tbuckley/cabot-search huggingface dataset:
Lipoxins, Aspirin-Triggered Epi-Lipoxins, Lipoxin Stable Analogues, and the Resolution of Inflammation
Authors: Siobhan Mitchell, Graham Thomas, Killeen Harvey, David Cottell, Keira Reville, Giovanni Berlasconi, Nicos A Petasis, Lars Erwig, Andrew J Rees, John Savill, Hugh R Brady, Catherine Godson
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA<sub>4</sub> stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (Mφ) <i>in vitro</i>, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA<sub>4</sub>, LXB<sub>4</sub>, the aspirin-triggered LX (ATL) epimer, 15-epi-LXB<sub>4</sub>, and a stable synthetic analogue 15(<i>R/S</i>)-methyl-LXA<sub>4</sub> stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (Mφ) <i>in vivo</i> in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis <i>in vivo</i> was observed with 15-min exposure to LX and with intraperitoneal doses of LXA<sub>4</sub>, LXB<sub>4</sub>, 15(<i>R/S</i>)-methyl-LXA<sub>4</sub>, and 15-epi-LXB<sub>4</sub> of 2.5 to 10 μg/kg. Non-phlogistic LX-stimulated phagocytosis by Mφ was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor–β<sub>1</sub> (TGF-β<sub>1</sub>). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of Mφ to β1,3-glucan, suggesting a novel Mφ-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA<sub>4</sub> receptor (MYFINITL and LESIFRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-β<sub>1</sub> release. These data provide the first demonstration that LXA<sub>4</sub>, LXB<sub>4</sub>, ATL, and LX stable analogues rapidly promote Mφ phagocytosis of PMN <i>in vivo</i> and support a role for LX as rapidly acting, pro-resolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain.E-mail: cgodson@mater.ie
Type II alveolar epithelial cell in vitro culture in aerobiosis
Authors: C Aerts, C Voisin, B Wallaert
Journal: European Respiratory Journal (1988)

A method of Type II alveolar epithelial cell culture in aerobiosis has been developed. Isolation of Type II cells was performed by digesting guinea-pig lung tissue with crude trypsin and elastase and using discontinuous Percoll density gradients. The Type II cells, as identified by light and electron microscopy, were cultured in aerobiosis for up to six days, in direct contact with the atmosphere in conditions mimicking those present in the lower respiratory tract. Significant activities of cellular superoxide dismutase (SOD), manganese dependent superoxide dismutase (Mn-SOD), catalase and glutathione peroxidase (GSH-Px) were found at the time of isolation. In contrast, cell glutathione content varied widely from one experiment to another. Changes of antioxidant enzymes were evaluated during cell culture in aerobiosis. SOD, Mn-SOD and catalase were significantly decreased after three days but were not significantly different between a three day and six day culture. Antioxidant changes did not influence the cell culture. In marked contrast, decrease in cell glutathione was associated with rapid cell death, whereas good cell survival was obtained at high levels of cell glutathione. Cell culture in aerobiosis will permit a precise evaluation of the effects of gases, particularly oxidant gases, on a primary culture of Type II alveolar epithelial cells.
Noncancer Causes of Death in Survivors of Testicular Cancer
Authors: Sophie D Fosså, Ethel Gilbert, Graça M Dores, Jinbo Chen, Katherine A McGlynn, Sara Schonfeld, Hans Storm, Per Hall, Eric Holowaty, Aage Andersen, Heikki Joensuu, Michael Andersson, Magnus Kaijser, Mary Gospodarowicz, Randi Cohen, Eero Pukkala, Lois B Travis
Journal: JNCI Journal of the National Cancer Institute (2007)

