tbuckley/cabot-search huggingface dataset:
Abnormal Glucose Tolerance and Increased Risk for Cardiovascular Disease in Japanese-Americans With Normal Fasting Glucose
Authors: David Liao, Jane B. Shofer, Edward J. Boyko, Marguerite J. McNeely, Donna L. Leonetti, Steven E. Kahn, Wilfred Y. Fujimoto
Journal: Diabetes Care (2001)

OBJECTIVE— To compare the American Diabetes Association (ADA)fasting glucose and the World Health Organization (WHO) oral glucose tolerance test (OGTT) criteria for diagnosing diabetes and detecting people at increased risk for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS— Study subjects were 596 Japanese-Americans. Fasting insulin, lipids, and C-peptide levels; systolic and diastolic blood pressures (BPs); BMI (kg/m2); and total and intra-abdominal body fat distribution by computed tomography (CT) were measured. Study subjects were categorized by ADA criteria as having normal fasting glucose (NFG), impaired fasting glucose (IFG), and diabetic fasting glucose and by WHO criteria for a 75-g OGTT as having normal glucose tolerance(NGT), impaired glucose tolerance (IGT), and diabetic glucose tolerance(DGT). RESULTS— Of 503 patients with NFG, 176 had IGT and 20 had DGT. These patients had worse CVD risk factors than those with NGT. The mean values for NGT, IGT, and DGT, respectively, and analysis of covariance Pvalues, adjusted for age and sex, are as follows: intra-abdominal fat area by CT 69.7, 95.0, and 101.1 cm2 (P &amp;lt; 0.0001); total CT fat area 437.7, 523.3, and 489.8 cm2 (P &amp;lt; 0.0001); fasting triglycerides 1.40, 1.77, and 1.74 mmol/l (P = 0.002); fasting HDL cholesterol 1.56, 1.50, and 1.49 mmol/l (P = 0.02); C-peptide 0.80,0.90, 0.95 nmol/l (P = 0.002); systolic BP 124.9, 132.4, and 136.9 mmHg (P = 0.0035); diastolic BP 74.8, 77.7, and 78.2 mmHg (P= 0.01). CONCLUSIONS— NFG patients who had IGT or DGT had more intra-abdominal fat and total adiposity; higher insulin, C-peptide, and triglyceride levels; lower HDL cholesterol levels; and higher BPs than those with NGT. Classification by fasting glucose misses many Japanese-Americans with abnormal glucose tolerance and less favorable cardiovascular risk profiles.
Apparent response of small cell lung cancer to an extract of mistletoe and homoeopathic treatment.
Authors: G W Bradley, A Clover
Journal: Thorax (1989)

A patient with small cell lung carcinoma was treated initially with extracts of mistletoe and homoeopathic treatment and appeared to respond. Subsequently radiotherapy was given and the patient lived for five years seven months, which is much longer than is usual with this type of tumour.
When Translation Meets Metabolism: Multiple Links to Diabetes
Authors: Yuguang Shi, Simeon I. Taylor, Seng-Lai Tan, Nahum Sonenberg
Journal: Endocrine Reviews (2003)

Abstract Type 2 diabetes is a polygenic disorder characterized by multiple biochemical defects including transcriptional, translational, and posttranslational abnormalities. Although major progress has been made in elucidation of factors at the transcriptional and posttranslational levels, defects at the translational level remain elusive. Mutation of a kinase that regulates translation initiation has been implicated in the etiology of a monogenic form of diabetes known as Wolcott-Rallison syndrome. Characterization of mice rendered deficient in eukaryotic initiation factors has provided model systems to study the involvement of translation in regulating insulin synthesis and secretion, hepatic function, peripheral insulin resistance, and diabetic complications. Recent progress in the understanding of endoplasmic reticulum overload by unfolded proteins has begun to uncover mechanisms leading to pancreatic β-cell exhaustion. Future advances in this area may lead to identification of the missing links in the pathogenesis of β-cell failures due to conditions such as hyperinsulinemia, hyperglycemia, and long-term treatment with sulfonylureas, and thus may identify novel therapeutic targets for diabetes.
Précis of <i>The illusion of conscious will</i>
Authors: Daniel M. Wegner
Journal: Behavioral and Brain Sciences (2004)

