tbuckley/cabot-search huggingface dataset:
Sphingolipids and Atherosclerosis
Authors: Ira Tabas
Journal: Circulation (2004)

hen inhibitors of biochemical pathways are fed to experimental animals, the goals are to understand physiological or pathophysiological consequences of the inhibited pathway and possibly to obtain evidence for new therapeutic strategies for diseases affected by the pathway.In this issue of Circulation, Park et al 1 fed Apoe Ϫ/Ϫ mice a compound isolated from fungi, myriocin, that inhibits the rate-limiting enzyme in ceramide and sphingolipid biosynthesis, serine palmitoyl transferase (SPT).The study was founded on a series of previous observations that implicated sphingomyelin (SM) and ceramide in lipoprotein metabolism and atherosclerosis, including a study showing that plasma SM is an independent risk factor for coronary artery disease in humans. 2 The goal of the study by Park et al 1 was to test the effect of myriocin on plasma lipoprotein levels and atherogenesis in a well-defined animal model of atherosclerosis.The authors found that myriocin treatment in Apoe Ϫ/Ϫ mice was associated with a protective lipoprotein profilenamely, a decrease in ␤VLDL and LDL, an increase in HDL, and a reduction in atherosclerosis.
Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia
Authors: Tom Nijenhuis, Volker Vallon, Annemiete W.C.M. van der Kemp, Johannes Loffing, Joost G.J. Hoenderop, René J.M. Bindels
Journal: Journal of Clinical Investigation (2005)

Thiazide diuretics enhance renal Na+ excretion by blocking the Na+-Cl- cotransporter (NCC), and mutations in NCC result in Gitelman syndrome. The mechanisms underlying the accompanying hypocalciuria and hypomagnesemia remain debated. Here, we show that enhanced passive Ca2+ transport in the proximal tubule rather than active Ca2+ transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na+ and Ca2+ in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca2+ reabsorption in distal convolution appeared unaffected. Second, HCTZ administration still induced hypocalciuria in transient receptor potential channel subfamily V, member 5-knockout (Trpv5-knockout) mice, in which active distal Ca2+ reabsorption is abolished due to inactivation of the epithelial Ca2+ channel Trpv5. Third, HCTZ upregulated the Na+/H+ exchanger, responsible for the majority of Na+ and, consequently, Ca2+ reabsorption in the proximal tubule, while the expression of proteins involved in active Ca2+ transport was unaltered. Fourth, experiments addressing the time-dependent effect of a single dose of HCTZ showed that the development of hypocalciuria parallels a compensatory increase in Na+ reabsorption secondary to an initial natriuresis. Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6). Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation.
A viral CTL escape mutation leading to immunoglobulin-like transcript 4–mediated functional inhibition of myelomonocytic cells
Authors: Mathias Lichterfeld, Daniel G. Kavanagh, Katie L. Williams, Beenu Moza, Stanley K. Mui, ToshiYuki Miura, Rohini Sivamurthy, Rachel Allgaier, Florencia Pereyra, Alicja Trocha, Margaret Feeney, Rajesh T. Gandhi, Eric S. Rosenberg, Marcus Altfeld, Todd M. Allen, Rachel Allen, Bruce D. Walker, Eric J. Sundberg, Xu G. Yu
Journal: The Journal of Experimental Medicine (2007)

Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8+ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide–major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705–restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1–specific CD8+ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1–specific CD8+ T cells, the HLA-B2705–KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I–specific receptor expressed on myelomonocytic cells. Binding of the B2705–KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversification.
Nabiximols as an Agonist Replacement Therapy During Cannabis Withdrawal
Authors: David J. Allsop, Jan Copeland, Nicholas Lintzeris, Adrian J. Dunlop, Mark Montebello, Craig Sadler, Gonzalo R. Rivas, Rohan M. Holland, Peter Muhleisen, Melissa M. Norberg, Jessica Booth, Iain S. McGregor
Journal: JAMA Psychiatry (2014)

