bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved Detection of Respiratory Pathogens by Use of High-Quality Sputum with TaqMan Array Card Technology
Authors: Wolff Bernard J. , Bramley Anna M. , Thurman Kathleen A. , Whitney Cynthia G. , Whitaker Brett , Self Wesley H. , Arnold Sandra R. , Trabue Christopher , Wunderink Richard G. , McCullers Jon , Edwards Kathryn M. , Jain Seema , Winchell Jonas M. 
Published: October 2016

ABSTRACT

New diagnostic platforms often use nasopharyngeal or oropharyngeal (NP/OP) swabs for pathogen detection for patients hospitalized with community-acquired pneumonia (CAP). We applied multipathogen testing to high-quality sputum specimens to determine if more pathogens can be identified relative to NP/OP swabs. Children (<18 years old) and adults hospitalized with CAP were enrolled over 2.5 years through the Etiology of Pneumonia in the Community (EPIC) study. NP/OP specimens with matching high-quality sputum (defined as ≤10 epithelial cells/low-power field [lpf] and ≥25 white blood cells/lpf or a quality score [q-score] definition of 2+) were tested by TaqMan array card (TAC), a multipathogen real-time PCR detection platform. Among 236 patients with matched specimens, a higher proportion of sputum specimens had ≥1 pathogen detected compared with NP/OP specimens in children (93% versus 68%;
P
< 0.0001) and adults (88% versus 61%;
P
< 0.0001); for each pathogen targeted, crossing threshold (

C
T

) values were earlier in sputum. Both bacterial (361 versus 294) and viral detections (245 versus 140) were more common in sputum versus NP/OP specimens, respectively, in both children and adults. When available, high-quality sputum may be useful for testing in hospitalized CAP patients.
Identification of Novel Kaposi's Sarcoma-Associated HerpesvirusOrf50Transcripts: Discovery of New RTA Isoforms with Variable Transactivation Potential
Authors: Wakeman Brian S. , Izumiya Yoshihiro , Speck Samuel H. 
Published: October 2016

ABSTRACTKaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that has been associated with primary effusion lymphoma and multicentric Castleman's disease, as well as its namesake Kaposi's sarcoma. As a gammaherpesvirus, KSHV is able to acutely replicate, enter latency, and reactivate from this latent state. A key protein involved in both acute replication and reactivation from latency is the replication and transcriptional activator (RTA) encoded by the geneOrf50. RTA is a known transactivator of multiple viral genes, allowing it to control the switch between latency and virus replication. We report here the identification of six alternatively splicedOrf50transcripts that are generated from four distinct promoters. These newly identified promoters are shown to be transcriptionally active in 293T (embryonic kidney), Vero (African-green monkey kidney epithelial), 3T12 (mouse fibroblast), and RAW 264.7 (mouse macrophage) cell lines. Notably, the newly identifiedOrf50transcripts are predicted to encode four different isoforms of the RTA which differ by 6 to 10 residues at the amino terminus of the protein. We show the global viral transactivation potential of all four RTA isoforms and demonstrate that all isoforms can transcriptionally activate an array of KSHV promoters to various levels. The pattern of transcriptional activation appears to support a transcriptional interference model within the Orf50 region, where silencing of previously expressed isoforms by transcription initiation from upstream Orf50 promoters has the potential to modulate the pattern of viral gene activation.IMPORTANCEGammaherpesviruses are associated with the development of lymphomas and lymphoproliferative diseases, as well as several other types of cancer. The human gammaherpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), is tightly associated with the development of Kaposi's sarcoma and multicentric Castleman's disease, as well as a rare form of B cell lymphoma (primary effusion lymphoma) primarily observed in HIV-infected individuals. RTA is an essential viral gene product involved in the initiation of gammaherpesvirus replication and is conserved among all known gammaherpesviruses. We show here for KSHV that transcription of the gene encoding RTA is complex and leads to the expression of several isoforms of RTA with distinct functions. This observed complexity in KSHV RTA expression and function likely plays a critical role in the regulation of downstream viral and cellular gene expression, leading to the efficient production of mature virions.
JunD/AP-1 Antagonizes the Induction of
DAPK1
To Promote the Survival of v-Src-Transformed Cells
Authors: Maślikowski Bart M. , Wang Lizhen , Wu Ying , Fielding Ben , Bédard Pierre-André 
Published: October 2016

