tbuckley/cabot-search huggingface dataset:
THU0036 Roles of IL-8 in rank-l- and acpa-mediated osteoclastogenesis
Authors: A Cîrciumaru, Y Liu, A Krishnamurthy, SM Mia, V Joshua, M Engström, V Malmström, M Sun, H Wähämaa, B Rethi, A Catrina
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> We have shown previously in various experimental models that anti-citrullinated protein antibodies (ACPAs) can contribute to bone erosion and arthralgia through IL-8 dependent mechanisms. <h3>Objectives</h3> In cell cultures osteoclasts (OCs) played a prominent role in the ACPA-induced IL-8 secretion and therefore we decided to characterize in detail the autocrine regulation of OC differentiation by IL-8 in the presence or absence of ACPAs. <h3>Methods</h3> Peripheral blood CD14-positive monocytes were used to generate OCs in the presence of M-CSF and RANKL. Expression levels of IL-8 and CXCR1/2 were monitored during OCs maturation using intracellular flow cytometry, cytometric bead array, immunohistochemistry and RT-PCR. Inhibition of IL-8 and its receptors were performed in OC cultures using IL-8 neutralizing antibodies and small molecule CXCR1 and CXCR2 antagonists (Reparixin, SB-332235), in the presence or absence of polyclonal ACPAs. OC numbers were counted using light microscope after TRAP staining. <h3>Results</h3> Macrophages and developing OCs secreted high levels of IL-8 in response to the cytokine M-CSF. IL-8 expression kinetic was characterized by transient peaks when new cytokine was added, followed by very low level of steady-state production. In the presence of ACPAs IL-8 production increased 3–4 fold during late phases of OC differentiation. With the help of IL-8 neutralizing antibodies or inhibitors acting on the IL-8 binding chemokine receptors CXCR1 and CXCR2 we showed that the M-CSF induced IL-8 plays a crucial role in OC differentiation in the presence of exogenous RANK-L. In the presence of ACPAs OC differentiation was further enhanced in response to the ACPA-mediated increase in IL-8 production. The CXCR1 and CXCR2 inhibitors Reparixin and SB-332235 significantly inhibited the RANKL-mediated osteoclastogenesis at 100μM and 10μM respectively, both in the presence or absence of ACPAs. By using the inhibitors at low concentrations we could counteract the ACPA-mediated increase in OC development without interfering with steady state OC differentiation. <h3>Conclusions</h3> Our findings further support an important role for IL-8 in bone biology and in the ACPA-mediated OC differentiation both under physiological conditions and in the presence of ACPAs. Together with previous data showing in vivo, our data indicated that small molecule CXCR1 and CXCR2 antagonists could provide novel therapeutic tools for targeting OCs in ACPA+ individuals. <h3>Disclosure of Interest</h3> None declared
Estimating tumor mutation burden using next-generation sequencing assay.
Authors: Ruchi Chaudhary, John Bishop, Adam Broomer, Dinesh Cyanam, David Mandelman, Goutam Nistala, Fiona Hyland, Seth Sadis
Journal: Journal of Clinical Oncology (2017)

e14529 Background: High tumor mutation burden is a promising biomarker shown in some cancer types to predict positive response to immune checkpoint inhibitors. We show the ability of a targeted cancer research panel to estimate tumor mutation burden per megabase. Methods: We present a single sample analysis workflow for estimating tumor mutation burden from FFPE research samples. Our assay utilizes a PCR-based target enrichment panel that interrogates 409 known key cancer genes covering ~1.7 megabase of genomic space. Our customized workflow requires only 20 ng of input DNA, and enables a 2 day turn-around time from sample to the result. The ease of our workflow enables less than 60 minutes of hands-on time for automated library preparation and templating on a batch of 8 samples. Next-generation Sequencing is performed using high throughput semiconductor sequencing platform to achieve sufficient depth (~500x coverage) and accuracy. Our custom analysis pipeline calls variants with optimized parameters on the tumor sample only, with no matched normal sample required, and applies filters to remove germ-line variants and background noise. Results: Through in silico analysis performed on The Cancer Genome Atlas (TCGA) data we demonstrate that the panel achieves high sensitivity ( &gt; 90%) and specificity ( &gt; 95%) necessary to separate high and low mutation burden samples. Our workflow provides clear separation between allele ratio of somatic and germ-line variants. Our filters consistently eliminate ~98% of germ-line variants from the set of all variants called in single sample analysis workflow. Evidence from tumor-normal analyses on matched tumor and normal samples suggests that our single sample analysis, on the tumor sample only, detects somatic mutations with high sensitivity and specificity with residual of &lt; 3% germ-line variants. Our pipeline identifies mutational signatures consistent with specific mechanisms such as spontaneous deamination of 5-methyl-cytosine, as well as base-damage from FFPE processing. Conclusions: A simple workflow has been developed on the Ion Torrent sequencing platform to estimate per megabase somatic mutational burden from a single tumor FFPE sample. This solution can help advance research in immuno-oncology.
New generation of anilino-substituted pyridopyrazine-urea derivatives show highly selective PI3K-inhibition
Authors: Irene Seipelt, Eckhard Claus, Tilmann Schuster, Emmanuel Polymeropoulos, Michael Teifel, Eckhard Guenther
Journal: Cancer Research (2007)

