tbuckley/cabot-search huggingface dataset:
Reversal of Tumor-Mediated Immunosuppression
Authors: Johannes Vieweg, Zhen Su, Philipp Dahm, Sergei Kusmartsev
Journal: Clinical Cancer Research (2007)

Abstract Therapeutic cancer vaccines, one form of active immunotherapy, have long been under investigation; consequently, several vaccine-based strategies have now moved from the bench to the clinical arena. Despite their tremendous promise, current vaccine strategies have shown only limited success in clinical settings, even in renal cell carcinoma (RCC), a prototypical malignancy for the application of immunotherapy. There is ample evidence that, especially in RCC, multiple immunosuppressive mechanisms exist that considerably dampen antitumor responses and weaken the activity of current immunotherapeutic regimens. Therefore, it will be necessary to reverse tumor-mediated immunosuppression before immunotherapies can successfully be applied. Recent insights into the nature and characteristics of the regulatory elements of the immune system have provided new opportunities to enhance vaccine-mediated antitumor immunity and, thereby, increase the chance for improving patient outcome. These new insights represent important considerations for the future design and application of more effective cancer vaccines against RCC and other cancers.
The Relationship Between Microsatellite Slippage Mutation Rate and the Number of Repeat Units
Authors: Y. Lai
Journal: Molecular Biology and Evolution (2003)

Microsatellite markers are widely used for genetic studies, but the relationship between microsatellite slippage mutation rate and the number of repeat units remains unclear. In this study, microsatellite distributions in the human genome are collected from public sequence databases. We observe that there is a threshold size for slippage mutations. We consider a model of microsatellite mutation consisting of point mutations and single stepwise slippage mutations. From two sets of equations based on two stochastic processes and equilibrium assumptions, we estimate microsatellite slippage mutation rates without assuming any relationship between microsatellite slippage mutation rate and the number of repeat units. We use the least squares method with constraints to estimate expansion and contraction mutation rates. The estimated slippage mutation rate increases exponentially as the number of repeat units increases. When slippage mutations happen, expansion occurs more frequently for short microsatellites and contraction occurs more frequently for long microsatellites. Our results agree with the length-dependent mutation pattern observed from experimental data, and they explain the scarcity of long microsatellites.
DC-SIGN–mediated Infectious Synapse Formation Enhances X4 HIV-1 Transmission from Dendritic Cells to T Cells
Authors: Jean-François Arrighi, Marjorie Pion, Eduardo Garcia, Jean-Michel Escola, Yvette van Kooyk, Teunis B. Geijtenbeek, Vincent Piguet
Journal: The Journal of Experimental Medicine (2004)

Dendritic cells (DCs) are essential for the early events of human immunodeficiency virus (HIV) infection. Model systems of HIV sexual transmission have shown that DCs expressing the DC-specific C-type lectin DC-SIGN capture and internalize HIV at mucosal surfaces and efficiently transfer HIV to CD4+ T cells in lymph nodes, where viral replication occurs. Upon DC–T cell clustering, internalized HIV accumulates on the DC side at the contact zone (infectious synapse), between DCs and T cells, whereas HIV receptors and coreceptors are enriched on the T cell side. Viral concentration at the infectious synapse may explain, at least in part, why DC transmission of HIV to T cells is so efficient. Here, we have investigated the role of DC-SIGN on primary DCs in X4 HIV-1 capture and transmission using small interfering RNA–expressing lentiviral vectors to specifically knockdown DC-SIGN. We demonstrate that DC-SIGN− DCs internalize X4 HIV-1 as well as DC-SIGN+ DCs, although binding of virions is reduced. Strikingly, DC-SIGN knockdown in DCs selectively impairs infectious synapse formation between DCs and resting CD4+ T cells, but does not prevent the formation of DC–T cells conjugates. Our results demonstrate that DC-SIGN is required downstream from viral capture for the formation of the infectious synapse between DCs and T cells. These findings provide a novel explanation for the role of DC-SIGN in the transfer and enhancement of HIV infection from DCs to T cells, a crucial step for HIV transmission and pathogenesis.
The immunoreceptor adapter protein DAP12 suppresses B lymphocyte–driven adaptive immune responses
Authors: Takako Nakano-Yokomizo, Satoko Tahara-Hanaoka, Chigusa Nakahashi-Oda, Tsukasa Nabekura, Nadia K. Tchao, Momoko Kadosaki, Naoya Totsuka, Naoki Kurita, Kiyotaka Nakamagoe, Akira Tamaoka, Toshiyuki Takai, Teruhito Yasui, Hitoshi Kikutani, Shin-ichiro Honda, Kazuko Shibuya, Lewis L. Lanier, Akira Shibuya
Journal: The Journal of Experimental Medicine (2011)

