bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biallelic DICER1 Mutations in Sporadic Pleuropulmonary Blastoma
Authors: Seki Masafumi , Yoshida Kenichi , Shiraishi Yuichi , Shimamura Teppei , Sato Yusuke , Nishimura Riki , Okuno Yusuke , Chiba Kenichi , Tanaka Hiroko , Kato Keisuke , Kato Motohiro , Hanada Ryoji , Nomura Yuko , Park Myoung-Ja , Ishida Toshiaki , Oka Akira , Igarashi Takashi , Miyano Satoru , Hayashi Yasuhide , Ogawa Seishi , Takita Junko 
Published: March 2014

Abstract
Pleuropulmonary blastoma (PPB) is a rare pediatric malignancy whose pathogens are poorly understood. Recent reports suggest that germline mutations in the microRNA-processing enzyme DICER1 may contribute to PPB development. To investigate the genetic basis of this cancer, we performed whole-exome sequencing or targeted deep sequencing of multiple cases of PPB. We found biallelic DICER1 mutations to be very common, more common than TP53 mutations also found in many tumors. Somatic ribonuclease III (RNase IIIb) domain mutations were identified in all evaluable cases, either in the presence or absence of nonsense/frameshift mutations. Most cases had mutated DICER1 alleles in the germline with or without an additional somatic mutation in the remaining allele, whereas other cases displayed somatic mutations exclusively where the RNase IIIb domain was invariably affected. Our results highlight the role of RNase IIIb domain mutations in DICER1 along with TP53 inactivation in PPB pathogenesis. Cancer Res; 74(10); 2742–9. ©2014 AACR.
BCR-ABL–Induced Deregulation of the IL-33/ST2 Pathway in CD34(+) Progenitors from Chronic Myeloid Leukemia Patients
Authors: Levescot Anaïs , Flamant Stéphane , Basbous Sara , Jacomet Florence , Féraud Olivier , Anne Bourgeois Elvire , Bonnet Marie-Laure , Giraud Christine , Roy Lydia , Barra Anne , Chomel Jean-Claude , Turhan Ali , Guilhot François , Girard Jean-Philippe , Gombert Jean-Marc , Herbelin André 
Published: March 2014

Abstract
Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33–specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL–transfected bone marrow progenitors was less efficient in IL-33–deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance. Cancer Res; 74(10); 2669–76. ©2014 AACR.
Molecular Mechanisms of Bone Metastasis and Associated Muscle Weakness
Authors: Waning David L. , Guise Theresa A. 
Published: March 2014

Abstract
Bone is a preferred site for breast cancer metastasis and leads to pathologic bone loss due to increased osteoclast-induced bone resorption. The homing of tumor cells to the bone depends on the support of the bone microenvironment in which the tumor cells prime the premetastatic niche. The colonization and growth of tumor cells then depend on adaptations in the invading tumor cells to take advantage of normal physiologic responses by mimicking bone marrow cells. This concerted effort by tumor cells leads to uncoupled bone remodeling in which the balance of osteoclast-driven bone resorption and osteoblast-driven bone deposition is lost. Breast cancer bone metastases often lead to osteolytic lesions due to hyperactive bone resorption. Release of growth factors from bone matrix during resorption then feeds a “vicious cycle” of bone destruction leading to many skeletal-related events. In addition to activity in bone, some of the factors released during bone resorption are also known to be involved in skeletal muscle regeneration and contraction. In this review, we discuss the mechanisms that lead to osteolytic breast cancer bone metastases and the potential for cancer-induced bone-muscle cross-talk leading to skeletal muscle weakness. Clin Cancer Res; 20(12); 3071–7. ©2014 AACR.
Genetic Modification of T Cells Redirected toward CS1 Enhances Eradication of Myeloma Cells
Authors: Chu Jianhong , He Shun , Deng Youcai , Zhang Jianying , Peng Yong , Hughes Tiffany , Yi Ling , Kwon Chang-Hyuk , Wang Qi-En , Devine Steven M. , He Xiaoming , Bai Xue-Feng , Hofmeister Craig C. , Yu Jianhua 
Published: March 2014

