tbuckley/cabot-search huggingface dataset:
Is Radiation Therapy a Preferred Alternative to Surgery for Squamous Cell Carcinoma of the Base of Tongue?
Authors: William M. Mendenhall, Scott P. Stringer, Robert J. Amdur, Russell W. Hinerman, Giselle J. Moore-Higgs, Nicholas J. Cassisi
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To evaluate irradiation alone for treatment of base-of-tongue cancer. PATIENTS AND METHODS: Two hundred seventeen patients with squamous cell carcinoma of the base of tongue were treated with radiation alone and had follow-up for ≥ 2 years. RESULTS: Local control rates at 5 years were as follows: T1, 96%; T2, 91%; T3, 81%; and T4, 38%. Multivariate analysis revealed that T stage (P = .0001) and overall treatment time (P = .0006) significantly influenced local control. The 5-year rates of local-regional control were as follows: I, 100%; II, 100%; III, 83%; IVA, 64%; and IVB, 65%. Multivariate analysis revealed that the following parameters significantly affect the probability of this end point: T stage (P = .0001), overall treatment time (P = .0001), overall stage (P = .0131), and addition of a neck dissection (P = .0021). The rates of absolute and cause-specific survival at 5 years were as follows: I, 50% and 100%; II, 81% and 100%; III, 65% and 76%; IVA, 42% and 56%; and IVB, 44% and 52%. Severe radiation complications developed in eight patients (4%). CONCLUSION: The likelihood of cure after external-beam irradiation was related to stage, overall treatment time, and addition of a planned neck dissection. The local-regional control rates and survival rates after radiation therapy were comparable to those after surgery, and the morbidity associated with irradiation was less.
Monitoring of antiviral therapy with quantitative evaluation of hbeag: A comparison with HBV DNA testing
Authors: Robert Perrillo, Larry Mimms, Kenneth Schechtman, David Robbins, Carolyn Campbell
Journal: Hepatology (1993)

The serological endpoint of response in the treatment of chronic hepatitis B is the loss of hepatitis B virus DNA and HBeAg. Because the quantitative measurement of hepatitis B virus DNA in serum has been shown to be useful for monitoring and predicting response to interferon-alpha therapy, we decided to evaluate whether changes in HBeAg concentration could also be used in this manner. Twenty-nine patients who were initially positive for HBeAg and HBV DNA were serially evaluated for HBeAg concentration with a microparticle-capture enzyme immunoassay. HBeAg levels in serum were calculated by means of comparison with a standard curve of fluorescence rate vs. HBeAg concentration. The results, expressed in milliunits per milliliter, were compared with hepatitis B virus DNA levels determined by means of solution hybridization. The baseline HBeAg concentration proved to be the best independent predictor of response on stepwise Cox regression analysis (p = 0.026). Similar disappearance curves were observed for the two markers, although hepatitis B virus DNA became undetectable at an earlier interval in 13 of 16 cases (81%). In the 16 responders, a decline in HBeAg concentration of more than 90% was observed by wk 12 of therapy (mean +/- S.D., 95% +/- 13%). Nonresponders did not demonstrate such steep declines in HBeAg values by wk 12 (mean +/- S.D., 45% +/- 27%), and levels tended to increase at subsequent time points. We conclude that serial monitoring of HBeAg concentration with a technique that should be readily adaptable to clinical laboratories may be useful in the initial evaluation and monitoring of patients undergoing antiviral therapy.
Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus
Authors: John Wahren, Philip Felig, Erol Cerasi, Rolf Luft
Journal: Journal of Clinical Investigation (1972)

