tbuckley/cabot-search huggingface dataset:
Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity
Authors: Eiji Suzuki, Veena Kapoor, Arminder Singh Jassar, Larry R. Kaiser, Steven M. Albelda
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Myeloid suppressor (Gr-1+/CD11b+) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8+ T cells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist. Experimental Design: The effect of the chemotherapy drug gemcitabine on the number of (Gr-1+/CD11b+) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-β. Results: This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4+ T cells, CD8+ T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8+ T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-β markedly enhanced antitumor efficacy. Conclusions: These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.
Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study
Authors: Daniel J Wallace, Kenneth Kalunian, Michelle A Petri, Vibeke Strand, Frederic A Houssiau, Marilyn Pike, Brian Kilgallen, Sabine Bongardt, Anna Barry, Lexy Kelley, Caroline Gordon
Journal: Annals of the Rheumatic Diseases (2013)

To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE).A phase IIb, multicentre, randomised controlled study (NCT00624351) was conducted with 227 patients (37-39 per arm) receiving either: placebo, epratuzumab 200 mg cumulative dose (cd) (100 mg every other week (EOW)), 800 mg cd (400 mg EOW), 2400 mg cd (600 mg weekly), 2400 mg cd (1200 mg EOW), or 3600 mg cd (1800 mg EOW). The primary endpoint (not powered for significance) was the week 12 responder rate measured using a novel composite endpoint, the British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA).Proportion of responders was higher in all epratuzumab groups than with placebo (overall treatment effect test p=0.148). Exploratory pairwise analysis demonstrated clinical improvement in patients receiving a cd of 2400 mg epratuzumab (OR for 600 mg weekly vs placebo: 3.2 (95% CI 1.1 to 8.8), nominal p=0.03; OR for 1200 mg EOW vs placebo: 2.6 (0.9 to 7.1), nominal p=0.07). Post-hoc comparison of all 2400 mg cd patients versus placebo found an overall treatment effect (OR=2.9 (1.2 to 7.1), nominal p=0.02). Incidence of adverse events (AEs), serious AEs and infusion reactions was similar between epratuzumab and placebo groups, without decreases in immunoglobulin levels and only partial reduction in B-cell levels.Treatment with epratuzumab 2400 mg cd was well tolerated in patients with moderately to severely active SLE, and associated with improvements in disease activity. Phase III studies are ongoing.
Acute low back pain: systematic review of its prognosis
Authors: L. H M Pengel
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objectives</b> To describe the course of acute low back pain and sciatica and to identify clinically important prognostic factors for these conditions. <b>Design</b> Systematic review. <b>Data sources</b> Searches of Medline, Embase, Cinahl, and Science Citation Index and iterative searches of bibliographies. <b>Main outcome measures</b> Pain, disability, and return to work. <b>Results</b> 15 studies of variable methodological quality were included. Rapid improvements in pain (mean reduction 58% of initial scores), disability (58%), and return to work (82% of those initially off work) occurred in one month. Further improvement was apparent until about three months. Thereafter levels for pain, disability, and return to work remained almost constant. 73% of patients had at least one recurrence within 12 months. <b>Conclusions</b> People with acute low back pain and associated disability usually improve rapidly within weeks. None the less, pain and disability are typically ongoing, and recurrences are common.
Comment on Kahn and Davidson. The Reality of Type 2 Diabetes Prevention. Diabetes Care 2014;37:943–949
Authors: David C. Goff, Jeffrey A. Katula, Caroline S. Blackwell, Scott P. Isom, Carolyn F. Pedley, Mara Z. Vitolins
Journal: Diabetes Care (2014)

Kahn and Davidson (1) conclude that inadequacies in the evidence base support inaction on diabetes prevention in the community. Because we lack evidence from randomized controlled trials of community-based translations of the Diabetes Prevention Program (DPP) showing long-term maintenance of weight loss and prevention of diabetes and diabetes complications, they state that “… it is premature to siphon off precious national health care resources or revenue going into health plans toward an intervention that has no clear clinical benefit” (1).

