tbuckley/cabot-search huggingface dataset:
Type III Allergy to Insulin Detemir: Response to Darmon et al.
Authors: Lars Stechemesser, Manuela Hofmann, Thomas Hawranek, Raimund Weitgasser
Journal: Diabetes Care (2006)

In their letter to the editor, Damon et al. (1) presented their observation of a local allergic reaction to insulin detemir. According to the patient’s clinical appearance, they classified it as a type III allergy. Another case of a severe injection site reaction to insulin detemir was recently reported by Blumer (2). The described reactions to insulin …
Structural Basis for Recognition of SMRT/N-CoR by the MYND Domain and Its Contribution to AML1/ETO's Activity
Authors: Yizhou Liu, Wei Chen, Justin Gaudet, Matthew D. Cheney, Liya Roudaia, Tomasz Cierpicki, Rachel C. Klet, Kari Hartman, Thomas M. Laue, Nancy A. Speck, John H. Bushweller
Journal: Cancer Cell (2007)
The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study
Authors: Naomi B Klarenbeek, Melek Güler-Yüksel, Sjoerd M van der Kooij, K Huub Han, H Karel Ronday, Pit J S M Kerstens, Patrick E H Seys, Tom W J Huizinga, Ben A C Dijkmans, Cornelia F Allaart
Journal: Annals of the Rheumatic Diseases (2011)

Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up. Methods 508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS &gt;2.4 next treatment step; if DAS ≤2.4 during ≥6 months taper to maintenance dose; if DAS &lt;1.6 during ≥6 months stop antirheumatic treatment). Primary and secondary outcomes were functional ability, joint damage progression, health-related quality of life and (drug-free) remission percentages. Results After 5 years, 48% of patients were in clinical remission (DAS &lt;1.6) and 14% in drug-free remission, irrespective of initial treatment. After an earlier improvement in functional ability and quality of life with initial combination therapy, from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years. The initial combination groups showed less joint damage in year 1. In years 2–5 annual progression was comparable across the groups. After 5 years, initial combination therapy resulted in significantly less joint damage progression, reflecting the earlier clinical response. Conclusion Irrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.
Adenovirus infection inhibits the phosphorylation of major histocompatibility complex class I proteins.
Authors: R Lippé, E Luke, Y T Kuah, C Lomas, W A Jefferies
Journal: The Journal of Experimental Medicine (1991)

Major histocompatibility complex (MHC) class I molecules act as peptide receptors to direct the recognition of foreign antigens by cytolytic T cells. The cell surface expression and trafficking of these peptide receptors is thought to be controlled by the conformation of the MHC molecule and possibly by the phosphorylation of the cytoplasmic portion of the heavy chain protein. It is of some interest that adenoviruses (Ads) have evolved proteins that interfere with the expression of MHC molecules. One of these proteins, called E3/19k, binds to newly synthesized MHC molecules in the rough endoplasmic reticulum (RER) and inhibits their trafficking to the cell surface. Here we show that during the infection of a human cell line with Ad2, the phosphorylation of the endogenous MHC molecules is inhibited. We also observe that the phosphorylation of the endogenous HLA molecules is grossly impaired in a human cell line transfected with the Ad2 EcoRI D fragment containing the E3/19k gene. We conclude that the E3/19k protein inhibits the phosphorylation of the MHC heavy chains and that this may be one of the important functions of this protein in infected cells. In addition, we show that a mutant of the E3/19k protein, which lacks an RER retention signal but which retains its ability to bind to HLA molecules, does not inhibit the phosphorylation of HLA molecules and that phosphorylated molecules are not Endo H sensitive. This suggests that HLA molecules are phosphorylated after leaving the medial-Golgi compartment, thus providing the most compelling evidence yet that HLA molecules are phosphorylated at or near the cell surface. Finally, to our knowledge, this is the first study under which the phosphorylation of MHC molecules is shown to be altered and may have some relevance for other pathogenic conditions.
Infectious Diseases Associated With Renal Homotransplantation
Authors: David Rifkind, Thomas L. Marchioro, William R. Waddell, Thomas E. Starzl
Journal: JAMA (1964)