The experience of conscious will is the feeling that we are doing things. This feeling occurs for many things we do, conveying to us again and again the sense that we consciously cause our actions. But the feeling may not be a true reading of what is happening in our minds, brains, and bodies as our actions are produced. The feeling of conscious will can be fooled. This happens in clinical disorders such as alien hand syndrome, dissociative identity disorder, and schizophrenic auditory hallucinations. And in people without disorders, phenomena such as hypnosis, automatic writing, Ouija board spelling, water dowsing, facilitated communication, speaking in tongues, spirit possession, and trance channeling also illustrate anomalies of will – cases when actions occur without will or will occurs without action. This book brings these cases together with research evidence from laboratories in psychology to explore a theory of apparent mental causation. According to this theory, when a thought appears in consciousness just prior to an action, is consistent with the action, and appears exclusive of salient alternative causes of the action, we experience conscious will and ascribe authorship to ourselves for the action. Experiences of conscious will thus arise from processes whereby the mind interprets itself – not from processes whereby mind creates action. Conscious will, in this view, is an indication that we think we have caused an action, not a revelation of the causal sequence by which the action was produced.
The pathophysiology of autoimmune blistering diseases
Authors: Kim B. Yancey
Journal: Journal of Clinical Investigation (2005)

Knowledge of the pathophysiology of immunobullous diseases has been advanced by the demonstration that passive transfer of antibodies against skin autoantigens can induce blisters in experimental animals with clinical, histologic, and immunopathologic features similar to those seen in human patients. In this issue of the JCI, Liu et al. extend their earlier observations regarding an experimental murine model of bullous pemphigoid by showing that the plasminogen/plasmin signaling cascade synergizes with MMP-9 during the early phase of antibody-induced blister formation in vivo. In a separate study, Sitaru et al. show for the first time to my knowledge that passive transfer of experimental antibodies against type VII collagen create subepidermal blisters in mice that mimic those seen in patients with epidermolysis bullosa acquisita (see the related article beginning on page 870). While the articles by Liu, Sitaru, and their colleagues identify pathways of inflammation and tissue injury that, if interrupted, may abrogate blister formation, in a third study, Payne et al. utilized phage display technologies to isolate human anti-desmoglein monoclonal antibodies from a patient with pemphigus vulgaris and show that such antibodies have restricted patterns of heavy and light chain gene usage — findings suggesting that autoantibodies may represent an additional target for therapeutic interventions in patients with immunobullous diseases (see the related article beginning on page 888).
Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity
Authors: Cheryl M. Koh, Ekta Khattar, Shi Chi Leow, Chia Yi Liu, Julius Muller, Wei Xia Ang, Yinghui Li, Guido Franzoso, Shang Li, Ernesto Guccione, Vinay Tergaonkar
Journal: Journal of Clinical Investigation (2015)

Constitutively active MYC and reactivated telomerase often coexist in cancers. While reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with cofactors, confers several growth advantages to cancer cells. It is known that the reactivation of TERT, the catalytic subunit of telomerase, is limiting for reconstituting telomerase activity in tumors. However, while reactivation of TERT has been functionally linked to the acquisition of several "hallmarks of cancer" in tumors, the molecular mechanisms by which this occurs and whether these mechanisms are distinct from the role of telomerase on telomeres is not clear. Here, we demonstrated that first-generation TERT-null mice, unlike Terc-null mice, show delayed onset of MYC-induced lymphomagenesis. We further determined that TERT is a regulator of MYC stability in cancer. TERT stabilized MYC levels on chromatin, contributing to either activation or repression of its target genes. TERT regulated MYC ubiquitination and proteasomal degradation, and this effect of TERT was independent of its reverse transcriptase activity and role in telomere elongation. Based on these data, we conclude that reactivation of TERT, a direct transcriptional MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis.
Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets
Authors: Kathrin Kastenmüller, Ulrike Wille-Reece, Ross W.B. Lindsay, Lauren R. Trager, Patricia A. Darrah, Barbara J. Flynn, Maria R. Becker, Mark C. Udey, Björn E. Clausen, Botond Z. Igyarto, Daniel H. Kaplan, Wolfgang Kastenmüller, Ronald N. Germain, Robert A. Seder
Journal: Journal of Clinical Investigation (2011)

