tbuckley/cabot-search huggingface dataset:
Role of Glucagon, Catecholamines, and Growth Hormone in Human Glucose Counterregulation
Authors: Robert A. Rizza, Philip E. Cryer, John E. Gerich
Journal: Journal of Clinical Investigation (1979)

To further characterize mechanisms of glucose counterregulation in man, the effects of pharmacologically inducd deficiencies of glucagon, growth hormone, and catecholamines (alone and in combination) on recovery of plasma glucose from insulin-induced hypoglycemia and attendant changes in isotopically ([3-3H]glucose) determined glucose fluxes were studied in 13 normal subjects. In control studies, recovery of plasma glucose from hypoglycemia was primarily due to a compensatory increase in glucose production; the temporal relationship of glucagon, epinephrine, cortisol, and growth hormone responses with the compensatory increase in glucose appearance was compatible with potential participation of all these hormones in acute glucose counterregulation. Infusion of somatostatin (combined deficiency of glucagon and growth hormone) accentuated insulin-induced hypoglycemia (plasma glucose nadir: 36±2 ng/dl during infusion of somatostatin vs. 47±2 mg/dl in control studies, P < 0.01) and impaired restoration of normoglycemia (plasma glucose at min 90: 73±3 mg/dl at end of somatostatin infusion vs. 92±3 mg/dl in control studies, P<0.01). This impaired recovery of plasma glucose was due to blunting of the compensatory increase in glucose appearance since glucose disappearance was not augmented, and was attributable to suppression of glucagon secretion rather than growth hormone secretion since these effects of somatostatin were not observed during simultaneous infusion of somatostatin and glucagon whereas infusion of growth hormone along with somatostatin did not prevent the effect of somatostatin. The attenuated recovery of plasma glucose from hypoglycemia observed during somatostatin-induced glucagon deficiency was associated with plasma epinephrine levels twice those observed in control studies. Infusion of phentolamine plus propranolol (combined α-and β-adrenergic blockade) had no effect on plasma glucose or glucose fluxes after insulin administration. However, infusion of somatostatin along with both phentolamine and propranolol further impaired recovery of plasma glucose from hypoglycemia compared to that observed with somatostatin alone (plasma glucose at end of infusions: 52±6 mg/dl for somatostatin-phentolamine-propranolol vs. 72±5 mg/dl for somatostatin alone, P < 0.01); this was due to further suppression of the compensatory increase in glucose appearance (maximal values: 1.93±0.41 mg/kg per min for somatostatin-phentolamine-propranolol vs. 2.86±0.32 mg/kg per min for somatostatin alone, P < 0.05). These results indicate that in man (a) restoration of normoglycemia after insulin-induced hypoglycemia is primarily due to a compensatory increase in glucose production; (b) intact glucagon secretion, but not growth hormone secretion, is necessary for normal glucose counterregulation, and (c) adrenergic mechanisms do not normally play an essential role in this process but become critical to recovery from hypoglycemia when glucagon secretion is impaired.
Lineage-Specific Modulation of Calcium Pump Expression During Myeloid Differentiation
Authors: Sophie Launay, Maurizio Giannı̀, Tünde Kovàcs, Raymonde Bredoux, Arlette Bruel, Pascal Gélébart, Fabien Zassadowski, Christine Chomienne, Jocelyne Enouf, Béla Papp
Journal: Blood (1999)
Abstract 16004: Nicotine Accelerates the Expansion of Abdominal Aortic Aneurysms in Mice; A Potential Role for miR-21 and miR-26a
Authors: Lars Maegdefessel, Junya Azuma, Joshua M Spin, Alicia Deng, Michael McConnell, Ronald L Dalman, Philip S Tsao
Journal: Circulation (2010)
Designing nanoparticles for delivery of neurotrophic proteins
Authors: Angelina Angelova, Borislav Angelov, Sylviane Lesieur
Journal: Molecular Neurodegeneration (2013)