Infectious diseases occurred in 26 of 30 renal homotransplantation patients and contributed to eight of the 12 deaths in this series. There were 52 infections, 17 occurring before and 35 after transplantation. Infections were produced primarily by staphylococci, Pseudomonas species, and the enteric gram-negative bacilli. Staphylococcal infections occurred in 17 of 19 carriers of this organism and in only one of 11 noncarriers. Thirty-three of the 35 postoperative infections followed the intensification of immunosuppressive therapy for treatment of attempted homograft rejection. Granulocytopenia, steroid-induced diabetes, and hypogammaglobulinemia, from suppressive drug therapy, routinely preceded the onset of these complications. The infections, largely of endogenous origin, occurred when the host's defense mechanisms were depressed.
A Randomized Clinical Trial of Cisplatin/Paclitaxel Versus Carboplatin/Paclitaxel as First-Line Treatment of Ovarian Cancer
Authors: A. du Bois
Journal: JNCI Journal of the National Cancer Institute (2003)

Despite considerable improvement in the treatment of advanced ovarian cancer, the optimization of efficacy and tolerability remains an important issue. Therefore, we performed a randomized, phase III non-inferiority trial comparing paclitaxel plus cisplatin (PT) with paclitaxel plus carboplatin (TC) in patients with advanced ovarian cancer.A total of 798 patients with International Federation of Gynecology and Obstetrics stage IIB-IV were randomly assigned to receive six courses of either PT or TC at 3-week intervals. The primary endpoint was the proportion of patients without progression at 2 years. Secondary endpoints included toxicity, response to treatment, quality of life, and overall and progression-free survival time. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30, version 2.0. Survival curves were calculated using the Kaplan-Meier method, and hazard ratios were estimated using the Cox proportional hazards model.The proportion of patients without progression at 2 years was not statistically significantly different between the two treatment arms (40.0% for PT versus 37.5% for TC, difference = 2.5%, one-sided 95% confidence interval [CI] = - infinity to 8.2%). Median progression-free survival time in the TC arm (17.2 months, 95% CI = 15.2 to 19.3 months) and the PT arm (19.1 months, 95% CI = 16.7 to 21.5 months) were also not statistically significantly different; the same was true of median overall survival time (43.3 months, 95% CI = 37.2 to 47.8 months versus 44.1 months, 95% CI = 40.2 to 49.4 months, for the TC and PT arms, respectively). The TC regimen was associated with a higher frequency of hematologic toxicity, but a lower frequency of gastrointestinal and neurologic toxicity, than the PT regimen. Mean global quality-of-life scores at the end of treatment were statistically significantly better in the TC arm than in the PT arm (65.25 versus 51.97, respectively; difference = -13.28, 95% CI = -18.88 to -7.68).The TC regimen achieved comparable efficacy to the PT regimen but was associated with better tolerability and quality of life, and should, therefore, be considered as an important alternative for standard first-line chemotherapy in patients with advanced ovarian cancer.
Preclinical Assessment of<i>FHIT</i>Gene Replacement Therapy in Human Leukemia Using a Chimeric Adenovirus, Ad5/F35
Authors: Flavia Pichiorri, Francesco Trapasso, Tiziana Palumbo, Rami I. Aqeilan, Alessandra Drusco, Bradley W. Blaser, Dimitrios Iliopoulos, Michael A. Caligiuri, Kay Huebner, Carlo M. Croce
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Expression of the FHIT protein is lost or reduced in most solid tumors and a significant fraction of hematopoietic malignancies. Adenovirus 5 (Ad5) virus or adeno-associated viral vectors have been used to study the tumor suppressor function of FHIT in solid tumors, but these tools have not been effective in leukemias. We have generated a chimeric FHIT-containing adenovirus composed of Ad5 and the group B adenovirus called F35 with which we have been able to efficiently infect hematopoietic cells. Experimental Design: Infection efficiency of Ad5/F35-FHIT and Ad5/F35-GFP viruses was tested in leukemia cell lines that lacked FHIT expression, and biological effects of successful infection were assessed. An acute myelogenous leukemia, a chronic myelogenous leukemia, and four acute lymphoblastic leukemia human cell lines were examined as well as two EBV-transformed B lymphoblastoid cell lines that expressed endogenous FHIT. Results: Two of four acute lymphoblastic leukemia cell lines, Jurkat and MV4;11, which were efficiently infected with Ad5/F35-FHIT, underwent growth suppression and massive induction of apoptosis without apparent activation of caspase-8 or caspase-2 and late activation of caspase-3. Treatment of infected cells with caspase-9 and caspase-3 inhibitors partially blocked FHIT-induced apoptosis. The two remaining infected acute lymphoblastic leukemia cell lines, Molt-3 and RS4;11, were apparently unaffected. Restoration of FHIT expression in the chronic myelogenous leukemia K562 cell line and the acute myelogenous leukemia KG1a cell line also induced apoptosis but at later time points than seen in the acute lymphoblastic leukemia Jurkat and MV4;11 cell lines. I.v. injection of Ad5/F35-FHIT-infected Jurkat cells resulted in abrogation of tumorigenicity in the NOD/SCID xenogeneic engraftment model. Conclusion: FHIT restoration in some FHIT-deficient leukemia cells induces both antiproliferative and proapoptotic effects involving the intrinsic caspase apoptotic pathway.
Compartmentation of Cyclic Nucleotide Signaling in the Heart
Authors: Kimberly L. Dodge-Kafka, Lorene Langeberg, John D. Scott
Journal: Circulation Research (2006)

