tbuckley/cabot-search huggingface dataset:
Treatment of Condyloma Acuminatum with Three Different Interferons Administered lntralesionally
Authors: RICHARD C. REICHMAN
Journal: Annals of Internal Medicine (1988)

Study Objective: To determine the efficacy and toxicity of intralesionally administered interferons in the treatment of condyloma acuminatum. Design: Randomized, double-blind, and placebo-controlled study. Setting: Outpatient clinics at university medical centers. Patients: Seventy-nine patients with biopsy-proved condyloma acuminatum that was refractory to conventional therapy were enrolled in the study. Interventions: Alpha-2b-, alpha-nl-, and beta-interferons were used. One wart on each patient was injected three times per week for 4 weeks with either 1x106 units of interferon or placebo. Measurements and Main Results: Forty-seven percent of warts injected with interferon resolved completely, compared with 22% of placebo-injected warts (P = 0.009). In addition, more recipients of interferon had a complete resolution of uninjected lesions. No differences in rates of response were noted among the different interferon groups. Approximately one third of interferon-injected warts recurred, compared with none of four placebo-injected warts. Intralesionally administered interferon was nontoxic and well tolerated, although transient pain on injection was observed frequently. Conclusions: Intralesional administration of each of these three interferons appears to be useful in treating condyloma acuminatum. However, the frequent recurrence of disease and the failure of many lesions to resolve indicate that different regimens, such as longer courses of therapy or different routes of administration, should be evaluated to maximize beneficial effects of interferon for treating this common sexually transmitted disease.
Pulmonary Vasodilator Responses to Nitroprusside and Nitroglycerin in the Dog
Authors: Philip J. Kadowitz, Premanand Nandiwada, Carl A. Gruetter, Louis J. Ignarro, Albert L. Hyman
Journal: Journal of Clinical Investigation (1981)

The objective of this study was to determine the direct actions of nitroprusside and nitroglycerin on the pulmonary vascular bed in the intactchest dog. These widely used nitrogen oxide-containing vasodilator agents decreased pulmonary arterial pressure and increased cardiac output without altering left atrial pressure. Reductions in pulmonary arterial pressure and pulmonary vascular resistance were small under resting conditions, but were enhanced when pulmonary vascular tone was elevated by infusion of a stable prostaglandin analog that increases pulmonary vascular resistance by constricting intrapulmonary veins and upstream segments. In studies in which pulmonary blood flow to the left lower lobe was maintained constant, nitroprusside and nitroglycerin caused small but significant reductions in lobar arterial and small-vein pressures without significantly affecting left atrial pressure. With constant blood flow, lobar vascular pressures that were reduced in response to the vasodilators were more greatly reduced when lobar vascular resistance was increased by infusion of the prostaglandin analog or serotonin. However, when lobar vascular pressures were elevated by passive obstruction of lobar venous outflow, vasodilator responses to nitroprusside and nitroglycerin were not enhanced. These data suggest that nitroprusside and nitroglycerin decrease pulmonary vascular resistance by dilating intrapulmonary veins and upstream segments. These responses were minimal under control conditions but were enhanced when vascular tone was increased. This vasodilator action is independent of passive factors such as changes in pulmonary blood flow or left atrial pressure and is not secondary to an effect of these agents on the systemic circulation. Pulmonary vasodilator responses to nitroprusside and nitroglycerin were, however, found to be dependent on the existing level of vasomotor tone in the pulmonary vascular bed.
Lactate-Induced IL-8 Pathway in Endothelial Cells—Letter
Authors: Céline Pinheiro, Adhemar Longatto-Filho, Rosete Nogueira, Fernando Schmitt, Fátima Baltazar
Journal: Cancer Research (2012)

Végran and colleagues proposed a model in which the lactate released from tumor cells through MCT4 would be taken up by endothelial cells via the MCT1 transporter and stimulate angiogenesis, using human umbilical vein endothelial cells (HUVECs) as model of tumor endothelial cells. By analyzing a total of 505 cases of human tumor samples immunostained for MCT1, we do not confirm plasma membrane expression of MCT1 in the endothelial cells of tumor-associated vessels.
Molecular Pathways: Current Role and Future Directions of the Retinoic Acid Pathway in Cancer Prevention and Treatment
Authors: Roisin M. Connolly, Nguyen K. Nguyen, Saraswati Sukumar
Journal: Clinical Cancer Research (2013)