Splanchnic and leg exchange of glucose, lactate, pyruvate, and individual plasma amino acids was studied in diabetics 24 hr after withdrawal of insulin and in healthy controls. Measurements were made in the basal postabsorptive state and during the administration of glucose at a rate of 2 mg/kg per min for 45 min. In the basal state, net splanchnic glucose production did not differ significantly between diabetics and controls. However, splanchnic uptake of alanine and other glycogenic amino acids was 1(1/2)-2 times greater in the diabetics, while lactate and pyruvate uptake was increased by 65-115%. Splanchnic uptake of these glucose precursors could account for 32% of hepatic glucose output in the diabetics, as compared to 20% in the controls. This increase in precursor uptake was a consequence of a two- to threefold increment in fractional extraction of these substrates inasmuch as arterial levels of alanine, glycine, and threonine were reduced in the diabetics, while the levels of the remaining substrates were similar in the two groups. Peripheral output of alanine and other glycogenic amino acids as reflected in arterio-femoral venous differences was similar in both groups. An elevation in arterial valine, leucine, and isoleucine was observed in the diabetics, but could not be accounted for on the basis of alterations in splanchnic or peripheral exchange of these amino acids. Administration of glucose (2 mg/kg per min) for 45 min resulted in an 80% reduction in splanchnic glucose output in controls, but failed to inhibit hepatic glucose release in the diabetics despite a twofold greater increment in arterial glucose levels. In both groups no consistent changes in arterial glucagon were observed during the infusion. It is concluded that in nonketotic diabetics (a) total splanchnic output of glucose is comparable to controls, but the relative contribution of gluconeogenesis may be increased by more than 50%; (b) accelerated splanchnic uptake of glucose precursors is a consequence of increased hepatic extraction of available substrates rather than a result of augmented substrate supply; and (c) the failure of glucose infusion to inhibit hepatic glucose output suggests that the exquisite sensitivity of the liver to the infusion of glucose in normal man is a consequence of glucose-induced insulin secretion.
Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis
Authors: Anatol Kontush, M. John Chapman
Journal: Pharmacological Reviews (2006)

High-density lipoproteins (HDL) possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, and anti-oxidative and anti-inflammatory activities. Plasma HDL particles are highly heterogeneous in physicochemical properties, metabolism, and biological activity. Within the circulating HDL particle population, small, dense HDL particles display elevated cellular cholesterol efflux capacity, afford potent protection of atherogenic low-density lipoprotein against oxidative stress and attenuate inflammation. The antiatherogenic properties of HDL can, however be compromised in metabolic diseases associated with accelerated atherosclerosis. Indeed, metabolic syndrome and type 2 diabetes are characterized not only by elevated cardiovascular risk and by low HDL-cholesterol (HDL-C) levels but also by defective HDL function. Functional HDL deficiency is intimately associated with alterations in intravascular HDL metabolism and structure. Indeed, formation of HDL particles with attenuated antiatherogenic activity is mechanistically related to core lipid enrichment in triglycerides and cholesteryl ester depletion, altered apolipoprotein A-I (apoA-I) conformation, replacement of apoA-I by serum amyloid A, and covalent modification of HDL protein components by oxidation and glycation. Deficient HDL function and subnormal HDL-C levels may act synergistically to accelerate atherosclerosis in metabolic disease. Therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and quality of HDL particles is the target of innovative pharmacological approaches to HDL raising, including inhibition of cholesteryl ester transfer protein, enhanced lipidation of apoA-I with nicotinic acid and infusion of reconstituted HDL or apoA-I mimetics. A preferential increase in circulating concentrations of HDL particles possessing normalized antiatherogenic activity is therefore a promising therapeutic strategy for the treatment of common metabolic diseases featuring dyslipidemia, inflammation, and premature atherosclerosis.
Regulation of FAS Ligand Expression during Activation-Induced Cell Death in T Cells by p38 Mitogen-Activated Protein Kinase and C-Jun Nh2-Terminal Kinase
Authors: Jian Zhang, Jian-Xin Gao, Kostantin Salojin, Qing Shao, Marsha Grattan, Craig Meagher, Dale W. Laird, Terry L. Delovitch
Journal: The Journal of Experimental Medicine (2000)

