tbuckley/cabot-search huggingface dataset:
06.04 Comparison of abatacept influence on disease activity and functional status in patients with different stages of rheumatoid arthritis
Authors: Maria A Borisova, Galina V Lukina, Yakov A Sigidin, Evgeniya Sergeevna A, Svetlana I Glukhova, Elena L Luchihina, Dmitriy E Karateev, Evgeniy L Nasonov
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To assess the impact of ABA on disease activity and functional status in patients with different duration of RA. <h3>Materials and methods</h3> 85 patients (pts) with early (less than three years, 51%) and LS (more than three years, 49%) RA were enrolled in the study. Most of them were females (48,8±13,5 years) with high disease activity (DAS28=5,25±1,15), RF-positive (76,7%) and ACPA-positive (73,1%). ABA (10 mg/kg) was administered intravenously following the adult intravenous dosing regimen. Disease activity was assessed by DAS28, functional status by HAQ-DI and results by EULAR criteria every 12 weeks. <h3>Results</h3> Pts had high disease activity by DAS28 (ERA DAS28 - 5,1±0,9, LS RA - 5,3) and mild disability by HAQ-DI (ERA - 1,3±0,6, LS RA - 1,6±0,9) before treatment. Good and moderate response by EULAR criteria was achieved in 80% in the group of ERA and in 67% of pts with LS RA (p&lt;0.05) after 3 months of therapy. There was no significant difference in achieving good EULAR response between two groups after 6 months of therapy (43,75% - ERA; 38,4% - LS RA). The number of non-responders was similar after 3 months (ERA – 20%, LS RA – 31,4%) and 6 months (ERA – 18,7%, LS RA – 19,2%). After 3 months and 6 months the improvement of HAQ-DI in ERA group was significantly higher, than in LS RA group (p&lt;0.05). 28 adverse events (AE) in 17 (20%) pts were registered. <h3>Conclusion</h3> ABA has shown significant improvement in reduction of disease activity and improvement in functional status in pts with RA. No significant difference was seen between the groups of ERA and LS RA by EULAR criteria. However, pts in ERA group had significant improvement of HAQ-DI comparing with LS RA group.
Association of PIK3CA-activating mutations with more disseminated disease at presentation and earlier recurrence in glioblastoma.
Authors: Shota Tanaka, Tracy Batchelor, Anthony John Iafrate, Dora Dias-Santagata, Darrell R. Borger, Leif William Ellisen, Daniel Yang, David N. Louis, Daniel P. Cahill, Andrew S. Chi
Journal: Journal of Clinical Oncology (2013)

2029 Background: The PI3K signaling pathway is a potent pro-survival pathway and associated with increased grade of malignancy in glioma. Activating mutations in PIK3CA are observed in 6% to 15% of glioblastomas, although their clinical significance is unknown. Our objective was to examine whether PIK3CA activating mutation is associated with a specific phenotype in newly diagnosed glioblastoma patients. Methods: We molecularly profiled 183 consecutive adult glioblastomas from December 2009 to June 2012. We included in our analysis all newly diagnosed primary glioblastoma patients with a KPS score of 60 or greater who were treated with standard chemoradiation. Molecular profiling consisted of SNaPshot genotyping, FISH for gene amplification (EGFR, MET, PDGFRA), and methylation-specific PCR for MGMT promoter methylation. Results: 158 patients were included in the study (median age: 58 years (range, 23-85), 90 males, median KPS: 90). With a median follow-up of 13.8 months, median progression-free survival (PFS) and overall survival (OS) were 11.6 and 26.2 months, respectively. Established molecular prognostic factors such as IDH1 mutation and MGMT promoter methylation were associated with longer PFS and OS (IDH1: PFS p=0.001, OS p=0.02; MGMT: PFS p=0.0005, OS p=0.0002). 12 patients (7.6%) harbored PIK3CA activating mutation by SNaPshot assay (4 at R88, 4 at hotspots 542-546, 4 at H1047). PIK3CA mutation was associated with younger age (p=0.02) and shorter PFS (6.8 vs. 11.8 months, p=0.0004). Shorter PFS for PIK3CA mutation remained significant after adjusting for age, KPS, gross total resection, IDH1 mutation, and MGMT promoter methylation (p=0.01). There was a significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions. Eight of 12 (66.7%) PIK3CA mutant GBMs were disseminated versus 15.1% of PIK3CA wild-type tumors (p=0.0002). Conclusions: PIK3CA activating mutations are associated with younger age and early recurrence in primary glioblastoma. The aggressive behavior of these tumors may be related to their propensity to present with widespread disease.
Pharmacologic Approaches to Improve Mitochondrial Function in AKI and CKD
Authors: Hazel H. Szeto
Journal: Journal of the American Society of Nephrology (2017)