2379  The inhibition of phosphoinositide 3-kinase (PI3K) acting upstream of Akt, has been extensively reported to be valuable in the treatment of cancerous cell growth, particularly with regard to the catalytic PI3Kα subunit. A high proportion of cell-surface receptors, especially those linked to tyrosine kinases activate the class Ia PI3Ks. Among this class of enzymes, only the catalytic subunit of PI3Kα, encoded by the PIK3CA oncogene, has been found to be mutant in human cancers.  Here we present for the first time the profile of a new generation of pyridopyrazine derivatives with high selectivity for PI3K. The low molecular weight compound class of aryl-substituted pyridopyrazines has already been described as a class of potent dual inhibitors for Erk and PI3K. Our recent experimental results clearly indicate, that anilino-substituted pyridopyrazines lack Erk inhibitory potency but at the same time exhibit high PI3K selectivity.  These new PI3K-inhibitors were profiled in primary in-vitro kinase assays with recombinant PI3K and against more than 50 other recombinant human kinases. Cellular substrate phosphorylation studies targeting the inhibition of PI3K and functional cellular assays of tumor cell proliferation have been performed. In addition, physicochemical and initial ADMET data were collected.  An optimization process of the already known aryl-pyridopyrazine series led to the identification of the new lead compound D-106669, an anilino-substituted derivative. Since this compound showed an IC50 value of 129nM for PI3K and lack of Erk-inhibition, a medicinal chemistry program was initiated which resulted in the synthesis of about 50 new anilino-substituted pyridopyrazines. Out of this second generation series several derivatives with improved cellular efficacy and better drug-like properties were identified.  Here we report the in-vitro profile of our second generation pyridopyrazine-urea compound series, revealing highly selective PI3K-inhibition. Several derivatives are currently undergoing first pharmacokinetic in-vivo studies.
Oral vinorelbine in combination with carboplatin followed by maintenance therapy with oral vinorelbine concurrent with radiotherapy in locally advanced non small cell lung cancer.
Authors: Wael El-Sadda, Inas Ibraheim Abdel Halim, Mona Magdy, Mostafa El-Ebrashy, Hassan Ali Daghriri
Journal: Journal of Clinical Oncology (2015)