Although modern treatments for testicular cancer are associated with increased survival, the long-term health effects of these treatments are unclear. We conducted a population-based study to quantify the long-term risks of mortality from noncancer causes among men with testicular cancer.We identified 38,907 one-year survivors of testicular cancer within 14 population-based cancer registries in North America and Europe (from 1943 through 2002). We used data from these registries to calculate standardized mortality ratios (SMRs) for noncancer deaths and to evaluate associations between histology, age at testicular cancer diagnosis, calendar year of diagnosis, and initial treatment and the risk of noncancer mortality. All statistical tests were two-sided.A total of 2942 deaths from all noncancer causes were reported after a median follow-up of 10 years, exceeding the expected number of deaths from all noncancer causes in the general population by 6% (SMR = 1.06, 95% confidence interval [CI] = 1.02 to 1.10); the noncancer standardized mortality ratios did not differ statistically significantly between patients diagnosed before and after 1975, when cisplatin-based chemotherapy came into widespread use. Compared with the general population, testicular cancer survivors had higher mortality from infections (SMR = 1.28, 95% CI = 1.12 to 1.47) and from digestive diseases (SMR = 1.44, 95% CI = 1.26 to 1.64). Mortality from all circulatory diseases was statistically significantly elevated in men diagnosed with testicular cancer before age 35 years (1.23, 95% CI = 1.09 to 1.39) but not in men diagnosed at older ages (SMR = 0.94; 95% CI = 0.89 to 1.00). Men treated with chemotherapy (with or without radiotherapy) in 1975 or later had higher mortality from all noncancer causes (SMR = 1.34, 95% CI = 1.15 to 1.55), all circulatory diseases (SMR = 1.58, 95% CI = 1.25 to 2.01), all infections (SMR = 2.48, 95% CI = 1.70 to 3.50), and all respiratory diseases (SMR = 2.53, 95% CI = 1.26 to 4.53). Testicular cancer patients who were younger than 35 years at diagnosis and were treated with radiotherapy alone in 1975 or later had higher mortality from all circulatory diseases (SMR = 1.70, 95% CI = 1.21 to 2.31) compared with the general population.Men who have survived for at least 1 year after being diagnosed with testicular cancer have a slightly higher risk of dying from noncancer causes, including infections, digestive diseases, and circulatory diseases, than the general population. Men treated with chemotherapy in 1975 or later may be at particularly high risk.
New Metabolizable Immunologic Adjuvant for Human Use
Authors: Joseph Stokes
Journal: JAMA (1969)

Five lots of a new highly purified (filter-purified) killed influenza virus vaccine were tested in varying regimens in adjuvant 65 or in aqueous formulation in a total of 708 persons in an institution. Adjuvant 65-type formulation containing 300 or 600 chick-cell agglutination (CCA) units of pentavalent influenza virus vaccine caused roughly fourfold more antibody to develop than did the corresponding aqueous vaccines. A single dose of 300 CCA unit adjuvant vaccine was about as effective in stimulating antibody as 600 CCA unit adjuvant vaccine and was greatly superior to two doses of 600 CCA unit aqueous vaccine. The antibody stimulated by the adjuvant was retained well for at least four months, at which time the responses to aqueous vaccine had usually declined substantially. Neither aqueous nor adjuvant vaccines caused significant local or systemic clinical reaction.
Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy
Authors: Stephen Johnston, Maureen Trudeau, Bella Kaufman, Hamouda Boussen, Kimberley Blackwell, Patricia LoRusso, Donald P. Lombardi, Slim Ben Ahmed, Dennis L. Citrin, Michelle L. DeSilvio, Jennifer Harris, Ron E. Westlund, Vanessa Salazar, Tal Z. Zaks, Neil L. Spector
Journal: Journal of Clinical Oncology (2008)

Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity.Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected.Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib.Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.
A Polymorphism in the Cyclooxygenase 2 Gene as an Inherited Protective Factor Against Myocardial Infarction and Stroke
Authors: Francesco Cipollone
Journal: JAMA (2004)

