tbuckley/cabot-search huggingface dataset:
Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression
Authors: Regina Lin, Ling Chen, Gang Chen, Chunyan Hu, Shan Jiang, Jose Sevilla, Ying Wan, John H. Sampson, Bo Zhu, Qi-Jing Li
Journal: Journal of Clinical Investigation (2014)

CD8(+) cytotoxic T lymphocytes (CTLs) have potent antitumor activity and therefore are leading candidates for use in tumor immunotherapy. The application of CTLs for clinical use has been limited by the susceptibility of ex vivo-expanded CTLs to become dysfunctional in response to immunosuppressive microenvironments. Here, we developed a microRNA-targeting (miRNA-targeting) approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor BLIMP-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CTLs, and expression correlated with impaired antitumor potential of patient CTLs. We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CTLs that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGF-β-mediated tumor immune-evasion pathway.
Effect of Sildenafil on Diabetic Gastropathy
Authors: Alessandro Bianco, Dario Pitocco, Venanzio Valenza, Salvatore Caputo, Ant Grieco, Luca Miele, Aldo Virgilio Greco, Giovanni Ghirlanda
Journal: Diabetes Care (2002)

Diabetic gastropathy (DG) is the most serious neuromuscular dysfunction of the stomach that may affect diabetic patients. DG is a syndrome of delayed gastric emptying correlated to alterations of gastric tone, contractility, and myoelectrical activity. Gastric dysrhythmias, antral hypomotility, antral dilation, antroduodenal incoordination, and pylorospasm variously relate to DG.

DG pathogenesis is multifactorial: autonomic neuropathy, microangiopathy, and the degenerative impairment of gastric neuromuscular structure are possible mechanisms of gastric dysfunction. Also, the acute increase in blood glucose might reversibly delay gastric emptying (1,2). Gastric dysrhythmias correlate with a disturbance of gastric electrical slow waves (ESWs). ESW rhythm, which is generated by interstitial cells of Cajal, coordinates gastric peristalsis (3,4). Cajal cells, distributed in specific locations …
Antibiotic Self-stewardship: Trainee-Led Structured Antibiotic Time-outs to Improve Antimicrobial Use
Authors: Todd C. Lee, Charles Frenette, Dev Jayaraman, Laurence Green, Louise Pilote
Journal: Annals of Internal Medicine (2014)

Antibiotic use is an important quality improvement target. Nearly 50% of antibiotic use is unnecessary or inappropriate. To combat overuse, the Centers for Disease Control and Prevention (CDC) proposed "time-outs" to reevaluate antibiotics.To optimize antibiotic use through trainee-led time-outs.Before-after study.Internal medicine (2 units, 46 beds) at a university hospital.Inpatients (n = 679).From January 2012 until June 2013, while receiving monthly education on antimicrobial stewardship, resident physicians adjusted patients' antibiotic therapy through twice-weekly time-out audits using a structured electronic checklist.Antibiotic costs were standardized and compared in the year before and after the audits. Use was measured as World Health Organization defined daily doses (DDDs) per 1000 patient-days. Total antibiotic use and the use of moxifloxacin, carbapenems, antipseudomonal penicillins, and vancomycin were compared by using interrupted time series. Rates of nosocomial Clostridium difficile infection were compared by using incidence rate ratios.Total costs in the units decreased from $149,743CAD (January 2011 to January 2012) to $80,319 (January 2012 to January 2013), for a savings of $69,424 (46% reduction). Of the savings, $54,150 (78%) was related to carbapenems and $15,274 (22%) was due to other antibiotic classes. Adherence with the auditing process was 80%. In the time-series analyses, the only reliable and statistically significant change was a reduction in the rate of moxifloxicin use, by -1.9 DDDs per 1000 patient-days per month (95% CI, -3.8 to -0.02; P = 0.048). Rates of C. difficile infection decreased from 24.2 to 19.6 per 10,000 patient-days (incidence rate ratio, 0.8 [CI, 0.5 to 1.3]).Other temporal factors may confound the findings.An antibiotic self-stewardship bundle to implement the CDC's suggested time-outs seems to have reduced overall costs and targeted antibiotic use.None.
Crx, a Novel Otx-like Paired-Homeodomain Protein, Binds to and Transactivates Photoreceptor Cell-Specific Genes
Authors: Shiming Chen, Qing-Liang Wang, Zuqin Nie, Hui Sun, Gregory Lennon, Neal G Copeland, Debra J Gilbert, Nancy A Jenkins, Donald J Zack
Journal: Neuron (1997)