AKI is associated with high morbidity and mortality, and it predisposes to the development and progression of CKD. Novel strategies that minimize AKI and halt the progression of CKD are urgently needed. Normal kidney function involves numerous different cell types, such as tubular epithelial cells, endothelial cells, and podocytes, working in concert. This delicate balance involves many energy-intensive processes. Fatty acids are the preferred energy substrates for the kidney, and defects in fatty acid oxidation and mitochondrial dysfunction are universally involved in diverse causes of AKI and CKD. This review provides an overview of ATP production and energy demands in the kidney and summarizes preclinical and clinical evidence of mitochondrial dysfunction in AKI and CKD. New therapeutic strategies targeting mitochondria protection and cellular bioenergetics are presented, with emphasis on those that have been evaluated in animal models of AKI and CKD. Targeting mitochondrial function and cellular bioenergetics upstream of cellular damage may offer advantages compared with targeting downstream inflammatory and fibrosis processes.
Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice
Authors: Michitaka Matsuda, Shinya Tsurusaki, Naoko Miyata, Eiko Saijou, Hitoshi Okochi, Atsushi Miyajima, Minoru Tanaka
Journal: Hepatology (2017)

Fibrosis is an important wound‐healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. Although oncostatin M (OSM) has been reported to play crucial roles for recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury (CLI) is yet to be elucidated. Here, we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during CLI. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely, continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis (LF) after hepatitis. In a primary coculture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up‐regulated the expression of fibrogenic factors, such as transforming growth factor‐β and platelet‐derived growth factor in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. Fluorescence‐activated cell sorting analyses using OSM‐HTVi and OSM knockout mice have revealed that bone‐marrow–derived monocyte/macrophage are responsive to OSM for profibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM‐induced fibrosis. Conclusion: OSM plays a crucial role in LF by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for LF. (H epatology 2018;67:296‐312).
Re: Assessment of Plasma DNA Levels, Allelic Imbalance, and CA 125 as Diagnostic Tests for Cancer
Authors: N. Pisal, M. Sindos, A. Singer
Journal: JNCI Journal of the National Cancer Institute (2003)

We read with interest the article by Chang et al. (1).This article assesses the feasibility of using a novel molecular technique for the early detection of ovarian cancer.The article suggests a very high sensitivity and specificity, making it a very suitable technique as a screening test.We would like to make the following comments:
AMPK活性化における年齢に関連した変化:上流シグナル伝達経路によるAMPKホスファターゼおよび抑制性りん酸化の役割【Powered by NICT】
Authors: Salminen Antero, Kaarniranta Kai, Kauppinen Anu
Journal: Ageing Research Reviews (2016)
Loss of <i>Igf2</i> Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth
Authors: Nathan A. Damaschke, Bing Yang, Sachin Bhusari, Mele Avilla, Weixiong Zhong, Michael L. Blute, Wei Huang, David F. Jarrard
Journal: Cancer Research (2017)

Abstract Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. Cancer Res; 77(19); 5236–47. ©2017 AACR.
Family History of CHD Is Associated With Severe CAC in South Asians
Authors: Jaideep Patel, Mahmoud Al Rifai, Miguel Cainzos-Achirica, Namratha R. Kandula, Alka M. Kanaya, Amit Khera, Roger S. Blumenthal, Khurram Nasir, Michael J. Blaha, Parag H. Joshi
Journal: JACC. Cardiovascular imaging (2017)
Abstract P125: Sunitinib-Induced Cardiomyopathy Is Due to PDGFR-á Inhibition and Can Be Prevented by Cotreatment with Thalidomide
Authors: Vishnu Chintalgattu, Meredith Rees, Nathan Bryan, Robert Langley, James Culver, Mary Dickinson, Mark L Entman, Aarif Y Khakoo
Journal: Circulation Research (2011)

