bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project
Authors: Karaa Amel , Rahman Shamima , Lombès Anne , Yu‐Wai‐Man Patrick , Sheikh Muniza K. , Alai‐Hansen Sherita , Cohen Bruce H. , Dimmock David , Emrick Lisa , Falk Marni J. , McCormack Shana , Mirsky David , Moore Tony , Parikh Sumit , Shoffner John , Taivassalo Tanja , Tarnopolsky Mark , Tein Ingrid , Odenkirchen Joanne C. , Goldstein Amy ,   on behalf of the Mito Working Group Member Participants:
Published: March 2017

AbstractObjectivesThe common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research.MethodsNine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use.ResultsThe NINDS Mito CDEs and supporting documents are publicly available on the NINDS CDE website (https://commondataelements.ninds.nih.gov/), organized into domain categories such as Participant/Subject Characteristics, Assessments, and Examinations.ConclusionWe developed a comprehensive set of CDE recommendations, data definitions, case report forms (CRFs), and guidelines for use in Mito clinical research. The widespread use of CDEs is intended to enhance Mito clinical research endeavors, including natural history studies, clinical trial design, and data sharing. Ongoing international collaboration will facilitate regular review, updates and online publication of Mito CDEs, and support improved consistency of data collection and reporting.
Human mass balance study and metabolite profiling of 14C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer
Authors: van Andel Lotte , Zhang Z. , Lu S. , Kansra V. , Agarwal S. , Hughes L. , Tibben M. M. , Gebretensae A. , Lucas L. , Hillebrand M. J. X. , Rosing H. , Schellens J. H. M. , Beijnen J. H. 
Published: March 2017

SummaryNiraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status. This study evaluates the absorption, metabolism and excretion (AME) of 14C–niraparib, administered to six patients as a single oral dose of 300 mg with a radioactivity of 100 μCi. Total radioactivity (TRA) in whole blood, plasma, urine and faeces was measured using liquid scintillation counting (LSC) to obtain the mass balance of niraparib. Moreover, metabolite profiling was performed on selected plasma, urine and faeces samples using liquid chromatography – tandem mass spectrometry (LC-MS/MS) coupled to off-line LSC. Mean TRA recovered over 504 h was 47.5% in urine and 38.8% in faeces, indicating that both renal and hepatic pathways are comparably involved in excretion of niraparib and its metabolites. The elimination of 14C–radioactivity was slow, with t1/2 in plasma on average 92.5 h. Oral absorption of 14C–niraparib was rapid, with niraparib concentrations peaking at 2.49 h, and reaching a mean maximum concentration of 540 ng/mL. Two major metabolites were found: the known metabolite M1 (amide hydrolysed niraparib) and the glucuronide of M1. Based on this study it was shown that niraparib undergoes hydrolytic, and conjugative metabolic conversions, with the oxidative pathway being minimal.
Should Genetic Testing be Offered for Children? The Perspectives of Adolescents and Emerging Adults in Families with Li‐Fraumeni Syndrome
Authors: Alderfer Melissa A. , Lindell Robert B. , Viadro Claire I. , Zelley Kristin , Valdez Jessica , Mandrell Belinda , Ford Carol A. , Nichols Kim E. 
Published: March 2017

AbstractWhether children should be offered genetic testing for cancer risk is much debated but young voices are rarely heard in these conversations. The current study explored perspectives of genetic testing held by adolescents and emerging adults in families with Li Fraumeni syndrome (LFS). Twelve 12‐ to 25‐year‐olds in families with LFS completed qualitative interviews for this study. All believed that testing should be offered for children but many qualified this statement saying parental approval would be needed and testing should be optional. Genetic testing was seen as way to learn of risk status, allow for disease prevention efforts, and reduce uncertainty and anxiety. Perceived disadvantages included negative emotions associated with the testing result. Participants generally felt that children should be involved in the testing decision, but that parents could unilaterally decide to have a child tested in certain circumstances (e.g., young age, high risk). All who were aware of having been tested and of their test result (n= 7; 4 positive) said testing had no negative impact on their outlook and they agreed with the decision to undergo testing. Implications of these findings for clinical practice and future research are discussed.
BP: Time for a Change
Authors: Townsley Jesse R 
Published: March 2017

AbstractThis article proposes a solution to the problem of defining the “present” in the BP time scale as 1950. Discouraging the use of “Before Present,” as well as “Before Physics,” and promoting Radiocarbon’s official definition of “BP is understood as a symbol meaning precisely ‘conventional radiocarbon years before AD 1950’” is advised.
Accurate Radiocarbon Dating of Archaeological Ash Using Pyrogenic Aragonite
Authors: Toffolo Michael B , Regev Lior , Mintz Eugenia , Poduska Kristin M , Shahack-Gross Ruth , Berthold Christoph , Miller Christopher E , Boaretto Elisabetta 
Published: March 2017

