tbuckley/cabot-search huggingface dataset:
Indibulin, a Novel Microtubule Inhibitor, Discriminates between Mature Neuronal and Nonneuronal Tubulin
Authors: Anke Wienecke, Gerald Bacher
Journal: Cancer Research (2008)

Microtubule inhibitors interfere with microtubule dynamics, causing cell cycle arrest and apoptosis. These effects are responsible for the chemotherapeutic activities of members of the taxane and Vinca alkaloid families in oncology. Unfortunately, a major side effect of the taxanes and Vinca alkaloids is the development of peripheral neuropathies. Indibulin (N-[pyridin-4-yl]-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid; D-24851; ZIO-301), a novel synthetic small molecule microtubule inhibitor, destabilizes microtubules and has antitumor activity but does not exhibit neurotoxicity in preclinical animal studies. In the present study, it has been found that indibulin is able to discriminate between highly posttranslationally modified tubulin present in mature neuronal microtubules, and less-modified tubulin present in immature neuronal or nonneuronal microtubules. Vincristine and colchicine act on either tubulin equally well. The binding site of indibulin on mature neuronal microtubules seems to be inaccessible due to the posttranslational modifications, a theory that is supported by the observation that indibulin did not disrupt the integrity of highly modified microtubules present in neurites of pheochromocytoma (PC12) cells. The specificity of indibulin for unmodified microtubules seems to be dependent on the pyridyl moiety of indibulin because derivatives that have the pyridyl moiety replaced are not able to discriminate between highly and less-modified tubulins. The observed broad antitumor activity of indibulin and the lack of central and peripheral nervous system toxicity in preclinical studies make it a promising candidate for development as a cancer treatment. Indibulin is currently in phase I clinical trials.
Synergistic Cytotoxicity of Pyrazoloacridine with Doxorubicin, Etoposide, and Topotecan in Drug-Resistant Tumor Cells
Authors: YanPing Hu, Awtar Krishan, WeiJia Nie, Kasi S. Sridhar, Lawrence D. Mayer, Marcel Bally
Journal: Clinical Cancer Research (2004)

Abstract Pyrazoloacridine (NSC 366140, PD115934, PZA) is a new class of acridine anticancer agents under investigation in Phase II clinical trials in patients with advanced cancers. Although poor responses in patients to the treatment with PZA alone have been observed, this class of agents remains of interest because of its distinct mechanism of action from other topoisomerase poisons. Therefore, the combination of PZA with conventional anticancer agents presents an attractive approach to treat drug-resistant human tumors. In the present study, the cytotoxic effects of PZA combined with doxorubicin, topotecan, and etoposide were determined using paired parental and doxorubicin-resistant human colon carcinoma (SW-620 and SW620/AD-300) and breast cancer cell lines (MCF-7 and MCF-7/TH). Cytotoxicity was measured by soft agar clonogenic assays. Dose effect and combination effects were analyzed by the method of Chou and Talalay. The combination of PZA with doxorubicin, topotecan, and etoposide in fixed ratios demonstrated synergistic cytotoxicity on both SW-620 and SW620/AD-300 cell lines. The combination of PZA with doxorubicin also exhibited synergistic cytotoxicity against both MCF-7 and MCF-7/TH cell lines. The mechanism of synergism appeared independent of topoisomerase I and II inhibition, and interference with protein-DNA complexes. Strategies to define optimal drug combinations are proving to be of significant value when considering potential clinical applications of new and established agents.
Urinary Excretion of β2-Microglobulin and IgG Predict Prognosis in Idiopathic Membranous Nephropathy
Authors: Amanda J W Branten, Peggy W du Buf-Vereijken, Ina S Klasen, Frank H Bosch, Geert W Feith, Daan A Hollander, Jack F Wetzels
Journal: Journal of the American Society of Nephrology (2004)