Fortunately, Kahn and Davidson are not responsible for developing public health policy. Many sound health policies are based on evidence that would fall short …
Human Enhancer of Filamentation 1 Is a Mediator of Hypoxia-Inducible Factor-1α–Mediated Migration in Colorectal Carcinoma Cells
Authors: Sun-Hee Kim, Dianren Xia, Sang-Wook Kim, Vijaykumar Holla, David G. Menter, Raymond N. DuBois
Journal: Cancer Research (2010)

Abstract Human enhancer of filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is a scaffolding protein that is implicated in regulating diverse cellular processes, such as cellular attachment, motility, cell cycle progression, apoptosis, and inflammation. Here, we identify HEF1 as a novel hypoxia-inducible factor-1α (HIF-1α)–regulated gene and reveal that HEF1 mediates hypoxia-induced migration of colorectal carcinoma cells. HEF1 is highly expressed in cultured colorectal carcinoma cells exposed to hypoxia and in the hypoxic areas of human colorectal cancer (CRC) specimens. Moreover, our data show that HIF-1α mediates the effects of hypoxia on induction of HEF1 expression via binding to a hypoxia-responsive element of the HEF1 promoter. Importantly, the induction of HEF1 expression significantly enhances hypoxia-stimulated HIF-1α transcriptional activity by modulating the interaction between HIF-1α and its transcriptional cofactor p300. Inhibition of HEF1 expression also reduced the levels of hypoxia-inducible genes, including those that regulate cell motility. Cell migration was reduced dramatically following knockdown of HEF1 expression under hypoxic conditions. Thus, this positive feedback loop may contribute to adaptive responses of carcinoma cells encountering hypoxia during cancer progression. Cancer Res; 70(10); 4054–63. ©2010 AACR.
Cardiac tamponade complicating proximal aortic dissection. Is pericardiocentesis harmful?
Authors: E M Isselbacher, J E Cigarroa, K A Eagle
Journal: Circulation (1994)

Cardiac tamponade frequently complicates acute proximal aortic dissection and is one of the most common causes of death from aortic dissection. Well-defined strategies for the management of acute aortic dissection now exist; however, little is known about how best to manage the hemopericardium that may complicate it.Using a computer-based review, we retrospectively identified 10 patients presenting to our hospital over a 13-year period who were diagnosed with both aortic dissection and cardiac tamponade. All 10 had proximal dissections. Three of the 10 presented as the sudden onset of fatal electromechanical dissociation, 6 presented with hypotension, and 1 was normotensive on presentation. Of the 7 hypotensive or normotensive patients diagnosed with cardiac tamponade, 4 underwent successful pericardiocentesis while awaiting surgery. At time intervals of 5 to 40 minutes after their pericardiocenteses, 3 of the 4 patients experienced sudden onset of electromechanical dissociation and death; the fourth patient survived and underwent surgical repair. Of the 3 hypotensive or normotensive patients who had either no pericardiocentesis or an unsuccessful pericardiocentesis, all 3 underwent successful surgical repair and survived.In this study, patients with an aortic dissection complicated by cardiac tamponade have an early mortality of 60%. While 3 of the 10 died from electromechanical dissociation immediately upon presentation, the 3 other deaths all occurred shortly after successful pericardiocentesis, a procedure undertaken to stabilize them. While the number of patients in this series is small, the observations do raise the possibility that in patients with cardiac tamponade complicating aortic dissection pericardiocentesis could be harmful rather than beneficial. Possible mechanisms for why the performance of pericardiocentesis might destabilize such patients are proposed.
Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune and chronic inflammatory disease
Authors: Myriam Chimen, Helen M McGettrick, Bonita Apta, Sahithi J Kuravi, Clara M Yates, Amy Kennedy, Arjun Odedra, Mohammed Alassiri, Matthew Harrison, Ashley Martin, Francesca Barone, Saba Nayar, Jessica R Hitchcock, Adam F Cunningham, Karim Raza, Andrew Filer, David A Copland, Andrew D Dick, Joseph Robinson, Neena Kalia, Lucy S K Walker, Christopher D Buckley, Gerard B Nash, Parth Narendran, G Ed Rainger
Journal: Nature Medicine (2015)
Successful pregnancy with scleroderma renal disease and pulmonary hypertension in a patient using angiotensin converting enzyme inhibitors.
Authors: B A Baethge, R E Wolf
Journal: Annals of the Rheumatic Diseases (1989)