Introduction: Suntinib malate (SM) is a small molecule tyrosine kinase inhibitor used for the treatment of metastatic renal cell carcinoma. However, nearly 20% of SM treated patients develop cardiomyopathy. We recently reported that the cardiomyocyte PDGFR-β regulates both cardiac and coronary microvascular function. In this study, we sought to define the mechanisms of SM-induced cardiomyopathy. Methods: C57BL/6 mice were divided into 4 groups: vehicle control (Ctrl), SM, Ctrl+transverse aortic constriction (Ctrl-TAC) and SM-TAC. SM was given at 40 mg/kg/d. An additional group was treated with either SM (40mg/kg/d) plus vehicle control or SM plus thalidomide (75mg/kg/d) for 14 days and allowed to recover until day 28. Left ventricular ejection fraction (LVEF) and coronary flow reserve (CFR, a measurement of coronary microvascular function) were assessed by cardiac MRI and ultrasound, respectively. Pericyte coverage was assessed by immunofluorescent co-staining of CD31 (vessel) and NG2 (pericyte). Results: SM induced cardiac and coronary microvascular dysfunction and impaired cardiac response to stress in a similar manner to that seen in PDGFR-β knockout mice. These functional impairments were accompanied by structural vascular defects and significant loss of microvascular pericyte coverage. This was recapitulated in aged (1 year) PDGFR-β knockout mice as well as with the drug CP673,541, which is a potent, more specific PDGFR inhibitor . Thalidomide is known to enhance vascular stability through enhancement of vascular pericyte coverage. Co-treatment with Thal prevented sunitinib-induced reduction in LVEF (SM-LVEF-41%; SM+thalidomide-49%, p&lt;0.01) and preserved CFR (SM-CFR-2.14; SM+thalidomide 2.95). Thalidomide also significantly increased microvascular pericyte coverage. Conclusion: SM-induced cardiac and microvascular dysfunction is most likely due to PDGFR-β inhibition and can be prevented by co-treatment with thalidomide. Our findings not only suggest a novel cardioprotective strategy for cancer patients at high-risk for sunitinib-induced cardiomyopathy but also suggest a critical role for pericytes in coronary microvascular and cardiac function.
The Association of Arsenic Metabolism with Cancer, Cardiovascular Disease, and Diabetes: A Systematic Review of the Epidemiological Evidence
Authors: Chin-Chi Kuo, Katherine A. Moon, Shu-Li Wang, Ellen Silbergeld, Ana Navas-Acien
Journal: Environmental Health Perspectives (2017)

The available evidence on the role of arsenic metabolism in individual susceptibility to the development of cancer, cardiovascular disease, and diabetes has not been formally and comprehensively reviewed.Our goal was to systematically investigate the association of arsenic metabolism with cancer, cardiovascular disease, and diabetes-related outcomes in epidemiologic studies. As a secondary objective, we characterized the variation of arsenic metabolism in different populations worldwide.We searched Medline/PubMed and EMBASE from inception to January 2016 and applied predetermined exclusion criteria. Compositional data analysis was used to describe the distribution of arsenic metabolism biomarkers and evaluate the association between arsenic exposure and metabolism.Twenty-eight studies met the inclusion criteria, 12 on cancer, nine on cardiovascular disease, and seven on diabetes-related outcomes. The median (interquartile range) for mean iAs%, MMA%, and DMA% was 11.2 (7.8-14.9)%, 13.0 (10.4-13.6)%, and 74.9 (69.8-80.0)%, respectively. Findings across studies suggested that higher arsenic exposure levels were associated with higher iAs% and lower DMA% and not associated with MMA%. For cancer, most studies found a pattern of higher MMA% and lower DMA% associated with higher risk of all-site, urothelial, lung, and skin cancers. For cardiovascular disease, higher MMA% was generally associated with higher risk of carotid atherosclerosis and clinical cardiovascular disease but not with hypertension. For diabetes-related outcomes, the pattern of lower MMA% and higher DMA% was associated with higher risk of metabolic syndrome and diabetes.Population level of iAs% and DMA%, but not MMA%, were associated with arsenic exposure levels. Overall, study findings suggest that higher MMA% was associated with an increased risk of cancer and cardiovascular disease, while lower MMA% was associated with an increased risk of diabetes and metabolic syndrome. Additional population-based studies and experimental studies are needed to further evaluate and understand the role of arsenic exposure in arsenic metabolism and the role of arsenic metabolism in disease development. https://doi.org/10.1289/EHP577.
Human blood T <sub>fr</sub> cells are indicators of ongoing humoral activity not fully licensed with suppressive function
Authors: Valter R. Fonseca, Ana Agua-Doce, Ana Raquel Maceiras, Wim Pierson, Filipa Ribeiro, Vasco C. Romão, Ana Rita Pires, Susana Lopes da Silva, João Eurico Fonseca, Ana E. Sousa, Michelle A. Linterman, Luis Graca
Journal: Science Immunology (2017)

