tbuckley/cabot-search huggingface dataset:
Mechanism of Action of the Microtubule-Targeted Antimitotic Depsipeptide Tasidotin (Formerly ILX651) and Its Major Metabolite Tasidotin C-Carboxylate
Authors: Anasuya Ray, Tatiana Okouneva, Tapas Manna, Herbert P. Miller, Steven Schmid, Larry Arthaud, Richard Luduena, Mary Ann Jordan, Leslie Wilson
Journal: Cancer Research (2007)

Tasidotin (ILX-651), an orally active synthetic microtubule-targeted derivative of the marine depsipeptide dolastatin-15, is currently undergoing clinical evaluation for cancer treatment. Tasidotin inhibited proliferation of MCF7/GFP breast cancer cells with an IC(50) of 63 nmol/L and inhibited mitosis with an IC(50) of 72 nmol/L in the absence of detectable effects on spindle microtubule polymer mass. Tasidotin inhibited the polymerization of purified tubulin into microtubules weakly (IC(50) approximately 30 micromol/L). However, it strongly suppressed the dynamic instability behavior of the microtubules at their plus ends at concentrations approximately 5 to 10 times below those required to inhibit polymerization. Its major actions were to reduce the shortening rate, the switching frequency from growth to shortening (catastrophe frequency), and the fraction of time the microtubules grew. In contrast with all other microtubule-targeted drugs thus far examined that can inhibit polymerization, tasidotin did not inhibit the growth rate. In contrast to stabilizing plus ends, tasidotin enhanced microtubule dynamic instability at minus ends, increasing the shortening length, the fraction of time the microtubules shortened, and the catastrophe frequency and reducing the rescue frequency. Tasidotin C-carboxylate, the major intracellular metabolite of tasidotin, altered dynamic instability of purified microtubules in a qualitatively similar manner to tasidotin but was 10 to 30 times more potent. The results suggest that the principal mechanism by which tasidotin inhibits cell proliferation is by suppressing spindle microtubule dynamics. Tasidotin may be a relatively weak prodrug for the functionally active tasidotin C-carboxylate.
Nuclear localization of the nerve growth factor (NGF) receptor, TRK-A in liver cells
Authors: A. Bonacchi, L. Taddei, E. Efsen, R. DeFranco, D. Nosi, I. Petrai, M. Torcia, P. Rosini, L. Formigli, S. Zecchi, S. Milani, M. Pinzani, G. Laffi, P. Gentilini, F. Marra
Journal: Journal of Hepatology (2003)
FUTURE OF MAN
Authors: D. Hubble
Journal: BMJ (1961)

<h3>Abstract</h3> Adaptation is often described in behavioral ecology as individuals maximizing their inclusive fitness. Under what conditions does this hold and how does this relate to the gene-centered perspective of adaptation? We unify and extend the literature on these questions to class-structured populations. We demonstrate that the maximization (in the best-response sense) of class-specific inclusive fitness obtains in uninvadable population states (meaning that all deviating mutant go extinct). This defines a genuine actor-centered perspective on adaptation. But this inclusive fitness is assigned to all bearers of a mutant allele in a given class and depends on distributions of demographic and genetic contexts. These distributions, in turn, usually depend on events in previous generations and are thus not under individual control. This prevents, in general, from envisioning individuals themselves as autonomous fitness-maximizers, each with its own inclusive fitness. For weak selection, however, the dependence on earlier events can be neglected. We then show that each individual in each class appears to maximize its own inclusive fitness when all other individuals exhibit fitness-maximizing behavior. This defines a genuine individual-centered perspective of adaptation and justifies formally, as a first-order approximation, the long-heralded view of individuals appearing to maximize their own inclusive fitness.
Increased frequency of CD16+ monocytes and the presence of activated dendritic cells in salivary glands in primary Sjögren syndrome
Authors: M E Wildenberg, J M C Welzen-Coppens, C G van Helden-Meeuwsen, H Bootsma, A Vissink, N van Rooijen, J P van de Merwe, H A Drexhage, M A Versnel
Journal: Annals of the Rheumatic Diseases (2008)