An accurate prediction of the prognosis of patients with idiopathic membranous nephropathy (iMN) should allow restriction of immunosuppressive treatment to patients who are at highest risk for ESRD. On the basis of retrospective studies, it has previously been suggested that the urinary excretions of beta2-microglobulin (Ubeta2m) and IgG (UIgG) are useful predictors of renal insufficiency in patients with iMN. The threshold values of 0.5 micro/min (Ubeta2m) and 250 mg/24 h (UIgG) have been validated in a new and larger patient cohort. From 1995 onward, 57 patients with iMN (38 men, 19 women; age 48 +/- 16 yr), a nephrotic syndrome, and a serum creatinine level </=1.5 mg/dl were studied prospectively. At baseline, a standardized measurement was carried out to determine renal function and protein excretion. The end point renal death was defined as a serum creatinine exceeding 1.5 mg/dl or a rise of serum creatinine of >50%. Mean (+/-SD) follow-up was 53 +/- 23 mo. Thus far, 25 (44%) of the patients have reached the end point renal death. Multivariate analysis confirmed Ubeta2m as the strongest independent predictor for the development of renal insufficiency. Sensitivity and specificity were 88 and 91%, respectively, for Ubeta2m, and both were 88% for UIgG. When the excretions of both proteins were combined, specificity improved to 97%. It is concluded that the present data validate the accuracy of Ubeta2m and of UIgG in predicting renal outcome in patients with iMN. These markers can be used to guide decisions on the start of immunosuppressive treatment.
Disruption of the myocardial extracellular matrix leads to cardiac dysfunction
Authors: Henry E. Kim, Seema S. Dalal, Erik Young, Marianne J. Legato, Myron L. Weisfeldt, Jeanine D’Armiento
Journal: Journal of Clinical Investigation (2000)

MMP activity with disruption of structural collagen has been implicated in the pathophysiology of dilated cardiomyopathy. To examine the role of this enzyme in cardiac function, a transgenic mouse was created that constitutively expressed human collagenase (MMP-1) in the heart. At 6 months of age, these animals demonstrated compensatory myocyte hypertrophy with an increase in the cardiac collagen concentration due to elevated transcription of type III collagen. Chronic myocardial expression of MMP-1 produced loss of cardiac interstitial collagen coincident with a marked deterioration of systolic and diastolic function at 12 months of age. This is the first animal model demonstrating that direct disruption of the extracellular matrix in the heart reproduces the changes observed in the progression of human heart failure.
HDAC Inhibitor SNDX-275 Induces Apoptosis in erbB2-Overexpressing Breast Cancer Cells via Down-regulation of erbB3 Expression
Authors: Xiaoping Huang, Lizhi Gao, Shuiliang Wang, Choon-Kee Lee, Peter Ordentlich, Bolin Liu
Journal: Cancer Research (2009)

Breast cancer is a highly heterogeneous disease with distinct histologic subtypes. Targeted therapies such as endocrine therapy and growth factor receptor inhibitors have had a significant impact on the treatment of metastatic breast cancer patients. Unfortunately, resistance to these agents eventually occurs, and currently represents a significant clinical problem in the management of breast cancers. Inhibitors of histone deacetylases (HDACi) exhibit anticancer activity in a variety of tumor cell models and have been shown to target mechanisms of resistance to a number of targeted agents. It is unclear, however, if there are specific breast cancer subtypes for which an HDACi may be more or less effective. Here, we report that the class I isoform-selective HDACi entinostat (SNDX-275) preferentially inhibits cell proliferation/survival and inactivates downstream signaling in erbB2-overexpressing compared with basal breast cancer cells. SNDX-275 reduces the levels of both erbB2 and erbB3, as well as significantly decreases P-erbB2, P-erbB3, P-Akt, and P-MAPK in erbB2-overexpressing cells. Additionally, SNDX-275 promotes apoptosis and induces cell cycle arrest predominantly at G(1) phase in erbB2-overexpressing cells, whereas SNDX-275 mainly induces G(2)-M arrest in basal breast cancer cells. The cellular bias of SNDX-275 is shown to be related partly to the levels of erbB3 expression that directly impact the ability of SNDX-275 to inhibit proliferation/survival of the erbB2-overexpressing breast cancer cells. These findings show that SNDX-275 may be developed as a novel therapeutic agent to treat breast cancers with coexpression of both erbB2 and erbB3.
Airway inflammation, bronchial hyperresponsiveness and asthma in elite ice hockey players
Authors: A. Lumme, T. Haahtela, J. Öunap, P. Rytilä, Y. Obase, M. Helenius, V. Remes, I. Helenius
Journal: European Respiratory Journal (2003)

