tbuckley/cabot-search huggingface dataset:
The Role of NMDA Receptors in Information Processing
Authors: N W Daw, P S Stein, K Fox
Journal: Annual Review of Neuroscience (1993)

In this review, we have concentrated on the parallels between the cellular properties of the NMDA receptor and a variety of functional properties within sensory and motor systems. Of course, the NMDA channel exists within the cell in conjunction with a variety of other channels, including non-NMDA channels. Although the NMDA receptor is unique in a cellular sense--it is the only ligand-gated channel that is also voltage dependent and calcium permeable--it is not unique in a functional sense. A cell that has non-NMDA receptors and voltage-sensitive channels will also exhibit nonlinear behavior. Moreover, Buhrle & Sonnhof (1983) demonstrated some time ago that calcium flows into frog motor neurons through more than one type of calcium channel. The contribution to the inflow of calcium from NMDA channels may vary from cell to cell and could easily be a minor proportion of the total. Many authors have pointed out that the NMDA channel has a low conductance at a resting potential of -70 mV. However, many cells in the nervous system are depolarized from -70 mV by excitatory input. Thus, as pointed out above. NMDA receptors make a contribution to the tonic or spontaneous activity of cells in both visual cortex and spinal cord. In practice, many cells are probably working in a range of membrane potentials where the NMDA channels are always open to some extent. Even in the hippocampal slice where a substantial amount of afferent input is removed, NMDA receptors contribute to spontaneous activity (Sah et al 1989). Does the NMDA receptor act as a switch? Does it act as an AND gate? The suggestion that it may act as a switch comes from work on LTP in the hippocampus, which is readily produced by high-frequency stimulation and is abolished by APV. However, activation of the NMDA receptor is only the first in a sequence of reactions leading to LTP: In theory, switch-like behavior could also be produced by calcium-buffering systems within dendritic spines, or by enzymatic processes (Lisman 1985; Zador et al 1990). Fox & Daw (1992) have modeled the action of NMDA and non-NMDA receptors that are activated in parallel with each other, and shown that the occurrence of switch-like behavior depends on the relative density of NMDA versus non-NMDA receptors. Switch-like behavior is not seen in the visual cortex, but might be seen in the hippocampus if the relative density of NMDA receptors there was higher than in the visual cortex.(ABSTRACT TRUNCATED AT 400 WORDS)
Predicted vs Observed Clinical Event Risk for Cardiovascular Disease—Reply
Authors: Amit Pursnani, Joseph M. Massaro, Udo Hoffmann
Journal: JAMA (2015)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma.
Authors: J L Grem, E Jordan, M E Robson, R A Binder, J M Hamilton, S M Steinberg, S G Arbuck, R A Beveridge, A N Kales, J A Miller
Journal: Journal of Clinical Oncology (1993)

PURPOSE To test the activity of a regimen of interferon alfa-2a (IFN alpha-2a) 5 x 10(6) U/m2 subcutaneously (SC) days 1 through 7 combined with leucovorin 500 mg/m2/d intravenously (IV) over 30 minutes and fluorouracil (5-FU) 370 mg/m2/d through IV push 1 hour after leucovorin days 2 through 6 in a phase II study. PATIENTS AND METHODS Forty-six patients with a good performance status (PS) with measurable colorectal cancer and no prior therapy for metastatic disease were entered. Cycles were repeated at 3-week intervals if toxicity had resolved. The 5-FU dose was increased by 15% if toxicity was mild, and decreased by 15% for grade 3 to 4 nonhematologic or grade 4 hematologic toxicity. RESULTS Three complete responses (CRs) and 21 partial responses (PRs) were seen among 44 assessable patients (54%; 95% confidence interval, 39% to 70%). A moderately strong association was noted between PS and response: PS O (n = 26), two CRs and 15 PRs (65%); PS 1 (n = 13), one CR and six PRs (54%); PS 2 (n = 5), zero CRs and zero PRs (0%; two-tailed P = .026). With a median follow-up duration of 18.8 months, the median time to treatment failure (TTF) and survival were 7.8 months and 16.3 months, respectively. Doses were escalated to 425 mg/m2/d 5-FU in 10 patients, but only four tolerated the higher dose. When expressed as the most severe degree of toxicity experienced by each patient across all cycles, grade 3 to 4 toxicity of the following types was observed; mucositis, 37%; diarrhea, 40%; rash, 7%; fatigue, 14%; granulocytopenia, 13%. Dose-limiting toxicity at 370 mg/m2/d 5-FU eventually occurred in 28 patients (61%). Twelve patients (26%) required an IFN alpha-2a dose reduction for constitutional toxicity. CONCLUSION This regimen has promising activity in advanced colorectal cancer, particularly in patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1.
Acute myeloid leukemia—Major progress over four decades and glimpses into the future
Authors: Hagop Kantarjian
Journal: American Journal of Hematology (2015)