In the salivary glands of patients with primary Sjögren Syndrome (pSjS) an accumulation of dendritic cells (DCs) is seen, which is thought to play a role in stimulating local inflammation. Aberrancies in subsets of monocytes, generally considered the blood precursors for DCs, may play a role in this accumulation of DCs. This study is aimed at determining the level of mature CD14lowCD16+ monocytes in pSjS and their contribution to the accumulation of DCs in pSjS.Levels of mature and immature monocytes in patients with pSjS (n = 19) and controls (n = 15) were analysed by flow cytometry. The reverse transmigration system was used for generation of DCs generated from monocyte subsets. The phenotype of DCs in pSjS salivary glands was analysed using immunohistochemistry. In vivo tracking of monocyte subsets was performed in a mouse model.Increased levels of mature CD14lowCD16+ monocytes were found in patients with pSjS (mean (SD) 14.5 (5.5)% vs 11.4 (3.4)%). These cells showed normal expression of chemokine receptor and adhesion molecules. Mature monocytes partly developed into DC-lysosome-associated membrane glycoprotein (LAMP)+ (19.6 (7.5)%) and CD83+ (16 (9)%) DCs, markers also expressed by DCs in pSjS salivary glands. Monocyte tracking in the non-obese diabetic (NOD) mouse showed that the homologue population of mature mouse monocytes migrated to the salivary glands, and preferentially developed into CD11c+ DCs in vivo.Mature monocytes are increased in pSjS and patient and mouse data support a model where this mature monocyte subset migrates to the salivary glands and develops into DCs.
Nonspecific T-cell homing during inflammation in atopic dermatitis: Expression of cutaneous lymphocyte-associated antigen and integrin αEβ7 on skin-infiltrating T cells
Authors: I.Jolanda M. de Vries, Elisabeth G. Langeveld-Wildschut, Frank C. van Reijsen, Ilse C. Bihari, Carla A.F.M. Bruijnzeel-Koomen, Theo Thepen
Journal: Journal of Allergy and Clinical Immunology (1997)
Impact of Apolipoprotein(a) Phenotypes on Long-Term Renal Transplant Survival
Authors: FRIEDERIKE WAHN, VOLKER DANIEL, FLORIAN KRONENBERG, GERHARD OPELZ, DIETRICH V. MICHALK, UWE QUERFELD
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The long-term success of renal transplantation is limited because of chronic rejection (CR), which shows histologic parallels to atherosclerosis. Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis, but its role in CR has not been investigated. Plasma levels of Lp(a) are determined mainly by the inherited isoform (phenotype) of apolipoprotein(a) [apo(a)] and show an inverse correlation with the molecular weight of apo(a). Apo(a) isoforms were identified in frozen sera of 327 patients who received a renal transplant during 1982 to 1992. Long-term graft survival in recipients with high molecular weight (HMW) or low molecular weight (LMW) apo(a) phenotypes were compared retrospectively. Mean (95% confidence interval) transplant survival was 12.8 yr (range, 11.9 to 13.6 yr) in patients with HMW and 11.9 yr (range, 10.8 to 13.1 yr) in patients with LMW apo(a) phenotypes ( P = 0.2065). In patients who were 35 yr or younger at the time of transplantation, mean transplant survival was more than 3 yr longer in recipients with HMW apo(a) phenotypes compared with those with LMW apo(a) phenotypes (13.2 yr [range, 12.1 to 14.4 yr] versus 9.9 yr (range, 8.5 to 11.5 yr); P = 0.0156). In a Cox's proportional hazards regression model, the presence of LMW phenotypes—but not gender, immunosuppression, or HLA mismatches—in young patients was associated with a statistically significant risk of CR ( P = 0.0434). These retrospective data indicate that young renal transplant recipients with LMW apo(a) phenotypes have a significantly shorter long-term graft survival, regardless of the number of HLA mismatches, gender, or immunosuppressive treatment.
Out of proportion PH in COPD: Report of a small case series
Authors: Davide Piloni, Tiberio Oggionni, Liudmyla Diachyshyna, Laura Scelsi, Stefano Ghio, Claudia Raineri, Isa Cerveri, Alessandro Cascina, Federica Meloni
Journal: European Respiratory Journal (2013)

Recent interest has focused on the subset of COPD patients with severe pulmonary hypertension despite a mild to moderate airflow obstruction, named out of proportion (OoP) PH in COPD. Despite a lack of specific guidelines, a general consensus on a cut off of mPAP≥ 40-45 mmHg has been reached. Here we describe a case series of 11 naive patients screened at the center for PH and lung transplant of S. Matteo Hospital, from jan 2011 to dec 2012. Overall we screened with RHC 25 COPD patients on the basis of Echocardiographic signs of PH. Among them 8 had normal hemodynamics while 19 had mPAP >25 mmHg. 11 of these pts met the following criteria: previous diagnosis of COPD, emphysema at CT without fibrosis, mPAP≥ 40 mmHg, FEV1 > 50% of predicted, thus were defined OoP-PH in COPD.