The success of a non-live vaccine requires improved formulation and adjuvant selection to generate robust T cell immunity following immunization. Here, using protein linked to a TLR7/8 agonist (conjugate vaccine), we investigated the functional properties of vaccine formulation, the cytokines, and the DC subsets required to induce protective multifunctional T cell immunity in vivo. The conjugate vaccine required aggregation of the protein to elicit potent Th1 CD4+ and CD8+ T cell responses. Remarkably, the conjugate vaccine, through aggregation of the protein and activation of TLR7 in vivo, led to an influx of migratory DCs to the LN and increased antigen uptake by several resident and migratory DC subsets, with the latter effect strongly influenced by vaccine-induced type I IFN. Ex vivo migratory CD8-DEC205+CD103-CD326- langerin-negative dermal DCs were as potent in cross-presenting antigen to naive CD8+ T cells as CD11c+CD8+ DCs. Moreover, these cells also influenced Th1 CD4+ T cell priming. In summary, we propose a model in which broad-based T cell-mediated responses upon vaccination can be maximized by codelivery of aggregated protein and TLR7/8 agonist, which together promote optimal antigen acquisition and presentation by multiple DC subsets in the context of critical proinflammatory cytokines.
Follicular lymphoma-like B cells in healthy individuals: a novel intermediate step in early lymphomagenesis
Authors: Sandrine Roulland, Jean-Marc Navarro, Pierre Grenot, Michèle Milili, Julie Agopian, Bertrand Montpellier, Pascal Gauduchon, Pierre Lebailly, Claudine Schiff, Bertrand Nadel
Journal: The Journal of Experimental Medicine (2006)

Follicular lymphoma is one of the most common adult lymphoma, and remains virtually incurable despite its relatively indolent nature. t(14;18)(q32;q21) translocation, the genetic hallmark and early initiating event of follicular lymphoma (FL) pathogenesis, is also present at low frequency in the peripheral blood of healthy individuals. It has long been assumed that in healthy individuals t(14;18) is carried by circulating quiescent naive B cells, where its oncogenic potential would be restrained. Here, we question this current view and demonstrate that in healthy individuals, t(14;18) is actually carried by an expanding population of atypical B cells issued from germinal centers, displaying genotypic and phenotypic features of FL, and prone to constitute potent premalignant FL niches. These findings strongly impact both on the current understanding of disease progression and on the proper handling of t(14;18) frequency in blood as a potential early biomarker for lymphoma.
AKT2 Confers Protection Against Aortic Aneurysms and Dissections
Authors: Ying H. Shen, Lin Zhang, Pingping Ren, Mary T. Nguyen, Sili Zou, Darrell Wu, Xing Li Wang, Joseph S. Coselli, Scott A. LeMaire
Journal: Circulation Research (2012)

Rationale: Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown. Objective: In this study, we examined the role of AKT2 in protecting the aorta from developing AAD. Methods and Results: AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2- deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II, these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2 -deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. In addition, angiotensin II–infused Akt2- deficient mice showed significantly elevated expression of matrix metalloproteinase-9 (MMP-9) and reduced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 to the MMP-9 and TIMP-1 promoters. Conclusions: Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.
Direct-to-consumer genetic tests: beyond medical regulation?
Authors: David Magnus, Mildred K Cho, Robert Cook-Deegan
Journal: Genome Medicine (2009)

The availability of personalized genomic tests, ordered directly by consumers, is rapidly growing. These tests are unlike other genetic or biochemical tests in the sheer amount of data they provide, but interpretation of these genome-wide analyses for health remains uncertain because of the lack of information about environmental and other factors, and because for the vast majority of genetic loci the associations with disease are weak. Although these tests could provide value to customers by offering tools for social networking or genealogy, there are questions about whether and how to regulate these tests and about the extent to which they provide medical information.
Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast Cancers
Authors: Xiaoyan Zhou, Ming Tan, Valerie Stone Hawthorne, Kristine S. Klos, Keng-Hsueh Lan, Ying Yang, Wentao Yang, Terry L. Smith, Daren Shi, Dihua Yu
Journal: Clinical Cancer Research (2004)