The activation of the cyclic nucleotide protein kinase A (PKA) and PKG by their respective second messengers is responsible for the modulation of many cellular functions in the heart including cardiac hypertrophy, strength of contraction, and ion flux. However, several studies have revealed that a general increase in cyclic nucleotide concentration in the cell is not sufficient for the specific regulation of target proteins. These studies found that PKA and PKG must be colocalized with their targets to ensure spatial-temporal control of substrate phosphorylation. This compartmentation of cyclic nucleotide signaling is accomplished by tethering the protein kinases with their respective substrates through the association with scaffolding proteins. For cAMP signaling, A-kinase anchoring proteins (AKAPs) provide a molecular mechanism for cAMP compartmentation, allowing for the precise control of PKA-mediated phosphorylation events. (cAMP, PKA, AKAP, PKG).
1,25-Dihydroxyvitamin D3-Independent Stimulatory Effect of Estrogen on the Expression of ECaC1 in the Kidney
Authors: Monique van Abel, Joost G. J. Hoenderop, Olivier Dardenne, René St. Arnaud, Carel H. van Os, Hans J. P. T. M. van Leeuwen, René J. M. Bindels
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Estrogen deficiency results in a negative Ca2+ balance and bone loss in postmenopausal women. In addition to bone, the intestine and kidney are potential sites for estrogen action and are involved in Ca2+ handling and regulation. The epithelial Ca2+ channel ECaC1 (or TRPV5) is the entry channel involved in active Ca2+ transport. Ca2+ entry is followed by cytosolic diffusion, facilitated by calbindin-D28K and/or calbindin-D9k, and active extrusion across the basolateral membrane by the Na+/Ca2+-exchanger (NCX1) and plasma membrane Ca2+-ATPase (PMCA1b). In this transcellular Ca2+ transport, ECaC1 probably represents the final regulatory target for hormonal control. The aim of this study was to determine whether 17β-estradiol (17β-E2) is involved in Ca2+ reabsorption via regulation of the expression of ECaC1. The ovariectomized rat model was used to investigate the regulation of ECaC1, at the mRNA and protein levels, by 17β-E2 replacement therapy. Using real-time quantitative PCR and immunohistochemical analyses, this study demonstrated that 17β-E2 treatment at pharmacologic doses increased renal mRNA levels of ECaC1, calbindin-D28K, NCX1, and PMCA1b and increased the protein abundance of ECaC1. Furthermore, the involvement of 1,25-dihydroxyvitamin D3 in the effects of 17β-E2 was examined in 25-hydroxyvitamin D3-1α-hydroxylase-knockout mice. Renal mRNA expression of calbindin-D9K, calbindin-D28K, NCX1, and PMCA1b was not significantly altered after 17β-E2 treatment. In contrast, ECaC1 mRNA and protein levels were both significantly upregulated. Moreover, 17β-E2 treatment partially restored serum Ca2+ levels, from 1.63 ± 0.06 to 2.03 ± 0.12 mM. In conclusion, this study suggests that 17β-E2 is positively involved in renal Ca2+ reabsorption via the upregulation of ECaC1, an effect independent of 1,25-dihydroxyvitamin D3.
Damage of the Endothelial Glycocalyx in Dialysis Patients
Authors: Carmen A. Vlahu, Bregtje A. Lemkes, Dirk G. Struijk, Marion G. Koopman, Raymond T. Krediet, Hans Vink
Journal: Journal of the American Society of Nephrology (2012)