Germinal center (GC) responses are controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells and are crucial for the generation of high-affinity antibodies. Although the biology of human circulating and tissue Tfh cells has been established, the relationship between blood and tissue Tfr cells defined as CXCR5+Foxp3+ T cells remains elusive. We found that blood Tfr cells are increased in Sjögren syndrome, an autoimmune disease with ongoing GC reactions, especially in patients with high autoantibody titers, as well as in healthy individuals upon influenza vaccination. Although blood Tfr cells correlated with humoral responses, they lack full B cell-suppressive capacity, despite being able to suppress T cell proliferation. Blood Tfr cells have a naïve-like phenotype, although they are absent from human thymus or cord blood. We found that these cells were generated in peripheral lymphoid tissues before T-B interaction, as they are maintained in B cell-deficient patients. Therefore, blood CXCR5+Foxp3+ T cells in human pathology indicate ongoing humoral activity but are not fully competent circulating Tfr cells.
Gender differences in expression of drug transporter genes in human livers: Microarray and real-time PCR analysis
Authors: Beverly Lyn-Cook, Athena Starlard-Davenport, Beverly Word, Bridgette Green, Carolyn Wise, Baitang Ning, Ying Huang
Journal: Clinical Cancer Research (2008)

B34  Membrane transporters and ion channels are encoded by numerous gene families. These genes code for a number of proteins involved in many physiologic processes, such as lipid transport, sterol homeostasis, immune mechanisms and drug transport. Gender differences in adverse drug reactions have been reported with a number of chemotherapeutic drugs suggesting a possible role for drug transporters. Using Illumina Human Whole-Genome beadchips (Human-6-v1), males (50) and females (52) age- matched liver samples were analyzed for differentially expressed genes according to gender. Microarray filtered analysis identified 1,640 genes differentially expressed according to gender. Of the 1,640 genes, 26 were molecular transporters. Seventeen genes from the solute carrier (SLC) family (SLC30A1, 43A1, 31A2, 31A1, 35F5, 43A1, 4A1AP, 5A10, 5A6, 6A16, 9A1, 10A1,16A11, 22A12, 22A2, 22A9 25A13 and SLCO1B1) and three from the ATP-binding (ABC) family (ABCA5, ABCB6 and ACCN4) were differentially expressed between genders. Other transporters that were differentially expressed were OST beta, ATP7B, KCNK5, TRPC4AP, KCNJ8 and ATP2B2. Real-time PCR analyses validated the microarray results and further showed, in addition to expression by gender, intra-individual differences within gender. The ABC and SLC transporters mediate energy-dependent drug efflux and uptake, therefore playing a major role in chemoresistance and pharmacokinetic disposition of drugs. Gender differences in adverse reactions to certain drugs could be attributed to differences in transporters expression. Knowledge of gender differences in expression may, thereby, be a key component in ensuring optimal patient outcome.
Survival After Laparoscopic vs Abdominal Hysterectomy
Authors: Yue Yin, Xiaofei Tian
Journal: JAMA (2017)

To the Editor The study by Dr Janda and colleagues1 found that laparoscopic hysterectomy compared with abdominal hysterectomy had equivalent disease-free survival outcomes for women with early-stage endometrial cancer. We found some features of interest in the authors’ results.
皮弁潅流のより正確な評価のための穿通枝容器の短波長赤外窓における実時間および長時間in vivoイメージング【Powered by NICT】
Authors: Feng Shaoqing, Chen Jun, Wo Yan, Li Yunxia, Chen Shiyi, Zhang Yixin, Zhang Wenjie
Journal: Biomaterials (2016)
Lenalidomide and irinotecan in adults with recurrent malignant gliomas: Phase I results of the phase I/II trial.
Authors: Vinay K. Puduvalli, Morris D. Groves, Mark R. Gilbert, Kenneth R. Hess, Sanghee Kang, Sandra Ictech, Charles A. Conrad, Monica Elena Loghin, John Frederick De Groot, Victor A. Levin, W. K. Alfred Yung
Journal: Journal of Clinical Oncology (2012)