The otd/Otx gene family encodes paired-like homeodomain proteins that are involved in the regulation of anterior head structure and sensory organ development. Using the yeast one-hybrid screen with a bait containing the Ret 4 site from the bovine rhodopsin promoter, we have cloned a new member of the family, Crx (Cone rod homeobox). Crx encodes a 299 amino acid residue protein with a paired-like homeodomain near its N terminus. In the adult, it is expressed predominantly in photoreceptors and pinealocytes. In the developing mouse retina, it is expressed by embryonic day 12.5 (E12.5). Recombinant Crx binds in vitro not only to the Ret 4 site but also to the Ret 1 and BAT-1 sites. In transient transfection studies, Crx transactivates rhodopsin promoter-reporter constructs. Its activity is synergistic with that of Nrl. Crx also binds to and transactivates the genes for several other photoreceptor cell-specific proteins (interphotoreceptor retinoid-binding protein, β-phosphodiesterase, and arrestin). Human Crx maps to chromosome 19q13.3, the site of a cone rod dystrophy (CORDII). These studies implicate Crx as a potentially important regulator of photoreceptor cell development and gene expression and also identify it as a candidate gene for CORDII and other retinal diseases.
Effects of Aluminum Nicotinate and "Prudent Diet" in Hypercholesteremic Individuals.
Authors: William B. Parsons
Journal: Annals of Internal Medicine (1969)

s1 May 1969Effects of Aluminum Nicotinate and "Prudent Diet" in Hypercholesteremic Individuals.William B. Parsons Jr., M.D.William B. Parsons Jr., M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-70-5-1102_3 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo determine the effects of a "prudent diet" and small dosage of aluminum nicotinate (AIN), alone and combined, 60 hypercholesteremic outpatients were studied in a 12-week placebo period and 24 weeks of therapy; the patients were randomized as follows—group A, diet + placebo; group B, diet + AIN; group C, diet + placebo (12 weeks), then diet + AIN (12 weeks); group D, AIN alone (12 weeks), then diet + AIN (12 weeks). Aluminum nicotinate dosage was 0.5 g, three times daily. The diet contained approximately 23% calories as fat, 62% as carbohydrate, with ratio of polyunsaturated to saturated fatty... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: William B. ParsonsJr., M.D.Affiliations: Madison, Wisconsin PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1969Volume 70, Issue 5Page: 1102-1103KeywordsCarbohydratesDietFatsNiacinOutpatients ePublished: 1 December 2008 Issue Published: 1 May 1969 PDF downloadLoading ...
36Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T cell responsiveness
Authors: SCA De Jager, GH Van Pijvelde, AA Anas, M Bot, M Asbach, KLL Habets, AC Foks, G Pasterkamp, T Van Der Poll, J Kuiper
Journal: Cardiovascular Research (2014)

Background: Toll-like-receptors (TLRs) provide a critical link between innate and adaptive immune responses. It has been shown that TLR5 ligand Flagellin can enhance the suppressive capacity of regulatory T-cells (Treg), but can also functions as an adjuvant. The immune response in atherosclerosis is characterized by an imbalance of pro- and anti-atherogenic T-cells. We aimed to establish if the TLR5/Flagellin axis is involved in the immune response of atherosclerosis. Methods: We first assessed the effect of Flagellin exposure on macrophage maturation and T-cell polarization. Next, we created TLR5-/-/LDLr-/- chimeras to study the TLR5/Flagellin axis in atherosclerosis. Results: Flagellin exposure to primary macrophages did not result in clear polarization differences, but we did observe a less migratory phenotype (decreased MCP-1, CCR2 expression) in TLR5-/- macrophages. Interestingly, expression of the T-cell polarizing cytokine IL-6 was induced by Flagellin exposure, a phenomenon not observed in TLR5-/- macrophages. Next, we assessed potential T cell polarizing properties of Flagellin. Flagellin can induce expansion of regulatory T-cells, however this induction is completely overruled when Flagellin is used as an adjuvant. Hematopoietic absence of TLR5 significantly attenuates atherosclerotic lesion formation by 25% (1.03±0.06×106 μm2 vs 0.79±0.06 ×106 μm2 in TLR5-/-, p = 0.01). This was accompanied by a decrease in macrophage area (-46%, p = 0.01) and necrotic core size (-32%, p<0.05) while collagen content was similar between groups. Interestingly, plasma levels of IL-6 were significantly lower in TLR5-/- chimeras (40.2±6.3 in WT vs. 15.1±2.7 pg/ml in TLR5-/-, p=0.003). Concomitantly, TLR5-/- chimeras displayed defective T-cell responsiveness, as seen by impaired proliferation and decreased splenic T cell content. In conclusion, hematopoietic TLR5 deficiency inhibits atherosclerotic lesion formation by attenuated macrophage accumulation and defective T cell responsiveness.
NIH Consensus Panel Urges Antimicrobials For Ulcer Patients, Skeptics Concur With Caveats
Authors: Paul Cotton
Journal: JAMA (1994)