There is little information of lower respiratory symptoms, bronchial hyperresponsiveness and airway inflammation in elite ice hockey players. A total of 88 highly trained ice hockey players and 47 control subjects were studied. All the subjects were subjected to skin-prick tests, resting spirometry examinations and histamine-challenge tests. Adequate induced sputum samples were obtained from 68 of the ice hockey players and from 18 symptom-free control subjects on a separate day. Bronchial hyperresponsiveness in a histamine-challenge test was found in 21 (24%) of the athletes and in five (11%) of the controls. Current asthma (current asthmatic symptoms and increased bronchial responsiveness) was observed in 13 (15%) of the athletes and in one (2%) of the control subjects. Total asthma (current asthma or previously physician-diagnosed asthma) occurred in 19 (22%) of the athletes and in two (4%) of the controls. Atopy, according to skin-prick tests, was observed in 51 (58%) of the athletes and 17 (36%) of the control subjects. The differential cell counts of eosinophils (2.6 versus 0.2%) and neutrophils (80.9 versus 29.9%) in the sputum samples of the ice hockey players were significantly higher than in those of the control subjects. Asthma is common in elite ice hockey players and they show signs of a mixed type of neutrophilic and eosinophilic airway inflammation. Inhalation of cold air associated with exposure to indoor pollutants during intensive training is a possible causative factor.
C-Reactive Protein and Ischemia in Users and Nonusers of β-Blockers and Statins
Authors: Mary S. Beattie, Michael G. Shlipak, Haiying Liu, Warren S. Browner, Nelson B. Schiller, Mary A. Whooley
Journal: Circulation (2003)

Background— Elevated levels of C-reactive protein (CRP) are associated with an increased risk of coronary events, but whether inflammation is associated with inducible ischemia in patients with stable coronary disease is unknown. Methods and Results— We recruited patients with known coronary disease from 2 VA Medical Centers and 1 University-based medical center for the Heart and Soul Study. We measured CRP levels in 118 participants who had exercise-induced ischemia and in 111 who did not have inducible ischemia, as determined by stress echocardiography. We used logistic regression to examine the risk of exercise-induced ischemia associated with elevated CRP. We found that 75% (39/52) of participants in the highest CRP category (&gt;0.38 mg/dL) had inducible ischemia, compared with 45% (79/177) in the lower 4 categories combined (adjusted odds ratio 4.2; 95% confidence interval 1.6 to 11; P =0.004). However, this association differed in users and nonusers of β-blockers and statins. Among 89 participants who did not use β-blockers, 93% in the highest CRP category had exercise-induced ischemia, compared with 42% in the lower 4 categories ( P =0.03). Among 67 participants who did not use statins, 94% in the highest CRP category had exercise-induced ischemia, compared with 44% in the lower 4 categories ( P =0.009). We did not observe a significant association between CRP and ischemia among participants who were treated with either of these medications. Conclusion— Elevated CRP levels are associated with inducible ischemia in patients with stable coronary disease, particularly among those not treated with β-blockers or statins.
Inherited predisposition to glioma
Authors: A. P. Kyritsis, M. L. Bondy, J. S. Rao, C. Sioka
Journal: Neuro-Oncology (2009)

In gliomas, germline gene alterations play a significant role during malignant transformation of progenitor glial cells, at least for families with occurrence of multiple cancers or with specific hereditary cancer syndromes. Scientific evidence during the last few years has revealed several constitutive genetic abnormalities that may influence glioma formation. These germline abnormalities are manifested as either gene polymorphisms or hemizygous mutations of key regulatory genes that are involved either in DNA repair or in apoptosis. Such changes, among others, include hemizygous alterations of the neurofibromatosis 1 (NF1) and p53 genes that are involved in apoptotic pathways, and alterations in multiple DNA repair genes such as mismatch repair (MMR) genes, x-ray cross-complementary genes (XRCC), and O6-methylguanine-DNA methyltransferase (MGMT) genes. Subsequent cellular changes include somatic mutations in cell cycle regulatory genes and genes involved in angiogenesis and invasion, leading eventually to tumor formation in various stages. Future molecular diagnosis may identify new genomic regions that could harbor genes important for glioma predisposition and aid in the early diagnosis of these patients and genetic counseling of their families.
1.59 Reduced inflammatory potential of circulating gammadelta T cells in pregnancy induced improvement of Rheumatoid Arthritis
Authors: M Tham, G Schlör, D Surbek, PM Villiger, F Förger
Journal: Annals of the Rheumatic Diseases (2014)