ContextMyocardial infarction (MI) and ischemic stroke are thought to be caused by matrix digestion by metalloproteinases (MMPs) leading to rupture of atherosclerotic plaques. Production of macrophage MMP-2 and MMP-9 is induced by cyclooxygenase 2 (COX-2) and prostaglandin E2 synthesis. Although COX-2 expression may be genetically determined, the relation between COX-2 polymorphisms and the risk of MI and stroke is unclear.ObjectiveTo investigate the relationship between the −765G→C polymorphism of the COX-2 gene and clinically evident plaque rupture.Design, Setting, and ParticipantsProspective, matched case-control study conducted between March 2002 and October 2003 among 864 patients with first MI or atherothrombotic ischemic stroke and 864 hospitalized controls. The groups were matched for age, sex, body mass index, smoking, hypertension, hypercholesterolemia, and diabetes. The −765G→C variant of the COX-2 gene was genotyped by restriction endonuclease digestion of polymerase chain reaction products.Main Outcome MeasuresPresence of the −765G→C polymorphism of the COX-2 gene; COX-2, MMP-2, and MMP-9 expression and activity in plaques and in peripheral monocytes; urinary 6-keto PGF1α (marker of endothelial prostacyclin); and endothelium-dependent and -independent forearm blood flow vasodilation.ResultsThe prevalence of −765GC was 2.41 times higher among controls than among cases (43.3% vs 17.9%; P&lt;.001). The prevalence of −765CC homozygosity was 5.81 times higher (6.4% vs 1.1%; P = .04). Among participants carrying the −765GC and −765CC genotypes, the prevalence ratios for MI or stroke were 0.48 (95% CI, 0.36-0.68) and 0.33 (95% CI, 0.24-0.55), respectively. Expression of COX-2 and MMPs was significantly lower in atherosclerotic plaques from participants carrying the −765C allele, while the −765G→C polymorphism did not affect endothelial prostacyclin biosynthesis or endothelium-dependent vasodilation in vivo. In subgroup analyses (n = 224 cases), serum high-sensitivity C-reactive protein was significantly lower in patients carrying the −765C allele (mean [SD], 0.78 [0.1] vs 2.56 [0.4] mg/L; P = .04).ConclusionsWe found that the −765G→C polymorphism of the COX-2 gene is associated with a decreased risk of MI and stroke. Detection of this genotype may be useful for predicting genetic risk of MI and stroke.
Propranolol ameliorates the development of portal-systemic shunting in a chronic murine schistosomiasis model of portal hypertension.
Authors: S K Sarin, R J Groszmann, P G Mosca, M Rojkind, M J Stadecker, R Bhatnagar, A Reuben, Y Dayal
Journal: Journal of Clinical Investigation (1991)

We investigated the role of early portal hypotensive pharmacotherapy in preventing the development of portal-systemic shunting in a portal hypertensive model of chronic murine schistosomiasis induced by infecting C3H mice with 60 cercariae of Schistosoma mansoni. Propranolol was administered in drinking water to 20 animals for a period of 6 wk at a dose of 10 mg.kg-1d-1, starting at 5 wk of schistosomal infection. 32 age-matched mice with chronic schistosomal infection served as controls. All animals were studied 11 wk after the infection. Compared with controls the portal pressure (10.8 +/- 0.40 mmHg) was significantly lower (P less than 0.001) in the propranolol-treated animals (7.9 +/- 0.80 mmHg). Portal-systemic shunting was decreased by 79%, from 12.2 +/- 3.34% in controls to 2.5 +/- 0.99% in the propranolol group (P less than 0.05). Portal venous inflow was reduced by 38% in the propranolol treated animals (2.50 +/- 0.73 ml/min; n = 6) compared with controls (4.00 +/- 0.34 ml/min; n = 8; P less than 0.05). The worm burden, the granulomatous reaction, the collagen content of the liver, and the serum bile acid levels were not significantly different between the two groups of animals. These results demonstrate that in chronic liver disease induced by schistosomiasis, the development of portal-systemic shunting can be decreased or prevented by the reduction of flow and pressure in the portal system.
Contrast Echocardiography in Apical Hypertrophic Cardiomyopathy
Authors: Harun Otieno, Yoel Vivas, Darren Traub, Asha Raman, Chandra Polam
Journal: Circulation (2006)