Abstract
Purpose: Our goal is to test whether CS1 could be targeted by chimeric antigen receptor (CAR) T cells to treat multiple myeloma (MM).
Experimental Design: We generated a retroviral construct of a CS1-specific CAR and engineered primary human T cells expressing the CAR. We then tested the capacity of CS1–CAR T cells to eradicate human MM tumor cells in vitro, ex vivo, and in vivo using orthotopic MM xenograft mouse models.
Results: In vitro, compared with mock-transduced T cells, upon recognizing CS1-positive MM cells, CS1–CAR-transduced T cells secreted more IFN-γ as well as interleukin (IL)-2, expressed higher levels of the activation marker CD69, showed higher capacity for degranulation, and displayed enhanced cytotoxicity. Ectopically forced expression of CS1 in MM cells with low CS1 expression enhanced recognition and killing by CAR T cells. Ex vivo, CS1–CAR T cells also showed similarly enhanced activities when responding to primary MM cells. More importantly, in orthotopic MM xenograft mouse models, adoptive transfer of human primary T cells expressing CS1–CAR efficiently suppressed the growth of human MM.1S and IM9 myeloma cells and significantly prolonged mouse survival.
Conclusions: CS1 is a promising antigen that can be targeted by CAR-expressing T cells for treatment of MM. Clin Cancer Res; 20(15); 3989–4000. ©2014 AACR.
Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia
Authors: Friedrich Matthias , Henn Anja , Raum Tobias , Bajtus Monika , Matthes Katja , Hendrich Larissa , Wahl Joachim , Hoffmann Patrick , Kischel Roman , Kvesic Majk , Slootstra Jerry W. , Baeuerle Patrick A. , Kufer Peter , Rattel Benno 
Published: March 2014

Abstract
There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell–engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid–binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3ϵ of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC50 values ranging between 0.4 pmol/L and 3 pmol/L (18–149 pg/mL) by previously resting, AMG 330–redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-γ, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG 330 warrants further development as a potential therapy for AML. Mol Cancer Ther; 13(6); 1549–57. ©2014 AACR.
The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Authors: Friboulet Luc , Li Nanxin , Katayama Ryohei , Lee Christian C. , Gainor Justin F. , Crystal Adam S. , Michellys Pierre-Yves , Awad Mark M. , Yanagitani Noriko , Kim Sungjoon , Pferdekamper AnneMarie C. , Li Jie , Kasibhatla Shailaja , Sun Frank , Sun Xiuying , Hua Su , McNamara Peter , Mahmood Sidra , Lockerman Elizabeth L. , Fujita Naoya , Nishio Makoto , Harris Jennifer L. , Shaw Alice T. , Engelman Jeffrey A. 
Published: March 2014

Abstract
Non–small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.
Significance: The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease. Cancer Discov; 4(6); 662–73. ©2014 AACR.
See related commentary by Ramalingam and Khuri, p. 634
This article is highlighted in the In This Issue feature, p. 621
Supporting Roles of Platelet Thrombospondin-1 and CD36 in Thrombus Formation on Collagen
Authors: Kuijpers Marijke J.E. , de Witt Susanne , Nergiz-Unal Reyhan , van Kruchten Roger , Korporaal Suzanne J.A. , Verhamme Peter , Febbraio Maria , Tjwa Marc , Voshol Peter J. , Hoylaerts Marc F. , Cosemans Judith M.E.M. , Heemskerk Johan W.M. 
Published: March 2014

Objective—
Platelets abundantly express the membrane receptor CD36 and store its ligand thrombospondin-1 (TSP1) in the α-granules. We investigated whether released TSP1 can support platelet adhesion and thrombus formation via interaction with CD36.

Approach and Results—
Mouse platelets deficient in CD36 showed reduced adhesion to TSP1 and subsequent phosphatidylserine expression. Deficiency in either CD36 or TSP1 resulted in markedly increased dissolution of thrombi formed on collagen, although thrombus buildup was unchanged. In mesenteric vessels in vivo, deficiency in CD36 prolonged the time to occlusion and enhanced embolization, which was in agreement with earlier observations in TSP1-deficient mice. Thrombi formed using wild-type blood stained positively for secreted TSP1. Releasate from wild-type but not from TSP1-deficient platelets enhanced platelet activation, phosphatidylserine expression, and thrombus formation on collagen. The enhancement was dependent on CD36 because it was without effect on thrombus formation by CD36-deficient platelets.

Conclusions—
These results demonstrate an anchoring role of platelet-released TSP1 via CD36 in platelet adhesion and collagen-dependent thrombus stabilization. Thus, the TSP1–CD36 tandem is another platelet ligand–receptor axis contributing to the maintenance of a stable thrombus.
Nicotinic Acid Activates the Capsaicin Receptor TRPV1
Authors: Ma Linlin , Lee Bo Hyun , Mao Rongrong , Cai Anping , Jia Yunfang , Clifton Heather , Schaefer Saul , Xu Lin , Zheng Jie 
Published: March 2014

Objective—
Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food.