All of these patients were males (mean age70 ± 6) and characterized by: history of severe hypoxemia lasting >2ys, significant decrease of DLCO (mean 27 ± 10 %) with severely impaired exercise capacity (6MWT 187 ±142mt.), despite preserved lung volumes (mean FEV1 91 ±21%). At RHC all patients had pre-capillary PH (mean PCWP 11.2 ± 2.82 mmHg, mean mPAP 48.91 ± 5,6 mmHg) with reduced cardiac index (2.08 ± 0.44 l/min/m2). 9/11 pts were submitted to compassionate treatment with sildenafil (+ inhaled Iloprost in 3), 1 was enrolled in a clinical trial and 1 had criteria for double lung transplant and was transplanted in 2 months. After 6 month treatment no significant change in hemodynamics was found. During treatment, 2 pts manifested signs of an associated collagen disease, 3 pts died after 0.5, 10 and 11 months follow-up. In conclusion OoP- PH in COPD is a rare but severe condition that is probably still underestimated and overlooked.
Emergency Aortocoronary Bypass
Authors: Fred K. Nakhjavan
Journal: JAMA (1971)

Seven weeks after onset of chest pain, diagnosed as subendocardial infarction, a 49-year-old woman developed frequent ventricular tachycardia and loss of consciousness. An emergency coronary cineangiography revealed significant constriction of the left main coronary artery. Aortocoronary artery bypass graft was performed. Ventricular tachycardia completely disappeared and the patient was discharged from the hospital.
Association Between Serum IGF-1 and Diabetes Among U.S. Adults
Authors: Srinivas Teppala, Anoop Shankar
Journal: Diabetes Care (2010)

OBJECTIVE Serum insulin-like growth factor (IGF)-1 may have a role in the maintenance of glucose homeostasis. We examined the association between serum IGF-1 and diabetes in a representative sample of U.S. adults. RESEARCH DESIGN AND METHODS Third National Health and Nutrition Examination Survey (NHANES III) participants aged ≥18 years (n = 5,511) were the subjects of the study. The main outcome was the presence of diabetes (n = 387). RESULTS Lower serum IGF-1 levels were positively associated with diabetes after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, BMI, hypertension, glomerular filtration rate, and serum cholesterol. Compared with quartile 4 of IGF-1 (referent), the odds ratio (OR) of diabetes associated with quartile 1 was OR 2.16 (95% CI 1.24–3.76); P-trend = 0.002. However, the observed association between IGF-1 and diabetes was present only in those &amp;lt;65 years of age (OR = 3.05; P-trend = 0.006) and disappeared in those ≥65 years of age (OR = 0.51; P-trend = 0.18); P-interaction = 0.0056. CONCLUSIONS Low IGF-1 levels are associated with diabetes among young subjects.
Postinfectious Glomerulonephritis in the Elderly
Authors: Samih H. Nasr, Mary E. Fidler, Anthony M. Valeri, Lynn D. Cornell, Sanjeev Sethi, Amy Zoller, Michael B. Stokes, Glen S. Markowitz, Vivette D. D'Agati
Journal: Journal of the American Society of Nephrology (2010)

Postinfectious glomerulonephritis (PIGN) is primarily a childhood disease that occurs after an upper respiratory tract infection or impetigo; its occurrence in older patients is not well characterized. Here, we report 109 cases of PIGN in patients ≥65 years old diagnosed by renal biopsy. The male to female ratio was 2.8:1. An immunocompromised background was present in 61%, most commonly diabetes or malignancy. The most common site of infection was skin, followed by pneumonia and urinary tract infection. The most common causative agent was staphylococcus (46%) followed by streptococcus (16%) and unusual gram-negative organisms. Hypocomplementemia was present in 72%. The mean peak serum creatinine was 5.1 mg/dl, and 46% of patients required acute dialysis. The most common light microscopic patterns were diffuse (53%), focal (28%), and mesangial (13%) proliferative glomerulonephritis. IgA-dominant PIGN occurred in 17%. Of the 72 patients with ≥3 months of follow-up (mean, 29 months), 22% achieved complete recovery, 44% had persistent renal dysfunction, and 33% progressed to ESRD. The presence of diabetes, higher creatinine at biopsy, dialysis at presentation, the presence of diabetic glomerulosclerosis, and greater tubular atrophy and interstitial fibrosis predicted ESRD. In summary, the epidemiology of PIGN is shifting as the population ages. Older men and patients with diabetes or malignancy are particularly at risk, and the sites of infection and causative organisms differ from the typical childhood disease. Prognosis for these older patients is poor, with fewer than 25% recovering full renal function.
The regional production of cytokines and lactate in sepsis-related multiple organ failure.
Authors: E E Douzinas, P D Tsidemiadou, M T Pitaridis, I Andrianakis, A Bobota-Chloraki, K Katsouyanni, D Sfyras, K Malagari, C Roussos
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