Retinoids and their naturally metabolized and synthetic products (e.g., all-trans retinoic acid, 13-cis retinoic acid, bexarotene) induce differentiation in various cell types. Retinoids exert their actions mainly through binding to the nuclear retinoic acid receptors (α, β, γ), which are transcriptional and homeostatic regulators with functions that are often compromised early in neoplastic transformation. The retinoids have been investigated extensively for their use in cancer prevention and treatment. Success has been achieved with their use in the treatment of subtypes of leukemia harboring chromosomal translocations. Promising results have been observed in the breast cancer prevention setting, where fenretinide prevention trials have provided a strong rationale for further investigation in young women at high risk for breast cancer. Ongoing phase III randomized trials investigating retinoids in combination with chemotherapy in non-small cell lung cancer aim to definitively characterize the role of retinoids in this tumor type. The limited treatment success observed to date in the prevention and treatment of solid tumors may relate to the frequent epigenetic silencing of RARβ. Robust evaluation of RARβ and downstream genes may permit optimized use of retinoids in the solid tumor arena.
Ceramide sphingolipid signaling mediates Tumor Necrosis Factor (TNF)-dependent toxicity via caspase signaling in dopaminergic neurons
Authors: Terina N Martinez, Xi Chen, Sibali Bandyopadhyay, Alfred H Merrill, Malú G Tansey
Journal: Molecular Neurodegeneration (2012)

Abstract Background Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinson’s disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. Chronic inhibition of soluble Tumor Necrosis Factor (TNF) with dominant-negative TNF inhibitors protects DA neurons in rat models of parkinsonism, yet the molecular mechanisms and pathway(s) that mediate TNF toxicity remain(s) to be clearly identified. Here we investigated the contribution of ceramide sphingolipid signaling in TNF-dependent toxicity. Results Ceramide dose-dependently reduced the viability of DA neuroblastoma cells and primary DA neurons and pharmacological inhibition of sphingomyelinases (SMases) with three different inhibitors during TNF treatment afforded significant neuroprotection by attenuating increased endoplasmic reticulum (ER) stress, loss of mitochondrial membrane potential, caspase-3 activation and decreases in Akt phosphorylation. Using lipidomics mass spectrometry we confirmed that TNF treatment not only promotes generation of ceramide, but also leads to accumulation of several atypical deoxy-sphingoid bases (DSBs). Exposure of DA neuroblastoma cells to atypical DSBs in the micromolar range reduced cell viability and inhibited neurite outgrowth and branching in primary DA neurons, suggesting that TNF-induced de novo synthesis of atypical DSBs may be a secondary mechanism involved in mediating its neurotoxicity in DA neurons. Conclusions We conclude that TNF/TNFR1-dependent activation of SMases generates ceramide and sphingolipid species that promote degeneration and caspase-dependent cell death of DA neurons. Ceramide and atypical DSBs may represent novel drug targets for development of neuroprotective strategies that can delay or attenuate the progressive loss of nigral DA neurons in patients with PD.
YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway
Authors: Bill H Chang, Kara Johnson, Dorian LaTocha, Joelle S J Rowley, Jade Bryant, Russell Burke, Rebecca L Smith, Marc Loriaux, Markus Müschen, Charles Mullighan, Brian J Druker, Jeffrey W Tyner
Journal: Journal of Hematology & Oncology (2015)

Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL.
IGRA and TST predictive value in immunocompetent close contacts
Authors: Teresa Gomes, Sérgio Campainha, Aurora Carvalho, Raquel Duarte
Journal: European Respiratory Journal (2011)