DAP12, an immunoreceptor tyrosine-based activation motif-bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II-deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II-deficient B cells suppressed B cell receptor (BCR)-mediated proliferation. The chimeric MAIR-II-DAP12 receptor recruited the SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1) after BCR stimulation. DAP12-deficient mice showed elevated serum antibodies against self-antigens and enhanced humoral immune responses against T cell-dependent and T cell-independent antigens. Thus, DAP12-coupled MAIR-II negatively regulates B cell-mediated adaptive immune responses.
Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors
Authors: M Domenicali
Journal: Gut (2005)

<b>Background and aims:</b> Anandamide is an endocannabinoid that evokes hypotension by interaction with peripheral cannabinoid CB1 receptors and with the perivascular transient receptor potential vanilloid type 1 protein (TRPV1). As anandamide has been implicated in the vasodilated state in advanced cirrhosis, the study investigated whether the mesenteric bed from cirrhotic rats has an altered and selective vasodilator response to anandamide. <b>Methods:</b> We assessed vascular sensitivity to anandamide, mRNA and protein expression of cannabinoid CB1 receptor and TRPV1 receptor, and the topographical distribution of cannabinoid CB1 receptors in resistance mesenteric arteries of cirrhotic and control rats. <b>Results:</b> Mesenteric vessels of cirrhotic animals displayed greater sensitivity to anandamide than control vessels. This vasodilator response was reverted by CB1 or TRPV1 receptor blockade, but not after endothelium denudation or nitric oxide inhibition. Anandamide had no effect on distal femoral arteries. CB1 and TRPV1 receptor protein was higher in cirrhotic than in control vessels. Neither CB1 mRNA nor protein was detected in femoral arteries. Immunochemistry showed that CB1 receptors were mainly in the adventitia and in the endothelial monolayer, with higher expression observed in vessels of cirrhotic rats than in controls. <b>Conclusions:</b> These results indicate that anandamide is a selective splanchnic vasodilator in cirrhosis which predominantly acts via interaction with two different types of receptors, CB1 and TRPV1 receptors, which are mainly located in perivascular sensory nerve terminals of the mesenteric resistance arteries of these animals.
MicroRNA roles in beta-catenin pathway
Authors: Kai Huang, Jun-Xia Zhang, Lei Han, Yong-Ping You, Tao Jiang, Pei-Yu Pu, Chun-Sheng Kang
Journal: Molecular Cancer (2010)

Abstract β-catenin, a key factor in the Wnt signaling pathway, has essential functions in the regulation of cell growth and differentiation. Aberrant β-catenin signaling has been linked to various disease pathologies, including an important role in tumorigenesis. Here, we review the regulation of the Wnt signaling pathway as it relates to β-catenin signaling in tumorigenesis, with particular focus on the role of microRNAs. Finally, we discuss the potential of β-catenin targeted therapeutics for cancer treatment.
Fortnightly Review: Bone densitometry in clinical practice
Authors: J E Compston, C Cooper, J A Kanis
Journal: BMJ (1995)