A CONSENSUS PANEL seems to be convincing some skeptics that at least most patients with peptic ulcers who have<i>Helicobacter pylori</i>infections should receive antimicrobial therapy. The biomedical literature has been littered for a decade with mostly small studies suggesting that eradication of<i>H pylori</i>drastically reduces ulcer recurrence, which plagues up to 70% of patients receiving standard antisecretory, antacid, or ulcer-coating therapy. However, most clinicians have been hesitant to switch patients from these safe and easy standard regimens. Therapy to eradicate<i>H pylori</i>involves two- or three-drug regimens with side effects that are often unpleasant and in rare instances can be serious. Compliance can be a problem. Whether<i>H pylori</i>itself causes ulcers remains in question as well. While 90% or more of patients with duodenal ulcers and up to 75% of patients with gastric ulcers have<i>H pylori</i>infections, most people who have<i>H pylori</i>infections never develop
Benign Symmetric Lipomatosis
Authors: David E. Comings
Journal: JAMA (1968)

To the Editor:—  A rapidly growing supraclavicular mass is a disconcerting sign to both the patient and the physician. It is disconcerting to the patient because he is sure it is some form of cancer. It is disconcerting to the physician because he is sure the patient is right. We report here a form of rapidly growing supraclavicular mass, which, though unpleasant in appearance is pleasant in prognosis, for in contrast to the carcinoma and lymphoma usually found in this area, it is benign. Its three most characteristic features are described in the title, benign symmetric lipomatosis. A sufficient number of cases have been reported that it may be considered a distinct entity. 1-5 The cervical area is most frequently affected, showing bilateral accumulation of soft masses which frequently extend in tongue-like projections between the cervical and upper thoracic muscles. As the lobulated masses progressively enlarge they may produce a
Extra NHS money spent on reviving previously neglected services
Authors: Adrian O'Dowd
Journal: BMJ (2005)

Extra investment in the NHS since 2002 has largely gone on compensating for chronic underfunding in the 1980s and 1990s, according to the NHS Confederation, the national body that represents NHS organisations. The confederation has published a report claiming that historic under investment in the health service has been “grossly underestimated.” It also says spending on more staff and paying them better is vital to maintain the improvements seen in the NHS in recent years.

The report comes halfway through the government's programme of extra investment in the NHS from 2002-3 to 2007-8 …
TCT-769 Intentional Underexpansion Of Balloon Expandable Transcatheter Heart Valves During Transcatheter Aortic Valve Replacement – 12 Month Follow-Up
Authors: John S. Tan, Jonathon A. Leipsic, Dion Stub, Danny Dvir, Nicolaj Hansson, Bjarne Nørgaard, Philipp Blanke, Bruce Precious, Adam J. Berger, Rekha Raju, Anson Cheung, Jian (James) Ye, Robert Moss, Kris Nowakowski, Leslie Achtem, Sandra Lauck, David A. Wood, John Webb
Journal: Journal of the American College of Cardiology (2014)
Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides.
Authors: Shosuke Kawanishi, Shinji Oikawa, Sumiko Inoue, Kohsuke Nishino
Journal: Environmental Health Perspectives (2002)

