bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment with apolipoprotein A1 protects mice against doxorubicin-induced cardiotoxicity in a scavenger receptor class B, type I-dependent manner
Authors: Durham Kristina K. , Kluck George , Mak Kei Cheng , Deng Yak D. , Trigatti Bernardo L. 
Published: April 2019

Doxorubicin, an agent used to treat a variety of cancers, is cardiotoxic by triggering cardiomyocyte apoptosis. We previously showed that treating cultured cardiomyocytes with human high-density lipoprotein in vitro or transgenic overexpression of human apolipoprotein A1, its main structural protein, protects against doxorubicin-induced cardiomyocyte apoptosis in a manner dependent on the scavenger receptor class B type I [Durham KK, Chathely KM, Mak KC, Momen A, Thomas CT, Zhao YY, MacDonald ME, Curtis JM, Husain M, Trigatti BL. HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, phosphatidylinositol 3-kinase-, and Akt-dependent manner. Am J Physiol Heart Circ Physiol 314: H31–H44, 2018]. This was due to high-density lipoprotein-induced activation of Akt signaling in cardiomyocytes. We now demonstrate that mice lacking the scavenger receptor class B, type I exhibit increased sensitivity to doxorubicin-induced cardiomyocyte apoptosis in vivo. Cardiomyocytes expressing scavenger receptor class B, type I are protected from doxorubicin-induced apoptosis by preincubation with high-density lipoprotein isolated from wild-type mice, whereas high-density lipoprotein from scavenger receptor class B, type 1 knockout mice is less effective. Cardiomyocytes from scavenger receptor class B, type I knockout mice, however, are not protected by high-density lipoprotein in vitro, and hearts from knockout mice are more sensitive to doxorubicin in vivo. Pharmacological administration of purified apolipoprotein A1 dramatically protected wild-type mice from doxorubicin-induced cardiotoxicity and left ventricular dysfunction, whereas this protection was lost in scavenger receptor class B, type I-deficient mice. This demonstrates, at least in mice, that high-density lipoprotein therapy can confer protection against doxorubicin-induced cardiomyocyte apoptosis in a manner mediated by the scavenger receptor class B, type I.NEW & NOTEWORTHY We show that scavenger receptor class B, type I (SR-B1) mediates HDL-dependent protection against doxorubicin-induced cardiomyocyte apoptosis and that this is a property of SR-B1 in cardiomyocytes in vitro and in hearts in vivo. We also demonstrate that pharmacological treatment with apolipoprotein A1, the major HDL structural protein, protects mice against doxorubicin-induced cardiomyocyte apoptosis and left ventricular dysfunction in an SR-B1-dependent manner. This suggests that HDL-targeted pharmacological therapy may hold promise for protecting against the deleterious, cardiotoxic side effects of this commonly used chemotherapeutic drug.
Chemotherapy acutely impairs neurovascular and hemodynamic responses in women with breast cancer
Authors: Sales Allan Robson Kluser , Negrão Marcelo Vailati , Testa Laura , Ferreira-Santos Larissa , Groehs Raphaela Villar Ramalho , Carvalho Bruna , Toschi-Dias Edgar , Rocha Natalia Galito , Laurindo Francisco Rafael Martins , Debbas Victor , Rondon Maria Urbana P. B. , Mano Max Sena , Hajjar Ludhmila Abrahao , Hoff Paulo Marcelo Gehm , Filho Roberto Kalil , Negrão Carlos Eduardo 
Published: April 2019