e18507 Background: Navelbine (N) and Carboplatin (C) are both active drugs in the treatment of non small cell lung cancer (NSCLC). N is a semisynthetic drug belongs to the vinca alkaloid, its oral form has proved to be effective as the iv form. Maintenance therapy in NSCLC is a new treatment paradigm following 1st line combination chemotherapy. We investigated the efficacy and safety of oral N plus C for 4 cycles then maintenance therapy; N weekly concurrent with thoracic radiotherapy in patients with locally advanced NSCLC. Methods: Thirty pts with histologically proven NSCLC (stages III A&B) were enrolled in the study. Patients had WHO PS < 2, chemonaive with measurable disease, adequate marrow, renal & liver functions. All pts recieved 4 cycles of N 60 mg/m2 D1,8,15 in the first cycle then 80 mg/m2 (cycle 2-4 in absence of neutropenia G3/4). The dose of C is AUC 5 D1 every 3 weeks followed by maintenance therapy for pts did not have PD, N 60 mg/m2 weekly for the first 3 weekly administration followed by N 80 mg/m2 until progression. Radiation delivered using conventional fractionation (2 Gy/d, 5 f/w, a total dose 40 Gy) with concurrent weekly N. Response was assessed by CT scan after 2 cycles of chemotherapy, after completion of RT and every 6 weeks during maintenance. Results: All pts were evaluable for response, toxicity and survival. The median age was 55 years (range 48-65y), 20 males & 10 females. 24 pts (80%) were stage IIIA & 6 pts (20%) IIIB. 21 pts (70%) had PS 0. The response rate after chemotherapy was 50% PR , SD 33.4% and PD 6.6%, the overall response after CRT was 64.2% (CR 14.2% & PR 50%), SD 25% and PD 10.8%, No WHO G3/G4 toxicities were noted, 3 pts (10%) had G2 neutropenia, 3 pts (10%) had G2 anaemia. G2 esophagitis and neutropenia in 2 pts (7%) during CRT. In maintenance therapy 89.3% of pts had dose escalation from 60 to 80 mg/m2 which was not feasible in 3 pts (10.7%) due to G3 neutropenia. Median time to progression & median survival were 11 & 20 months respectively. Conclusions: Combination therapy of oral Navelbine and carboplatin followed by Navelbine maintenance therapy concomitant with RT is an effective, safe and tolerable treatment regimen for locally advanced NSCLC.
An all-positive correlation matrix is not evidence of domain-general intelligence
Authors: Rosalind Arden, Brendan P Zietsch
Journal: Behavioral and Brain Sciences (2017)

Abstract We welcome the cross-disciplinary approach taken by Burkart et al. to probe the evolution of intelligence. We note several concerns: the uses of g and G , rank-ordering species on cognitive ability, and the meaning of general intelligence. This subject demands insights from several fields, and we look forward to cross-disciplinary collaborations.
Killer Cell Immunoglobulin-like Receptor Ligand Matching Determines the Post-Transplant High Risk Groups Among Patients with Permissive HLA Mismatch in Unrelated Donor Hematopoietic Cell Transplantation
Authors: Yoo Jin Lee, Joon Ho Moon, In Hee Lee, Jae-Ho Yoon, Byung-Sik Cho, Jae-Sook Ahn, Hyeoung Joon Kim, Silvia Park, Jun Ho Jang, Chul Won Jung, Hyunsung Park, June-Won Cheong, Je-Hwan Lee, Sang Kyun Sohn, Hee-Je Kim
Journal: Blood (2016)
自己免疫疾患:全身性エリテマトーデス患者での低用量インターロイキン2投与はCD4+T細胞サブセットを選択的に変化させる
Authors: He Jing, Zhang Xia, Sun Xiaolin, Jin Yuebo, Gan Yuzhou, Jia Rulin, XU Chuanhui, Zhu Lei, An Yuan, Jia Yuan, Li Chun, Liu Xu, Ye Hua, Ren Limin, Li Ru, Yao Haihong, LI Yuhui, Chen Shi, Zhang Xuewu, Su Yin, Guo Jianping, LI Zhanguo, Wei Yunbo, Hou Zhaohua, Feng Jinhong, Yu Di, Chen Yaping, Hu Xin, Leong Yew Ann, Deng Jun, Shen Nan, Morand Eric F
Journal: Nature Medicine (2016)
The Benefits of Purposeful Life Engagement on Later-Life Physical Function
Authors: Carol D. Ryff
Journal: JAMA Psychiatry (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
骨髄炎の治療のための抗菌活性を有する生分解性Mg‐Cu合金インプラント:in vitroおよびin vivo評価【Powered by NICT】
Authors: Li Yang, Liu Lina, Wan Peng, Zhai Zanjing, Mao Zhenyang, Ouyang Zhengxiao, Yu Degang, Sun Qi, Tan Lili, Ren Ling, Zhu Zhenan, Hao Yongqiang, Qu Xinhua, Yang Ke, Dai Kerong
Journal: Biomaterials (2016)
Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks’ gestation in France in 2011: EPIPAGE-2 cohort study
Authors: Véronique Pierrat, Laetitia Marchand-Martin, Catherine Arnaud, Monique Kaminski, Matthieu Resche-Rigon, Cécile Lebeaux, Florence Bodeau-Livinec, Andrei S Morgan, François Goffinet, Stéphane Marret, Pierre-Yves Ancel
Journal: BMJ (2017)