Damage to the endothelial glycocalyx, which helps maintain vascular homeostasis, heightens the sensitivity of the vasculature to atherogenic stimuli. Patients with renal failure have endothelial dysfunction and increased risk for cardiovascular morbidity and mortality, but the state of the endothelial glycocalyx in these patients is unknown. Here, we used Sidestream Darkfield imaging to detect changes in glycocalyx dimension in dialysis patients and healthy controls from in vivo recordings of the sublingual microcirculation. Dialysis patients had increased perfused boundary region and perfused diameters, consistent with deeper penetration of erythrocytes into glycocalyx, indicating a loss of glycocalyx barrier properties. These patients also had higher serum levels of the glycocalyx constituents hyaluronan and syndecan-1 and increased hyaluronidase activity, suggesting the shedding of these components. Loss of residual renal function had no influence on the imaging parameters but did associate with greater shedding of hyaluronan in blood. Furthermore, patients with higher levels of inflammation had more significant damage to the glycocalyx barrier. In conclusion, these data suggest that dialysis patients have an impaired glycocalyx barrier and shed its constituents into blood, likely contributing to the sustained endothelial cell activation observed in ESRD.
MicroRNA modulators of epigenetic regulation, the tumor microenvironment and the immune system in lung cancer
Authors: Anna Maria Rusek, Mohammed Abba, Andrzej Eljaszewicz, Marcin Moniuszko, Jacek Niklinski, Heike Allgayer
Journal: Molecular Cancer (2015)

Cancer is an exceedingly complex disease that is orchestrated and driven by a combination of multiple aberrantly regulated processes. The nature and depth of involvement of individual events vary between cancer types, and in lung cancer, the deregulation of the epigenetic machinery, the tumor microenvironment and the immune system appear to be especially relevant. The contribution of microRNAs to carcinogenesis and cancer progression is well established with many reports and investigations describing the involvement of microRNAs in lung cancer, however most of these studies have concentrated on single microRNA-target relations and have not adequately addressed the complexity of their interactions. In this review, we focus, in part, on the role of microRNAs in the epigenetic regulation of lung cancer where they act as active molecules modulating enzymes that take part in methylation-mediated silencing and chromatin remodeling. Additionally, we highlight their contribution in controlling and modulating the tumor microenvironment and finally, we describe their role in the critical alteration of essential molecules that influence the immune system in lung cancer development and progression.
Uncontrolled Expression of Vascular Endothelial Growth Factor and Its Receptors Leads to Insufficient Skin Angiogenesis in Patients With Systemic Sclerosis
Authors: Oliver Distler, Jörg H. W. Distler, Annette Scheid, Till Acker, Astrid Hirth, Janine Rethage, Beat A. Michel, Renate E. Gay, Ulf Müller-Ladner, Marco Matucci-Cerinic, Karl H. Plate, Max Gassmann, Steffen Gay
Journal: Circulation Research (2004)

