tbuckley/cabot-search huggingface dataset:
Ehlers-Danlos type IV: non-invasive techniques as diagnostic support
Authors: P. Autio, M. Turpeinen, J. Risteli, M. Kalliolnen, U. Kiistala, A. Oikarinen
Journal: British Journal of Dermatology (1997)

Journal Article Ehlers‐Danlos type IV: non‐invasive techniques as diagnostic support Get access P. Autio, P. Autio Departments of Dermatology, University of Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar M. Turpeinen, M. Turpeinen Departments of Pediatric Allergic Diseases, University of Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar J. Risteli, J. Risteli Departments of Medical Biochemistry and Clinical Chemistry, University Hospital of Oulu, Oulu, Finland Search for other works by this author on: Oxford Academic Google Scholar M. Kalliolnen, M. Kalliolnen Departments of Pathology, University Hospital of Oulu, Oulu, Finland Search for other works by this author on: Oxford Academic Google Scholar U. Kiistala, U. Kiistala Departments of Dermatology, University Hospital of Oulu, Oulu, Finland Search for other works by this author on: Oxford Academic Google Scholar A. Oikarinen A. Oikarinen Department of Dermatology Central Military Hospital, Helsinki, Finland Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 137, Issue 4, 1 October 1997, Pages 653–655, https://doi.org/10.1111/j.1365-2133.1997.tb03811.x Published: 01 October 1997
An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist
Authors: Ivona Aksentijevich, Seth L. Masters, Polly J. Ferguson, Paul Dancey, Joost Frenkel, Annet van Royen-Kerkhoff, Ron Laxer, Ulf Tedgård, Edward W. Cowen, Tuyet-Hang Pham, Matthew Booty, Jacob D. Estes, Netanya G. Sandler, Nicole Plass, Deborah L. Stone, Maria L. Turner, Suvimol Hill, John A. Butman, Rayfel Schneider, Paul Babyn, Hatem I. El-Shanti, Elena Pope, Karyl Barron, Xinyu Bing, Arian Laurence, Chyi-Chia R. Lee, Dawn Chapelle, Gillian I. Clarke, Kamal Ohson, Marc Nicholson, Massimo Gadina, Barbara Yang, Benjamin D. Korman, Peter K. Gregersen, P. Martin van Hagen, A. Elisabeth Hak, Marjan Huizing, Proton Rahman, Daniel C. Douek, Elaine F. Remmers, Daniel L. Kastner, Raphaela Goldbach-Mansky
Journal: New England Journal of Medicine (2009)

Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone.We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer
Authors: Justin F. Gainor, Alice T. Shaw
Journal: Journal of Clinical Oncology (2013)

The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.
<i>Plasmodium falciparum</i> Produces Prostaglandins that are Pyrogenic, Somnogenic, and Immunosuppressive Substances in Humans
Authors: B. Kilunga Kubata, Naomi Eguchi, Yoshihiro Urade, Kouwa Yamashita, Toshihide Mitamura, Kumiko Tai, Osamu Hayaishi, Toshihiro Horii
Journal: The Journal of Experimental Medicine (1998)

Plasmodium falciparum causes the most severe form of human malaria, which kills ∼1.5–2.7 million people every year, but the molecular mechanisms underlying the clinical symptoms and the host–parasite interaction remain unclear. We show here that P. falciparum produces prostaglandins (PGs) D2, E2, and F2α. After incubation with 1 mM arachidonic acid (AA), cell homogenates of P. falciparum produced PGs as determined by enzyme immunoassay and gas chromatography–selected ion monitoring. PG production in the parasite homogenate was not affected by the nonsteroidal antiinflammatory drugs aspirin and indomethacin, and was partially heat resistant, whereas PG biosynthesis by mammalian cyclooxygenase was completely inhibited by these chemicals and by heat treatment. Addition of AA to the parasite cell culture markedly increased an ability of the parasite cell homogenate to produce PGs and of parasitized red blood cells to accumulate PGs in the culture medium. PGD2 and PGE2 accumulated in the culture medium at the stages of trophozoites and schizonts more actively than at the ring stage. These findings are the first evidence of the direct involvement of a malaria parasite in the generation of substances that are pyrogenic and injurious to the host defenses. We will discuss a possible contribution of the parasite-produced PGs to pathogenesis and host-parasite interaction of P. falciparum.
<i>IRS1</i> Genotype Modulates Metabolic Syndrome Reversion in Response to 2-Year Weight-Loss Diet Intervention
Authors: Qibin Qi, Min Xu, Hongyu Wu, Liming Liang, Catherine M. Champagne, George A. Bray, Frank M. Sacks, Lu Qi
Journal: Diabetes Care (2013)