AbstractObtaining accurate age determinations from minerals in archaeological ash is a major unsolved issue in radiocarbon (14C) dating. This is because the original14C content of calcite, the main component of ash, is altered by isotopic exchange. Pyrogenic aragonite, another mineral phase recently discovered in ash, might preserve its14C signature through time. Using a new method based on density separation and step combustion, we were able to isolate and date aragonitic ash from an archaeological destruction horizon of known age. Here we show that the14C age of aragonite matches the age of the destruction horizon. Our results demonstrate that pyrogenic aragonite is a short-lived material suitable for14C dating and directly related to human activities involving the use of fire, thus bearing major implications for the establishment of absolute chronologies for the past 50,000 yr.
A revised model for the crustal structure of the SW Grenville Province, Ontario, Canada
Authors: DICKIN ALAN , STRONG JACOB , ARCURI GABRIEL , VAN KESSEL ANNIKA , KRIVANKOVA-SMAL LUCIA 
Published: March 2017

AbstractThe Grenville Province forms the exhumed remnants of a 1.1 Ga collisional orogeny that telescoped an older continental margin. Terranes with distinct crustal formation ages can be mapped using Nd isotopes, revealing a ramp–flat thrust structure. The ramp is identified by the presence of retrogressed eclogites, and its trajectory is refined using Nd model ages. The main allochthon is locally overlain by the Parry Sound klippe, but is also underlain by a tectonic duplex. Northwest-directed nappes represent remnants of a corrugated thrust sheet, but a ring-shaped remnant was also preserved where the thrust sheet was down-buckled under the dense rocks of Parry Sound domain.
Lurasidone for major depressive disorder with mixed features and irritability: a post-hoc analysis
Authors: Swann Alan C. , Fava Maurizio , Tsai Joyce , Mao Yongcai , Pikalov Andrei , Loebel Antony 
Published: March 2017

ObjectiveThe aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating major depressive disorder (MDD) with mixed features including irritability.MethodsThe data in this analysis were derived from a study of patients meeting DSM–IV–TR criteria for unipolar MDD, with a Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, and who were randomized to 6 weeks of double-blind treatment with either lurasidone 20–60 mg/d (n=109) or placebo (n=100). We defined “irritability” as a score ≥2 on both the Young Mania Rating Scale (YMRS) irritability item (#5) and the disruptive-aggressive item (#9). Endpoint change in the MADRS and YMRS items 5 and 9 were analyzed using a mixed model for repeated measures for patients with and without irritability.ResultsSome 20.7% of patients met the criteria for irritability. Treatment with lurasidone was associated with a significant week 6 change vs. placebo in MADRS score in both patients with (–22.6 vs. –9.5,p<0.0001, effect size [ES]=1.4) and without (–19.9 vs. –13.8,p<0.0001,ES=0.7) irritability. In patients with irritable features, treatment with lurasidone was associated with significant week 6 changes vs. placebo in both the YMRS irritability item (–1.4 vs. –0.3,p=0.0012,ES=1.0) and the YMRS disruptive-aggressive item (–1.0 vs. –0.3,p=0.0002,ES=1.2).ConclusionsIn our post-hoc analysis of a randomized, placebo-controlled, 6-week trial, treatment with lurasidone significantly improved depressive symptoms in MDD patients with mixed features including irritability. In addition, irritability symptoms significantly improved in patients treated with lurasidone.
Changes in social engagement and depression predict incident loneliness among seriously ill home care clients
Authors: Fernandes Samantha , Davidson Jacob G.S. , Guthrie Dawn M. 
Published: March 2017

ABSTRACTObjective:This study identified the predictors of incident loneliness in a group of seriously ill older adults (aged 65+) receiving home care.Method:Existing data collected with the Resident Assessment Instrument for Home Care (RAI–HC) were utilized. A cohort of clients (N = 2,499) with two RAI–HC assessments and no self-reported loneliness at time 1 were included. Self-reported loneliness, upon reassessment, was the outcome of interest. Clients with a prognosis of less than six months or severe health instability were included.Results:The average length of time between assessments was 5.9 months (standard deviation = 4.10). During that time, 7.8% (n = 181) of the sample developed loneliness. In a multivariate regression model, worsening symptoms of depression, a decline in social activities, and not living with a primary caregiver all increased the risk of loneliness.Significance of results:These results highlight how changes in psychosocial factors over time can contribute to loneliness, which can inform clinicians as they seek to identify those who may be at risk for loneliness.
Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death
Authors: De Simone Veronica , Bevivino Gerolamo , Sedda Silvia , Izzo Roberta , Laudisi Federica , Dinallo Vincenzo , Franzè Eleonora , Colantoni Alfredo , Ortenzi Angela , Salvatori Silvia , Rossi Piero , Sica Giuseppe S , Fantini Massimo C , Stolfi Carmine , Monteleone Giovanni 
Published: March 2017