The purpose of the present study was to test the hypothesis that doxorubicin (DX) and cyclophosphamide (CY) adjuvant chemotherapy (CHT) acutely impairs neurovascular and hemodynamic responses in women with breast cancer. Sixteen women (age: 47.0 ± 2.0 yr; body mass index: 24.2 ± 1.5 kg/m) with stage II-III breast cancer and indication for adjuvant CHT underwent two experimental sessions, saline (SL) and CHT. In the CHT session, DX (60 mg/m2) and CY (600 mg/m2) were administered over 45 min. In the SL session, a matching SL volume was infused in 45 min. Muscle sympathetic nerve activity (MSNA) from peroneal nerve (microneurography), calf blood flow (CBF; plethysmography) and calf vascular conductance (CVC), heart rate (HR; electrocardiography), and beat-to-beat blood pressure (BP; finger plethysmography) were measured at rest before, during, and after each session. Venous blood samples (5 ml) were collected before and after both sessions for assessment of circulating endothelial microparticles (EMPs; flow cytometry), a surrogate marker for endothelial damage. MSNA and BP responses were increased ( P < 0.001), whereas CBF and CVC responses were decreased ( P < 0.001), during and after CHT session when compared with SL session. Interestingly, the vascular alterations were also observed at the molecular level through an increased EMP response to CHT ( P = 0.03, CHT vs. SL session). No difference in HR response was observed ( P > 0.05). Adjuvant CHT with DX and CY in patients treated for breast cancer increases sympathetic nerve activity and circulating EMP levels and, in addition, reduces muscle vascular conductance and elevates systemic BP. These responses may be early signs of CHT-induced cardiovascular alterations and may represent potential targets for preventive interventions. NEW & NOTEWORTHY It is known that chemotherapy regimens increase the risk of cardiovascular events in patients treated for cancer. Here, we identified that a single cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide in women treated for breast cancer dramatically increases sympathetic nerve activity and circulating endothelial microparticle levels, reduces the muscle vascular conductance, and elevates systemic blood pressure.
A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and Extrinsic Contributions to Consensus Molecular Subtypes in Primary and Metastatic Colon Cancer
Authors: Piskol Robert , Huw Ling , Sergin Ismail , Kljin Christiaan , Modrusan Zora , Kim Doris , Kljavin Noelyn , Tam Rachel , Patel Rajesh , Burton Jeremy , Penuel Elicia , Qu Xueping , Koeppen Hartmut , Sumiyoshi Teiko , de Sauvage Frederic , Lackner Mark R. , de Sousa e Melo Felipe , Kabbarah Omar 
Published: April 2019

Abstract

Purpose:
Four consensus molecular subtypes (CMS1–4) of colorectal cancer were identified in primary tumors and found to be associated with distinctive biological features and clinical outcomes. Given that distant metastasis largely accounts for colorectal cancer–related mortality, we examined the molecular and clinical attributes of CMS in metastatic colorectal cancer (mCRC).

Experimental Design:
We developed a colorectal cancer–focused NanoString-based CMS classifier that is ideally suited to interrogate archival tissues. We successfully used this panel in the CMS classification of formalin-fixed paraffin-embedded (FFPE) tissues from mCRC cohorts, one of which is composed of paired primary tumors and metastases. Finally, we developed novel mouse implantation models to enable modeling of colorectal cancer in vivo at relevant sites.

Results:
Using our classifier, we find that the biological hallmarks of mCRC, including CMS, are in general highly similar to those observed in nonmetastatic early-stage disease. Importantly, our data demonstrate that CMS1 has the worst outcome in relapsed disease, compared with other CMS. Assigning CMS to primary tumors and their matched metastases reveals mostly concordant subtypes between primary and metastasis. Molecular analysis of matched discordant pairs reveals differences in stromal composition at each site. The development of two novel in vivo orthotopic implantation models further reinforces the notion that extrinsic factors may impact on CMS identification in matched primary and metastatic colorectal cancer.

Conclusions:
We describe the utility of a NanoString panel for CMS classification of FFPE clinical samples. Our work reveals the impact of intrinsic and extrinsic factors on colorectal cancer heterogeneity during disease progression.
A Constitutional Activating MET Mutation Makes the Genetic Link between Malignancies and Chronic Inflammatory Diseases
Authors: El Bouchtaoui Morad , Do Cruzeiro Marcio , Leboeuf Christophe , Loisel-Ferreira Irmine , Fedronie Carèle , Ferreira Chrystophe , Ait El Far Rachida , Ziol Marianne , Espié Marc , Falgarone Géraldine , Cassinat Bruno , Kiladjian Jean-Jacques , Feugeas Jean-Paul , Janin Anne , Bousquet Guilhem 
Published: April 2019

Abstract

Purpose:
The genesis of all cancers results from an accumulation of mutations, constitutional and/or acquired when induced by external mutagenic factors. High-speed technologies for genome sequencing have completely changed the study of disease genetics, but with limited knowledge of the functional value of most genetic changes.

Experimental Design:
Here, we proposed an innovative individual approach by studying tissue samples from a young woman with an unusual association of breast cancer, polycythemia vera, and rheumatoid arthritis. We performed genomic analyses for copy number variations and point mutations on laser-microdissected tumor cells from the breast cancer, and on CD34+ cells sorted from bone marrow aspiration, to identify gene abnormalities common to these two types of cell populations.