ABSTRACT

The increase in AP-1 activity is a hallmark of cell transformation by tyrosine kinases. Previously, we reported that blocking AP-1 using the c-Jun dominant negative mutant TAM67 induced senescence, adipogenesis, or apoptosis in v-Src-transformed chicken embryo fibroblasts (CEFs) whereas inhibition of JunD by short hairpin RNA (shRNA) specifically induced apoptosis. To investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEFs expressing either TAM67 or the JunD shRNA. Our study revealed a cluster of 18 probe sets upregulated exclusively in response to AP-1/JunD impairment and v-Src transformation. Four of these probe sets correspond to genes involved in the interferon pathway. One gene in particular, death-associated protein kinase 1 (
DAPK1
), is a C/EBPβ-regulated mediator of apoptosis in gamma interferon (IFN-γ)-induced cell death. Here, we show that inhibition of DAPK1 abrogates cell death in v-Src-transformed cells expressing the JunD shRNA. Chromatin immunoprecipitation data indicated that C/EBPβ was recruited to the DAPK1 promoter while the expression of a dominant negative mutant of C/EBPβ abrogated the induction of DAPK1 in response to the inhibition of AP-1. In contrast, as determined by chromatin immunoprecipitation (ChIP) assays, JunD was not detected on the DAPK1 promoter under any conditions, suggesting that JunD promotes survival by indirectly antagonizing the expression of DAPK1 in v-Src transformed cells.

IMPORTANCE
Transformation by the v-Src oncoprotein causes extensive changes in gene expression in primary cells such as chicken embryo fibroblasts. These changes, determining the properties of transformed cells, are controlled in part at the transcriptional level. Much attention has been devoted to transcription factors such as AP-1 and NF-κB and the control of genes associated with a more aggressive phenotype. In this report, we describe a novel mechanism of action determined by the JunD component of AP-1, a factor enhancing cell survival in v-Src-transformed cells. We show that the loss of JunD results in the aberrant activation of a genetic program leading to cell death. This program requires the activation of the tumor suppressor death-associated protein kinase 1 (DAPK1). Since DAPK1 is phosphorylated and inhibited by v-Src, these results highlight the importance of this kinase and the multiple mechanisms controlled by v-Src to antagonize the tumor suppressor function of DAPK1.
Maternal perceptions of underweight and overweight for 6–8 years olds from a Canadian cohort: reporting weights, concerns and conversations with healthcare providers
Authors: McDonald Sheila W , Ginez Heather K , Vinturache Angela E , Tough Suzanne C 
Published: October 2016

ObjectivesThe majority of mothers do not correctly identify their child's weight status. The reasons for the misperception are not well understood. This study's objective was to describe maternal perceptions of their child's body mass index (BMI) and maternal report of weight concerns raised by a health professional.DesignProspective, community-based cohort.ParticipantsData were collected in 2010 from 450 mothers previously included in a longitudinal birth cohort. Mothers of children aged 6–8 years reported their child's anthropometric measures and were surveyed concerning their opinion about their child's weight. They were also asked if a healthcare provider raised any concerns regarding their child's body weight. Child BMI was categorised according to the WHO Growth Charts adapted for Canada. Descriptive statistics and bivariate analyses were used to evaluate mothers' ability to correctly identify their children's body habitus.Results74% of children had a healthy BMI, 10% were underweight, 9% were overweight and 7% were obese. 80%, 89% and 62% of mothers with underweight, overweight and obese children, respectively, believed that their child was at the right weight. The proportion of mothers who recalled a health professional raising concerns about their child being underweight, overweight, and obese was low (12.5%).ConclusionsThe majority of mothers with children at unhealthy weights misclassified and normalised their child's weight status, and they did not recall a health professional raising concerns regarding their child's weight. The highest rates of child body weight misclassification occurred in overweight children. This suggests that there are missed opportunities for healthcare professionals to improve knowledge exchange and early interventions to assist parents to recognise and support healthy weights for their children.
Lower and upper bounds on the mass of light quark–antiquark scalar resonance in the SVZ sum rules
Authors: Afonin S. S. 
Published: October 2016