AbstractUpregulation of Smad7, an inhibitor of transforming growth factor-β1 (TGF-β1), occurs in sporadic colorectal cancer (CRC) and knockdown of Smad7 inhibits CRC cell growth, a phenomenon that associates with decreased expression of cell division cycle 25 homolog A and arrest of cells in the S phase of the cell cycle. These findings occur in CRC cells unresponsive to TGF-β1, thus suggesting the existence of a Smad7-mediated TGF-β1-independent mechanism that controls CRC cell behavior. Here we show that Smad7 inhibition with a specific Smad7 antisense oligonucleotide upregulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, a transcription factor involved in the regulation of cell cycle arrest and induction of cell death, and induces activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homology protein (CHOP), two downstream targets of eIF2α. Among the upstream kinases that control eIF2α phosphorylation, the serine–threonine protein kinase RNA (PKR), but not general control non-derepressible 2 (GCN2) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), is activated by Smad7 knockdown. PKR silencing abolishes Smad7 antisense-induced eIF2α phosphorylation and ATF4/CHOP induction, thereby preventing Smad7 antisense-driven cell death. Smad7 inhibition diminishes interaction of PKR with protein kinase inhibitor p58 (p58IPK), a cellular inhibitor of PKR, but does not change the expression and/or activity of other factors involved in the control of PKR activation. These findings delineate a novel mechanism by which Smad7 knockdown promotes CRC cell death.
Cysteine-linked dimerization of BST-2 confers anoikis resistance to breast cancer cells by negating proapoptotic activities to promote tumor cell survival and growth
Authors: Mahauad-Fernandez Wadie D , Okeoma Chioma M 
Published: March 2017

AbstractAlmost all breast tumors express the antiviral protein BST-2 with 67%, 25% and 8.2% containing high, medium or low levels of BST-2, respectively. Breast tumor cells and tissues that contain elevated levels of BST-2 are highly aggressive. Suppression of BST-2 expression reprograms tumorigenic properties of cancer cells and diminishes cancer cell aggressiveness. Using structure/function studies, we report that dimerization of BST-2 through cysteine residues located in the BST-2 extracellular domain (ECD), leads to anoikis resistance and cell survival through proteasome-mediated degradation of BIM—a key proapoptotic factor. Importantly, BST-2 dimerization promotes tumor growth in preclinical breast cancer models in vitro and in vivo. Furthermore, we demonstrate that restoration of the ECD cysteine residues is sufficient to rescue cell survival and tumor growth via a previously unreported pathway—BST-2/GRB2/ERK/BIM/Cas3. These findings suggest that disruption of BST-2 dimerization offers a potential therapeutic approach for breast cancer.
Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity
Authors: Liu Yong , Chen Xiao-Dong , Yu Jiang , Chi Jun-Lin , Long Fei-Wu , Yang Hong-Wei , Chen Ke-Ling , Lv Zhao-Ying , Zhou Bin , Peng Zhi-Hai , Sun Xiao-Feng , Li Yuan , Zhou Zong-Guang 
Published: March 2017

AbstractSevere acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of l-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor-κB (NF-κB) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-κB activation and less release of TNF-α and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.
NCAPH plays important roles in human colon cancer
Authors: Yin Liang , Jiang Li-Ping , Shen Qiu-Shuo , Xiong Qiu-Xia , Zhuo Xiao , Zhang Long-Long , Yu Hai-Jing , Guo Xiang , Luo Ying , Dong Jian , Kong Qing-Peng , Yang Cui-Ping , Chen Yong-Bin 
Published: March 2017