Background:  Limited data is available on the predictive values of Interferon-g release assays (IGRAs) and tuberculin skin test (TST) for progression to active tuberculosis (TB).   Aim:  To access the positive and negative predictive values (PPV and NPV) of IGRA and TST for progression to TB disease, in recently exposed immunocompetents of positive smear sputum TB patients who did not do preventive treatment.   Methodology:  Retrospective cohort of close contacts of smear-positive TB cases screened for TB from January 2007 to December 2009 – follow up until February 2011. Screening included: symptom inquiry, TST and IGRA (to confirm a positive TST ≥ 10 mm), chest radiography – negative results were re-evaluated 8-12 weeks later.   Results:  106 contacts were studied. Considering only those who did not do preventive therapy (79) - 70 tested positive for TST and 19 tested positive for IGRA (54 were already positive for TST and 16 were positive for IGRA in the first evaluation). Three contacts developed active TB: one positive for TST and IGRA at first evaluation (refused preventive treatment) and two (TST+/IGRA-) missed revaluation.  In the first evaluation, TST presented a PPV of 5.7% and a NPV of 100%; IGRA presented a PPV of 5.3% and a NPV of 96.1%. In the second evaluation, both TST and IGRA had a PPV of 0% and a NPV of 100%.   Conclusions:  TST and IGRA had a better PPV for progression to TB in the initial evaluation (after index case diagnosis). A negative IGRA in the first evaluation could not exclude progression to TB.
Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans
Authors: Hao-Yang Tan, Kristin K. Nicodemus, Qiang Chen, Zhen Li, Jennifer K. Brooke, Robyn Honea, Bhaskar S. Kolachana, Richard E. Straub, Andreas Meyer-Lindenberg, Yoshitasu Sei, Venkata S. Mattay, Joseph H. Callicott, Daniel R. Weinberger
Journal: Journal of Clinical Investigation (2008)

AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis.
TLR2 and MyD88 Contribute to <i>Lactobacillus casei</i> Extract–Induced Focal Coronary Arteritis in a Mouse Model of Kawasaki Disease
Authors: Margalit E. Rosenkranz, Danica J. Schulte, Lucila M.A. Agle, Michelle H. Wong, Wenxuan Zhang, Lionel Ivashkiv, Terence M. Doherty, Michael C. Fishbein, Thomas J.A. Lehman, Kathrin S. Michelsen, Moshe Arditi
Journal: Circulation (2005)

Background— Kawasaki disease is the most common cause of acquired cardiac disease and acute vasculitis in children, targets the coronary arteries, and can occasionally be fatal. The pathogenesis and the molecular mechanisms remain unknown. After injection of Lactobacillus casei cell-wall extract (LCCWE), mice develop a focal coronary arteritis that histopathologically resembles Kawasaki disease, but the mechanism remains unclear. Here, we tested the hypothesis that signaling by Toll-like receptors (TLRs) through their key downstream adaptor molecule myeloid differentiation factor 88 (MyD88) is required for the cellular activation and coronary arteritis produced by LCCWE. Methods and Results— Bone marrow–derived macrophages from TLR2- or MyD88-deficient mice were unresponsive to LCCWE-induced stimulation. In contrast, macrophages obtained from TLR4-deficient mice produced the same amount of interleukin-6 as macrophages from wild-type mice after stimulation with LCCWE. Intraperitoneal injection of LCCWE produced severe focal coronary arteritis in TLR4 −/− and C57BL/6 control mice but not in TLR2 −/− or MyD88 −/− mice. Collectively, these results indicate that LCCWE is a potent inducer of nuclear factor-κB via TLR2 but not TLR4 and that this activation proceeds via the MyD88-dependent signaling pathway. In vivo studies suggest that TLR2 −/− mice are protected from LCCWE-induced coronary arteritis and that this protection is mediated through the adaptor molecule MyD88. Conclusions— Our results provide important insights into the molecular signaling in this mouse model of coronary arteritis. We show here that LCCWE-induced coronary arteritis is dependent on intact TLR2 and MyD88 signaling.
Treatment of actinic prurigo with PUVA: mechanism of action
Authors: P.M. FARR, B.L. DIFFEY
Journal: British Journal of Dermatology (1989)