Nanoparticulate systems for neurotrophic factor delivery are currently studied in an attempt to solve some of the challenges in neurodegenerative disease treatment. Nanomedicine for brain disorders has faced difficulties in cerebral administraton of fragile neurotrophic proteins and high costs. According to recent studies, the signaling protein brain-derived neurotrophic factor (BDNF), being a main mammalian neurotrophin, is regarded as a therapeutic target for a number of neurodegenerative and psychiatric diseases (Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, depression, schizophrenia, etc). However, a beneficial BDNF treatment is still not clinically available for patients. Thanks to their safety and feasibility for large-scale production, lipid nanoparticles (NPs) and nanostructured vehicles are considered as key candidates for delivery of BDNF-based therapeutics. Nanoparticles may serve as reservoirs for controlled drug release and may influence the biodistribution and bioavailability of the administered protein. Nanoencapsulation in lipid particles provides protein stabilization against degradation and a possibility for targeted delivery. Lipid nanostructure types and liquid-crystalline phase transformations are suggested to govern the cell uptake mechanisms. Fusogenic lipids, like the cubic-phase forming monoolein, characterized by pore-inducing propensity and significant structural influence on biomembranes, have drawn the attention in designing BDNF delivery vehicles. Nanoparticles were prepared from self-assembly mixtures of lipids and BDNF and functionalized by stabilizing amphiphilic polymer derivatives. The resulting nanoscale organizations were revealed by cryogenic transmission electron microscopy (cryo-TEM) and X-ray structural analysis (SAXS) in order to evaluate the ability of the investigated particles for protein upload. The interaction of differentiated human neuroblastoma SH-SY5Y cells (a cellular model of neurodegeneration) with lipid nanocarriers of BDNF was studied by means of confocal fluorescence microscopy imaging. The obtained nanoparticles, encapsulating neurotrophic protein, may be anticipated to show therapeutic potential in repairing damaged neurons by regulation of the neuronal survival and plasticity.
471. Efficient Non-Viral Vectorisation of siRNA in the Brains of Newborn Mice
Authors: Hong Sung Kim, Keun Sik Kim, Myung Min Choi, Ji Eun Lee, Yong Serk Park
Journal: Molecular Therapy (2004)

It has been well documented that Sendai viral F(fusion)/HN (hemagglutination-neuraminidase)proteins possess fusogenic activity, even at neutral pH on the cell surface. We have tried to adopt the fusogenic activity of Sendai F/HN proteins to cationic liposomes for systemic gene delivery. The cationic Sendai virosomes were prepared by simply mixing cationic liposomes (1,2-Dioleoyl-3-trimethylammonium-propane/cholesterol, DOTAP/Chol) and a purified Sendai F/HN protein solution. The Sendai F/HN proteins were purified by a series of centrifugation after viral particle lysis with detergent, Triton X-100. Hemolytic activity of the Sendai F/HN proteins was more efficiently maintained at 1:1~2 ratios of Sendai virus and Triton X-100 ratio (wt:wt), which was determined by a hemolyssis assay. The optimized cationic Sendai FHN virosomes, prepared at 1:6~12 ratios of F/HN proteins and cationic liposomes (wt:wt), exhibited more efficient transfection activity than the conventional cationic lipoplex, which was determined by three different assay systems of luciferase, green fluorescence protein, and b-galactosidase. The direct effect of the Sendai F/HN proteins on gene transfection was confirmed by endocytosis blocking and inactivation of Sendai F/HN proteins. Addition of cationic polymers, such as protamine sulfate, further enhanced the gene transfection activity of the Sendai virosomes even in the presence of 50% serum. The cationic Sendai FHN virosomes also exhibited more efficient in vivo gene expression in a mouse model. The Sendai virosomes encapsulating pDNA encoding luciferase gene were intravenously administered to mice via tail vein. The luciferase expression mediated by the cationic Sendai F/HN virosomes was much higher in various organs including lungs and liver than by the DOTAP/Chol lipoplex. Interestingly the gene expression in the liver was most significantly enhanced. This study suggests that the cationic Sendai F/HN virosomes may be utilized as an efficient in vivo gene delivery vector, especially for hepatic gene expression.
Hepatitis C virus clearance correlates with HLA-DR expression on proliferating CD8+ T cells in immune-primed chimpanzees
Authors: Iryna Zubkova, Hongying Duan, Frances Wells, Howard Mostowski, Esther Chang, Kathleen Pirollo, Kris Krawczynski, Robert Lanford, Marian Major
Journal: Hepatology (2013)