AbstractColon cancer (CC) is one of the major malignancies worldwide, whose pathogenesis is complex and requires the accumulated alteration of multiple genes and signaling pathways. Condensins are multi-protein complexes that play pivotal roles in chromosome assembly and segregation during mitosis, meiosis and even tumorigenesis. Using tissue microarrays by immunohistochemistry and hematoxylin–eosin staining, we found that non-SMC condensin I complex subunit H (NCAPH) in colon cancerous tissues was higher than that in all corresponding adjacent non-cancerous tissues. We then characterized the exact function of the NCAPH in CC. We provided evidences showing that NCAPH is highly expressed in colorectal cancer cell lines comparing with normal human colonic epithelial cells, and identified many NCAPH mutations in CC patients. We found that depletion of NCAPH inhibits CC cell proliferation, migration in vitro and xenograft tumor formation in vivo. Furthermore, NCAPH knockdown promotes cell apoptosis and cell cycle arrest at G2/M phase. Interestingly, the NCAPH high expression in tumor tissues of colon patients had a significantly better prognosis and survival rate than low-expression patients, suggesting that NCAPH high expression promotes colonic cancerous cell proliferation; on the other hand, it may also sensitize these cells responding to chemo- or radio-therapies. Collectively, these findings reveal an important role of NCAPH in CC, indicating that NCAPH could be used as a new therapeutic target in future.
IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis
Authors: Chang Kai-Kai , Liu Li-Bing , Jin Li-Ping , Zhang Bing , Mei Jie , Li Hui , Wei Chun-Yan , Zhou Wen-Jie , Zhu Xiao-Yong , Shao Jun , Li Da-Jin , Li Ming-Qing 
Published: March 2017

AbstractEndometriosis is an estrogen-dependent inflammatory disease. The anti-inflammatory cytokine IL-10 is also increased in endometriosis. IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. However, the mechanism of inducing IL-10-producing Th17 cells is still largely unknown. The present study investigated the differentiation mechanism and role of IL-10-producing Th17 cells in endometriosis. Here, we report that IL-10+Th17 cells are significantly increased in the peritoneal fluid of women with endometriosis, along with an elevation of IL-27, IL-6 and TGF-β. Compared with peripheral CD4+ T cells, endometrial CD4+ T cells highly expressed IL-27 receptors, especially the ectopic endometrium. Under external (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and local (estrogen, IL-6 and TGF-β) environmental regulation, IL-27 from macrophages and endometrial stromal cells (ESCs) induces IL-10 production in Th17 cells in vitro and in vivo. This process may be mediated through the interaction between c-musculoaponeurotic fibrosarconna (c-Maf) and retinoic acid-related orphan receptor gamma t (RORγt), and associated with the upregulation of downstream B lymphocyte-induced maturation protein-1 (Blimp-1). IL-10+Th17 cells, in turn, stimulate the proliferation and implantation of ectopic lesions and accelerate the progression of endometriosis. These results suggest that IL-27 is a pivotal regulator in endometriotic immune tolerance by triggering Th17 cells to produce IL-10 and promoting the rapid growth and implantation of ectopic lesions. This finding provides a scientific basis for potential therapeutic strategies aimed at preventing the development of endometriosis, especially for patients with high levels of IL-10+Th17 cells.
Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures
Authors: Croft Cara L , Wade Matthew A , Kurbatskaya Ksenia , Mastrandreas Pavlina , Hughes Martina M , Phillips Emma C , Pooler Amy M , Perkinton Michael S , Hanger Diane P , Noble Wendy 
Published: March 2017

AbstractThe spatiotemporal transmission of pathological tau in the brain is characteristic of Alzheimer’s disease. Release of both soluble and abnormal tau species from healthy neurons is increased upon stimulation of neuronal activity. It is not yet understood whether the mechanisms controlling soluble tau release from healthy neurons is the same as those involved in the spread of pathological tau species. To begin to understand these events, we have studied tau distribution and release using organotypic brain slice cultures. The slices were cultured from postnatal wild-type and 3xTg-AD mice for up to 1 month. Tau distribution in subcellular compartments was examined by western blotting, and tau release into culture medium was determined using a sensitive sandwich ELISA. We show here that 3xTg-AD cultures have an accelerated development of pathological tau abnormalities including the redistribution of tau to synaptic and membrane compartments. The 3xTg-AD slice cultures show elevated basal tau release relative to total tau when compared with wild-type cultures. However, tau release from 3xTg-AD slices cannot be further stimulated when neuronal activity is increased with potassium chloride. Moreover, we report that there is an increased pool of dephosphorylated membrane-associated tau in conditions where tau release is increased. These data suggest that there may be differential patterns of tau release when using integrated slice culture models of wild-type and transgenic mouse brain, although it will be important to determine the effect of tau overexpression for these findings. These results further increase our knowledge of the molecular mechanisms underlying tau release and propagation in neurodegenerative tauopathies.