Abstract The Akt/mammalian target of rapamycin (mTOR)/4E-BP1 pathway is considered to be a central regulator of protein synthesis, involving the regulation of cell proliferation, differentiation, and survival. The inhibitors of mTOR as anticancer reagents are undergoing active evaluation in various malignancies including breast cancer. However, the activation status of the Akt/mTOR/4E-BP1 pathway and its potential roles in breast cancers remain unknown. Thus, we examined 165 invasive breast cancers with specific antibodies for the phosphorylation of Akt, mTOR, and 4E-BP1 by immunohistochemistry and compared them with normal breast epithelium, fibroadenoma, intraductal hyperplasia, and ductal carcinoma in situ. We discovered that the phosphorylation of Akt, mTOR, and 4E-BP1 increased progressively from normal breast epithelium to hyperplasia and abnormal hyperplasia to tumor invasion. Phosphorylated Akt, mTOR, and 4E-BP1 were positively associated with ErbB2 overexpression. Survival analysis showed that phosphorylation of each of these three markers was associated with poor disease-free survival independently. In vitro, we further confirmed the causal relationship between ErbB2 overexpression and mTOR activation, which was associated with enhanced invasive ability and sensitivity to a mTOR inhibitor, rapamycin. Our results, for the first time, demonstrate the following: (a) high levels of phosphorylation of Akt, mTOR, and 4E-BP1 in breast cancers, indicating activation of the Akt/mTOR/4E-BP1 pathway in breast cancer development and progression; (b) a link between ErbB2 and the Akt/mTOR/4E-BP1 pathway in breast cancers in vitro and in vivo, indicating the possible role of Akt/mTOR activation in ErbB2-mediated breast cancer progression; and (c) a potential role for this pathway in predicting the prognosis of patients with breast cancer, especially those treated with mTOR inhibitors.
Therapeutic Advantage of Pretargeted Radioimmunotherapy Using a Recombinant Bispecific Antibody in a Human Colon Cancer Xenograft
Authors: Habibe Karacay, Pierre-Yves Brard, Robert M. Sharkey, Chien-Hsing Chang, Edmund A. Rossi, William J. McBride, Dan R. Ragland, Ivan D. Horak, David M. Goldenberg
Journal: Clinical Cancer Research (2005)

To assess if pretargeting, using a combination of a recombinant bispecific antibody (bsMAb) that binds divalently to carcinoembryonic antigen (CEA) and monovalently to the hapten histamine-succinyl-glycine and a (90)Y-peptide, improves therapeutic efficacy in a human colon cancer-nude mouse xenograft compared with control animals given (90)Y-humanized anti-CEA immunoglobulin G (IgG).Clearance and biodistribution were monitored by whole-body readings and necropsy. Animals were monitored for 34 weeks with a determination of residual disease and renal pathology in survivors. Hematologic toxicity was assessed separately in non-tumor-bearing NIH Swiss mice.Hematologic toxicity was severe at doses of 100 to 200 microCi of (90)Y-IgG, yet mild in the pretargeted animals given 500 or 700 microCi of the (90)Y-peptide. Evidence of end-stage renal disease was found at 900 microCi of the pretargeted (90)Y-peptide whereas animals given 700 microCi showed only mild renal pathology, similar to that seen in control animals given (90)Y-IgG. Biodistribution data indicated that the average amount of tumor radioactivity by a 700-microCi dose of the pretargeted peptide over a 96-hour period was increased 2.5-fold (48 microCi/g) compared with 150 microCi of (90)Y-IgG (18.9 microCi/g). At these doses, survival (i.e., time to progression to 2.5 cm(3)) was significantly improved (P < 0.04) compared with (90)Y-IgG, with ablation of about one third of the tumors, whereas viable tumor was present in all of the (90)Y-IgG-treated animals.Pretargeting increases the amount of radioactivity delivered to colorectal tumors sufficiently to improve the therapeutic index and responses as compared with conventional radioimmunotherapy.
The Effect of Adrenergic Blockade and Norepinephrine on Renal and Cardiovascular Hemodynamics Following Hemorrhage
Authors: J. H. MOYER, C. A. HANDLEY, R. A. HUGGINS
Journal: Circulation Research (1954)