Results:
Using ONCOSCAN technology, we identified a constitutional pR988C, c2962C&gt;T mutation of MET. Using CRISPR-Cas9 technology, we established pR988C MET-mutated transgenic mice, which reproduced the autoimmune diseases and myeloproliferation found in our index-case; one of the transgenic mice spontaneously developed a skin squamous cell carcinoma. We also showed that additional mutagenic factors were required to induce cancers, including skin squamous cell carcinoma and thyroid cancer. Using an anti-MET drug, cabozantinib, we demonstrated for the first time the functional role of this mutation in the maintenance of myeloproliferation and rheumatoid arthritis, and in cancer genesis.

Conclusions:
Our study opens a considerable field of application in the domain of constitutional genetics, to establish genetic links between cancers and other very different severe diseases.
Comparative Analysis of AR Variant AR-V567es mRNA Detection Systems Reveals Eminent Variability and Questions the Role as a Clinical Biomarker in Prostate Cancer
Authors: Bernemann Christof , Humberg Verena , Thielen Barbara , Steinestel Julie , Chen Xin , Duensing Stefan , Schrader Andres J. , Boegemann Martin 
Published: April 2019

Abstract

Purpose:
Androgen receptor splice variants are known to facilitate resistance of prostate cancer cells toward antihormonal therapies. However, detection of the most prominent variant, AR-V7, on its own, is not sufficiently accurate for prediction of response. Thus, simultaneous detection of other variants might improve prediction. AR-V567es has been shown to be expressed in late stages of prostate cancer. Yet, there have been discrepant results regarding incidence of AR-V567es. We therefore aimed to perform a comprehensive comparison of different detection approaches for AR-V567es mRNA.

Experimental Design:
We compared a custom-made, probe-based PCR assay with 6 published AR-V567es detection PCR assays in distinct samples, that is, cancer cell lines, LuCaP xenografts, primary and metastatic tumor samples, and circulating tumor cells (CTC).

Results:
Using distinct approaches, we concordantly detected expression of AR-V567es in only three of 45 samples (LuCaP xenografts 86.2 and 136s2 as well as one CTC sample). We observed varying results in all other samples. Specificity analysis displayed nonspecific binding of 5 previously published PCR assays to AR full-length mRNA in the absence of AR-V567es.

Conclusions:
Validation of biomarker detection approaches is one of the most critical steps before transfer into clinical application. By performing comparative analysis of different detection approaches, we revealed eminent variability among previously described systems. Furthermore, we demonstrate an overestimation of AR-V567es in prostate cancer, presumably due to nonspecific detection of AR-FL mRNA. Therefore, any correlation between AR-V567es expression and clinical responses is highly doubtful and does not reflect the biological nature of the disease.
Phenotypic and Genomic Determinants of Immunotherapy Response Associated with Squamousness
Authors: Goodman Aaron M. , Kato Shumei , Chattopadhyay Ranajoy , Okamura Ryosuke , Saunders Ila M. , Montesion Meagan , Frampton Garrett M. , Miller Vincent A. , Daniels Gregory A. , Kurzrock Razelle 
Published: April 2019

Abstract
Advanced and metastatic squamous cell carcinomas (SCC) are common and difficult-to-treat malignancies. We assessed 75 immunotherapy-treated patients with SCC from a clinically annotated database of 2,651 patients, as well as 9,407 patients from a deidentified database for molecular features that might influence checkpoint blockade response. SCCs had higher tumor mutational burdens (TMB) than non-SCCs (P &lt; 0.0001). Cutaneous SCCs had the highest TMB (P &lt; 0.0001), with 41.3% demonstrating a very high TMB (≥50 mutations/Mb). In immunotherapy-treated patients with SCC, higher TMB (≥12 mutations/Mb) correlated with a trend to higher clinical benefit rate [stable disease ≥ 6 months or partial/complete remission; 60% vs. 29%; (high vs. low TMB); P = 0.06] and significantly longer median time-to-treatment failure (TTF; 9.9 vs. 4.4 months; P = 0.0058). Cutaneous SCCs had the highest clinical benefit [11/15 patients (73%) vs. 20/60 (33%) non-cutaneous (P = 0.008)], TTF (P = 0.0015), and overall survival (P = 0.06) with immunotherapy treatment. In conclusion, among a diverse set of SCCs, higher TMB and cutaneous disease associated with better immunotherapy outcome.
СИНТЕЗ ТА ПРОТИПУХЛИННА АКТИВНІСТЬ 2-(1H-БЕНЗІМІДАЗОЛ-2-ІЛ)- І 2-БЕНЗТІАЗОЛ-2-ІЛ-3-(5-АРИЛФУРАН-2-ІЛ)АКРИЛОНІТРИЛІВ
Authors: Matiichuk Yu. Е. , Ogurtsov V. V. , Matiychuk V. S. 
Published: April 2019