Objectives To describe neurodevelopmental outcomes at 2 years corrected age for children born alive at 22-26, 27-31, and 32-34 weeks' gestation in 2011, and to evaluate changes since 1997.Design Population based cohort studies, EPIPAGE and EPIPAGE-2.Setting France.Participants 5567 neonates born alive in 2011 at 22-34 completed weeks' gestation, with 4199 survivors at 2 years corrected age included in follow-up. Comparison of outcomes reported for 3334 (1997) and 2418 (2011) neonates born alive in the nine regions participating in both studies.Main outcome measures Survival; cerebral palsy (2000 European consensus definition); scores below threshold on the neurodevelopmental Ages and Stages Questionnaire (ASQ; at least one of five domains below threshold) if completed between 22 and 26 months corrected age, in children without cerebral palsy, blindness, or deafness; and survival without severe or moderate neuromotor or sensory disabilities (cerebral palsy with Gross Motor Function Classification System levels 2-5, unilateral or bilateral blindness or deafness). Results are given as percentage of outcome measures with 95% confidence intervals.Results Among 5170 liveborn neonates with parental consent, survival at 2 years corrected age was 51.7% (95% confidence interval 48.6% to 54.7%) at 22-26 weeks' gestation, 93.1% (92.1% to 94.0%) at 27-31 weeks' gestation, and 98.6% (97.8% to 99.2%) at 32-34 weeks' gestation. Only one infant born at 22-23 weeks survived. Data on cerebral palsy were available for 3599 infants (81.0% of the eligible population). The overall rate of cerebral palsy at 24-26, 27-31, and 32-34 weeks' gestation was 6.9% (4.7% to 9.6%), 4.3% (3.5% to 5.2%), and 1.0% (0.5% to 1.9%), respectively. Responses to the ASQ were analysed for 2506 children (56.4% of the eligible population). The proportion of children with an ASQ result below threshold at 24-26, 27-31, and 32-34 weeks' gestation were 50.2% (44.5% to 55.8%), 40.7% (38.3% to 43.2%), and 36.2% (32.4% to 40.1%), respectively. Survival without severe or moderate neuromotor or sensory disabilities among live births increased between 1997 and 2011, from 45.5% (39.2% to 51.8%) to 62.3% (57.1% to 67.5%) at 25-26 weeks' gestation, but no change was observed at 22-24 weeks' gestation. At 32-34 weeks' gestation, there was a non-statistically significant increase in survival without severe or moderate neuromotor or sensory disabilities (P=0.61), but the proportion of survivors with cerebral palsy declined (P=0.01).Conclusions In this large cohort of preterm infants, rates of survival and survival without severe or moderate neuromotor or sensory disabilities have increased during the past two decades, but these children remain at high risk of developmental delay.
Umbilical Cord Blood (UCB) Transplantation in Children with Acute Leukemia: Impact of Conditioning Regimen on Transplant Outcomes
Authors: Mary Eapen, Joanne Kurtzberg, Mei-Jie Zhang, Adam M. Mendizabal, Ka Wah Chang, Michel Duval, Mingwei Fei, Steven Neudorf, Satiro N. De Oliveira, Donna A. Wall, Kirk R. Schultz, Mary M Horowitz, John E. Wagner
Journal: Blood (2016)
Summary of available surveillance data on hepatitis C virus infection from eight Arctic countries, 2012 to 2014
Authors: Prabhu P Gounder, Anders Koch, Ginger Provo, Astrid Lovlie, Josefine Lundberg Ederth, Maria Axelsson, Chris P Archibald, Brendan Hanley, Angie Mullen, Myrna Matheson, David Allison, Henrik Trykker, Thomas W Hennessy, Markku Kuusi, Vladimir Chulanov, Brian J McMahon
Journal: Eurosurveillance (2018)