There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal.To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal.A 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers.A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission.Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes.Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F8,377.97 = 2.39; P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37]; P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ21 = 0.79; P = .67), and those receiving nabiximols did not report greater intoxication (F1,6 = 0.22; P = .97). The number (F1,50 = 0.3; P = .59) and severity (F1,50 = 2.69; P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F1,48 = 0.29; P = .75), cannabis-related problems (F1,49 = 2.33; P = .14), or cannabis dependence (F1,50 < 0.01; P = .89).In a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations.anzctr.org.au Identifier: ACTRN12611000398909.
Embryonic Stem Cells Proliferate and Differentiate when Seeded into Kidney Scaffolds
Authors: Edward A. Ross, Matthew J. Williams, Takashi Hamazaki, Naohiro Terada, William L. Clapp, Christopher Adin, Gary W. Ellison, Marda Jorgensen, Christopher D. Batich
Journal: Journal of the American Society of Nephrology (2009)

The scarcity of transplant allografts for diseased organs has prompted efforts at tissue regeneration using seeded scaffolds, an approach hampered by the enormity of cell types and complex architectures. Our goal was to decellularize intact organs in a manner that retained the matrix signal for differentiating pluripotent cells. We decellularized intact rat kidneys in a manner that preserved the intricate architecture and seeded them with pluripotent murine embryonic stem cells antegrade through the artery or retrograde through the ureter. Primitive precursor cells populated and proliferated within the glomerular, vascular, and tubular structures. Cells lost their embryonic appearance and expressed immunohistochemical markers for differentiation. Cells not in contact with the basement membrane matrix became apoptotic, thereby forming lumens. These observations suggest that the extracellular matrix can direct regeneration of the kidney, and studies using seeded scaffolds may help define differentiation pathways.
AB0619 Effectiveness of D-Penicillamine plus Corticosteroids versus Corticosteroids Alone in the Treatment Severe Eosinophilic Fasciitis
Authors: F.A. Mendoza, R. Bai, A. Kebede, S. Jimenez
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Eosinophilic fasciitis is an uncommon cutaneous fibrosing disorder characterized by fascial fibrosis often accompanied by tissue eosinophilic inflammation and peripheral eosinophilia. Corticosteroids (CS) are used as a first line treatment. Despite of its high relapse rate, there is no consensus on the use and choice of additional treatment. <h3>Objectives</h3> To evaluate the efectiveness of D-Penicillamine (D-Pen) plus CS versus CS alone for the treatment of severe eosinophilic fasciitis. <h3>Methods</h3> A 20 year (1993-2013) retrospective chart review identified 16 patients with clinical and histopathological diagnosis of severe eosinophilic fasciitis. This was defined as clinically apparent fibrotic involvement of more than 15% of the body suface area and/or the presence of fibrotic lesions crossing joints in patients with confirmed histopathology who had been treated with either D-Pen plus CS or CS alone. Analysis of disease characteristics, comorbidities, efficacy, adverse events (AE) and relapse was performed in this cohort. <h3>Results</h3> Eosinophilic fasciitis lesions involved an average of 25% of BSA and 68.8% of the subjects developed a joint contractures during the course of the disease. 10/16 (62.5%) patients were treated with D-Pen plus CS and 6/16 (37.5%) with CS alone. Both groups were comparable in terms of involved body surface area, time from the first symptoms, age and co-morbidites. All of the patients initially treated with D-Pen plus CS, responded to the treatment. In contrast, only 33.3% of patients treated with CS alone had a favorable response (p=0.008). Rates of AEs were not statistically significant among the groups (80% vs 66.67% in the group treated with D-Pen plus CS vs CS alone). The most common AE reported in the D-Pen plus CS group was proteinuria which occurred in 33.3% of the subjects. However 16.6% of the patients on CS alone also developed proteinuria. <h3>Conclusions</h3> In this cohort with severe eosinophilic fasciitis, a very high rate of subsequent joint contractions was observed. The treatment with D-Pen plus CS was associated with a significantly greater improvement as compared to CS alone. Proteinuria was unexpectedly common in both groups although it was more frequent in the D-Pen plus CS group. A high frequency of relapse was seen in both treatment groups. <h3>References</h3> Shulman LE. Diffuse Fasciitis with Hypergammaglobulinemia and eosinophilia: A new syndrome. J Rheumatol 1974; (suppl 1) 1:46 Barnes L, Rodnan GP, Medsger TA, Short D. Eosinophilic fasciitis. A pathologic study of twenty cases. Am J Pathol. 1979 Aug;96(2):493-518. Lebeaux D, Sène D. Eosinophilic fasciitis (Shulman disease). Best Pract Res Clin Rheumatol. 2012 Aug;26(4):449-58 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4513
Tenascin-C Stimulates Glioma Cell Invasion through Matrix Metalloproteinase-12
Authors: Susobhan Sarkar, Robert K. Nuttall, Shuhong Liu, Dylan R. Edwards, V. Wee Yong
Journal: Cancer Research (2006)