The calculation of the mass of light scalar isosinglet meson within the Shifman–Vainshtein–Zakharov (SVZ) sum rules is revisited. We develop simple analytical methods for estimation of hadron masses in the SVZ approach and try to reveal the origin of their numerical values. The calculations of hadron parameters in the SVZ sum rules are known to be heavily based on a choice of the perturbative threshold. This choice requires some important ad hoc information. We show analytically that the scalar mass under consideration has a lower and upper bound which are independent of this choice: [Formula: see text] GeV.
Blood pressure reduction after gastric bypass surgery is explained by a decrease in cardiac output
Authors: van Brussel Peter M. , van den Bogaard Bas , de Weijer Barbara A. , Truijen Jasper , Krediet C.T. Paul , Janssen Ignace M. , van de Laar Arnold , Kaasjager Karin , Fliers Eric , van Lieshout Johannes J. , Serlie Mireille J. , van den Born Bert-Jan H. 
Published: October 2016

Blood pressure (BP) decreases in the first weeks after Roux-and-Y gastric bypass surgery. Yet the pathophysiology of the BP-lowering effects observed after gastric bypass surgery is incompletely understood. We evaluated BP, systemic hemodynamics, and baroreflex sensitivity in 15 obese women[mean age 42 ± 7 standard deviation (SD) yr, body mass index 45 ± 6 kg/m2] 2 wk before and 6 wk following Roux-and-Y gastric bypass surgery. Six weeks after gastric bypass surgery, mean body weight decreased by 13 ± 5 kg (10%, P < 0.001). Office BP decreased from 137 ± 10/86 ± 6 to 128 ± 12/81 ± 9 mmHg ( P < 0.001, P < 0.01), while daytime ambulatory BP decreased from 128 ± 14/80 ± 9 to 114 ± 10/73 ± 6 mmHg ( P = 0.01, P = 0.05), whereas nighttime BP decreased from 111 ± 13/66 ± 7 to 102 ± 9/62 ± 7 mmHg ( P = 0.04, P < 0.01). The decrease in BP was associated with a 1.6 ± 1.2 l/min (20%, P < 0.01) decrease in cardiac output (CO), while systemic vascular resistance increased (153 ± 189 dyn·s·cm−5, 15%, P < 0.01). The maximal ascending slope in systolic blood pressure decreased (192 mmHg/s, 19%, P = 0.01), suggesting a reduction in left ventricular contractility. Baroreflex sensitivity increased from 9.0 [6.4–14.3] to 13.8 [8.5–19.0] ms/mmHg (median [interquartile range]; P < 0.01) and was inversely correlated with the reductions in heart rate ( R = −0.64, P = 0.02) and CO ( R = −0.61, P = 0.03). In contrast, changes in body weight were not correlated with changes in either BP or CO. The BP reduction following Roux-and-Y gastric bypass surgery is correlated with a decrease in CO independent of changes in body weight. The contribution of heart rate to the reduction in CO together with enhanced baroreflex sensitivity suggests a shift toward increased parasympathetic cardiovascular control. NEW & NOTEWORTHY The reason for the decrease in blood pressure (BP) in the first weeks after gastric bypass surgery remains to be elucidated. We show that the reduction in BP following surgery is caused by a decrease in cardiac output. In addition, the maximal ascending slope in systolic blood pressure decreased suggesting a reduction in left ventricular contractility and cardiac workload. These findings help to understand the physiological changes following gastric bypass surgery and are relevant in light of the increased risk of heart failure in these patients.
Role of the Microenvironment in Liver Metastasis: From Pre- to Prometastatic Niches
Authors: Brodt Pnina 
Published: October 2016