The U.S. National Toxicology Program has shown clear evidence of carcinogenicity of nickel subsulfide (Ni(3)S(2)) and some evidence of carcinogenicity of NiO (green) in rats. In the present study, DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. In cultured HeLa cells, Ni(3)S(2) induced a significant increase in 8-hydroxydeoxyguanosine (8-OH-dG) formation, whereas NiO (black), NiO (green), and NiSO(4) did not. On the other hand, in rats, intratracheal instillation of all these nickel compounds significantly increased 8-OH-dG content in the lungs. The disparities in DNA damage between cultured cells and animals could be accounted for by two different mechanisms for nickel-induced oxidative DNA damage in lungs of rats. One is direct oxidative DNA damage: Ni(II) enters the cells and then reacts with endogenous and/or nickel sulfide-produced hydrogen peroxide (H(2)O(2)) to give reactive oxygen species that cause DNA damage. This mechanism is supported by oxidative damage to isolated DNA treated with Ni(II) and H(2)O(2). The other mechanism is indirect oxidative DNA damage due to inflammation. This double mechanism for DNA damage may explain the relatively high carcinogenic risk associated with Ni(3)S(2).
Determining the Noninfectious Complications of Indwelling Urethral Catheters
Authors: John M. Hollingsworth, Mary A.M. Rogers, Sarah L. Krein, Andrew Hickner, Latoya Kuhn, Alex Cheng, Robert Chang, Sanjay Saint
Journal: Annals of Internal Medicine (2013)

Although the epidemiology of catheter-associated urinary tract infection is well-described, little is known about noninfectious complications resulting from urethral catheter use.To determine the frequency of noninfectious complications after catheterization.MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, Conference Papers Index, BIOSIS Previews, Scopus, and ClinicalTrials.gov were searched for human studies without any language limits and through 30 July 2012.Clinical trials and observational studies assessing noninfectious complications of indwelling urethral catheters in adults.Relevant studies were sorted into 3 categories: short-term catheterization in patients without spinal cord injury (SCI), long-term catheterization in patients without SCI, and catheterization in patients with SCI. The proportion of patients who had bladder cancer, bladder stones, blockage, false passage, gross hematuria, accidental removal, urine leakage, or urethral stricture was then pooled using random-effects models.Thirty-seven studies (2868 patients) were pooled. Minor complications were common. For example, the pooled frequency of urine leakage ranged from 10.6% (95% CI, 2.4% to 17.7%) in short-term catheterization cohorts to 52.1% (CI, 28.6% to 69.5%) among outpatients with long-term indwelling catheters. Serious complications were also noted, including urethral strictures, which occurred in 3.4% (CI, 1.0% to 7.0%) of patients with short-term catheterization. For patients with SCI, 13.5% (CI, 3.4% to 21.9%) had gross hematuria and 1.0% (CI, 0.0% to 5.0%) developed bladder cancer.Although heterogeneity existed across studies for several outcomes, most could be accounted for by differences between studies with respect to quality and sex composition. Evidence published after 30 July 2012 is not included.Many noninfectious catheter-associated complications are at least as common as clinically significant urinary tract infections.Agency for Healthcare Research and Quality.
Endoscopic Ultrasonography in the Diagnosis of Chronic Pancreatitis
Authors: G. Zuccaro Jr., M. V. Sivak Jr.
Journal: Endoscopy (1992)

Endoscopic ultrasonography (EUS) is highly accurate in the diagnosis of chronic pancreatitis. Both parenchymal and ductal changes indicative of chronic pancreatitis can be identified. Parenchymal changes include small cystic abnormalities and hyperechoic foci scattered throughout the gland; the entire gland may be enlarged in early chronic pancreatitis, or small and atrophic in advanced disease. Ductal changes include enlargement of the main pancreatic duct or secondary branches, and the presence of stones or proteinaceous plugs within the ducts. Pseudocysts appear as cystic structures of mixed echogenicity; EUS is able to detect small pseudocysts or masses not identified by conventional imaging modalities. EUS has some difficulty in distinguishing benign from malignant pancreatic masses, particularly when the lesions are small. EUS should not supplant the use of CT scan or ERCP in the differential diagnosis of pancreatic disease, but is rather an adjunct to these studies. Future clinical research should focus on determining the appropriate indications for EUS in pancreatic disease, and determining if patient outcomes are favorably affected by the diagnostic information obtained.
Chronic Primary Chylopericardium
Authors: ISA A. FAWAL, LARRY KIRKLAND, RONALD DYKES, GLENN L. FOSTER
Journal: Circulation (1967)