Background and Objectives During pregnancy, gammadelta T cells expand at the fetomaternal interface where they induce a tolerogenic milieu. Patients with rheumatoid arthritis (RA) experience a spontaneous improvement of their disease during pregnancy and a postpartum aggravation. By contrast, pregnant patients with ankylosing spondylitis (AS) often experience persistent active disease. We hypothesised that the pregnancy related modulation of disease activity in RA patients versus AS patients is associated with numerical and functional changes of circulating gammadelta T cells. Material and Methods The frequency of surface markers and the intracellular cytokine profile of freshly isolated gammadelta T cells from RA (n = 54) and AS (n = 26) patients and healthy controls (n = 40) were analysed at each trimester during pregnancy and 6-8 weeks postpartum by flow cytometry. Results Very discrete changes of Vdelta1 or Vdelta2 frequency were seen during pregnancy and postpartum in healthy controls and AS patients. In RA, however, the frequency of Vdelta2 cells decreased in the third trimester when disease activity was low. Low percentages of Vdelta 2 cells were also found in non-pregnant RA patients with active arthritis, yet only pregnant RA patients showed reduced percentages of Vdelta2 cells positive for the activation marker CD69 and the intracellular cytokine TNFalpha. Similarly, Vdelta1 + TNFalpha + cells were lower in pregnant RA patients compared to non-pregnant RA patients. The percentage of Vdelta2 + TNFalpha + cells, Vdelta2+ CD69+ and Vdelta1+ CD69+ cells correlated with disease activity in RA. As for the receptors which modulate cytotoxicity, RA patients showed a rise of the anti-cytotoxic receptor NKG2A on Vdelta1 cells in the 2nd trimester and a decrease postpartum. Since the pro-cytotoxic receptor NKG2D remained unchanged, the NKG2D/NKG2A ratio on Vdelta1 cells was reduced in RA patients during pregnancy. In AS patients, persistent disease activity during pregnancy was reflected by an increased frequency of Vdelta2+ CD69+ cells and an unchanged frequency of Vdelta2+ TNFalpha+ cells. In addition, pregnant AS patients showed an increased frequency of Vdelta1+CD161+ cells. Conclusions Disease amelioration of RA during pregnancy correlates with changes of cell activation, pro-inflammatory cytokines and anti-cytotoxic receptors of gammadelta T cells. By contrast, active disease during pregnancy as found in AS is associated with unchanged inflammatory responses of gammadelta T cells. Since gammadelta T cells remain unchanged in healthy pregnant controls, the modulation of gammadelta T cells in RA rather seems to be an effect of improved disease than of pregnancy itself.
Inspiratory Resistive Breathing Induces Acute Lung Injury
Authors: Dimitris Toumpanakis, George A. Kastis, Panagiotis Zacharatos, Ioanna Sigala, Tatiana Michailidou, Maroussa Kouvela, Constantinos Glynos, Maziar Divangahi, Charis Roussos, Stamatios E. Theocharis, Theodoros Vassilakopoulos
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation.To determine the effects of resistive breathing on the healthy lung.Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing.After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by (99m)Tc-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and IκBα (nuclear factor-κB inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing.Resistive breathing induces acute lung injury and inflammation.
Trends in the Health of the Elderly
Authors: Eileen M. Crimmins
Journal: Annual Review of Public Health (2004)

Health among the older population as measured by most dimensions has improved during the last two decades. Mortality has continued to decline, and disability and functioning loss are less common now than in the past. However, the prevalence of most diseases has increased in the older population as people survive longer with disease, and the reduction in incidence does not counter the effect of increased survival. On the other hand, having a disease appears to be less disabling than in the past.
Involvement of IsK-Associated K <sup>+</sup> Channel in Heart Rate Control of Repolarization in a Murine Engineered Model of Jervell and Lange-Nielsen Syndrome
Authors: Milou-Daniel Drici, Isabelle Arrighi, Christophe Chouabe, Jeffrey R. Mann, Michel Lazdunski, Georges Romey, Jacques Barhanin
Journal: Circulation Research (1998)