Vaccination of chimpanzees against hepatitis C virus (HCV) using T-cell-based vaccines targeting nonstructural proteins has not resulted in the same levels of control and clearance as those seen in animals reexposed after HCV clearance. We hypothesized that the outcome of infection depends on the different subtypes of activated T cells. We used multicolor flow cytometry to evaluate activation (CD38+/HLA-DR+) and proliferation (Ki67+/Bcl-2-low) profiles of CD4+ and CD8+ T cells in peripheral blood before and after challenge in chimpanzees vaccinated using DNA/adenovirus, mock-vaccinated, and chimpanzees that had spontaneously cleared infection (rechallenged). The frequencies of activated or proliferating CD8+ T cells peaked at 2 weeks postchallenge in the vaccinated and rechallenged animals, coinciding with reductions in viral titers. However, the magnitude of the responses did not correlate with outcome or sustained control of viral replication. In contrast, proliferation of the CD8+ T cells coexpressing HLA-DR either with or without CD38 expression was significantly higher at challenge in animals that rapidly cleared HCV and remained so throughout the follow-up period. Our data suggest that the appearance of proliferating HLA-DR+/CD8+ T cells can be used as a predictor of a successfully primed memory immune response against HCV and as a marker of effective vaccination in clinical trials.
907. T Lymphocyte-Directed Gene Therapy for IL-12Rβ1 Deficiency
Authors: Marita Bosticardo, Claire Fieschi, Francesco Novelli, Jean-Laurent Casanova, Fabio Candotti
Journal: Molecular Therapy (2004)

Genetic deficiency of human IL-12 and IL-23 receptor β1 chain (IL-12Rβ1) results in increased vulnerability to weakly pathogenic strains of Mycobacteria and Salmonella. The main pathogenic mechanism in IL-12Rβ1 deficiency is the insufficient production of interferon gamma (IFN-γ) by T lymphocytes in response to IL-12 and IL-23, which prevents the efficient elimination of pathogens by effector cells. Despite early diagnosis and treatment with antibiotics and IFN-γ, IL12Rβ1-deficient patients can still succumb to complications of serious infections. Reversion of patients' susceptibility by corrective gene transfer could prevent the infectious episodes, thus providing a beneficial alternative. Because T cell development is intact in IL12Rβ1-deficiency, T lymphocyte-directed IL-12Rβ1 gene transfer correction could theoretically restore IL-12/IL-23 responsiveness and provide a polyclonal pool of gene-corrected T cells able to produce IFN-γ in response to exposure to pathogens. We therefore set out to investigate the feasibility of retroviral-mediated gene correction of T lymphocytes from IL-12Rβ1-deficient patients. Transduction of the human IL-12Rβ1 cDNA into immortalized and primary T cells from three IL-12Rβ1-deficient patients restored the expression of IL-12Rβ1 and reconstituted IL-12 signaling, as demonstrated by STAT4 phosphorylation and IFN-γ indicated that the biological defects of T cells from IL-12Rβ1 deficiency could be corrected by gene transfer. To evaluate the feasibility of T lymphocyte-directed gene therapy of IL-12Rβ1 deficiency in vivo, we used the IL-12Rβ1 knockout mouse model that closely mimics the human phenotype. These mice present with normal development of T cells that, however, fail to produce IFN-γ and proliferate in response to IL-12 and show impaired ability to produce IFN-γ in response to endotoxin (LPS) administration in vivo. Retroviral-mediated transduction of the murine IL-12Rβ1 cDNA into splenocytes from IL-12Rβ1 knockout mice activated with Concavalin A plus IL-2 was followed by FACS sorting of IL-12Rβ1-positive cells to obtain 100% gene-corrected cells. Sorted cells were stimulated with IL-12 and showed restored production of IFN-γ at levels comparable to normal control cells. In a preliminary experiment, five million IL-12Rβ1-positive cells were then injected intraperitoneally into two IL-12Rβ1 knockout mice and expression of IL-12Rβ1 was assessed in PBMCs from the recipient animals 2 weeks after transplantation. No clear evidence of gene corrected cells was demonstrated. Additional experiments are being performed to assess the optimal numbers of corrected T cells to be infused and to follow their survival in recipient animals.
Predictive factors for latency period and a prognostic model for survival in patients with therapy‐related acute myeloid leukemia
Authors: Moshe C. Ornstein, Sudipto Mukherjee, Sanjay Mohan, Paul Elson, Ramon V. Tiu, Yogenthiran Saunthararajah, Cassie Kendeigh, Anjali Advani, Matt Kalaycio, Jaroslaw P. Maciejewski, Mikkael A. Sekeres
Journal: American Journal of Hematology (2013)