Abstract The capacity of glioma cells to invade extensively within the central nervous system is a major cause of the high morbidity rate of primary malignant brain tumors. Glioma cell invasion involves the attachment of tumor cells to extracellular matrix (ECM), degradation of ECM components, and subsequent penetration into adjacent brain structures. These processes are accomplished in part by matrix metalloproteinases (MMP) within a three-dimensional milieu of the brain parenchyma. As the majority of studies have used a two-dimensional monolayer culture system, we have used a three-dimensional matrix of collagen type I gel to address glioma-secreted proteases, ECM, and invasiveness of glioma cells. We show that in a three-dimensional collagen type I matrix, the presence of tenascin-C, commonly elevated in high-grade gliomas, increased the invasiveness of glioma cells. The tenascin-C–mediated invasiveness was blocked by metalloproteinase inhibitors, but this did not involve the gelatinases (MMP-2 and MMP-9) commonly implicated in two-dimensional glioma growth. A thorough analysis of 21 MMPs and six members of a disintegrin and metalloproteinase domain showed that MMP-12 was increased in gliomas by tenascin-C in three-dimensional matrix. Furthermore, examinations of resected specimens revealed high MMP-12 levels in the high-grade glioblastoma multiforme tumors. Finally, a function-blocking antibody as well as small interfering RNA to MMP-12 attenuated the tenascin-C–stimulated glioma invasion. These results identify a new factor, MMP-12, in regulating glioma invasiveness through interaction with tenascin-C. (Cancer Res 2006; 66(24): 11771-80)
IQGAP1 Plays an Important Role in the Invasiveness of Thyroid Cancer
Authors: Zhi Liu, Dingxie Liu, Ermal Bojdani, Adel K. El-Naggar, Vasily Vasko, Mingzhao Xing
Journal: Clinical Cancer Research (2010)