Мета роботи. Синтез та дослідження протипухлинної активності 2-(1H-бензімідазол-2-іл)- і 2-бензтіазол-2-іл-3-(5-арилфуран-2-іл)акрилонітрилів.
Матеріали і методи. Органічний синтез, 1Н ЯМР спектроскопія, елементний аналіз, фармакологічний скринінг.
Результати й обговорення. Взаємодією 5-арилфурфуролів з (1H-бензімідазол-2-іл)- та бензтіазол-2-ілацетонітрилом отримано ряд нових 2-(1H-бензімідазол-2-іл)- та 2-бензтіазол-2-іл-3-(5-арилфуран-2-іл)акрилонітрилів. Структуру синтезованих сполук підтверджено елементним аналізом та спектроскопією 1Н ЯМР. Здійснено дослідження біологічної активності синтезованих сполук. Встановлено, що вони проявляють протипухлинну дію різного рівня зі значеннями mean GP = 32.11 – 102.31%.
Висновки. Розроблено методику синтезу 2-(1H-бензімідазол-2-іл)- та 2-бензтіазол-2-іл-3-(5-арилфуран-2-іл)акрилонітрилів. Досліджено протипухлинну активність синтезованих сполук. Ідентифіковано сполуку-хіт – 2-(1H-бензімідазол-2-іл)-3-[5-(4-хлорофеніл)фуран-2-іл]-акрилонітрил, перспективну для подальшої оптимізації.
A Pragmática comunicativa em uma feira de Belém
Authors: Xavier Fábio Rodrigo de Moraes , Castro Marina Ramos Neves de , Castro Fábio Fonseca de 
Published: April 2019

Este artigo objetiva refletir sobre a pragmática comunicativa existente na feira do Guamá, localizada em Belém do Pará, na Amazônia brasileira. Nós procuramos observar, a partir de uma aproximação etnográfica, a movimentação social e as práticas de interação comunicativa os sujeitos ali presentes em relação às dinâmicas de ocupação do espaço e à disposição dos produtos ali vendidos. A investigação evidencia a estruturação organizacional em sua dinâmica intersubjetiva e, a partir dessa perspectiva, observamos o desenvolvimento da ideia de lugar e a identificação que as pessoas desenvolvem com a localidade dentro de processos estéticos. Para reflexão, neste artigo utilizamos textos do teórico Maffesoli em que trata de localidade e práticas sociais no cotidiano. Também utilizamos a obra de Schutz quando interpretamos as práticas sociais através de tipificação nas estruturas sociais; assim como usamos a compreensão de forma social de Simmel.
On the Role of the Atmospheric Energy Transport in 2 × CO2–Induced Polar Amplification in CESM1
Authors: Graversen Rune G. , Langen Peter L. 
Published: April 2019

AbstractA doubling of the atmospheric CO2 content leads to global warming that is amplified in the polar regions. The CO2 forcing also leads to a change of the atmospheric energy transport. This transport change affects the local warming induced by the CO2 forcing. Using the Community Earth System Model (CESM), the direct response to the transport change is investigated. Divergences of the transport change associated with a CO2 doubling are implemented as a forcing in the 1 × CO2 preindustrial control climate. This forcing is zero in the global mean. In response to a CO2 increase in CESM, the northward atmospheric energy transport decreases at the Arctic boundary. However, the transport change still leads to a warming of the Arctic. This is due to a shift between dry static and latent transport components, so that although the dry static transport decreases, the latent transport increases at the Arctic boundary, which is consistent with other model studies. Because of a greenhouse effect associated with the latent transport, the cooling caused by a change of the dry static component is more than compensated for by the warming induced by the change of the latent transport. Similar results are found for the Antarctic region, but the transport change is larger in the Southern Hemisphere than in its northern counterpart. As a consequence, the Antarctic region warms to the extent that this warming leads to global warming that is likely enhanced by the surface albedo feedback associated with considerable ice retreat in the Southern Hemisphere.
Using A-Train Observations to Evaluate Cloud Occurrence and Radiative Effects in the Community Atmosphere Model during the Southeast Asia Summer Monsoon
Authors: Berry Elizabeth , Mace Gerald G. , Gettelman Andrew 
Published: April 2019