Therapy-related acute myeloid leukemia (t-AML) is an increasingly recognized sequela in patients receiving chemotherapy or radiotherapy for a primary malignancy or autoimmune disease. This study assessed factors related to the latency period (LP) between the antecedent disorder (AD) and t-AML diagnosis and developed a comprehensive prognostic model to predict overall survival (OS). We evaluated a cohort of newly diagnosed t-AML patients treated with cytarabine-based induction therapy from 2001 to 2011. Multivariable linear and proportional hazards models were used to assess the impact of different classes of chemotherapy on the LP and to identify independent prognostic factors for OS. Of 730 treated AML patients, 58 (7.9%) had t-AML. Median LP to t-AML was 5.6 years (range, 0.5-38.4). 64% of patients achieved CR and median OS was 10.7 months. Independent prognostic factors of short LP were age at AD (P < 0.0001) and prior treatment with mitotic inhibitors (P = 0.05). Unfavorable cytogenetics (P = 0.004), antecedent hematologic or autoimmune disease (P = 0.01), age >60 (P = 0.03), and platelet count <30,000 μL (P = 0.04) at the time of t-AML diagnosis were prognostic for inferior OS. A prognostic model using these factors was developed that risk stratified t-AML patients into two groups: favorable and unfavorable. Patients in the favorable group had a median OS of 37.6 months compared with 6.4 months in patients comprising the unfavorable group (P < 0.0001). Multicomponent prognostic models integrating disease or treatment-related covariates can help better understand how t-AML evolves; and can be clinically useful in risk stratifying t-AML patients undergoing induction therapy.
Vitamin Supplementation and Risk of Stroke
Authors: David S Wald
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab
Authors: I S Nijhof, R W J Groen, H M Lokhorst, B van Kessel, A C Bloem, J van Velzen, R de Jong-Korlaar, H Yuan, W A Noort, S K Klein, A C M Martens, P Doshi, K Sasser, T Mutis, N W C J van de Donk
Journal: Leukemia (2015)

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.
Molecular Analysis of 11q13 Breakpoints in Multiple Myeloma
Authors: Domenica Ronchetti, Palma Finelli, Raffaella Richelda, Luca Baldini, Mariano Rocchi, Luigi Viggiano, Antonio Cuneo, Silvia Bogni, Sonia Fabris, Luigia Lombardi, Anna Teresa Maiolo, Antonino Neri
Journal: Blood (1999)
Abstract 9757: Atrial Rhythm Influences Catheter Tissue Contact During Radiofrequency Ablation of Atrial Fibrillation
Authors: Hisao Matsuda, Abdul S Parwani, Philipp Attanasio, Martin Huemer, Alexander Wutzler, Florian Blaschke, Wilhelm Haverkamp, Leif-Hendrik Boldt
Journal: Circulation (2014)