Activation-induced cell death (AICD) is a mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). Although c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in apoptosis in various cell types, the mode of regulation of FasL expression during AICD in T cells by these two MAPKs is incompletely understood. To investigate the regulatory roles of these two MAPKs, we analyzed the kinetics of TCR-induced p38 MAPK and JNK activity and their regulation of FasL expression and AICD. We report that both JNK and p38 MAPK regulate AICD in T cells. Our data suggest a novel model of T cell AICD in which p38 MAPK acts early to initiate FasL expression and the Fas-mediated activation of caspases. Subsequently, caspases stimulate JNK to further upregulate FasL expression. Thus, p38 MAPK and downstream JNK converge to regulate FasL expression at different times after T cell receptor stimulation to elicit maximum AICD.
CANNABINOID RECEPTORS AND THEIR ENDOGENOUS AGONISTS
Authors: Christian C. Felder, Michelle Glass
Journal: The Annual Review of Pharmacology and Toxicology (1998)

▪ Abstract Marijuana has been in use for over 4000 years as a therapeutic and as a recreational drug. Within the past decade, two cannabinoid receptor types have been identified, their signal transduction characterized, and an endogenous lipid agonist isolated from mammalian tissues. The CB1 cannabinoid receptor is widely distributed in mammalian tissues, with the highest concentrations found in brain neurons. CB1 receptors are coupled to modulation of adenylate cyclase and ion channels. The CB2 receptor is found in cells of the immune system and is coupled to inhibition of adenylate cyclase. Both receptor types selectively bind Δ 9 -THC, the active principle in marijuana, and anandamide (arachidonylethanolamide), an endogenous cannabimimetic eicosanoid. Progress is being made in the development of novel agonists and antagonists with receptor subtype selectivity, mice with genetic deletion of the cannabinoid receptors, and receptor-specific antibodies, which should help in providing a better understanding of the physiological role of the cannabinoid receptors.
Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD
Authors: Yun Wang, Anlin Liang, Jinlong Luo, Ming Liang, Guofeng Han, William E. Mitch, Jizhong Cheng
Journal: Journal of the American Society of Nephrology (2014)

Neointima formation causes the failure of 60% of arteriovenous fistulas (AVFs) within 2 years. Neointima-forming mechanisms are controversial but possibly linked to excess proinflammatory responses and dysregulated Notch signaling. To identify how AVFs fail, we anastomosed the carotid artery to the internal jugular vein in normal and uremic mice and compared these findings with those in failed AVFs from patients with ESRD. Endothelial cells (ECs) of AVFs in uremic mice or patients expressed mesenchymal markers (FSP-1 and/or α-SMA) and exhibited increased expression and nuclear localization of Notch intracellular domain compared with ECs of AVFs in pair-fed control mice. Furthermore, expression of VE-Cadherin decreased, whereas expression of Notch1 and -4, Notch ligands, the downstream transcription factor of Notch, RBP-Jκ, and Notch target genes increased in ECs of AVFs in uremic mice. In cultured ECs, ectopic expression of Notch ligand or treatment with TGF-β1 triggered the expression of mesenchymal markers and induced endothelial cell barrier dysfunction, both of which were blocked by Notch inhibition or RBP-Jκ knockout. Furthermore, Notch-induced defects in barrier function, invasion of inflammatory cells, and neointima formation were suppressed in mice with heterozygous knockdown of endothelial-specific RBP-Jκ. These results suggest that increased TGF-β1, a complication of uremia, activates Notch in endothelial cells of AVFs, leading to accelerated neointima formation and AVF failure. Suppression of Notch activation could be a strategy for improving AFV function in uremia.
Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes
Authors: Delphine Haouzi, Mounia Lekéhal, Alain Moreau, Claude Moulis, Gérard Feldmann, Marie-Anne Robin, Philippe Lettéron, Daniel Fau, Dominique Pessayre
Journal: Hepatology (2000)