In this Review, the progress in research and therapy of acute myeloid leukemia is detailed. Am. J. Hematol. 91:131–145, 2016. © 2015 Wiley Periodicals, Inc.
Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes
Authors: Morganna Freeman-Keller, Youngchul Kim, Heather Cronin, Allison Richards, Geoffrey Gibney, Jeffrey S. Weber
Journal: Clinical Cancer Research (2015)

Retrospective analysis of irAEs in melanoma patients treated with nivolumab.Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs.IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P ≤ 0.001), and OS benefit was noted in patients who reported three or more irAE events (P ≤ 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243-0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036-0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis).Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses.
Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma.
Authors: C G Moertel, D S Childs, J R O'Fallon, M A Holbrook, A J Schutt, R J Reitemeier
Journal: Journal of Clinical Oncology (1984)

Sixty-two patients with resectable but poor-prognosis gastric carcinoma were randomized to either no surgical adjuvant therapy or treatment with 5-fluorouracil (15 mg/kg by rapid intravenous injection X 3) plus radiation (3,750 rad in 24 fractions) initiated 3 1/2 to six weeks postoperatively. Informed consent was obtained after randomization and only from the 39 randomized to treatment. Ten patients refused their treatment assignment. The five-year survival rate for patients randomized to treatment was 23%, and for those randomized to no treatment, 4% (P less than .05). Both the survival distributions and the alive-without-recurrence distributions were significantly different for the two groups (P = .024) and favored treatment assignment. When the treatment assignment group was broken down to those patients actually receiving treatment and those refusing, five-year survival rates were: treated, 20%; treatment refusal, 30%; controls, 4%; the three survival distributions were not significantly different. Thirty-nine percent of patients actually treated had a local-regional component of first clinical recurrence compared with 54% of those who received no treatment. This study does not establish 5-fluorouracil plus radiation as effective surgical adjuvant therapy for gastric cancer but suggests this approach as a possible fruitful area for continued research. This study also illustrates the potential problems that may be encountered in interpreting results when patients are randomized to a study before consent is obtained.
Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation
Authors: Jessica A. Couch, Gu Zhang, Joseph C. Beyer, Christina L. Zuch de Zafra, Priyanka Gupta, Amrita V. Kamath, Nicholas Lewin-Koh, Jacqueline Tarrant, Krishna P. Allamneni, Gary Cain, Sharon Yee, Sarajane Ross, Ryan Cook, Siao Ping Tsai, Jane Ruppel, John Brady Ridgway, Maciej Paluch, Philip E. Hass, Jayme Franklin, Minhong Yan
Journal: Clinical Cancer Research (2015)

Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody.The F(ab')2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab')2) was generated and assessed in efficacy and toxicity studies.Anti-DLL4 F(ab')2 enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab')2 can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition.PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab')2 also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans.
Abstract 17882: Cardiac Deletion of Brg1 Chromatin Remodeling Atpase Causes Dilated Cardiomyopathy
Authors: Bo Ye
Journal: Circulation (2012)

Background: Brahma-related gene 1 (Brg1) is the ATPase subunit of a large chromatin-remodeling complex. Chromatin changes mediated by this complex play essential roles in cell proliferation and differentiation. Mammalian cardiomyocytes (CMs) switch from proliferation to hypertrophy with concomitant transition from fetal to adult gene programming during neonatal development. Whether Brg1 is involved in the neonatal transition of CMs from a fetal to an adult phenotype remains unclear. Methods: Using the Cre recombinase driven by alpha-myosin heavy chain promoter (MHC-Cre), we created a Brg1 loss-of-function by deleting 2 exons in the ATPase domain floxed by LoxP sites in the brg1 gene. Homozygous Brg1 deletion (KO) and wild-type (WT) mice were phenotyped by real-time RT-PCR, Western blotting, immunohistochemistry, and histology. Results: Unlike global or SM22α-cre mediated Brg1 deletion, cardiac-specific homozygous deletion of Brg1 by MHC-Cre was compatible with neonatal viability, but caused increased mort...
Bactericidal and synergistic activity of double-carbapenem regimen for infections caused by carbapenemase-producing Klebsiella pneumoniae
Authors: A. Oliva, F. Gizzi, M.T. Mascellino, A. Cipolla, A. D'Abramo, C. D'Agostino, V. Trinchieri, G. Russo, F. Tierno, M. Iannetta, C.M. Mastroianni, V. Vullo
Journal: Clinical Microbiology and Infection (2015)