Approach and Results—

We observed that the nicotinic acid–induced increase in blood flow was substantially reduced in
Trpv1
–/–
knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1.

Conclusions—
Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.
Crucial Role of Rho-Kinase in Pressure Overload–Induced Right Ventricular Hypertrophy and Dysfunction in Mice
Authors: Ikeda Shohei , Satoh Kimio , Kikuchi Nobuhiro , Miyata Satoshi , Suzuki Kota , Omura Junichi , Shimizu Toru , Kobayashi Kenta , Kobayashi Kazuto , Fukumoto Yoshihiro , Sakata Yasuhiko , Shimokawa Hiroaki 
Published: March 2014

Objective—
Right ventricular (RV) failure is the leading cause of death in various cardiopulmonary diseases, including pulmonary hypertension. It is generally considered that the RV is vulnerable to pressure overload as compared with the left ventricle (LV). However, as compared with LV failure, the molecular mechanisms of RV failure are poorly understood, and hence therapeutic targets of the disorder remain to be elucidated. Thus, we aimed to identify molecular therapeutic targets for RV failure in a mouse model of pressure overload.

Approach and Results—
To induce pressure overload to respective ventricles, we performed pulmonary artery constriction or transverse aortic constriction in mice. We first performed microarray analysis and found that the molecules related to RhoA/Rho-kinase and integrin pathways were significantly upregulated in the RV with pulmonary artery constriction compared with the LV with transverse aortic constriction. Then, we examined the responses of both ventricles to chronic pressure overload in vivo. We demonstrated that compared with transverse aortic constriction, pulmonary artery constriction caused greater extents of mortality, Rho-kinase expression (especially ROCK2 isoform), and oxidative stress in pressure-overloaded RV, reflecting the weakness of the RV in response to pressure overload. Furthermore, mice with myocardial-specific overexpression of dominant-negative Rho-kinase showed resistance to pressure overload–induced hypertrophy and dysfunction associated with reduced oxidative stress. Finally, dominant-negative Rho-kinase mice showed a significantly improved long-term survival in both pulmonary artery constriction and transverse aortic constriction as compared with littermate controls.

Conclusion—
These results indicate that the Rho-kinase pathway plays a crucial role in RV hypertrophy and dysfunction, suggesting that the pathway is a novel therapeutic target of RV failure in humans.
Consistency of Blood Pressure Control After Ischemic Stroke
Authors: Towfighi Amytis , Markovic Daniela , Ovbiagele Bruce 
Published: March 2014

Background and Purpose—
Blood pressure (BP) reduction lowers vascular risk after stroke; however, little is known about the relationship between consistency of BP control and risk of subsequent vascular events.

Methods—
In this post hoc analysis of the Vitamin Intervention for Stroke Prevention trial (n=3680), individuals with recent (<120 days) stroke, followed up for 2 years, were divided according to proportion of visits in which BP was controlled (<140/90 mm Hg): <25%, 25% to 49%, 50% to 74%, and ≥75%. Multivariable models adjusting for demographic and clinical variables determined the association between consistency of BP control versus primary (stroke) and secondary (stroke, myocardial infarction, or vascular death) outcomes.

Results—
Only 30% of participants had BP controlled ≥75% of the time. Consistency of BP control affected outcomes in individuals with baseline systolic BP >132 mm Hg. Among individuals with baseline systolic BP >75th percentile (>153 mm Hg), risks of primary and secondary outcomes were lower in those with BP controlled ≥75% versus <25% of visits (adjusted hazard ratio, 0.46; 95% confidence interval, 0.26–0.84 and adjusted hazard ratio, 0.51; 95% confidence interval, 0.32–0.82). Individuals with mean follow-up BP <140/90 mm Hg had lower risk of primary and secondary outcomes than those with BP ≥140/90 mm Hg (adjusted hazard ratio, 0.76; 95% confidence interval, 0.59–0.98 and adjusted hazard ratio, 0.76; 95% confidence interval, 0.62–0.92).