Systemic sclerosis (SSc) skin lesions are characterized by disturbed vessel morphology with enlarged capillaries and an overall reduction in capillary density, suggesting a deregulated, insufficient angiogenic response. It has been postulated that this phenomenon is due to reduced expression of the potent angiogenic factor vascular endothelial growth factor (VEGF). In contrast to this hypothesis, we demonstrate that the expression of both VEGF and its receptors VEGFR-1 and VEGFR-2 is dramatically upregulated in skin specimens of SSc patients throughout different disease stages. Interestingly, upregulation of VEGF was not mediated by hypoxia-inducible transcription factor-1 (HIF-1) as indicated by only a weak expression of the oxygen-sensitive alpha-subunit of HIF-1 in the skin of SSc patients. This was unexpected on measuring low Po2 values in the SSc skin by using a polarographic oxygen microelectrode system. Considering our observation that PDGF and IL-1beta costimulated VEGF expression, we propose that chronic and uncontrolled VEGF upregulation that is mediated by an orchestrated expression of cytokines rather than VEGF downregulation is the cause of the disturbed vessel morphology in the skin of SSc patients. Consequently, for therapeutic approaches aiming to improve tissue perfusion in these patients, a controlled expression and timely termination of VEGF signaling appears to be crucial for success of proangiogenic therapies.
Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis
Authors: Amanda Kirane, Kathleen F. Ludwig, Noah Sorrelle, Gry Haaland, Tone Sandal, Renate Ranaweera, Jason E. Toombs, Miao Wang, Sean P. Dineen, David Micklem, Michael T. Dellinger, James B. Lorens, Rolf A. Brekken
Journal: Cancer Research (2015)

Abstract Repurposing “old” drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K “antagonist” used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors. Cancer Res; 75(18); 3699–705. ©2015 AACR.
Prohevein-like defense protein of tobacco is a cross-reactive allergen for latex-allergic patients
Authors: Anna-Riitta Hänninen, Nisse Kalkkinen, Jari H. Mikkola, Jari Helin, Kristiina Turjanmaa, Timo Reunala, Timo Palosuo
Journal: Journal of Allergy and Clinical Immunology (2000)
Effectiveness and economic evaluation of a nurse delivered home exercise programme to prevent falls. 2: Controlled trial in multiple centres
Authors: M C. Robertson
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To assess the effectiveness of trained nurses based in general practices individually prescribing a home exercise programme to reduce falls and injuries in elderly people and to estimate the cost effectiveness of the programme. <b>Design:</b> Controlled trial with one year9s follow up. <b>Setting:</b> 32 general practices in seven southern New Zealand centres. <b>Participants:</b> 450 women and men aged 80 years and older. <b>Intervention:</b> 330 participants received the exercise programme (exercise centres) and 120 received usual care (control centres); 87% (371 of 426) completed the trial. <b>Main outcome measures:</b> Number of falls, number of injuries resulting from falls, costs of implementing the programme, and hospital costs as a result of falls. <b>Results:</b> Falls were reduced by 30% in the exercise centres (incidence rate ratio 0.70, 95% confidence interval 0.59 to 0.84). The programme was equally effective in men and women. The programme cost $NZ418 (£121) (at 1998 prices) per person to deliver for one year or $NZ1519 (£441) per fall prevented. Fewer participants had falls resulting in injuries, but there was no difference in the number who had serious injuries and no difference in hospital costs resulting from falls in exercise centres compared with control centres. <b>Conclusions:</b> An individually tailored exercise programme, delivered by trained nurses from within general practices, was effective in reducing falls in three different centres. This strategy should be combined with other successful interventions to form part of home programmes to prevent falls in elderly people.
Patients’ illness perceptions and coping as predictors of functional status in psoriasis: a 1-year follow-up
Authors: M. Scharloo, A.A. Kaptein, J. Weinman, W. Bergman, B.J. Vermeer, H.G.M. Rooijmans
Journal: British Journal of Dermatology (2000)

In a longitudinal study (two measurements with a 1-year interval), 69 patients with psoriasis completed the Illness Perception Questionnaire, the Medical Outcomes Study SF-20 Health Survey, and the Hospital Anxiety and Depression Scale. Data on coping (Utrecht Coping List) and severity of illness (body surface scores) were also collected. The results of regression analyses indicated that a strong illness identity was associated with more visits to the outpatient clinic, and worse outcome on physical health, social functioning, mental health, health perceptions and depression. Strong beliefs that the disease is controllable/curable and that the disease has disabling consequences were also related to more clinic visits and more negative perceived health, respectively. Patients who initially engaged in coping characterized by more expression of emotions, seeking more social support, seeking more distraction, and less passive coping were prescribed a lower number of different therapies, were less anxious, less depressed, and had a better physical health 1 year later. These results have implications for the management of patients with psoriasis, which reinforces current views on integrating psychosocial aspects into clinical care.