Five patients with actinic prurigo were treated twice weekly with PUVA. One area on the back was shielded from UVA throughout the 15‐week treatment period. Before PUVA, all patients had increased erythemal sensitivity to UVA and showed abnormal augmentation of UVB erythema by topical indomethacin. After PUVA, all patients were free of photosensitive symptoms and skin that had been exposed to UVA showed normal erythemal responses. By contrast, the areas of skin that had been protected from UVA showed erythemal responses that were unchanged from pre‐PUVA values. Augmentation of UVB erythema by topical indomethacin persisted, both on UVA exposed and UVA protected skin. These results show that, although PUVA is an effective treatment in actinic prurigo, it does not alter the underlying mechanism of photosensitivity. The protective effect is local and is due presumably to an increase in melanin pigmentation and epidermal thickness.
Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo.
Authors: J P Portanova, Y Zhang, G D Anderson, S D Hauser, J L Masferrer, K Seibert, S A Gregory, P C Isakson
Journal: The Journal of Experimental Medicine (1996)

The role of prostaglandin E2 (PGE2) in the development of inflammatory symptoms and cytokine production was evaluated in vivo using a neutralizing anti-PGE2 monoclonal antibody 2B5. In carrageenan-induced paw inflammation, pretreatment of rats with 2B5 substantially prevented the development of tissue edema and hyperalgesia in affected paws. The antibody was shown to bind the majority of PGE2 produced at the inflammatory site. In adjuvant-induced arthritis, the therapeutic administration of 2B5 to arthritic rats substantially reversed edema in affected paws. Anti-PGE2 treatment also reduced paw levels of IL-6 RNA and serum IL-6 protein without modifying tumor necrosis factor RNA levels in the same tissue. In each model, the antiinflammatory efficacy of 2B5 was indistinguishable from that of the nonsteroidal antiinflammatory drug indomethacin, which blocked the production of all PGs. These results indicate that PGE2 plays a major role in tissue edema, hyperalgesia, and IL-6 production at sites of inflammation, and they suggest that selective pharmacologic modulation of PGE2 synthesis or activity may provide a useful means of mitigating the symptoms of inflammatory disease.
Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans.
Authors: A D Baron, H O Steinberg, H Chaker, R Leaming, A Johnson, G Brechtel
Journal: Journal of Clinical Investigation (1995)

Whether insulin-mediated vasodilation is important in determining insulin's overall action to stimulate glucose uptake is unknown. To this end, we measured leg glucose uptake during euglycemic hyperinsulinemic clamps performed at two insulin doses (40 mU/m2 per min, n = 6 and 120 mU/m2 per min, n = 15) alone and during a superimposed intrafemoral artery infusion of GN-monomethyl-L-arginine (L-NMMA) designed to blunt insulin-mediated vasodilation. During the higher dose study, hyperinsulinemia resulted in about a twofold rise in basal leg blood flow from 0.24 +/- 0.02 to 0.45 +/- 0.05 liter/min, P < 0.0001. L-NMMA infusion resulted in a net 21% reduction in leg glucose uptake from 114 +/- 18 mg/min to 85 +/- 13 mg/min, P < 0.001. We also found a significant relationship between the rate of insulin-stimulated whole body glucose uptake and the magnitude of flow dependent glucose uptake (r = 0.57, P = 0.02). Data obtained during the lower dose insulin infusion resulted in similar findings. In conclusion, in healthy lean subjects, insulin-stimulated muscle blood flow contributes to both insulin responsiveness and insulin sensitivity. The most insulin-sensitive subjects appear to be the most reliant on muscle perfusion for insulin action. Insulin-mediated vasodilation is an important physiological determinant of insulin action.
Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis
Authors: Joseph Loscalzo
Journal: Circulation Research (2001)