Abstract —The Jervell and Lange-Nielsen (JLN) syndrome affects the human cardioauditory system, associating a profound bilateral deafness with an abnormally long QT interval on the ECG. It results from mutations in KVLQT1 and ISK genes that encode the 2 subunits forming the K + channel responsible for the cardiac and inner ear slowly activating component of the delayed rectifier K + current ( I Ks ). A JLN mouse model that presents typical inner ear defects has been created by knocking out the isk gene ( isk −/−). This study specifically reports on the cardiac phenotype counterpart, determined in the whole animal and at mRNAs and cellular levels. Surface ECG recordings of isk −/− mice showed a longer QT interval at slow heart rates, a paradoxical shorter QT interval at fast heart rates, and an overall exacerbated QT–heart rate adaptation compared with wild-type (WT) mice. A 300-ms increase in the heart rate cycle length induces a 309±21% increase in the QT duration of the WT mice versus a 500±50% in isk −/− mice ( P &lt;0.001). It is concluded that the isk gene product and/or I Ks , when present, blunts the QT adaptation to heart rate variations and that steeper QT-RR relationships reflect a greater susceptibility to arrhythmias in patients lacking I Ks .
Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document
Authors: S A Khan, B R Davidson, R Goldin, S P Pereira, W M C Rosenberg, S D Taylor-Robinson, A V Thillainayagam, H C Thomas, M R Thursz, H Wasan
Journal: Gut (2002)

2 or 3 studies; D=level 5 evidence or inconsistent or inconclusive studies of any level.
OBSERVATIONS ON THE BLOOD CYTOLOGY IN EXPERIMENTAL SYPHILIS
Authors: Paul D. Rosahn
Journal: The Journal of Experimental Medicine (1934)

The mean blood cell levels of 35 latent syphilitic rabbits in which all lesions had undergone spontaneous regression and complete healing were compared with weighted values for normal rabbits. The only differences noted were in the red cell count and hemoglobin content, both of which were significantly lower in the experimental group than the normal values. A parallelism was observed between the blood cell changes of the experimental disease after spontaneous regression of lesions, and the cell changes in the human disease after treatment. This parallelism lends additional weight to deductions drawn from the experimental disease as applied to human syphilis.
Mechanism of the antiproteinuric effect of cyclosporine in membranous nephropathy.
Authors: S Ambalavanan, J P Fauvel, R K Sibley, B D Myers
Journal: Journal of the American Society of Nephrology (1996)

Forty-one patients with a nephrotic syndrome and biopsy-proven membranous nephropathy were administered a 3 to 6-month course of cyclosporine (CsA;4 to 5 mg/kg per day). Differential solute clearances were used to evaluate glomerular function, before and after therapy. CsA lowered median proteinuria by 56%, from 7.3 to 3.2 g/24 h (P < 0.0001). Corresponding mean increments in serum albumin, immunoglobulin G, and oncotic pressure values were 31, 32, and 26%, respectively (all P < 0.0001). Arterial pressure, GFR, and renal plasma flow remained constant, but CsA restored the dextran-sieving curve toward normal, lowering the computed fraction of shunt-like pores by 25% (P < 0.05). In 14 instances, a cross-over design was used to randomly assign patients to 3 months of CsA versus 3 months of enalapril (10 to 30 mg daily), separated by a 1-month washout interval. Although enalapril lowered arterial pressure by 8 mm Hg (P < 0.01), it had no effect on proteinuria, plasma protein composition, filtration dynamics, or dextran sieving (all P = not significant). CsA dependence of proteinuria, indicated by relapsing nephrosis after CsA withdrawal, required additional courses of CsA to maintain proteinuria subnephrotic in most patients. In six patients with declining GFR during prolonged CsA treatment, a repeat biopsy showed more prominent immune deposits and a thicker glomerular basement membrane than at baseline. It was concluded that: (1) CsA lowers proteinuria in MN in part, by enhancing barrier size-selectivity; (2) lack of comparable efficacy of enalapril suggests that the antiproteinuric effect of CsA is related to its immuno-suppressive rather than glomerulodepressor properties; but (3) judged by repeat biopsy, CsA does not prevent continuing autoantibody formation in this disorder.