<h3>Summary points</h3> Osteoporosis is a major health problem in the elderly population. It causes more than 150000 fractures each year in the United Kingdom with an estimated cost of pounds sterling742 million Bone mass is a major determinant of risk of fracture and can be assessed by non-invasive techniques such as dual energy x ray absorptiometry Densitometric criteria based on standard deviation scores expressed in relation to reference values in premenopausal women (T scores) provide diagnostic categories from which thresholds for prevention and treatment can be defined on the basis of risk of fracture Population based screening for low bone mass in perimenopausal women cannot at present be justified. In clinical practice, however, bone densitometry has an important role in the diagnosis of osteoporosis in high risk groups and in the monitoring of treatment in some patients For these indications, it is estimated that about 175 bone scans per 100000 population would be needed annually, requiring an annual expenditure for the average health district of pounds sterling25200 At present, bone densitometry resources in the United Kingdom are inadequate to meet these needs. There is an urgent need to improve existing facilities so that effective strategies for the prevention and treatment of osteoporosis in clinical practice can be implemented
Bevacizumab Plus Interferon Alfa Compared With Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: CALGB 90206
Authors: Brian I. Rini, Susan Halabi, Jonathan E. Rosenberg, Walter M. Stadler, Daniel A. Vaena, San-San Ou, Laura Archer, James N. Atkins, Joel Picus, Piotr Czaykowski, Janice Dutcher, Eric J. Small
Journal: Journal of Clinical Oncology (2008)

Purpose Bevacizumab is an antibody that binds to vascular endothelial growth factor (VEGF) and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN) is a historic standard first-line treatment for RCC. A prospective, randomized phase III trial of bevacizumab plus IFN versus IFN monotherapy was conducted. Patients and Methods Patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or the same dose and schedule of IFN monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Results Between October 2003 and July 2005, 732 patients were enrolled. The prespecified stopping rule for OS has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P &lt; .0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P &lt; .0001). Bevacizumab plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% [95% CI, 9.5% to 17.3%]; P &lt; .0001). Overall toxicity was greater for bevacizumab plus IFN, including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%). Conclusion Bevacizumab plus IFN produces a superior PFS and ORR in untreated patients with metastatic RCC as compared with IFN monotherapy. Toxicity is greater in the combination therapy arm.
Blood Flow, Oxygen Consumption, and Free Fatty Acid Release in Subcutaneous Adipose Tissue during Hemorrhagic Shock in Control and Phenoxybenzamine-Treated Dogs
Authors: A. G. B. KOVÁCH, SUNE ROSELL, PÉTER SÁNDOR, EDITH KOLTAY, EMMA KOVÁCH, NATÁLIA TOMKA
Journal: Circulation Research (1970)

Dogs were anesthetized with α-D (+)-glucochloralose. After bleeding to a mean arterial pressure of 55 mm Hg, blood flow in subcutaneous adipose tissue decreased from 6 ± 0.9 (mean ± SE) to 0.6 ± 0.21 ml/min/100 g (P &lt; 0.001), and remained at that low level during bleeding to 35 mm Hg for an additional 90-minute period. In five out of nine experiments the blood flow ceased completely. Sixty minutes after reinfusion, the blood flow was significantly lower than control, and in two there was no blood flow after reinfusion. In animals previously treated with phenoxybenzamine (5 mg/kg), the decrease in blood flow was significant only at 35 mm Hg arterial pressure (2.6 ± 0.67 ml/min/100 g). After reinfusion blood flow increased to a mean above 10 ml/min/100 g, significantly higher than resting blood flow (P &lt; 0.05). There was no significant change in arterial FFA concentration or FFA release in subcutaneous adipose tissue during bleeding and after reinfusion. In phenoxybenzamine-treated animals there was a tendency to have higher arterial FFA concentration and FFA release. The oxygen uptake fell from 0.47 ± 0.07 to 0.13 ± 0.05 ml/min/100 g (P&lt;0.01) during 55 mm Hg arterial pressure and remained significantly lower also during 35 mm Hg arterial pressure. Previous treatment with phenoxybenzamine prevented a fall in O 2 uptake in subcutaneous adipose tissue. The decrease in blood flow in subcutaneous adipose tissue during bleeding was more pronounced than found in other organs with same hemorrhagic shock procedure. After reinfusion, flow in subcutaneous adipose tissue could not be restored, indicating irreversible vascular damage, α-receptor activity seems to play a significant part in the development of vascular and metabolic changes in subcutaneous adipose tissue during bleeding.
CX<sub>3</sub>C Chemokine Fractalkine in Pulmonary Arterial Hypertension
Authors: Karl Balabanian, Arnaud Foussat, Peter Dorfmüller, Ingrid Durand-Gasselin, Francis Capel, Laurence Bouchet-Delbos, Alain Portier, Anne Marfaing-Koka, Roman Krzysiek, Anne-Cécile Rimaniol, Gérald Simonneau, Dominique Emilie, Marc Humbert
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Perivascular infiltrates composed of macrophages and lymphocytes have been described in lung biopsies of patients displaying pulmonary arterial hypertension (PAH), suggesting that circulating inflammatory cells can be recruited in affected vessels. CX3C chemokine fractalkine is produced by endothelial cells and promotes leukocyte recruitment, but unlike other chemokines, it can capture leukocytes rapidly and firmly in an integrin-independent manner under high blood flow. We therefore hypothesized that fractalkine may contribute to pulmonary inflammatory cell recruitment in PAH. Expression and function of the fractalkine receptor (CX3CR1) were studied by use of triple-color flow cytometry on circulating T-lymphocyte subpopulations in freshly isolated peripheral blood mononuclear cells from control subjects and patients with PAH. Plasma-soluble fractalkine concentrations were measured by enzyme-linked immunosorbent assay. Finally, fractalkine mRNA and protein expression were analyzed in lung samples by reverse transcriptase-polymerase chain reaction or in situ hybridization and immunohistochemistry, respectively. In patients with PAH, CX3CR1 expression and function are upregulated in circulating T-lymphocytes, mostly of the CD4+ subset, and plasma soluble fractalkine concentrations are elevated, as compared with control subjects. Fractalkine mRNA and protein product are expressed in pulmonary artery endothelial cells. We conclude that inflammatory mechanisms involving chemokine fractalkine and its receptor CX3CR1 may have a role in the natural history of PAH.
Losartan-Dependent Regression of Myocardial Fibrosis Is Associated With Reduction of Left Ventricular Chamber Stiffness in Hypertensive Patients
Authors: Javier Díez, Ramón Querejeta, Begoña López, Arantxa González, Mariano Larman, José L. Martínez Ubago
Journal: Circulation (2002)