Although cytochrome P-450 (CYP)-generated reactive metabolites can cause hepatocyte apoptosis, the mechanism of this effect is incompletely understood. In the present study, we assessed the hepatotoxicity of skullcap, a diterpenoid-containing herbal remedy. Male rat hepatocytes were incubated for 2 hours with skullcap diterpenoids (100 microg/mL). This treatment decreased cell glutathione and protein thiols and increased cell [Ca(2+)]. This activated Ca(2+)-dependent tissue transglutaminase, forming a cross-linked protein scaffold, and also opened the mitochondrial permeability transition pore, causing outer mitochondrial membrane rupture, increased cytosolic cytochrome c, activation of procaspase 3, internucleosomal DNA fragmentation, and ultrastructural features of apoptosis. Cell death was increased by a CYP3A inducer (dexamethasone) or a sulfur amino acid-deficient diet increasing glutathione depletion. In contrast, cell death was prevented by decreasing CYP3A activity (with troleandomycin), preventing glutathione depletion (with cysteine or cystine), blocking Ca(2+)-modulated events (with calmidazolium), preventing mitochondrial permeability transition (with cyclosporin A), or inhibiting caspase 3 (with acetyl-Asp-G u-Va-Asp-a dehyde). Both calmidazolium and cyclosporin A also prevented the increase in cytosolic cytochrome c and procaspase 3 activation. In conclusion, CYP3A activates skullcap diterpenoids into reactive metabolites that deplete cellular thiols and increase cell [Ca(2+)]. This activates Ca(2+)-dependent transglutaminase and also opens the mitochondrial permeability transition pore, causing outer mitochondrial membrane rupture, cytochrome c release, and caspase activation. Preventing mitochondrial permeability transition pore opening and/or caspase activity blocks apoptosis, showing the fundamental role of these final events in metabolite-mediated hepatotoxicity.
Morin (3,5,7,2′,4′-Pentahydroxyflavone) Abolishes Nuclear Factor-κB Activation Induced by Various Carcinogens and Inflammatory Stimuli, Leading to Suppression of Nuclear Factor-κB–Regulated Gene Expression and Up-regulation of Apoptosis
Authors: Sunil K. Manna, Rishi S. Aggarwal, Gautam Sethi, Bharat B. Aggarwal, Govindarajan T. Ramesh
Journal: Clinical Cancer Research (2007)

Morin is a flavone that exhibits antiproliferative, antitumor, and anti-inflammatory effects through a mechanism that is not well understood. Because of the role of transcription factor nuclear factor-kappaB (NF-kappaB) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-kappaB activation.We investigated the effect of morin on NF-kappaB pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-kappaB-regulated gene products involved in cell survival, proliferation, and invasion was also examined.We showed by DNA-binding assay that NF-kappaB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, lipopolysaccharide, ceramide, interleukin-1, and H(2)O(2) was suppressed by morin; the suppression was not cell type specific. The suppression of NF-kappaB by morin was mediated through inhibition of IkappaBalpha (inhibitory subunit of NF-kappaB) kinase, leading to suppression of phosphorylation and degradation of IkappaBalpha and consequent p65 nuclear translocation. Morin also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NF-kappaB-inducing kinase, IkappaB kinase, and the p65 subunit of NF-kappaB. NF-kappaB-regulated gene products involved in cell survival [inhibitor of apoptosis (IAP) 1, IAP2, X chromosome-linked IAP, Bcl-xL, and survivin], proliferation (cyclin D1 and cyclooxygenase-2), and invasion (matrix metalloproteinase-9) were down-regulated by morin. These effects correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents.Overall, our results indicate that morin suppresses the activation of NF-kappaB and NF-kappaB-regulated gene expression, leading to enhancement of apoptosis. This may provide the molecular basis for the ability of morin to act as an anticancer and anti-inflammatory agent.
Onset Timing, Thoughts of Self-harm, and Diagnoses in Postpartum Women With Screen-Positive Depression Findings
Authors: Katherine L. Wisner, Dorothy K. Y. Sit, Mary C. McShea, David M. Rizzo, Rebecca A. Zoretich, Carolyn L. Hughes, Heather F. Eng, James F. Luther, Stephen R. Wisniewski, Michelle L. Costantino, Andrea L. Confer, Eydie L. Moses-Kolko, Christopher S. Famy, Barbara H. Hanusa
Journal: JAMA Psychiatry (2013)