Available therapeutic options against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are limited because of the high level of resistance to other antimicrobial classes including polymyxins. The double-carbapenem regimen has been recently considered a possible therapeutic strategy. In the present study, we evaluated the in vitro bactericidal and synergistic activity of a double-carbapenem regimen consisting of ertapenem plus high-dose meropenem in a series of patients with healthcare-associated CR-Kp infections in whom the use of colistin was not indicated because of potential nephrotoxicity and/or resistance. In vitro synergy was evaluated using checkerboard and killing studies. A total of 15 patients were included in the study, with sepsis, severe sepsis and septic shock found in two (13.3%), five (33.3%) and one (6.7%) patients, respectively. Overall, the clinical/microbiological response was 12/15 (80%). Synergy was observed in 11/14 (78.6%) isolates using the checkerboard method whereas in killing studies 12/14 (85.7%) and 14/14 (100%) strains were synergistic and bactericidal at 24 h at concentrations of 1 × MIC MEM+1 × MIC ERT and 2 × MEM+1 × MIC ERT, respectively, with a significant decrease of log CFU/mL compared with other combinations (p <0.0001). The double-carbapenem regimen showed clinical and in vitro effectiveness in patients with CR-Kp infections.
Does knowledge guide practice? Another look at the management of non-small-cell lung cancer.
Authors: B Raby, J Pater, W J Mackillop
Journal: Journal of Clinical Oncology (1995)

PURPOSE To describe Canadian doctors' beliefs about the appropriate role of chemotherapy and radiotherapy in the management of non-small-cell lung cancer (NSCLC). METHODS A mail survey of a random sample of Canadian respirologists, thoracic surgeons, radiation oncologists, and medical oncologists was performed. Three cases of NSCLC were described and respondents were asked to estimate the prognosis in each case and to give their treatment recommendations. RESULTS Responses were obtained from 234 of 330 eligible subjects (74%). Doctors' treatment recommendations varied widely. After a complete resection for stage II NSCLC, 68% recommended no adjuvant treatment, 28% recommended radiotherapy, 1% recommended chemotherapy, and 3% recommended both radiotherapy and chemotherapy. For an asymptomatic patient with stage IIIb NSCLC, 17% recommended no active treatment, 65% recommended radiotherapy alone, 16% recommended radiation and chemotherapy, and 2% recommended chemotherapy alone. For an asymptomatic patient with a stage IV NSCLC, 80% recommended no active treatment and 20% recommended chemotherapy. Doctors' beliefs about the natural history of NSCLC and its response to treatment varied widely. Seventy-five percent of respondents believed that adjuvant radiotherapy did not increase survival in stage II disease, but 25% believed that it did. Thirty percent believed that the addition of chemotherapy to radiotherapy in stage III increased survival, but 70% believed that it did not. Fifty-five percent believed that chemotherapy increased the median survival in stage IV, but 45% believed that it did not. Doctors' beliefs about the efficacy of treatment were strongly associated with their treatment recommendations. CONCLUSION Personal beliefs, rather than universal knowledge, currently guide the management of NSCLC in Canada.
Cancer Prevention: Obstacles, Challenges, and the Road Ahead
Authors: Frank L. Meyskens, Hasan Mukhtar, Cheryl L. Rock, Jack Cuzick, Thomas W. Kensler, Chung S. Yang, Scott D. Ramsey, Scott M. Lippman, David S. Alberts
Journal: JNCI Journal of the National Cancer Institute (2015)

Approaches to reduce the global burden of cancer include two major strategies: screening and early detection and active preventive intervention. The latter is the topic of this Commentary and spans a broad range of activities. The genetic heterogeneity and complexity of advanced cancers strongly support the rationale for early interruption of the carcinogenic process and an enhanced focus on prevention as a priority strategy to reduce the burden of cancer; however, the focus of cancer prevention management should be on individuals at high risk and on primary localized disease in which screening and detection should also play a vital role. The timing and dose of (chemo-)preventive intervention also affects response. The intervention may be ineffective if the target population is very high risk or already presenting with preneoplastic lesions with cellular changes that cannot be reversed. The field needs to move beyond general concepts of carcinogenesis to targeted organ site prevention approaches in patients at high risk, as is currently being done for breast and colorectal cancers. Establishing the benefit of new cancer preventive interventions will take years and possibly decades, depending on the outcome being evaluated. We also propose that comparative effectiveness research designs and the value of information obtained from large-scale prevention studies are necessary in order for preventive interventions to become a routine part of cancer management.
Follicular lymphoma: prognostic factors for response and survival.
Authors: C J Gallagher, W M Gregory, A E Jones, A G Stansfeld, M A Richards, H S Dhaliwal, J S Malpas, T A Lister
Journal: Journal of Clinical Oncology (1986)