Background — This study was designed to investigate whether myocardial collagen content is related to myocardial stiffness in patients with essential hypertension. Methods and Results — The study was performed in 34 patients with hypertensive heart disease. Nineteen of these patients were also evaluated after 12 months of treatment with losartan. Transvenous endomyocardial biopsies of the interventricular septum were performed to quantify collagen volume fraction (CVF). Left ventricular (LV) chamber stiffness (K LV ) was determined from the deceleration time of the early mitral filling wave as measured by Doppler echocardiography. Histological analysis at baseline revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 26 with nonsevere fibrosis. Values of CVF and K LV were significantly higher in the 2 subgroups of hypertensives than in normotensives. In addition, compared with patients with nonsevere fibrosis, patients with severe fibrosis exhibited significantly increased values of CVF and K LV . After treatment, CVF and K LV decreased significantly in patients with severe fibrosis (n=7). None of these parameters changed significantly after treatment in patients with nonsevere fibrosis (n=12). CVF was directly correlated with K LV ( r =0.415, P &lt;0.02) in all hypertensives. Conclusions — These findings show a strong association between myocardial collagen content and LV chamber stiffness in patients with essential hypertension. Our results also suggest that the ability of losartan to induce regression of severe myocardial fibrosis is associated with diminution of myocardial stiffness in hypertensive patients.
Hospitalizations, Nursing Home Admissions, and Deaths Attributable to Diabetes
Authors: Louise B. Russell, Elmira Valiyeva, Sheila H. Roman, Leonard M. Pogach, Dong-Churl Suh, Monika M. Safford
Journal: Diabetes Care (2005)