Genetic variants near IRS1 are associated with features of the metabolic syndrome (MetS). We examined whether genetic variants near IRS1 might modulate the effects of diets varying in fat content on the MetS status in a 2-year weight-loss trial.Two variants near IRS1, rs1522813 and rs2943641, were genotyped in 738 overweight/obese adults (age 60 ± 9 years; BMI 32.7 ± 3.9 kg/m2) randomly assigned to one of four weight-loss diets (a deficit of 750 kcal/day of caloric intake from baseline) varying in macronutrient contents for 2 years. We compared MetS status of high-fat (40% of caloric intake; n = 370) and low-fat (20% caloric intake; n = 368) diet groups differentiated by genotypes (rs1522813 A-allele carriers and noncarriers and rs2943641T-allele carriers and noncarriers).Among rs1522813 A-allele carriers, the reversion rates of the MetS were higher in the high-fat diet group than those in the low-fat diet group over the 2-year intervention (P = 0.002), while no significant difference between diet groups was observed among noncarriers (P = 0.27). The genetic modulation on dietary effect was independent of weight changes. The odds ratio (OR) for the 2-year reversion of the MetS was 2.88 (95% CI 1.25-6.67) comparing the high-fat and low-fat diets among rs1522813 A-allele carriers, while the corresponding OR was 0.83 (0.36-1.92) in noncarriers. The variant rs2943641 was not observed to modulate dietary effects on the MetS status.Our data suggest that high-fat weight-loss diets might be more effective in the management of the MetS compared with low-fat diets among individuals with the A-allele of the rs1522813 variant near IRS1.
Monoclonal Antibody against Cell Surface GRP78 as a Novel Agent in Suppressing PI3K/AKT Signaling, Tumor Growth, and Metastasis
Authors: Ren Liu, Xiuqing Li, Wenming Gao, Yue Zhou, Shiuan Wey, Satyajit K. Mitra, Valery Krasnoperov, Dezheng Dong, Shuanglong Liu, Dan Li, Genyuan Zhu, Stan Louie, Peter S. Conti, Zibo Li, Amy S. Lee, Parkash S. Gill
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of the phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78 monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis. Experimental Design: MAb159 was characterized biochemically. Antitumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application. Results: MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not to normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159-treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN–loss-driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the antitumor activity, was nontoxic in mice, and had desirable pharmacokinetics. Conclusions: GRP78-specific antibody MAb159 modulates the PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly. Clin Cancer Res; 19(24); 6802–11. ©2013 AACR.
Mechanisms of lipid loss from the small intestinal mucosa.
Authors: R Waldram
Journal: Gut (1975)

Many water-soluble compounds have been shown to pass from the small intestinal mucosa into the lumen. In this work, the loss of lipids from the mucosa was investigated by perfusion experiments in rats, using 0-15M NaCl or buffer solutions over range of pH, with or without the addition of 5-7 or 11-4mM taurocholic acid. Perfusates were extracted for the estimation of individual lipids and for DNA, which is a measure of cell loss. The results suggest that free fatty acids reach the lumen by diffusion and that their solubility in the luminal fluid is a factor determining their rate of loss. Triglycerides, cholesterol, phosphatidyl ethanolamine, and phosphatidly choline are present onlyas the result of desquamation of mucosal cells.
Incidence and relative survival of anaplastic astrocytomas
Authors: N. R. Smoll, B. Hamilton
Journal: Neuro-Oncology (2014)

The purpose of this study was to investigate the relationship between age and the incidence and relative survival of anaplastic astrocytoma (AA). Data from the Surveillance, Epidemiology and End Results database were used to identify 3202 patients with AA. These data were analyzed to assess incidence rates, relative survival, and the standardized mortality ratio across age groups. Time trends were modeled using delayed-entry modeling. The overall incidence of AA was an age-adjusted rate of 3.5 per million person/years. The overall age-standardized 5- and 10-year relative survival rates of populations with AA were 23.6% and 15.1%, respectively. The overall standardized mortality ratio for the entire cohort was 46 (95% confidence interval: 45, 48). Patients with a diagnosis of AA are 46 times more likely to die than persons matched for age/sex/year of the general population. The effect of age on survival is present for only the first 2 years postdiagnosis. Measuring the effect of age on survival for populations with an AA is not amenable to using models with proportional hazards as an assumption because of the presence of a reverse fork–type interaction.
Financing universal health coverage—effects of alternative tax structures on public health systems: cross-national modelling in 89 low-income and middle-income countries
Authors: Aaron Reeves, Yannis Gourtsoyannis, Sanjay Basu, David McCoy, Martin McKee, David Stuckler
Journal: The Lancet (2015)

How to finance progress towards universal health coverage in low-income and middle-income countries is a subject of intense debate. We investigated how alternative tax systems affect the breadth, depth, and height of health system coverage.
Prostate Cancer Induces Bone Metastasis through Wnt-Induced Bone Morphogenetic Protein-Dependent and Independent Mechanisms
Authors: Jinlu Dai, Christopher L. Hall, June Escara-Wilke, Atsushi Mizokami, Jill M. Keller, Evan T. Keller
Journal: Cancer Research (2008)