Introduction:  Radiofrequency catheter ablation (RFCA) is an accepted treatment option for symptomatic atrial fibrillation (AF). Catheter tissue contact force(CF) is one of the critical factors for transmural and durable lesion. Low CF may lead to insufficient lesion formation, whereas excessively high CF is associated with potential major complications. Recent studies showed that CF correlates with clinical outcome in patients with AF undergoing RFCA. An average CF of 10-30g is considered as an optimal target to avoid gap formation. Since CF varies in the beating heart, atrial rhythm during ablation may influence tissue contact.   Hypothesis:  We assessed the hypothesis that atrial rhythm influences CF during RFCA of AF.   Methods:  In this prospective study, a CF-sensing catheter (Tacticath, St. Jude Medical) was used in 18 patients undergoing RFCA of AF. Each pulse was delivered point by point with use of a steerable sheath (Agilis, St. Jude Medical) and the operator blinded to the CF information. Type of contact (constant, variable and intermittent) and mean CF were analysed according to atrial rhythms (sinus rhythm (SR) vs. AF).   Results:  A total of 1003 points (694 points during SR and 309 points during AF) were analysed. Mean CF showed no significant difference between SR (16.6 ± 11.0g) and AF (17.1 ± 13.2g; p=0.54). The distribution of ablation points with a mean CF of >20g and  40g) was higher during AF (6.5%) compared with SR (3.5%; p   Conclusions:  Although mean CF was not different during AF and SR, constant contact was more often achievable during AF compared with SR. However, excessive high CF also seems to occur more frequent during AF.
Abstract 3818: Tumor budding and E-cadherin expression are useful predictors of nodal involvement in T1 esophageal squamous cell carcinoma
Authors: Naoshi Kubo, Masaichi Ohira, Katsunobu Sakurai, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Masakazu Yashiro, Kiyoshi Maeda, Naoyoshi Onoda, Kosei Hirakawa
Journal: Cancer Research (2014)

Abstract Background The endoscopic treatment has been increasingly used for T1 esophageal squamous cell carcinoma (ESCC). However, this therapy is sometimes incomplete if the depth of the T1 primary tumor reaches the muscularis mucosae (MM) or submucosal layer (SM) because these tumors have relatively high incidences of lymph node metastasis. However, no previous report on the predictive factor of nodal metastasis determined by evaluating primary tumor specimens of patients with ESCC is available. Patients and Methods A total of 55 patients with T1 ESCC invading as deep as the submucosal layer who underwent curative esophagectomy were examined. We investigated the significance of the immunohistochemical stainings of VEGF-C and E-cadherin in the primary tumor and tumor budding for prediction of nodal metastasis. Results Metastasis to the regional lymph nodes was observed in 26 cases (47.3%) in this setting. VEGF-C expression and reduced E-cadherin expression in the primary tumor was observed in 32 (58.1%) and 38 cases (69.1%), respectively. High-grade tumor budding was observed in 29 cases (52.7%). E-cadherin expression and tumor budding were closely correlated with nodal metastasis (p = 0.039 and &amp;lt;0.01 respectively), whereas VEGF-C expression tended to correlate with lymph node metastasis (p = 0.055). In addition, high-grade tumor budding was significantly correlated (p &amp;lt; 0.01) with reduced E-cadherin expression. The accuracies of tumor budding and E-cadherin expression for nodal metastasis were 67.3% and 65.4% respectively, which were comparable with those of lymphatic involvement (63%). Tumor budding (p &amp;lt; 0.01), but not E-cadherin and VEGF-C expression, was significantly correlated with poor survival. Conclusion After the endoscopic treatment, additional therapy, such as surgery or chemoradiotherapy, may be required if reduced E-cadherin expression and high-grade tumor budding are observed in the primary tumor specimen. Citation Format: Naoshi Kubo, Masaichi Ohira, Katsunobu Sakurai, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Masakazu Yashiro, Kiyoshi Maeda, Naoyoshi Onoda, Kosei Hirakawa. Tumor budding and E-cadherin expression are useful predictors of nodal involvement in T1 esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3818. doi:10.1158/1538-7445.AM2014-3818