OBJECTIVE—To estimate all-cause hospitalizations, nursing home admissions, and deaths attributable to diabetes using a new methodology based on longitudinal data for a representative sample of older U.S. adults. RESEARCH DESIGN AND METHODS—A simulation model, based on data from the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Followup Study, was used to represent the natural history of diabetes and control for a variety of baseline risk factors. The model was applied to 6,265 NHANES III adults aged 45–74 years. The prevalence of risk factors in NHANES III, fielded in 1988–1994, better represents today’s adults. RESULTS—For all NHANES III adults aged 45–74 years, a diagnosis of diabetes accounted for 8.6% of hospitalizations, 12.3% of nursing home admissions, and 10.3% of deaths in 1988–1994. For people with diabetes, diabetes alone was responsible for 43.4% of hospitalizations, 52.1% of nursing home admissions, and 47% of deaths. Adjusting for related cardiovascular conditions, which may provide more accurate estimates of attributable risks for people with diabetes, increased these estimates to 51.4, 57.1, and 56.8%, respectively. CONCLUSIONS—Risks of institutionalization and death attributable to diabetes are large. Efforts to translate recent trials of primary prevention into practice and continued efforts to prevent complications of diabetes could have a substantial impact on hospitalizations, nursing home admissions, and deaths and their societal costs.
Automated Surveillance to Detect Postprocedure Safety Signals of Approved Cardiovascular Devices
Authors: Frederic S Resnic, Thomas P Gross, Danica Marinac-Dabic, Nilsa Loyo-Berrios, Sharon Donnelly, Sharon-Lise T Normand, Michael E Matheny
Journal: JAMA (2010)

Ensuring the safety of medical devices challenges current surveillance approaches, which rely heavily on voluntary reporting of adverse events. Automated surveillance of clinical registries may provide early warnings in the postmarket evaluation of medical device safety.
Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial
Authors: N. Normanno, A.M. Rachiglio, M. Lambiase, E. Martinelli, F. Fenizia, C. Esposito, C. Roma, T. Troiani, D. Rizzi, F. Tatangelo, G. Botti, E. Maiello, G. Colucci, F. Ciardiello, F. Giuliani, G. Simone, A. Febbraro, E. Tommaselli, S. Cinieri, M. Criscuolo, A. Perrino, A. Rinaldi, R. Bordonaro, M. Manusia, S. Romito, P. Bufo, G. Cartenì, M. Biglietto, O. Nappi, A. Cardarelli, E. Montesarchio, P. Micheli, G. Nasti, N. Chicchinelli, A. Iannaccone, A. Russo, D. Cabibi, P. Giaccone, C. Barone, G. Rindi, G. Tonini, A. Onetti Muda, G. Perrone, T. Latiano, P. Graziano, S. Pisconti, A. Sebastio
Journal: Annals of Oncology (2015)
Esophageal capsule endoscopy is a useful tool in patients with hemophilia
Authors: Anastasios Koulaouzidis, Yun Ang, Sarah Douglas, John Plevris
Journal: Endoscopy (2014)

Esophageal capsule endoscopy (ECE) is considered to be an alternative to conventional esophagogastroduodenoscopy (EGD); however, its indications continue to expand. This report presents results from the use of ECE in patients with hemophilia at a tertiary referral academic center over a 7-year period. A total of 16 patients with hemophilia, who were all at risk of new-variant Creutzfeldt-Jakob disease due to previous treatment with UK plasma-derived pooled blood products, underwent a total of 28 ECE examinations. Main outcomes were the diagnostic yield of ECE, requirement for subsequent conventional EGD, and any variceal bleeding episodes during the follow-up period. The overall diagnostic yield was 67.8 % (19 /28 ECEs). Only one patient underwent conventional EGD, for esophageal biopsies. There were no variceal hemorrhage events in any of the patients on variceal screening follow-up. ECE is a useful and acceptable alternative to conventional endoscopy in selected patient groups (i. e. patients with hemophilia). In this group, ECE can eliminate the need for prior administration of clotting factors.
Mediastinal angiomyolipomas in a male patient affected by tuberous sclerosis
Authors: A. Warth, E. Herpel, A. Schmähl, H. Hoffmann, F. J. F. Herth, P. Schirmacher, H. Dienemann, P. A. Schnabel
Journal: European Respiratory Journal (2008)

Classical angiomyolipomas are benign tumours composed of various tissues, including components of fat, abnormal blood vessels and smooth muscle cells. They are often found in association with tuberous sclerosis complex (TSC). The present study reports a male patient affected by TSC with intermittent, massive chylous pleural effusions, who developed recurrent mediastinal angiomyolipomas. The tumours were characterised via histological and immunohistochemical methods. Although angiomyolipomas frequently occur in the kidneys of TSC patients, this case is the first report of mediastinal angiomyolipomas associated with TSC. Besides lymphangioleiomyomatosis, this differential diagnosis has to be taken into account in the case of chylous pleural effusions and mediastinal masses in tuberous sclerosis complex patients.