In order to explore whether an organ-specific pattern in cytokine and lactate concentrations exists in patients with multiple organ failure (MOF), we measured the cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha), and lactate in blood taken from the hepatic vein, pulmonary capillaries, and peripheral veins of 10 patients with MOF with hepatic involvement (MOF-HI), eight patients with MOF and adult respiratory distress syndrome (MOF-ARDS), and five head-injured patients (controls). Ten additional patients participated in a study of arteriovenous pulmonary concentration gradients of these substances. For statistical analysis, nonparametric tests and analysis of variance (ANOVA) were used. The regional concentrations of these substances exhibited a different pattern in the two MOF groups. In the MOF-HI group, mean +/- SD cytokines IL-1beta and IL-6 (pg/ml) were respectively 216 +/- 100 and 461 +/- 343 in the hepatic sinusoidal blood; 149 +/- 52 and 293 +/- 204 in pulmonary capillary blood; and 148 +/- 105 and 234 +/- 162 in peripheral venous blood. In the MOF-ARDS group the corresponding levels were 180 +/- 103 and 235 +/- 124; 235 +/- 94 and 280 +/- 108; and 130 +/- 77 and 194 +/- 127. The TNF-alpha levels also exhibited the same pattern. The mean +/- SD corresponding levels (mmol/L) for lactate in the MOF-HI group were 3.1 +/- 1.8, 1.5 +/- 0.3, and 1.2 +/- 0.6, and in the MOF-ARDS group were 1.1 +/- 0.9, 1.8 +/- 1.1, and 1.0 +/- 0.2, respectively. The differences in the levels of all substances between the liver and lungs in the two MOF groups were statistically significant (p < 0.003). In the study of transpulmonary gradients it was shown that the levels of cytokine and lactate were lower in arterial blood than in mixed venous blood in MOF-HI patients, whereas the opposite was true in MOF-ARDS patients. In this study, we found that in MOF, cytokines and lactate are secreted from the most severely affected organs.
Solid Cancer Incidence in Atomic Bomb Survivors Exposed In Utero or as Young Children
Authors: Dale L. Preston, Harry Cullings, Akihiko Suyama, Sachiyo Funamoto, Nobuo Nishi, Midori Soda, Kiyohiko Mabuchi, Kazunori Kodama, Fumiyoshi Kasagi, Roy E. Shore
Journal: JNCI Journal of the National Cancer Institute (2008)

In utero exposure to radiation is known to increase risks of childhood cancers, and childhood exposure is associated with increased risks of adult-onset cancers. However, little is known about whether in utero exposure to radiation increases risks of adult-onset cancers. Solid cancer incidence rates were examined among survivors of the atomic bombings of Hiroshima and Nagasaki who were in utero (n = 2452) or younger than 6 years (n = 15388) at the time of the bombings. Poisson regression was used to estimate and compare the levels and temporal patterns of the radiation-associated excess risks of first primary solid cancers among these survivors at ages 12–55. All statistical tests were two-sided. There were 94 eligible cancers in the in utero group and 649 in the early childhood group. The excess relative risk (ERR) increased with dose for both in utero (age 50, ERR = 1.0 per Sv, 95% confidence interval [CI] = 0.2 to 2.3 per Sv) and early childhood (age 50, ERR = 1.7 per Sv, 95% CI = 1.1 to 2.5 Sv) exposures. The ERR declined (P = .046) with increasing attained age in the combined cohort. Excess absolute rates (EARs) increased markedly with attained age among those exposed in early childhood but exhibited little change in the in utero group. At age 50, the estimated EARs per 10000 person-years per Sv were 6.8 (95% CI = <0 to 49) for those exposed in utero and 56 (95% CI = 36 to 79) for those exposed as young children. Both the in utero and early childhood groups exhibited statistically significant dose-related increases in incidence rates of solid cancers. The apparent difference in EARs between the two groups suggests that lifetime risks following in utero exposure may be considerably lower than for early childhood exposure, but further follow-up is needed.
Cardiovascular and Renal Risk Assessment as a Guide for Treatment in Primary Hypertension
Authors: Roberto Pontremoli, Giovanna Leoncini, Francesca Viazzi, Denise Parodi, Elena Ratto, Simone Vettoretti, Maura Ravera, Cinzia Tomolillo, Giacomo Deferrari
Journal: Journal of the American Society of Nephrology (2004)