2036 Background: Patients with recurrent malignant gliomas have limited treatment options. We previously reported promising results using 6 month progression free survival [PFS6] endpoint combining irinotecan and thalidomide compared to historical controls. In this study, we tested the tolerability and efficacy of Irinotecan combined with Lenalidomide, a more potent thalidomide analogue with unique antiangiogenic and immunomodulatory properties. Methods: This phase I portion of the phase I/II study aimed to determine the maximum tolerated doses (MTD) of irinotecan and lenalidomide. Eligible patients were adults (&gt;=18 y) with recurrent WHO Grade 3 or 4 gliomas who were not on EIAED, had failed prior radiation therapy, had a KPS&gt;=60, had adequate marrow, renal and hepatic organ function, no major medical illnesses and no other concurrent malignancies. Each cycle was designated as 4 weeks in duration. Results: Two of the 4 patients enrolled at the starting dose level of Lenalidomide 10 mg/day on days 1-21 and irinotecan 200 mg/m2 q2 weeks developed rash as dose limiting toxicity (DLT). The trial was restarted with no change in irinotecan dose but with a lowered Lenalidomide dose of 7.5 mg/day for cycle 1 with escalation to 10 mg/day for cycle 2 and beyond. Of 3 eligible patients enrolled, no DLTs were noted even after cycle 2. The dose was hence escalated to Lenalidomide 10 mg/day with unchanged irinotecan dose. Only 1/6 patients experienced a DLT (pulmonary embolism); however, it was noted that 4/6 patients required dose reduction of irinotecan to 150 mg/m2 after cycle 1. One patient died during cycle 2 of unknown causes (autopsy declined) without reports of preceding toxicities. Non DLT toxicities included neutropenia, leukopenia, hypokalemia, diarrhea, fatigue and nausea/vomiting. Lenalidomide pharmacokinetic data, obtained by serial blood draws initially after one dose of the drug on day 0 and subsequently after irinotecan and lenalidomide dose on day 1 to examine drug interactions, will be presented. Conclusions: Based on these results, the maximum tolerated dose was Lenalidomide 10 mg/day on days 1-21 and irinotecan 150 mg/m2 q 2 weeks every 28 days which will be used in the phase II study that will open shortly.
寿命,癌および心血管疾患の制御における岐路に立つSIRT6の複数の経路【Powered by NICT】
Authors: Vitiello Milena, Zullo Alberto, Servillo Luigi, Mancini Francesco Paolo, Borriello Adriana, Giovane Alfonso, Della Ragione Fulvio, D’Onofrio Nunzia, Balestrieri Maria Luisa
Journal: Ageing Research Reviews (2017)
Nature Contact and Human Health: A Research Agenda
Authors: Howard Frumkin, Gregory N. Bratman, Sara Jo Breslow, Bobby Cochran, Peter H. Kahn Jr, Joshua J. Lawler, Phillip S. Levin, Pooja S. Tandon, Usha Varanasi, Kathleen L. Wolf, Spencer A. Wood
Journal: Environmental Health Perspectives (2017)

Background: At a time of increasing disconnectedness from nature, scientific interest in the potential health benefits of nature contact has grown. Research in recent decades has yielded substantial evidence, but large gaps remain in our understanding. Objectives: We propose a research agenda on nature contact and health, identifying principal domains of research and key questions that, if answered, would provide the basis for evidence-based public health interventions. Discussion: We identify research questions in seven domains: a) mechanistic biomedical studies; b) exposure science; c) epidemiology of health benefits; d) diversity and equity considerations; e) technological nature; f) economic and policy studies; and g) implementation science. Conclusions: Nature contact may offer a range of human health benefits. Although much evidence is already available, much remains unknown. A robust research effort, guided by a focus on key unanswered questions, has the potential to yield high-impact, consequential public health insights. https://doi.org/10.1289/EHP1663