Nitric oxide (NO) was originally discovered as a vasodilator product of the endothelium. Over the last 15 years, this vascular mediator has been shown to have important antiplatelet actions as well. By activating guanylyl cyclase, inhibiting phosphoinositide 3-kinase, impairing capacitative calcium influx, and inhibiting cyclooxygenase-1, endothelial NO limits platelet activation, adhesion, and aggregation. Platelets are also an important source of NO, and this platelet-derived NO pool limits recruitment of platelets to the platelet-rich thrombus. A deficiency of bioactive NO is associated with arterial thrombosis in animal models, individuals with endothelial dysfunction, and patients with a deficiency of the extracellular antioxidant enzyme glutathione peroxidase-3. This enzyme catalyzes the reduction of hydrogen and lipid peroxides, which limits the availability of these reactive oxygen species to react with and inactivate NO. The complex biochemical reactions that underlie the function and inactivation of NO in the vasculature represent an important set of targets for therapeutic intervention for the prevention and treatment of arterial thrombotic disorders.
Adenotonsillectomy improves slow-wave activity in children with obstructive sleep apnoea
Authors: N. Ben-Israel, Y. Zigel, A. Tal, Y. Segev, A. Tarasiuk
Journal: European Respiratory Journal (2010)

The aim of the present study was to estimate slow-wave activity (SWA), a marker of sleep homeostasis, in children with obstructive sleep apnoea (OSA) before and after adenotonsillectomy (AT) compared with untreated OSA children (comparison group). 14 children with OSA (mean ± sd age 6.4 ± 2.5 yrs; apnoea-hypopnoea index (AHI) 10.0 ± 10.3 events·h⁻¹) who underwent AT were consecutively recruited to the study. The comparison group comprised six retrospectively recruited children (age 5.4 ± 2.2 yrs; AHI 9.4 ± 7.6 events·h⁻¹) with OSA that did not undergo treatment. Electroencephalogram (derivation C3/A2) was analysed using spectral and waveform analysis to determine SWA energy and slow-wave slope. The same procedure was repeated 5.4 and 19 months later for the AT and comparison groups, respectively. AT improved respiration without a change in duration of sleep stages. Following AT, >50% elevation of SWA during the first two sleep cycles (p<0.01) and a more physiological decay of SWA across the night (p<0.0001) were noted. The slow-wave slope increased by >30% following AT (p<0.03). No significant changes were found in SWA in the comparison group. Sleep homeostasis is considerably impaired in pre-pubescent children with OSA. AT restores more physiological sleep homeostasis in children with OSA. SWA analysis may provide a useful addition to standard sleep-stage analyses in children with OSA.
The permeability of glomerular capillaries of aminonuceoside nephrotic rats to graded dextrans.
Authors: J P Caulfield, M G Farquhar
Journal: The Journal of Experimental Medicine (1975)

Graded dextrans were used as tracers to study glomerular permeability in nephrotic rats. Two narrow range fractions were used, one which was approximately the same size as albumin (62,000 mol wt) and one which was considerably larger (125,000 mol wt). Nephrosis was induced with daily injections of an aminonucleoside of puromycin, and the animals examined after 7 days, when proteinuria is minimal, or after 10 days, when proteinuria has almost reached a maximum. At both stages and with both dextran fractions the following results were obtained: (a) dextran was retained for up to 3 h (the longest interval studied) in the plasma at high concentration; (b) there was a sharp drop in the concentration of tracer between the inner, looser portions of the basement membrane (lamina rara interna) and its outer denser portions (lamina densa), (c) accumulation of dextran was seen in the mesangial areas with time; and (d) no accumulation of dextran was seen in the slits at any time. These results are the same as those reported earlier in normal animals, and they demonstrate that in nephrotics the basement membrane still behaves as the main filtration barrier retaining most of the plasma proteins. Certain differences from the findings in normals were also noted in that increased amounts of the tracer were present on the epithelial side of the basement membrane: (a) in the urinary spaces; (b) in the subepithelial portions of the basement membrane; and (c) within lysosomes (protein absorption droplets) in the epithelial cytoplasm. In addition areas of thinning of the dense portions of the basement membrane (lamina densa) were seen which were accompanied by a corresponding widening of the less dense, subendothelial and subepithelial layers (lamina rara interna and externa, respectively). The presence of increased quantities of dextran on the epithelial side of the basement membrane indicates that the filter, i.e. the basement membrane, is leaky and allows increased passage of dextrans and therefore plasma proteins.