The case of a 36-year-old white man who had recurrent milky pericardial effusion and repeated pericardiocenteses over a period of 1 year with minimal disability or symptoms is presented. Surgical management included thoracotomy with ligation of all structures resembling lymphatic channels in the chest in several places and hemipericardiectomy. Neither the source of chyle in the pericardium nor the etiological agent of this condition could be found. Criteria for successful management of this condition are re-emphasized.
THE OCCURRENCE OF LUPUS VULGARIS IN THE WIFE AND DAUGHTER OF A TUBERCULOUS SUBJECT.
Authors: JAMES MACFARLANE WINFIELD
Journal: JAMA (1896)

Allow me to make a quotation from Kaposi<sup>1</sup>as an excuse for the following paper: "No experimental proof has been offered that characteristic lupus vulgaris can be produced by inoculation of tubercle bacilli. The inoculation of lupus tissue and of the bacilli derived from it has given rise to inflammatory products, but not to lupus, nor has any clinical proof been found, unless we accept extremely careless statements. This is less true concerning a few published cases such as that of Besnier (lupus in a vaccination scar), Sachs (lupus after piercing the ear), etc. These and other similar, although less carefully observed cases, might demonstrate the occurrence of clinical lupus from inoculation of tubercle bacilli." The cases to be related are not experimental proof, but rather examples of clinical lupus from probable inoculation of the tubercular germ. There is very little, if any, reason to consider one of the
Cyclin-dependent kinase 1 plays a critical role in DNA replication control during rat liver regeneration
Authors: Delphine Garnier, Pascal Loyer, Catherine Ribault, Christiane Guguen-Guillouzo, Anne Corlu
Journal: Hepatology (2009)

Liver regeneration is a unique process to restore hepatic homeostasis through rapid and synchronous proliferation of differentiated hepatocytes. Previous studies have shown that hepatocyte proliferation is characterized by high expression levels of the "mitotic" cyclin-dependent kinase 1 (Cdk1) during S-phase compared to other mammalian cells. In the light of findings showing that Cdk1 compensates for the loss of Cdk2 and drives S-phase in Cdk2-deficient cells derived from Cdk2 knockout mice, we took advantage of the models of liver regeneration following partial hepatectomy and primary cultures of normal rat hepatocytes to further examine the involvement of Cdk1 during DNA replication in hepatocytes and to dissect specific cell cycle regulation in hepatocytes compared to control human foreskin fibroblasts. In hepatocytes, Cdk1 exhibited a biphasic activation pattern correlating S-phase and G2/M transition, bound to cyclin A or B1 and localized to the nucleus during DNA replication. Importantly, small interfering RNA (siRNA)-mediated silencing of Cdk1 led to a strong decrease in DNA synthesis without affecting centrosome duplication. Furthermore, in hepatocytes arrested by the iron chelator O-Trensox in early S-phase prior to DNA replication, Cdk1/cyclin complexes were active, while replication initiation components such as the minichromosome maintenance 7 (Mcm7) protein were loaded onto DNA. Moreover, Mcm7 expression and loading onto DNA were not modified by Cdk1 silencing. Conversely, in fibroblasts, Cdk1 expression and activation were low in S-phase and its silencing did not reduce DNA synthesis. Conclusion: Cdk1 is essential for DNA replication downstream formation of replication initiation complexes in hepatocytes but not in fibroblasts and, as such, our data exemplify crucial differences in the cell cycle regulation between various mammalian cell types. (HEPATOLOGY 2009.)
Skin metastasis of dermatofibrosarcoma protuberans with distinct morphological features, confirmed by COL1A1-PDGFB fusion gene analysis
Authors: Takenori Kabumoto, Hiroshi Fujiwara, Naoyuki Kariya, Tomotaka Tsujimoto, Kaoru Ito, Masaaki Ito, Hiroto Kobayashi
Journal: Journal of the American Academy of Dermatology (2009)
p210BCR-ABL reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription
Authors: D Buet, H Raslova, J-F Geay, P Jarrier, V Lazar, A Turhan, F Morlé, W Vainchenker, F Louache
Journal: Leukemia (2007)