Conclusions—
In this rigorous clinical trial, fewer than one third of patients with stroke had BP controlled ≥75% of the time for 2 years. Furthermore, consistency of BP control among those with elevated baseline systolic BP was linked to reduction in risk of recurrent stroke and stroke, myocardial infarction, and vascular death.
Methadone and oedema in the palliative care setting: a case report and review of the literature
Authors: Dawson Camilla , Paterson Fiona , McFatter Fiona , Buchanan Deans 
Published: March 2014

Introduction Methadone is a synthetic opioid which is being used with increased frequency in the palliative care setting for management of complex pain. There have been cases published reporting the development of oedema with methadone maintenance therapy but no cases on the association with methadone and peripheral oedema in the palliative care setting. As yet, the underlying mechanisms are unclear. Case presentation This case report describes a gentleman with ependymoma and difficult-to-control lower back pain and scrotal pain. This pain had failed to respond to other strong opioids. He was prescribed methadone and then subsequently developed bilateral peripheral oedema. Case management Peripheral oedema resolved following cessation of methadone. Conclusions This highlights an important potential adverse effect of methadone in a society of increased methadone prescription for pain control. The published literature to date is reviewed and possible underlying mechanisms explored.
The Relationship of Worry About Hypoglycemia With Diabetes-specific and Typical Youth Behavior Among Emerging Adults With Type 1 Diabetes
Authors: Hanna Kathleen M. , Weaver Michael T. , Stump Timothy E. , Fortenberry J. Dennis , DiMeglio Linda A. 
Published: March 2014

Purpose Little is known about the relationship of worry about hypoglycemia with diabetes-specific and typical youth behaviors among emerging adults with type 1 diabetes. This study’s purpose was to examine the relationship among worry about hypoglycemia, diabetes management, and glycemic control within the context of alcohol use, hypoglycemia-related weight control behaviors, depressive symptoms, and impulse control among emerging adults with type 1 diabetes. Research Design and Methods The sample was 181 emerging adults with type 1 diabetes who were part of a larger study. Path analysis was used to test associations among worry about hypoglycemia, diabetes management, hypoglycemia-related weight control behaviors (WCB), alcohol use, impulse control, depressive symptoms, and glycemic control. Results Path model fit and modification indices suggested that a feedback loop between worry about hypoglycemia and diabetes management should be incorporated into the original model. Youth with fewer depressive symptoms reported fewer hypoglycemia-related WCB and less worry about hypoglycemia; those with higher impulse control had less alcohol use and better diabetes management; those with lower alcohol use had more worry about hypoglycemia; and better glycemic control was associated with better diabetes management. Conclusions Health care professionals need to understand how multiple factors related to worry about hypoglycemia and diabetes management interact in emerging adults. In the context of depressive symptoms, impulse control, alcohol use, and hypoglycemia-related WCB, the path model results suggest several potential avenues for intervening to improve glycemic control in emerging adults.
Malignant Otitis Externa: Evolving Pathogens and Implications for Diagnosis and Treatment
Authors: Hobson Candace E. , Moy Jennifer D. , Byers Karin E. , Raz Yael , Hirsch Barry E. , McCall Andrew A. 
Published: March 2014

ObjectiveMalignant otitis externa (MOE) is an invasive infection of the temporal bone that is classically caused by Pseudomonas aeruginosa. Increasingly, however, nonpseudomonal cases are being reported. The goal of this study was to evaluate and compare the clinical presentation and outcomes of cases of MOE caused by Pseudomonas versus non‐Pseudomonas organisms.Study DesignRetrospective case series with chart review.SettingTertiary care institution.Subjects and MethodsAdult patients with diagnoses of MOE between 1995 and 2012 were identified. Charts were reviewed for history, clinical presentation, laboratory data, treatment, and outcomes.ResultsTwenty patients diagnosed with and treated for MOE at the University of Pittsburgh Medical Center between 1995 and 2012 were identified. Nine patients (45%) had cultures that grew P aeruginosa. Three patients (15%) had cultures that grew methicillin‐resistant Staphylococcus aureus (MRSA). Signs and symptoms at presentation were similar across groups. However, all of the patients with Pseudomonas had diabetes, compared with 33% of MRSA‐infected patients (P =. 046) and 55% of all non‐Pseudomonas‐infected patients (P =. 04). Patients infected with MRSA were treated for an average total of 4.7 more weeks of antibiotic therapy than Pseudomonas‐infected patients (P =. 10). Overall, patients with non‐Pseudomonas infections were treated for a total of 2.4 more weeks than Pseudomonas‐infected patients (P =. 25).ConclusionsA high index of suspicion for nonpseudomonal organisms should be maintained in patients with signs and symptoms of MOE, especially in those without diabetes. MRSA is an increasingly implicated organism in MOE.