This study was designed to explore the role of IQGAP1 in the invasiveness of thyroid cancer and its potential as a novel prognostic marker and therapeutic target in this cancer.We examined IQGAP1 copy gain and its relationship with clinicopathologic outcomes of thyroid cancer and investigated its role in cell invasion and molecules involved in the process.We found IQGAP1 copy number (CN) gain ≥ 3 in 1 of 30 (3%), 24 of 74 (32%), 44 of 107 (41%), 8 of 16 (50%), and 27 of 41 (66%) of benign thyroid tumor, follicular variant papillary thyroid cancer (FVPTC), follicular thyroid cancer (FTC), tall cell papillary thyroid cancer (PTC), and anaplastic thyroid cancer, respectively, in the increasing order of invasiveness of these tumors. A similar tumor distribution trend of CN ≥ 4 was also seen. IQGAP1 copy gain was positively correlated with IQGAP1 protein expression. It was significantly associated with extrathyroidal and vascular invasion of FVPTC and FTC and, remarkably, a 50%-60% rate of multifocality and recurrence of BRAF mutation-positive PTC (P = 0.01 and 0.02, respectively). The siRNA knockdown of IQGAP1 dramatically inhibited thyroid cancer cell invasion and colony formation. Coimmunoprecipitation assay showed direct interaction of IQGAP1 with E-cadherin, a known invasion-suppressing molecule, which was upregulated when IQGAP1 was knocked down. This provided a mechanism for the invasive role of IQGAP1 in thyroid cancer. In contrast, IQGAP3 lacked all these functions.IQGAP1, through genetic copy gain, plays an important role in the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer.
Within pair association between birth weight and blood pressure at age 8 in twins from a cohort study
Authors: T. Dwyer, L. Blizzard, R. Morley, A.-L. Ponsonby
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objectives:</b> To study the association between birth weight and blood pressure in children from multiple pregnancies (multiplets), mostly twins, to determine whether maternal or genetic factors are responsible for the association. <b>Design:</b> Cohort study. <b>Setting:</b> Southern Tasmania. <b>Subjects:</b> 888 children including 104 multiplets (32 monozygotic, 72 dizygotic). <b>Main outcome measure:</b> Systolic blood pressure (mm Hg). <b>Results:</b> Blood pressure decreased with birth weight and increased with current body mass. After adjustment for age and body mass, systolic blood pressure changed by −1.94 mm Hg (95% confidence interval −2.89 to −0.98) per 1 kg increase in birth weight of singletons. For multiplets, blood pressure changed by −7.0 mm Hg (−10.1 to −3.9) for each 1 kg increase in birth weight. This was little altered in within pair analyses (−5.3, −13.8 to 3.2) and was similar for both monozygotic (−6.5, −22.5 to 9.4) and dizygotic (−4.9, −15.8 to 6.0) pairs. <b>Conclusion:</b> Because the association between birth weight and blood pressure was largely unchanged in within pair analyses, exposures originating in the mother (such as nutritional status) cannot be wholly responsible. The association also remained within monozygotic pairs, suggesting that genetic predisposition is not wholly responsible either. The principal causal pathway must concern mechanisms within the fetoplacental unit. The stronger association in multiplets suggests that factors adversely influencing both blood pressure and birth weight are more prevalent in multiple pregnancies. <h3>Key messages</h3> Low birthweight is associated with high blood pressure from an early age Maternal factors, including diet during pregnancy, cannot wholly explain the association between fetal development and later risk of cardiovascular disease Because the association between blood pressure and birthweight remained in monozygotic twins, genetic factors are unlikely to be responsible for the association Important causes of the association seem to be operating within the fetoplacental unit during fetal life Further research should now focus on placental function and fetal exposures
T Cell–Based Immunotherapy of Metastatic Renal Cell Carcinoma: Modest Success and Future Perspective
Authors: Alaaeldin Shablak, Robert E. Hawkins, Dominic G. Rothwell, Eyad Elkord
Journal: Clinical Cancer Research (2009)

Abstract Metastatic renal cell carcinoma (MRCC) remains a challenging malignancy to treat. Cancer immunotherapies have been extensively explored in melanoma and RCC as they poorly respond to conventional cytotoxic agents but show responses to a variety of immunologic agents. The recent considerable success of T cell–based immunotherapy in melanoma warrants further efforts to apply this treatment to other cancers including MRCC. Although RCC is an immunosensitive cancer, similar attempts in MRCC have shown a very limited success. In this review, we summarize the clinical data on T cell–based immunotherapies for MRCC showing the modest success that has been achieved to date. More importantly, we discuss potential strategies for improving its efficacy for the treatment of MRCC in light of the important achievements for treating metastatic melanoma. In particular, the growing evidence of success by combining expanded tumor-infiltrating lymphocytes with lymphodepletion merits investigation in MRCC. Identifying new RCC-associated antigens, optimized methods, and conditions for detection, isolation, and/or modification and expansion of tumor-specific T cells are all important strategies to be pursued for improving T cell–based immunotherapy of MRCC. (Clin Cancer Res 2009;15(21):6503–10)
Circulating Tumor Cell as a Diagnostic Marker in Primary Lung Cancer
Authors: Fumihiro Tanaka, Kazue Yoneda, Nobuyuki Kondo, Masaki Hashimoto, Teruhisa Takuwa, Seiji Matsumoto, Yoshitomo Okumura, Shakibur Rahman, Noriaki Tsubota, Tohru Tsujimura, Kozo Kuribayashi, Kazuya Fukuoka, Takashi Nakano, Seiki Hasegawa
Journal: Clinical Cancer Research (2009)