BP levels per se may be an unreliable indicator of risk in the individual patient. In fact, the global cardiovascular profile, including the presence and degree of target organ damage, is a better predictor of future events and, therefore, should be used to choose both treatment and BP goals. However, the prevalence of target organ damage and therefore the percentage of patients who are at risk very much depends on the diagnostic techniques used. However, as a result of the high prevalence of hypertension and its financial impact on public health systems, limiting unnecessary and extensive diagnostic tests also should be a priority. The routine search for microalbuminuria may lead to the detection of a significantly greater percentage of patients who are at high risk while contributing the optimization of the cost-effectiveness of diagnostic workup in hypertensive patients.
CC Chemokine Receptor 7–dependent and –independent Pathways for Lymphocyte Homing
Authors: Golo Henning, Lars Ohl, Tobias Junt, Phillip Reiterer, Volker Brinkmann, Hideki Nakano, Werner Hohenberger, Martin Lipp, Reinhold Förster
Journal: The Journal of Experimental Medicine (2001)

Cognate interaction of chemokine receptor CCR7 on lymphocytes with its ligands CCL19 and CCL21 expressed on high endothelial venules (HEVs) is essential for effective migration of T and B cells across HEVs into secondary lymphoid organs. Plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on HEVs, as well as CCR7-deficient mice, have a defective cell migration and reduced homing of lymphocytes. FTY720, a novel immunosuppressant, causes a reduction of lymphocytes in peripheral blood and tissues and their sequestration into lymphoid tissues. In this study we demonstrate that FTY720 rescues the homing defect in both CCR7−/− mice and plt mice. After FTY720 treatment, the number of CD4+ and CD8+ T cells as well as B cells in peripheral blood is reduced while pertussis toxin–sensitive homing into peripheral lymph nodes, mesenteric lymph node, and Peyer's patches is increased. Immunohistology demonstrates that FTY720 enables these cells to enter lymphoid tissue through HEVs. Thus, our data suggest an alternative G-αi-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720.
Adipokines in obese children and adolescents with sleep-disordered breathing
Authors: Kim Van Hoorenbeeck, Hilde Franckx, Patrick Debode, Luc Van Gaal, Kristine Desager, Wilfried De Backer, Stijn Verhulst
Journal: European Respiratory Journal (2012)

Background: Sleep-disordered breathing (SDB) is prevalent in obesity. It has been linked to the metabolic syndrome. Possible mechanism is intermittent hypoxia of the fat tissue and alterations of adipokine secretion.

Aim: This study looked into the effects of intermittent hypoxia on adipokine levels before and after weight loss treatment.

Methods: Obese children and adolescents between 10-18 years were included while entering an inpatient weight loss treatment program. All patients had 2 visits: baseline and after 4-6 months of treatment. Leptin, adiponectin, TNF-alpha and IL-6 were determined at both visits and a sleep screening was performed at baseline and repeated in case of SDB.

Results: 158 patients participated in this study. Median age was 15.7 years (10.9-18.0). Mean BMI z-score was 2.75+/-0.42. 26% of participants had SDB at baseline. Mean nocturnal saturation correlated with leptin (r=0.19; P=0.02) and adiponectin (r=-0.17; P=0.04). IL-6 correlated with oxygen desaturation index (r=-0.20; P=0.02). TNF-alpha levels were not linked to sleep parameters. After weight loss 19% of subjects with SDB at baseline that participated in the follow-up study had residual SDB. Average weight loss was 29%. Correlation analysis did not show associations between improvements in sleep parameters and improvements in adipokines. These were mostly linked to a lowering in BMI z-score.

Conclusion: In an obese pediatric population SDB was linked to changes in the secretion profile of leptin, adiponectin and IL-6. After weight loss treatment levels of leptine, adiponectin, IL-6 and TNF-alpha did not improve in association with improvements in sleep parameters.