A patient with scleroderma renal disease and pulmonary hypertension who had a successful pregnancy with the use of angiotensin converting enzyme inhibitors is presented. The routine use of these inhibitors during pregnancy is not recommended, however, owing to the reported potential risks to the fetus.
A Randomized Trial of Low-Dose Tamoxifen on Breast Cancer Proliferation and Blood Estrogenic Biomarkers
Authors: A. Decensi, C. Robertson, G. Viale, F. Pigatto, H. Johansson, E. R. Kisanga, P. Veronesi, R. Torrisi, M. Cazzaniga, S. Mora, M. T. Sandri, G. Pelosi, A. Luini, A. Goldhirsch, E. A. Lien, U. Veronesi
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms, possibly in a dose-dependent fashion. We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the standard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker (Ki-67 expression) and blood biomarkers associated with breast cancer, cardiovascular disease, and bone fracture risk. Methods: We randomly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1, 5, or 20 mg/day for 4 weeks. Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer (insulin-like growth factor-I, sex hormone-binding globulin), cardiovascular disease (cholesterol, triglycerides, ultrasensitive C-reactive protein, fibrinogen, antithrombin-III), and bone fracture (type I collagen C-telopeptide) risk were determined before (baseline) and after treatment. All levels were compared with those in two nonrandomized control groups (34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer). Data were analyzed by analysis of covariance. All statistical tests were two-sided. Results: Expression of Ki-67 decreased in all three tamoxifen groups, with no difference in the magnitude of reduction among groups (P = .81). Relative to baseline, Ki-67 expression decreased by a median of 15.0% (95% confidence interval = 0.0% to 24.1%) among the tamoxifen groups but increased by 12.8% (95% confidence interval = 0.0% to 19.6%) among the nonrandomized control groups. Several blood biomarkers showed dose–response relationships with tamoxifen, including decreased insulin-like growth factor-I, increased sex hormone-binding globulin, and decreased low-density lipoprotein-cholesterol, ultrasensitive C-reactive protein, fibrinogen, and antithrombin-III levels. Conclusions: The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the standard dose, although the effects on blood biomarkers were variable. The effects of lower doses of tamoxifen should be assessed further in randomized trials.
Decreased nNOS in the PVN leads to increased sympathoexcitation in chronic heart failure: role for CAPON and Ang II
Authors: Neeru M. Sharma, Hong Zheng, Parmender P. Mehta, Yi-Fan Li, Kaushik P. Patel
Journal: Cardiovascular Research (2011)

AimsPreviously, we showed an enhanced excitatory (N-methyl d-aspartate receptor-NR1) and decreased inhibitory neuronal nitric oxide (NO) synthase (nNOS) influence within the paraventricular nucleus (PVN) of rats with chronic heart failure (CHF). Although NR1 and nNOS are normally linked, they can be disconnected by nNOS sequestering with nNOS-associated protein (CAPON). The aim of this study was to elucidate the underlying mechanism for the disconnection between increased expression of NR1 and decreased nNOS in the PVN of rats with CHF which leads to enhanced sympathoexcitation.
Optic nerve sheath diameter, intracranial pressure and acute mountain sickness on Mount Everest: a longitudinal cohort study
Authors: A I Sutherland, D S Morris, C G Owen, A J Bron, R C Roach
Journal: British Journal of Sports Medicine (2008)