The period prevalence of depression among women is 21.9% during the first postpartum year; however, questions remain about the value of screening for depression.
Plasma Biomarkers as Predictors of Outcome in Patients with Advanced Hepatocellular Carcinoma
Authors: Josep M. Llovet, Carol E.A. Peña, Chetan D. Lathia, Michael Shan, Gerold Meinhardt, Jordi Bruix
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Validated biomarkers of prognosis and response to drug have not been identified for patients with hepatocellular carcinoma (HCC). One of the objectives of the phase III, randomized, controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was to explore the ability of plasma biomarkers to predict prognosis and therapeutic efficacy. Experimental Design: In SHARP, 602 patients with advanced HCC were randomized to receive either oral sorafenib 400 mg twice a day per os or matching placebo daily on a continuous basis. Ten plasma biomarkers implicated in the pathogenesis of HCC were measured in 491 patients at baseline and in 305 after 12 weeks of treatment. The candidate biomarkers were analyzed to identify correlates of prognosis or predictors of response to sorafenib. Results: In both the entire patient population and the placebo cohort, baseline angiopoietin 2 (Ang2) and VEGF concentrations independently predicted survival. Clinical variables such as macroscopic vascular invasion, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline α-fetoprotein and alkaline phosphatase concentrations also independently predicted survival in these groups. In the sorafenib cohort, trends toward enhanced survival benefit from sorafenib were observed in patients with high s-c-KIT or low hepatocyte growth factor concentration at baseline (P of interaction = 0.081 and 0.073, respectively). Conclusions: The angiogenesis biomarkers Ang2 and VEGF were independent predictors of survival in patients with advanced HCC. In contrast, none of the biomarkers tested significantly predicted response to sorafenib. Clin Cancer Res; 18(8); 2290–300. ©2012 AACR.
THE SIGNIFICANCE OF ALPHA VARIANTS IN THE EEG, AND THEIR RELATIONSHIP TO AN EPILEPTIFORM SYNDROME
Authors: J. E. GOODWIN
Journal: American Journal of Psychiatry (1947)

1. Evidence has been presented to show that the cerebral psychomotor patterns of Gibbs, Gibbs and Lennox are related to certain variations of the 10-cycle or alpha rhythm of the brain, which have been termed alpha variants. The most common variants consist of a halving or doubling of the alpha rate. 2. Even in cases of known psychomotor epilepsy the amount of the alpha variants recorded in the EEG between attacks may vary widely both among and within individuals, but practically all such patients show traces of the variants between seizures. 3. There is a high incidence of alpha variants in certain other conditions, notably psychoneurosis and idiopathic epilepsy. Their presence in the so-called psychoneurotic group shows a high correlation with a symptom complex that includes cranialgia, episodic changes in levels of consciousness, and emotional and vasomotor disturbances. 4. A high incidence of alpha variants among patients with grand mal epilepsy has been noted. The alpha variants may be correlated in these cases with altered states of consciousness (which cannot be identified electroencephalographically with petit mal), or with neurotic traits superimposed on the major epilepsy. It is concluded that mixed epilepsy of a grand mal—psychic variant type is of frequent occurrence. 5. The alpha variants are not pathognomonic of the epileptiform states. The significance of their appearance in the EEG without the accompanying symptom complex, as in the case of a small proportion of presumably normal individuals, has not yet been elucidated. 6. The alpha variants are of diagnostic assistance in cases where the neurological findings are essentially negative, and where the EEG is otherwise within broad normal limits. Under these circumstances, their presence in the EEGs of patients with vasomotor instability (cranialgia, dizziness, etc.), emotional disturbances of an episodic nature, or changes in the state of consciousness, indicate that the condition may be related to an epileptiform syndrome, rather than to a purely psychosomatic etiology. 7. The term psychomotor epilepsy is inadequate to describe the entire range of psychic variants in the epileptiform syndrome, and in our opinion should either be replaced by a more descriptive term, or its use restricted to conditions in which motor manifestations of a bizarre nature are present.
Cellular Basis of Skin Allograft Rejection: An In Vivo Model of Immune-Mediated Tissue Destruction
Authors: A S Rosenberg, A Singer
Journal: Annual Review of Immunology (1992)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More