T he patient was a 43-year-old asymptomatic Indian male referred for evaluation of an abnormal ECG obtained at a routine check-up.His cardiovascular risk factors included hyperlipidemia and a family history of premature coronary artery disease.His physical examination was unremarkable.The ECG (Figure 1) showed sinus rhythm with evidence of left ventricular hypertrophy, ST-segment elevation in the inferior leads III and aVF, and giant negative T waves in the precordial leads.Twodimensional (Movie I) and contrast echocardiography (Movie II) with DEFINITY (Perflutren lipid microspheres, Bristol-Myers Squibb Medical Imaging, Inc, N. Billerica, Mass) were performed, revealing severe apical hypertrophy with the absence of a dynamic left ventricular outflow tract gradient.Radiocontrast left ventriculography (Figure 2) demonstrated the characteristic "ace-of-spades" left ventricular cavity, confirming the diagnosis of apical hypertrophic cardiomyopathy.The coronary arteries were free of obstructive disease.This case demonstrates the classical electrocardiographic, echocardiographic, and ventriculographic features of apical hy-
Let’s Empower and Prepare (LEAP): Evaluation of a Structured Transition Program for Young Adults With Type 1 Diabetes
Authors: Paola A. Sequeira, Elizabeth A. Pyatak, Marc J. Weigensberg, Cheryl P. Vigen, Jamie R. Wood, Valerie Ruelas, Lucy Montoya, Marisa Cohen, Heather Speer, Susan Clark, Anne L. Peters
Journal: Diabetes Care (2015)

OBJECTIVE To evaluate the efficacy of a structured transition program compared with usual care in improving routine follow-up, clinical, and psychosocial outcomes among young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS Eighty-one young adults in their last year of pediatric care were recruited from three clinics. Intervention group (IG) participants (n = 51) received a structured transition program incorporating tailored diabetes education, case management, group education classes, and access to a newly developed young adult diabetes clinic and transition website. Control group (CG) participants (n = 30) received usual care. The primary outcome was the number of routine clinic visits. Secondary outcomes included glycemic control, hypoglycemia, health care use, and psychosocial well-being. Assessments were conducted at baseline, and 6 and 12 months. RESULTS Limitations in CG follow-up prevented direct comparisons of adult care visits; however, at the 12-month follow-up among IG participants discharged from pediatric care (n = 32), 78% had one or more adult visits. Among IG participants, the total number of clinic visits did not differ between those who transitioned and those who remained in pediatric care (3.0 ± 1.24 vs. 3.11 ± 0.94, P = 0.74). IG compared with CG participants had improved glycemic control (−0.40 ± 1.16% vs. 0.42 ± 1.51% [4.4 ± 12.7 mmol/mol vs. 4.6 ± 16.5 mmol/mol], P = 0.01), incidence of severe hypoglycemia (0.0% vs. 16%, P = 0.02), and global well-being (P = 0.02) at 12 months. CONCLUSIONS A structured transition program was successful in facilitating transition to adult care without a decrease in clinical follow-up. Compared with usual care, the transition program facilitated improvements in glycemic control, hypoglycemia, and psychosocial well-being.
Very early rheumatoid arthritis is the major predictor of major outcomes: clinical ACR remission and radiographic non-progression
Authors: S. Bosello, A. L. Fedele, G. Peluso, E. Gremese, B. Tolusso, G. Ferraccioli
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> To identify predictors of clinical remission as well as of no x-ray progression in a cohort of early rheumatoid arthritis (ERA) treated with a tight-control protocol. <h3>Methods</h3> A total of 121 consecutive patients with ERA were treated to reach European League Against Rheumatism (EULAR) and/or American College of Rheumatology (ACR) clinical remission with methotrexate (MTX) for 3 months, then with a combination with anti-tumour necrosis factor if the patient did not achieve a 44-joint Disease Activity Score (DAS44) ≤2.4. At baseline and after 12 months all the patients had hand and foot joint radiographs. Very early rheumatoid arthritis (VERA) was defined as a disease with symptoms of less than 12 weeks. <h3>Results</h3> In all, 46.3% of the patients reached DAS remission and 24.8% achieved ACR remission. More than 60% of patients reached remission with MTX. Male sex and an erythrocyte sedimentation rate &lt;35 mm/h at onset arose as significant predictors of EULAR remission, while VERA disease was the only predictor of ACR remission. At baseline, 28.1% of the patients were erosive. Multivariate analysis demonstrated that the only independent predictor of erosiveness was 'not having VERA disease'. After 12 months, VERA was the only factor predicting a lack of new erosions. <h3>Conclusions</h3> VERA represents the best therapeutic opportunity in clinical practice to achieve a complete remission and to stop the erosive course of rheumatoid arthritis.
Impaired Angiogenesis After Hindlimb Ischemia in Type 2 Diabetes Mellitus
Authors: Surovi Hazarika, Ayotunde O. Dokun, Yongjun Li, Aleksander S. Popel, Christopher D. Kontos, Brian H. Annex
Journal: Circulation Research (2007)