We summarised available hepatitis C virus (HCV) surveillance data for 2012-14 from Arctic/sub-Arctic countries/regions. We sent a HCV data collection template by email to public health authorities in all jurisdictions. Population statistics obtained from census sources for each country were used to estimate rates of reported acute and chronic/undifferentiated HCV cases. Seven countries with Arctic regions (Canada, Denmark, Finland, Greenland, Norway, Sweden and the United States, represented by the state of Alaska), including three Canadian territories and one province, as well as 11 Russian subnational Arctic regions, completed the data collection template. Data on acute HCV infection during 2014 was available from three Arctic countries and all Russian Arctic regions (rate range 0/100,000 population in Greenland, as well as Nenets and Chukotka Automous Okrugs (Russian subnational Arctic regions) to 3.7/100,000 in the Russian Republic of Komi). The rate of people with chronic/undifferentiated HCV infection in 2014 ranged from 0/100,000 in Greenland to 171.2/100,000 in Alaska. In most countries/regions, the majority of HCV-infected people were male and aged 19-64 years. Differences in surveillance methods preclude direct comparisons of HCV surveillance data between Arctic countries/regions. Our data can inform future efforts to develop standardised approaches to HCV surveillance in the Arctic countries/regions by identifying similarities/differences between the surveillance data collected.
Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies
Authors: Tomoyuki Tanaka, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Shiro Tara, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Sha Si, Ichiro Manabe, Masashi Sanada, Manabu Nakayama, Masayoshi Masuko, Hirohito Sone, Haruhiko Koseki, Atsushi Iwama
Journal: The Journal of Experimental Medicine (2017)

Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (BcorΔE4/y ) compromised the repopulating capacity of hematopoietic stem cells, BcorΔE4/y thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. Myc, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in BcorΔE4/y T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to BcorΔE4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.
A 17-gene panel for prediction of adverse surgical pathology in the setting of MRI-guided prostate biopsy.
Authors: Amirali Salmasi, Jonathan W. Said, Steven Raman, Alan W Shindel, Debbie McCullough, Helen Bailey, Megan Rothney, Leonard S. Marks, Phillip G. Febbo, Robert Evan Reiter
Journal: Journal of Clinical Oncology (2017)

5063 Background: A 17 gene panel (Oncotype Dx Genomic Prostate Score, GPS) has been validated as an independent predictor of adverse pathology (AP, defined as pathological GS 4+3 or higher and/or pT3+) in men treated with radical prostatectomy (RP) for prostate cancer (PCa). Multiparametric Magnetic Resonance Imaging (mpMRI) may help guide prostate biopsies. We explored synergies between GPS and mpMRI to aid in PCa management decisions. Methods: A cohort of men with NCCN Low and Intermediate-Risk PCa who were managed with RP was identified from a clinical database. Patients were required to have had a simultaneous mpMRI-guided and systematic biopsy and to have undergone RP within 6 months. Biopsy tissue of the highest Gleason pattern was used for calculation of GPS. The primary endpoint was AP. Secondary endpoints included the range of GPS within UCLA prostate MRI risk groups and median GPS when there was discrepancy between MRI and systematic biopsy Gleason Score (GS). Logistic regression models were fit to evaluate the relationship between GPS (per 20 units) and AP. Results: 134 men met criteria for the primary endpoint. Median age was 62 years (range 46-77). NCCN Low &amp; Intermediate-Risk PCa was present in 16%, and 84% of men, respectively. Biopsy GS 3+3/3+4/4+3 was present in 19%, 67%, and 13%, respectively. In a univariable model, GPS was associated with AP (OR 3.8, 95% CI 2.1 to 7.4, p &lt; 0.001). After adjustment for highest biopsy GS and clinical T-stage, GPS remained significantly associated with AP (OR 3.4, 95% CI 1.8 to 6.8, p = 0.0004). A wide and overlapping distribution of GPS was noted across UCLA MRI prostate risk groups, indicating that GPS provides information that is distinct from what can be determined from mpMRI. When there was a discrepancy between mpMRI and systematic biopsy GS, mpMRI targeted lesions with higher GS had higher median GPS (33, range 13-70) than systematic biopsies with higher GS (median GPS 25, range 15-55). Conclusions: GPS provides independent and complementary prognostic information to mpMRI-guided biopsies. The combination of mpMRI for biopsy guidance and GPS for molecular analysis may optimize prediction of AP and improve patient selection for treatment versus surveillance.
In patients with chest pain, HEART score–guided and usual care did not differ for MACE or health care use
Authors: Benton R. Hunter
Journal: Annals of Internal Medicine (2017)

Source Citation Poldervaart JM, Reitsma JB, Backus BE, et al. Effect of using the HEART score in patients with chest pain in the emergency department: a stepped-wedge, cluster randomized trial. Ann Intern Med. 2017;166:689-97. 28437795