One hundred forty-eight patients with newly diagnosed follicular lymphoma were treated over a 12-year period. Twenty-two patients received radiotherapy for stage I and II disease, followed by adjuvant chemotherapy in 14 patients. One hundred thirteen were treated at presentation with short courses of chemotherapy, most often with single-agent chlorambucil for bulky stage II and stages III and IV disease. Thirteen patients were managed expectantly until there was evidence of disease progression. The median survival was 9 years. Patients treated with radiotherapy for stage I and II disease had an 83% relapse-free survival, but those with bulky stage II or stages III and IV disease treated with chemotherapy pursued a remitting and relapsing course with a 70% response rate at initial and subsequent retreatments, but a median duration of remission of 4 years in stage III and 1 year in stage IV disease (P = .041). Patients were observed in relapse and retreatment was administered as appropriate, once every 33 months on average. Poor prognosis patients could be identified by a combination of the presentation characteristics: B symptoms, hepatosplenomegaly, anemia, and abnormal liver function. These factors predicted a poor response to treatment and correlated with a short survival. Histologic subgroups were not associated with differences in survival, but transformation to a diffuse high-grade lymphoma was observed in 23 of the 72 patients (32%) at risk, with a median follow-up of 6 years and 6 months, and was associated with a very poor prognosis. The present treatment strategy has proved successful for most patients with localized disease and those older patients with indolent small volume disseminated follicular lymphoma. New approaches are being investigated for the younger poor prognosis patients.
Initiating Events of Acute Coronary Arterial Occlusion
Authors: J S Forrester, F Litvack, W Grundfest
Journal: Annual Review of Medicine (1991)

Acute myocardial infarction is caused by coronary thrombosis on an ulcerated atheroma. We now believe that the predominant cause of this intimal disruption is the rupture of the atheroma through the intimal surface, caused by enzymes released by activated macrophages. The subsequent clinical course following atheroma disruption is determined by the rate and size of thrombus formation. Partially occlusive thrombi produce unstable angina; completely occlusive thrombi produce myocardial infarction; clot embolization can produce sudden death. The localized thrombus lyses within days. The healing process, however, is frequently accompanied by rapid local progression of the size of the atheroma at the site ofintimal disruption. With healing of the intimal surface, the patient's clinical status stabilizes. Thus coronary disease is a cyclical phenomenon driven by cellular events within the atheroma and by the interaction of the atheroma with circulating blood elements.
Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage
Authors: Anannya Bhattacharya, Ahmed N. Hegazy, Nikolaus Deigendesch, Lindsay Kosack, Jovana Cupovic, Richard K. Kandasamy, Andrea Hildebrandt, Doron Merkler, Anja A. Kühl, Bojan Vilagos, Christopher Schliehe, Isabel Panse, Kseniya Khamina, Hatoon Baazim, Isabelle Arnold, Lukas Flatz, Haifeng C. Xu, Philipp A. Lang, Alan Aderem, Akinori Takaoka, Giulio Superti-Furga, Jacques Colinge, Burkhard Ludewig, Max Löhning, Andreas Bergthaler
Journal: Immunity (2015)

Highlights•Viral infection leads to redox dysregulation including the downregulation of SOD1•Sod1−/− mice exhibit aggravated viral hepatitis, which is rescued by antioxidants•IFN-I signaling via STAT1 drives SOD1 downregulation and early liver damage•Ablation of IFN-I signaling ameliorates viral hepatitis in Sod1−/− and WT miceSummaryTissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1−/− mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1−/− and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage.Video Abstract/cms/asset/b3f48d58-c2b3-4014-8e6f-19701d566f16/mmc5.mp4Loading ...Download video (mp4, 13 MB)Graphical abstract
After treating unprovoked PE with VKAs for 6 months, warfarin for 18 more months reduced a composite of VTE or major bleeding
Authors: Randolph J. Lipchik
Journal: Annals of Internal Medicine (2015)

Source Citation Couturaud F, Sanchez O, Pernod G, et al; PADIS-PE Investigators. Six months vs extended oral anticoagulation after a first episode of pulmonary embolism: the PADIS-PE randomized clinical trial. JAMA. 2015;314:31-40. 26151264