Abstract
Liver metastases remain a major barrier to successful management of malignant disease, particularly for cancers of the gastrointestinal tract but also for other malignancies, such as breast carcinoma and melanoma. The ability of metastatic cells to survive and proliferate in the liver is determined by the outcome of complex, reciprocal interactions between tumor cells and different local resident subpopulations, including the sinusoidal endothelium, stellate, Kupffer, and inflammatory cells that are mediated through cell–cell and cell–extracellular matrix adhesion and the release of soluble factors. Cross-communication between different hepatic resident cells in response to local tissue damage and inflammation and the recruitment of bone marrow cells further enhance this intercellular communication network. Both resident and recruited cells can play opposing roles in the progression of metastasis, and the balance of these divergent effects determines whether the tumor cells will die, proliferate, and colonize the new site or enter a state of dormancy. Moreover, this delicate balance can be tilted in favor of metastasis, if factors produced by the primary tumor precondition the microenvironment to form niches of activated resident cells that promote tumor expansion. This review aims to summarize current knowledge on these diverse interactions and the impact they can have on the clinical management of hepatic metastases. Clin Cancer Res; 22(24); 5971–82. ©2016 AACR.
An Open-Label, Dose–Escalation Phase I Study of Anti-TYRP1 Monoclonal Antibody IMC-20D7S for Patients with Relapsed or Refractory Melanoma
Authors: Khalil Danny N. , Postow Michael A. , Ibrahim Nageatte , Ludwig Dale L. , Cosaert Jan , Kambhampati Siva Rama Prasad , Tang Shande , Grebennik Dmitri , Kauh John Sae Wook , Lenz Heinz-Josef , Flaherty Keith T. , Hodi F. Stephen , Lawrence Donald P. , Wolchok Jedd D. 
Published: October 2016

Abstract
Purpose: Tyrosinase-related protein-1 (TYRP1) is a transmembrane glycoprotein that is specifically expressed in melanocytes and melanoma cells. Preclinical data suggest that mAbs targeting TYRP1 confer antimelanoma activity. IMC-20D7S is a recombinant human IgG1 mAb targeting TYRP1. Here, we report the first-in-human phase I/Ib trial of IMC-20D7S.
Experimental Design: The primary objective of this study was to establish the safety profile and the MTD of IMC-20D7S. Patients with advanced melanoma who progressed after or during at least one line of treatment or for whom standard therapy was not indicated enrolled in this standard 3 + 3 dose–escalation, open-label study. IMC-20D7S was administered intravenously every 2 or 3 weeks.
Results: Twenty-seven patients were enrolled. The most common adverse events were fatigue and constipation experienced by nine (33%) and eight (30%) patients, respectively. There were no serious adverse events related to treatment, no discontinuations of treatment due to adverse events, and no treatment-related deaths. Given the absence of dose-limiting toxicities, an MTD was not defined, but a provisional MTD was established at the 20 mg/kg every 2-week dose based on serum concentration and safety data. One patient experienced a complete response. A disease control rate, defined as stable disease or better, of 41% was observed.
Conclusion: IMC-20D7S is well tolerated among patients with advanced melanoma with evidence of antitumor activity. Further investigation of this agent as monotherapy in selected patients or as part of combination regimens is warranted. Clin Cancer Res; 22(21); 5204–10. ©2016 AACR.
Significant Effect of Polymorphisms inCYP2D6on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study
Authors: Zembutsu Hitoshi , Nakamura Seigo , Akashi-Tanaka Sadako , Kuwayama Takashi , Watanabe Chie , Takamaru Tomoko , Takei Hiroyuki , Ishikawa Takashi , Miyahara Kana , Matsumoto Hiroshi , Hasegawa Yoshie , Kutomi Goro , Shima Hiroaki , Satomi Fukino , Okazaki Minoru , Zaha Hisamitsu , Onomura Mai , Matsukata Ayami , Sagara Yasuaki , Baba Shinichi , Yamada Akimitsu , Shimada Kazuhiro , Shimizu Daisuke , Tsugawa Koichiro , Shimo Arata , Tan Ern Yu , Hartman Mikael , Chan Ching-Wan , Lee Soo Chin , Nakamura Yusuke 
Published: October 2016

AbstractPurpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 patients with hormone receptor–positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.
Preclinical Efficacy of an Antibody–Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET
Authors: Terwisscha van Scheltinga Anton G.T. , Ogasawara Annie , Pacheco Glenn , Vanderbilt Alexander N. , Tinianow Jeff N. , Gupta Nidhi , Li Dongwei , Firestein Ron , Marik Jan , Scales Suzie J. , Williams Simon-Peter 
Published: October 2016

Abstract
Antibody–drug conjugates (ADC) use monoclonal antibodies (mAb) as vehicles to deliver potent cytotoxic drugs selectively to tumor cells expressing the target. Molecular imaging with zirconium-89 (89Zr)-labeled mAbs recapitulates similar targeting biology and might help predict the efficacy of these ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was used to make comparisons between its efficacy as an ADC and its tumor uptake as measured by 89Zr immunoPET imaging. Mesothelin-targeted tumor growth inhibition by monomethyl auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), was measured in mice bearing xenografts of ovarian cancer OVCAR-3×2.1, pancreatic cancers Capan-2, HPAC, AsPC-1, and HPAF-II, or mesothelioma MSTO-211H. Ex vivo analysis of mesothelin expression was performed using immunohistochemistry. AMA-MMAE showed the greatest growth inhibition in OVCAR-3×2.1, Capan-2, and HPAC tumors, which showed target-specific tumor uptake of 89Zr-AMA. The less responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did not show 89Zr-AMA uptake despite confirmed mesothelin expression. ImmunoPET can demonstrate the necessary delivery, binding, and internalization of an ADC antibody in vivo and this correlates with the efficacy of mesothelin-targeted ADC in tumors vulnerable to the cytotoxic drug delivered. Mol Cancer Ther; 16(1); 134–42. ©2016 AACR.
Exosomal Annexin II Promotes Angiogenesis and Breast Cancer Metastasis
Authors: Maji Sayantan , Chaudhary Pankaj , Akopova Irina , Nguyen Phung M. , Hare Richard J. , Gryczynski Ignacy , Vishwanatha Jamboor K. 
Published: October 2016

AbstractTumor-derived exosomes are emerging mediators of tumorigenesis and tissue-specific metastasis. Proteomic profiling has identified Annexin II as one of the most highly expressed proteins in exosomes; however, studies focused on the biological role of exosomal Annexin II (exo-Anx II) are still lacking. In this study, mechanistic insight was sought regarding exo-Anx II and its function in angiogenesis and breast cancer metastasis. Multiple in vitro and in vivo techniques were used to study the role of exo-Anx II in angiogenesis. Using atomic force microscopy and Western blotting, exo-Anx II expression was characterized in normal and breast cancer cells. In addition, organ-specific metastatic breast cancer cells and animal models were used to define the role exo-Anx II in breast cancer metastasis. Results revealed that exo-Anx II expression is significantly higher in malignant cells than normal and premetastatic breast cancer cells. In vitro and in vivo studies demonstrated that exo-Anx II promotes tPA-dependent angiogenesis. Furthermore, in vivo analysis indicated that metastatic exosomes create a favorable microenvironment for metastasis, and exo-Anx II plays an important role in this process, as priming with Anx II-depleted exosomes reduces brain (∼4-fold) and lung (∼2-fold) metastasis. Upon delineating the mechanism, it was discovered that exo-Anx II causes macrophage-mediated activation of the p38MAPK, NF-κB, and STAT3 pathways and increased secretion of IL6 and TNFα. These data demonstrate an important role for exo-Anx II in breast cancer pathogenesis.Implications: Exosome-associated Annexin II plays an important role in angiogenesis and breast cancer metastasis, which can be exploited as a potential biomarker as well as a therapeutic target for diagnosis and treatment of metastatic breast cancer. Mol Cancer Res; 15(1); 93–105. ©2016 AACR.