone (–23.2%; P < 0.001) or bempedoic acid alone (–17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo. Conclusion The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk. Trial Registration ClinicalTrials.gov identifier: NCT03337308.
When “unclear headache” has an obvious reason—Applying ID-Migraine™ to referral letters
Authors: Kluser Stephanie , Chan Andrew , Meier Niklaus 
Published: July 2019

Background: Migraine is underdiagnosed especially by general practitioners and non-neurologists. In our experience, validated screening and diagnosing tools for migraine are generally not used outside neurology. The three-item identification of migraine (ID-Migraine™) is a short and validated screening/diagnosing tool; positive predictive value for migraine is 93% if at least two out of nausea, photophobia, or disability are present. Aim: To investigate the diagnostic yield of ID-Migraine™ when applied to the information provided in the referral letters. Methods: Retrospective analysis of 95 referral letters of patients referred for undetermined headache who were finally diagnosed with migraine at our Tertiary Care Headache Center. Results: Median age was 34 years, and 75% were women. Migraine was suspected by the referring physician in 33% of patients, whereas the remainder were classified as unclear. ID-Migraine™ criteria were fulfilled in 59% of patients with referral diagnosis of suspected migraine and 23% of patients with unclear headache, respectively. Clinical characteristics associated with migraine suspicion were photophobia and other visual symptoms. Conclusion: Applying ID-Migraine™ in primary care, emergency departments, or in specialists’ consultations outside neurology might lead to an increased frequency of migraine recognition. Knowledge about and access to those criteria should be increased, especially in the primary care setting.