Deficient angiogenesis after ischemia may contribute to worse outcomes of peripheral arterial disease in patients with diabetes mellitus (DM). Vascular endothelial growth factor (VEGF) and its receptors promote angiogenesis. We hypothesized that in peripheral arterial disease, maladaptive changes in VEGF ligand/receptor expression could account for impaired angiogenesis in DM. Skeletal muscle from diet-induced, type 2 diabetic (DM) and age-matched normal chow (NC)-fed mice was collected at baseline and 3 and 10 days after hindlimb ischemia and analyzed for expression of VEGF (n=10 per group), full-length VEGF receptor (VEGFR)-1, soluble VEGFR-1, and markers of downstream VEGF signaling (n=20 per group) using ELISA, reverse transcriptase-polymerase chain reaction, and Western blots. In the absence of ischemia, DM mice had increased VEGF (NC versus DM: 26.6±2.6 versus 53.5±8.8 pg/mg protein; P &lt;0.05), decreased soluble and membrane-bound VEGFR-1 (NC versus DM: 1.44±0.30 versus 0.85±0.08 and 1.03±0.10 versus 0.72±0.10, respectively; P &lt;0.05), decreased phospho-AKT/AKT and phospho–endothelial NO synthase/endothelial NO synthase (NC versus DM: 0.76±0.2 versus 0.38±0.1 and 0.36±0.06 versus 0.25±0.04, respectively; P &lt;0.05), and no change in VEGFR-2. After ischemia, both DM and NC had comparable increases in VEGF-A. VEGFR-1 and soluble VEGFR-1 expression increased in both groups, but the fold increase was significantly greater in DM. These data demonstrate that soluble VEGFR-1, an angiogenesis inhibitor, is regulated in skeletal muscle by type 2 DM and ischemia. In the absence of ischemia, despite reductions in both soluble VEGFR-1 and VEGFR-1, VEGF ligand signaling is lower in DM compared with controls. After ischemia, maladaptive upregulation of these receptors further reduces the capacity of VEGF to induce an angiogenic response, which may provide a novel target for therapy.
M-current preservation contributes to anticonvulsant effects of valproic acid
Authors: Hee Yeon Kay, Derek L. Greene, Seungwoo Kang, Anastasia Kosenko, Naoto Hoshi
Journal: Journal of Clinical Investigation (2015)

Valproic acid (VPA) has been widely used for decades to treat epilepsy; however, its mechanism of action remains poorly understood. Here, we report that the anticonvulsant effects of nonacute VPA treatment involve preservation of the M-current, a low-threshold noninactivating potassium current, during seizures. In a wide variety of neurons, activation of Gq-coupled receptors, such as the m1 muscarinic acetylcholine receptor, suppresses the M-current and induces hyperexcitability. We demonstrated that VPA treatment disrupts muscarinic suppression of the M-current and prevents resultant agonist-induced neuronal hyperexcitability. We also determined that VPA treatment interferes with M-channel signaling by inhibiting palmitoylation of a signaling scaffold protein, AKAP79/150, in cultured neurons. In a kainate-induced murine seizure model, administration of a dose of an M-channel inhibitor that did not affect kainate-induced seizure transiently eliminated the anticonvulsant effects of VPA. Retigabine, an M-channel opener that does not open receptor-suppressed M-channels, provided anticonvulsant effects only when administered prior to seizure induction in control animals. In contrast, treatment of VPA-treated mice with retigabine induced anticonvulsant effects even when administered after seizure induction. Together, these results suggest that receptor-induced M-current suppression plays a role in the pathophysiology of seizures and that preservation of the M-current during seizures has potential as an effective therapeutic strategy.