Objective: To investigate the association of optic nerve sheath diameter (ONSD), as a correlate of intracranial pressure (ICP), with acute mountain sickness (AMS). Design: Longitudinal cohort study of mountaineers from sea level to 6400 m. Setting: Mount Everest (North side). Participants: 13 mountaineers (10 men, 3 women; aged 23–52 years) on a British expedition to climb Mount Everest. Interventions: ONSD was measured ultrasonically, 3 mm behind the globe using B scans recorded with an OTI-Scan 3D scanner (Ophthalmic Technologies, Canada). Serial binocular scans were recorded at sea level, and 2000, 3700, 5200 and 6400 m. All ONSDs were measured by a blinded observer. Main outcome measures: ONSD, AMS score (using the Lake Louise scoring system), heart rate, and oxygen saturation levels. Results: All results were analysed by regression analysis with adjustment. ONSD was positively associated with increasing altitude above sea level (0.10 mm increase in ONSD per 1000 m, 95% CI 0.05 to 0.14 mm) and AMS score (0.12 mm per score, 95% CI 0.06 to 0.18 mm); further associations were found with resting heart rate (0.29 mm per 20 beats/min, 95% CI 0.17 to 0.41 mm) and oxygen saturations (0.20 mm per 10% decrease, 95% CI 0.11 to 0.29 mm). Conclusions: ONSD increases at high altitude, and this increase is associated with more severe symptoms of AMS. Given the linkage between ONSD and ICP, these results strongly suggest that intracranial pressure plays an important role in the pathophysiology of AMS.
Polymorphisms in the <i>FAS</i> and <i>FASL</i> Genes and Survival of Early Stage Non–small Cell Lung Cancer
Authors: Jae Yong Park, Won-Kee Lee, Duk-Ku Jung, Jin-Eun Choi, Tae-In Park, Eung-Bae Lee, Sukki Cho, Ji-Young Park, Sung-Ick Cha, Chang-Ho Kim, Sin Kam, Tae Hoon Jung, Sanghoon Jheon
Journal: Clinical Cancer Research (2009)

This study was conducted to investigate the impact of functional polymorphisms in the FAS and FASL genes on the survival of early stage non-small cell lung cancer (NSCLC) patients.Three hundred and thirty-eight consecutive patients with surgically resected NSCLC were enrolled. The FAS -1377G>A (rs2234767) and -670A>G (rs1800682) and FASL -844C>T (rs763110) polymorphisms were investigated. Immunohistochemistry was used to assess FAS protein expression in tumors. The genotype and haplotype associations with survival were analyzed using Cox proportional hazards model, Kaplan-Meier method, and the log-rank test.Patients with the GG and combined AG+GG genotypes of the FAS -670A>G locus had a significantly decreased survival when compared with patients with the AA genotype [adjusted hazard ratio=1.71, 95% confidence interval (95% CI)=1.06-2.77, and P=0.03; and adjusted hazard ratio=1.48, 95% CI=1.01-2.20, and P=0.047, respectively]. In addition, the FAS -1377G/-670G and -1377A/-670G haplotypes exhibited a significantly lower survival compared with the -1377G/-670A haplotype (adjusted hazard ratio=1.87, 95% CI=1.20-2.91, and P=0.006; and adjusted hazard ratio=1.31, 95% CI=1.05-1.65, P=0.02, respectively). Strongly positive FAS immunostaining was significantly less frequent in patients with the FAS -670 AG+GG genotype than in patients with the -670 AA genotype (4.5% versus 10.8%; P=0.04).The FAS -670A>G polymorphism may affect survival in early-stage NSCLC. The analysis of the FAS -670A>G polymorphism can help identify patients at high risk for a poor disease outcome.
Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial
Authors: Savino M Di Stasi, Antonella Giannantoni, Arcangelo Giurioli, Marco Valenti, Germano Zampa, Luigi Storti, Francesco Attisani, Andrea De Carolis, Giovanni Capelli, Giuseppe Vespasiani, Robert L Stephen
Journal: The Lancet Oncology (2005)
Resistance to Insulin Therapy Among Patients and Providers: Results of the Cross-National Diabetes Attitudes, Wishes, and Needs (DAWN) Study
Authors: Mark Peyrot, Richard R. Rubin
Journal: Diabetes Care (2006)