To investigate the diagnostic performance of circulating tumor cells (CTC) in discrimination between primary lung cancer and nonmalignant diseases as well as in prediction of distant metastasis.We prospectively evaluated CTCs in 7.5-mL samples of peripheral blood sampled from patients with a suspicion or a diagnosis of primary lung cancer. A semiautomated system was used to capture CTCs with an antibody against epithelial cell adhesion molecule.Of 150 eligible patients, 25 were finally diagnosed as having nonmalignant disease, and 125 were diagnosed as having primary lung cancer with (n = 31) or without (n = 94) distant metastasis. CTCs were detected in 30.6% of lung cancer patients and in 12.0% of nonmalignant patients. CTC count was significantly higher in lung cancer patients than in nonmalignant patients, but a receiver operating characteristic (ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between lung cancer and nonmalignant diseases with an area under ROC curve of 0.598 (95% confidence interval, 0.488-0.708; P = 0.122). Among lung cancer patients, CTC count significantly increased along with tumor progression, especially with development of distant metastasis. The area under ROC curve for CTC count in prediction of distant metastasis was 0.783 (95% confidence interval, 0.679-0.886; P < 0.001). When patients with one or more CTCs were judged as having metastatic disease, sensitivity and specificity of the CTC test were 71.0% and 83.0%, respectively.CTC is a useful surrogate marker of distant metastasis in primary lung cancer.
Urinary Amylase vs Serum Amylase in Patients With Pancreatic Carcinoma
Authors: Earl E. Gambill, Harold L. Mason
Journal: JAMA (1964)

IN A RECENT publication we presented data indicating that in the presence of pancreatitis the one-hour value for urinary amylase exceeded normal more often, in a larger number of patients, and frequently for a longer period of time, than did the values for serum amylase and serum lipase.<sup>1</sup>The encouraging results of those observations and of those made previously by Saxon and co-workers<sup>2</sup>led us to study the relative abnormality of the results obtained with these tests for these enzymes in pancreatic carcinoma. <h3>Material and Method</h3> The data on tests for serum amylase and lipase and urinary amylase were obtained from the records of 192 patients with pancreatic carcinoma proved by surgical exploration. Review of the case records included a search for evidence of concomitant or ancient pancreatitis as well as pancreatic carcinoma. The urinary excretion of amylase was measured by a modification of the method of Huggins
OPIATE WITHDRAWAL TREATED WITH INDUCED HYPOGLYCEMIC REACTIONS
Authors: SIDNEY J. TILLIM
Journal: American Journal of Psychiatry (1942)

This paper has presented additional experiences and discussion of the author's method of insulin therapy for the alleviation of suffering from opiate withdrawal. Fifteen patients have thus far been treated without failure to produce substantial freedom from distress. All patients accepted abrupt withdrawal although they were hospitalized on a voluntary status. Sedatives of any kind were unnecessary during the period of insulin treatments. Appetite, sleep and a sense of well-being were restored within a few days. This permitted an early return to normal activities, often at a higher level of efficiency than before treatment. Because abrupt withdrawal of the opiate was feasible the period of hospitalization was materially shorter than required by any other acceptable method of treatment. The rationale of the treatment is well supported by the present knowledge about addiction and hypoglycemic therapy.