Abstract Prostate cancer (PCa) is frequently accompanied by osteosclerotic (i.e., excessive bone production) bone metastases. Although bone morphogenetic proteins (BMP) and Wnts are mediators of PCa-induced osteoblastic activity, the relation between them in PCa bone metastases is unknown. The goal of this study was to define this relationship. Wnt3a and Wnt5a administration or knockdown of DKK-1, a Wnt inhibitor, induced BMP-4 and 6 expression and promoter activation in PCa cells. DKK-1 blocked Wnt activation of the BMP promoters. Transfection of C4-2B cells with axin, an inhibitor of canonical Wnt signaling, blocked Wnt3a but not Wnt5a induction of the BMP promoters. In contrast, Jnk inhibitor I blocked Wnt5a but not Wnt3a induction of the BMP promoters. Wnt3a, Wnt5a, and conditioned medium (CM) from C4-2B or LuCaP23.1 cells induced osteoblast differentiation in vitro. The addition of DKK-1 and Noggin, a BMP inhibitor, to CM diminished PCa CM–induced osteoblast differentiation in a synergistic fashion. However, pretreatment of PCa cells with DKK-1 before collecting CM blocked osteoblast differentiation, whereas pretreatment with Noggin only partially reduced osteoblast differentiation, and pretreatment with both DKK-1 and Noggin had no greater effect than pretreatment with DKK-1 alone. Additionally, knockdown of BMP expression in C4-2B cells inhibited Wnt-induced osteoblastic activity. These results show that PCa promotes osteoblast differentiation through canonical and noncanonical Wnt signaling pathways that stimulate both BMP-dependent and BMP-independent osteoblast differentiation. These results show a clear link between Wnts and BMPs in PCa-induced osteoblast differentiation and provide novel targets, including the noncanonical Wnt pathway, for therapy of PCa. [Cancer Res 2008;68(14):5785–94]
Bcl2 and Human Papilloma Virus 16 as Predictors of Outcome following Concurrent Chemoradiation for Advanced Oropharyngeal Cancer
Authors: Anthony C. Nichols, Dianne M. Finkelstein, William C. Faquin, William H. Westra, Edmund A. Mroz, Peter Kneuertz, Shahnaz Begum, William A. Michaud, Paul M. Busse, John R. Clark, James W. Rocco
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papilloma virus (HPV) is rapidly growing in incidence. Despite better prognosis than OPSCC associated with traditional risk factors, treatment failure still occurs in a significant proportion of patients. We had identified the antiapoptotic protein Bcl2 as a marker for poor outcome in advanced OPSCC treated with concurrent chemoradiation. To determine whether Bcl2 and HPV together might further characterize treatment response, we examined whether the prognostic value of Bcl2 was independent of HPV status. Experimental Design: Pretreatment tumor biopsies from 68 OPSCC patients were tested for HPV by in situ hybridization and were immunostained for Bcl2 to evaluate relations with disease-free (DFS) and overall survival following platin-based concurrent chemoradiation. Median follow-up among surviving patients was 47 months (range, 10-131 months). Results: Bcl2 and HPV independently predicted DFS and overall survival. Hazard ratios (with 95% confidence interval) for positive versus negative status in bivariate Cox proportional hazard analysis of DFS were 6.1 (1.8-21) for Bcl2 and 0.11 (0.035-0.37) for HPV. Only 1 of 32 HPV-positive/Bcl2-negative tumors recurred. Pretreatment Bcl2 expression was specifically associated with distant metastasis; five of six distant metastases occurred in the &amp;lt;40% of patients whose primary tumors were Bcl2 positive. Conclusions: Independent of HPV status, pretreatment Bcl2 expression identifies a subset of OPSCC patients having increased risk of treatment failure, particularly through distant metastasis, after concurrent chemoradiation. Considering HPV and Bcl2 together should help in devising better personalized treatments for OPSCC. Clin Cancer Res; 16(7); 2138–46. ©2010 AACR.
Identification of Novel Signaling Complexes by Functional Proteomics
Authors: Peipei Ping
Journal: Circulation Research (2003)

The rapid development of proteomic technologies, combined with the completion of the Human Genome Map, has enabled the compiling of an unprecedented inventory of cellular proteins. Functional proteomics is an emerging field that aims to utilize the enormous amount of information provided by these proteomic technologies to understand the functions of cellular proteins. The utility of functional proteomics has been recently exploited to elucidate cellular mechanisms in numerous fields, of particular salience in the area of signal transduction. This review presents a functional proteomic approach for the study of cardiac cell signaling. It illustrates the strategies by which the subproteome of a targeted signaling system is characterized in an unbiased fashion, the manner in which the biochemical functions of this subproteome are assessed using established molecular and protein chemistry methods, and the challenges associated with these studies.
Exclusive Breastfeeding and the Effect on Postpartum Multiple Sclerosis Relapses
Authors: Kerstin Hellwig, Milena Rockhoff, Sandra Herbstritt, Nadja Borisow, Aiden Haghikia, Birte Elias-Hamp, Sylvia Menck, Ralf Gold, Annette Langer-Gould
Journal: JAMA Neurology (2015)