Phillipov and Phillips (1) suggest that our finding (2) that U.S. physicians were significantly more disposed to delay insulin therapy than were physicians in all other countries surveyed contradicted reports from other studies of the proportion of patients with type 2 diabetes taking insulin in the U.S., Australia, and some European countries. Phillipov and Phillips conclude that …
Neuroimaging and Other Biomarkers for Alzheimer's Disease: The Changing Landscape of Early Detection
Authors: Shannon L. Risacher, Andrew J. Saykin
Journal: Annual Review of Clinical Psychology (2013)

The goal of this review is to provide an overview of biomarkers for Alzheimer's disease (AD), with emphasis on neuroimaging and cerebrospinal fluid (CSF) biomarkers. We first review biomarker changes in patients with late-onset AD, including findings from studies using structural and functional magnetic resonance imaging (MRI), advanced MRI techniques (diffusion tensor imaging, magnetic resonance spectroscopy, perfusion), positron emission tomography with fluorodeoxyglucose, amyloid tracers, and other neurochemical tracers, and CSF protein levels. Next, we evaluate findings from these biomarkers in preclinical and prodromal stages of AD including mild cognitive impairment (MCI) and pre-MCI conditions conferring elevated risk. We then discuss related findings in patients with dominantly inherited AD. We conclude with a discussion of the current theoretical framework for the role of biomarkers in AD and emergent directions for AD biomarker research.
CYCLINS AND CELL CYCLE CHECKPOINTS
Authors: D. G. Johnson, C. L. Walker
Journal: The Annual Review of Pharmacology and Toxicology (1999)

▪ Abstract The eucaryotic cell cycle is regulated by the periodic synthesis and destruction of cyclins that associate with and activate cyclin-dependent kinases. Cyclin-dependent kinase inhibitors, such as p21 and p16, also play important roles in cell cycle control by coordinating internal and external signals and impeding proliferation at several key checkpoints. Understanding how these proteins interact to regulate the cell cycle has become increasingly important to researchers and clinicians with the discovery that many of the genes that encode cell cycle regulatory activities are targets for alterations that underlie the development of cancer. Several therapeutic agents, such as DNA-damaging drugs, microtubule inhibitors, antimetabolites, and topoisomerase inhibitors, take advantage of this disruption in normal cell cycle regulation to target checkpoint controls and ultimately induce growth arrest or apoptosis of neoplastic cells. Other therapeutic drugs being developed, such as UCN-01, specifically inhibit cell cycle regulatory proteins.
Cyclic adenosine monophosphate and diacylglycerol. Mutually inhibitory second messengers in cultured rat inner medullary collecting duct cells.
Authors: I Teitelbaum
Journal: Journal of Clinical Investigation (1990)

Studies were performed to examine interactions between the adenylyl cyclase (AC) and phospholipase C (PLC) signaling systems in cultured rat inner medullary collecting duct cells. Stimulation of AC by either arginine vasopressin (AVP) or forskolin or addition of exogenous cAMP inhibits epidermal growth factor (EGF)-stimulated PLC. This inhibition is mediated by activation of cAMP-dependent kinase as it is prevented by pretreatment with the A-kinase inhibitor, N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H8) but not by the C-kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7). Exposure to EGF eliminates AVP-stimulated cAMP generation. This is not mediated by a cyclooxygenase product as inhibition by EGF is observed even in the presence of the cyclooxygenase inhibitor, flurbiprofen. Inhibition by EGF is not due to an increase in inositol trisphosphate (IP3) as exposure of saponin-permeabilized cells to exogenous IP3 is without effect. Inhibition by EGF is prevented by pretreatment with the C-kinase inhibitor, H7, but not by the A-kinase inhibitor, H8. Exposure to the synthetic diacylglycerol (DAG), dioctanoylglycerol, also inhibits AVP-stimulated AC activity; therefore, inhibition by EGF is due to activation of protein kinase C. Thus, in cultured rat inner medullary collecting duct cells, cAMP and DAG function as mutually inhibitory second messengers with each impairing formation of the other.