Renal blood flow and other renal functions are depressed when the normotensive animal is made hypertensive by the administration of norepinephrine.By contrast, when the blood pressure is increased to normal with norepinephrine in the animal previously made hypotensive by hemorrhage, renal function and cardiac output increase.V ASOPRESSOR.agents produce renal vasoconstrie.tionwhen administered to normotensive animals and man. 1 " 5 Because of this vasoconstrictor activity, the question has been raised whether these agents might not actually be harmful 5 ' G to the kidney when used to elevate blood pressure for the treatment of shock.Observations made recently 7 ' s indicate that when renal and cerebral blood flow are markedly depressed due to hypotension resulting from ganglionic blocking agents, administering a vasopressor agent will actually increase blood flow to these vascular beds.Although the circumstances are not analogous to shock, these results do suggest a paradox since, when vasopressor agents are administered to normotensive subjects, and the blood pressure is raised to hypertensive levels, cerebral and renal blood flow are depressed.The current observations were made on dogs in order to determine whether the administration of vasopressor agents would increase renal blood flow in the presence of hypotension due to hemorrhage.Concurrent observations were made on cardiac output.Since adrenergic blockade has been reported
Peroxynitrite induced nitration and inactivation of myofibrillar creatine kinase in experimental heart failure
Authors: M Mihm
Journal: Cardiovascular Research (2001)

Objective: Oxidative stress is implicated in the initiation and progression of congestive heart failure, but the putative reactive species and cellular targets involved remain undefined. We have previously shown that peroxynitrite (ONOO−, an aggressive biological oxidant and nitrating agent) potently inhibits myofibrillar creatine kinase (MM-CK), a critical controller of contractility known to be impaired during heart failure. Here we hypothesized that nitration and inhibition of MM-CK participate in cardiac failure in vivo. Methods: Heart failure was induced in rats by myocardial infarction (left coronary artery ligation) and confirmed by histological analysis at 8 weeks postinfarct (1.3±1.4 vs. 37.7±3.2% left ventricular circumference; sham control vs. CHF, n = 10 each). Results: Immunohistochemistry demonstrated significantly increased protein nitration in failing myocardium compared to control (optical density: 0.58±0.06 vs. 0.93±0.09, sham vs. CHF, P<0.05). Significant decreases in MM-CK activity and content were observed in failing hearts (MM-CK kcat: 6.0±0.4 vs. 3.0±0.3 μmol/nM M-CK/min, P<0.05; 6.8±1.3 vs. 4.7±1.2% myofibrillar protein, P<0.05), with no change in myosin ATPase activity. In separate experiments, isolated rat cardiac myofibrils were exposed to ONOO− (2–250 μM) and enzyme studies were conducted. Identical to in vivo studies, selective reductions in MM-CK were observed at ONOO− concentrations as low as 2 μM (IC50=92.5±6.0 μM); myosin ATPase was unaffected with ONOO− concentrations as high as 250 μM. Concentration dependent nitration of MM-CK occurred and extent of nitration was statistically correlated to extent of CK inhibition (P<0.001). Immunoprecipitation of MM-CK from failing left ventricle yielded significant evidence of tyrosine nitration. Conclusion: These data demonstrate that cardiac ONOO− formation and perturbation of myofibrillar energetic controllers occur during experimental heart failure; MM-CK may be a critical cellular target in this setting.
Swyer-James syndrome: bronchoalveolar lavage findings in two patients
Authors: F Bernardi, S Cazzato, V Poletti, D Tassinari, M Burnaccini, M Zompatori, E Cacciari
Journal: European Respiratory Journal (1995)

Swyer-James syndrome (SJS) is a rare constrictive bronchiolitis that appears to be the result of acute bronchiolitis in infancy or early childhood. In the present study the cytological and immunophenotypical profile of bronchoalveolar lavage (BAL) was studied in two patients with SJS who showed a different spectrum of clinical outcome. The total BAL yield was markedly increased in the patient with chronic cough and acute episodes of dyspnoea but not in the patient with decreased exercise tolerance and longer duration of disease. In the two patients, the differential cell counts in percentage were characterized by a significant increase of neutrophils and a slight increase of lymphocytes. The analysis of lymphocyte subsets showed a significant increase of CD8+ cells (T-suppressor-cytotoxic) in both cases, resulting in a decreased CD4/CD8 ratio. In addition, an increase of cells bearing a B-phenotype (CD19+ cells) was noted in the fluid recovered from the patient with chronic cough and acute episodes of dyspnoea. In conclusion, our data suggest that SJS is an active process with inflammatory characteristics. Further studies are needed to explain the mechanism leading to the expansion in situ of immunocompetent cells.