<h3>Importance</h3> Women with multiple sclerosis (MS) experience an elevated risk of relapse after giving birth. The effect of exclusive breastfeeding on postpartum risk of MS relapse is unclear. <h3>Objectives</h3> To determine the effect of exclusive breastfeeding on postpartum risk of MS relapse and to investigate the effect of introducing supplemental feedings on that risk. <h3>Design, Setting, and Participants</h3> Data on 201 pregnant women with relapsing-remitting MS were collected prospectively from January 1, 2008, to June 30, 2012, with 1 year follow-up post partum in the nationwide German MS and pregnancy registry. The effect of the intention to breastfeed exclusively (no regular replacement of breastfeeding meals with supplemental feedings) for at least 2 months compared with nonexclusive breastfeeding (partial or no breastfeeding) on the first postpartum MS relapse, using Cox proportional hazards regression model adjusted for age and disease activity, before and during pregnancy was analyzed. Data analysis was performed from August 30, 2013, to May 25, 2015. <h3>Exposure</h3> Exclusive breastfeeding defined as at least 2 months of breastfeeding without regular replacement of any meal by supplemental feeding. <h3>Main Outcome and Measure</h3> First postpartum MS relapse. <h3>Results</h3> Of 201 women, 120 (59.7%) intended to breastfeed exclusively for at least 2 months and 81 (40.3%) breastfed and included supplemental feeding (42 [20.9%]) or did not breastfeed (39 [19.4%]). Thirty-one women (38.3%) who did not breastfeed exclusively had a relapse within the first 6 months post partum compared with 29 women (24.2%) who intended to breastfeed exclusively for at least 2 months (unadjusted hazard ratio, 1.80; 95% CI, 1.09-2.99;<i>P</i> = .02; adjusted hazard ratio, 1.70; 95% CI, 1.02-2.85;<i>P</i> = .04). The time to first postpartum relapse after the introduction of supplemental feedings did not differ significantly between women who previously breastfed exclusively and those who did not (<i>P</i> = .60). <h3>Conclusions and Relevance</h3> The findings of this study suggest that exclusive breastfeeding is a modestly effective MS treatment with a natural end date. Our study provides further evidence that women with MS who breastfeed exclusively should be supported to do so since it does not increase the risk of postpartum relapse.
Interleukin 1β Enhances Invasive Ability of Gastric Carcinoma through Nuclear Factor-κB Activation
Authors: Naoki Yamanaka, Takashi Morisaki, Hiroshi Nakashima, Akira Tasaki, Makoto Kubo, Hirotaka Kuga, Chihiro Nakahara, Katsuya Nakamura, Hirokazu Noshiro, Takashi Yao, Masazumi Tsuneyoshi, Masao Tanaka, Mitsuo Katano
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We examined the role of interleukin (IL)-1β in activation of nuclear factor κB (NF-κB) and the biological function of activated NF-κB in gastric carcinoma cells. Experimental Design: Human gastric carcinoma cell line GCTM-1 was used to examine NF-κB activation by immunostaining and electrophoretic mobility shift assay. Matrix metalloproteinase (MMP)-9 expression, which plays an important role in tumor invasion, was assessed by semiquantitative reverse transcription-PCR, Western blotting, and immunostaining. The invasive ability of GCTM-1 cells was measured by Matrigel invasion assay. In vivo expression of IL-1β and MMP-9 and activation of NF-κB in 10 surgically resected gastric carcinoma specimens were examined immunohistochemically. Results: IL-1β enhanced NF-κB activation, MMP-9 expression, and the invasive ability of GCTM-1. A NF-κB inhibitor, pyrrolidine dithiocarbamate, suppressed both MMP-9 expression and invasiveness of IL-1β-treated GCTM-1 cells. IL-1β did not increase the invasive ability of GCTM-1 cells transfected with MMP-9 antisense oligonucleotide. Concomitant expression of IL-1β and nuclear NF-κB was observed in 3 of 10 gastric carcinoma specimens. Cells producing IL-1β were tumor-infiltrating macrophages in two specimens and gastric carcinoma cells in one specimen. Conclusions: One of the molecules that may play a role in NF-κB activation in some gastric carcinomas is IL-1β. The present results suggest that IL-1β increases the invasive ability of carcinoma cells through activation of NF-κB and the resulting MMP-9 expression.