AbstractThe distribution of clouds and their radiative effects in the Community Atmosphere Model, version 5 (CAM5), are compared to A-Train satellite data in Southeast Asia during the summer monsoon. Cloud radiative kernels are created based on populations of observed and modeled clouds separately in order to compare the sensitivity of the TOA radiation to changes in cloud fraction. There is generally good agreement between the observation- and model-derived cloud radiative kernels for most cloud types, meaning that the clouds in the model are heating and cooling like clouds in nature. Cloud radiative effects are assessed by multiplying the cloud radiative kernel by the cloud fraction histogram. For ice clouds in particular, there is good agreement between the model and observations, with optically thin cirrus producing a moderate warming effect and cirrostratus producing a slight cooling effect, on average. Consistent with observations, the model also shows that the median value of the ice water path (IWP) distribution, rather than the mean, is a more representative measure of the ice clouds that are responsible for heating. In addition, in both observations and the model, it is cirrus clouds with an IWP of 20 g m−2 that have the largest warming effect in this region, given their radiative heating and frequency of occurrence.
Fractionation of impulsive and compulsive trans-diagnostic phenotypes and their longitudinal associations
Authors: Chamberlain Samuel R , Tiego Jeggan , Fontenelle Leonardo F , Hook Roxanne , Parkes Linden , Segrave Rebecca , Hauser Tobias U , Dolan Ray J , Goodyer Ian M , Bullmore Ed , Grant Jon E , Yücel Murat 
Published: April 2019

Objective: Young adulthood is a crucial neurodevelopmental period during which impulsive and compulsive problem behaviours commonly emerge. While traditionally considered diametrically opposed, impulsive and compulsive symptoms tend to co-occur. The objectives of this study were as follows: (a) to identify the optimal trans-diagnostic structural framework for measuring impulsive and compulsive problem behaviours, and (b) to use this optimal framework to identify common/distinct antecedents of these latent phenotypes. Method: In total, 654 young adults were recruited as part of the Neuroscience in Psychiatry Network, a population-based cohort in the United Kingdom. The optimal trans-diagnostic structural model capturing 33 types of impulsive and compulsive problem behaviours was identified. Baseline predictors of subsequent impulsive and compulsive trans-diagnostic phenotypes were characterised, along with cross-sectional associations, using partial least squares. Results: Current problem behaviours were optimally explained by a bi-factor model, which yielded dissociable measures of impulsivity and compulsivity, as well as a general disinhibition factor. Impulsive problem behaviours were significantly explained by prior antisocial and impulsive personality traits, male gender, general distress, perceived dysfunctional parenting and teasing/arguments within friendships. Compulsive problem behaviours were significantly explained by prior compulsive traits and female gender. Conclusion: This study demonstrates that trans-diagnostic phenotypes of 33 impulsive and compulsive problem behaviours are identifiable in young adults, utilising a bi-factor model based on responses to a single questionnaire. Furthermore, these phenotypes have different antecedents. The findings yield a new framework for fractionating impulsivity and compulsivity, and suggest different early intervention targets to avert emergence of problem behaviours. This framework may be useful for future biological and clinical dissection of impulsivity and compulsivity.
Pediatric Tracheostomy Decannulation: 11‐Year Experience
Authors: Seligman Kristen L. , Liming Bryan J. , Smith Richard J. H. 
Published: April 2019

ObjectiveTo determine the successful decannulation rate with a published pediatric tracheostomy decannulation protocol.Study DesignCase series with chart review.SettingA single tertiary care institution.Subjects and MethodsA chart review was performed for patients aged ≤5 years who underwent tracheostomy. Extracted data included demographic data, indication for tracheostomy, age at tracheostomy and decannulation, comorbidities, and surgical complications. Records were searched for documentation of early decannulation failure (within 1 month of decannulation) or late failure (within 1 year).ResultsForty patients with a tracheostomy aged ≤5 years underwent attempted decannulation during the 11‐year study period. Seventeen patients were excluded from the study for documentation of nonprotocol decannulation. The final study population of 23 patients underwent a total of 27 decannulations, 26 of which were performed by protocol. Of the 26 protocol decannulations, 22 were successful, for a failure rate of 15%.ConclusionTwenty‐six protocol decannulations were attempted among 23 patients, 4 of which were unsuccessful for an overall failure rate of 15%. This result is consistent with rates reported in other published decannulation protocols. We believe that our protocol minimizes resource utilization in its use of pulse oximetry over polysomnography, while maximizing patient safety and success through the use of capping trials for very young and very small pediatric patients.