tbuckley/cabot-search huggingface dataset:
745. CD4-T Cell Responses Mediated by IFNγ and Perforin Eliminate Adenoviral-Mediated Transgene Expression from the CNS of Mice by Cytolytic and Non-Cytolytic Mechanisms
Authors: Jeffrey M. Zirger, Carlos Barcia, Chunyan Liu, Maria Castro, Pedro Lowenstein
Journal: Molecular Therapy (2005)

Gene therapy approaches using first generation adenoviral vectors (RAds) can achieve long-term transgene expression in the brain, and therapeutic effects in animal models of brain tumors and neurodegeneration. However, long term expression and vectors' efficiency can be limited by immune responses, characterized by inflammation in the brain and the eventual elimination of transgene expression. Injection of first generation RAds into the striatum followed by peripheral immunization has allowed us to determine the cellular and molecular mechanisms by which the adaptive immune response regulates transgene expression in the CNS. Our experiments provided the following results: (1) systemic immunization against RAd reduced transgene expression by 30 days post-immunization; (2) the time course of entry of lymphocytes into the brain is as follows: first, CD4+, followed by CD45+ and F4/80+, and lastly, CD8+ T cells; (3) lymphocytes and macrophages contacted and phagocytosed transduced cells; (4) transgene expression persisted in the CNS of Rag1(|[minus]|/|[minus]|), CD4(|[minus]|/|[minus]|), IFN|[gamma]|(|[minus]|/|[minus]|) and perforin(|[minus]|/|[minus]|) animals; and (5) even in the absence of transgene expression, we could detect the presence of RAd genomes by quantitative TaqMan PCR. In summary, our data suggest the existence of a CD4-T cell response mediated by IFN|[gamma]| and potentially perforin that eliminates transgene expressing cells from the CNS. The continued presence of viral vector genomes, suggests the presence of non-cytolytic mechanisms as well. The balance of cytotoxic, and non-cytotoxic mechanisms is currently being investigated further.
CD4+CD25++ T Cells in Peripheral Blood Correlate with Total and Pollen-Specific IgE in Young Children
Authors: K.A. Burmeister, C. Seroogy, C. Tisler, M. Evans, L. Franco, L. Pleiss, R. Gangnon, R.F. Lemanske, J.E. Gern
Journal: Journal of Allergy and Clinical Immunology (2006)
Style and substance: a new look for <i>JRSM</i>
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2013)

If you are reading the print edition of JRSM or have opened a pdf of a journal article on our website, you may notice that the design has changed. Medical journals tend to favour a dull and serious look, and you may still consider that JRSM does, but our intention was to modernize our pages, offer authors a better showcase for their work, and make reading more pleasurable. Journal articles should not be inscrutable.

The most obvious change is that JRSM is now in colour throughout, which means that tables, figures, and images will come to life. You might ask why these particular colours have been chosen. The Royal Society of Medicine, like any sensible organization with a public profile, has a designated palette of colours to use for all its publications. JRSM was free to select whichever colours it wished but it made most sense for JRSM to be recognizable as an RSM publication. JRSM remains editorially independent of the Society but it is still the Society's journal.

Apart from colour, the pages have been redesigned. The cover has been tweaked. Inside, titles and authors are now more prominent. Abstracts and summaries are moved to a single column with a colour background to make them stand out and easier to read. Declarations are moved to the end of each article. None of this is revolutionary, or especially original, but JRSM is now comparable with leading medical journals in terms of presentation.

Naturally, the primary challenge for any medical journal is to publish high-quality articles while maintaining exemplary publication ethics. Publication ethics are in the hands of the editorial team, and JRSM editorial policies on competing interests, contributorship statements, provenance statements, patient consent and open peer review place it among the more progressive medical journals. High-quality articles cannot always be guaranteed, however, despite the best intentions of authors and editors, but when we do publish these better papers we can now publish them in a fitting manner.

A scientific journal should never be a triumph of style over substance but anything of substance deserves to be presented in style.
The MKK6–p38 MAPK pathway prolongs the cardiac contractile calcium transient, downregulates SERCA2, and activates NF-AT
Authors: C Andrews
Journal: Cardiovascular Research (2003)

Objective: Our goal was to determine if the MKK6–p38 MAPK pathway regulates cardiac intracellular calcium ([Ca2+]i). We also tested if MKK6 might influence expression of SERCA2, a calcium regulatory molecule involved in relaxation, and the activity of nuclear factor of activated T-cells (NF-AT), a calcium-regulated transcription factor that participates in pathological responses to pressure-overload. Methods: Neonatal rat ventricular myocytes were transfected with MKK6(Glu), an activator of p38 MAPK. Green fluorescent protein (GFP) was used as transfection marker and [Ca2+]i was evaluated via indo-1. SERCA2 expression was assayed via Northern and Western techniques. The activity of the rat SERCA2 gene promoter and NF-AT-dependent gene expression were monitored with reporter genes. Myocyte contractility was regulated by electrical pacing. Results: MKK6(Glu) prolonged decay of the contractile calcium transients, downregulated SERCA2 expression, and reduced the activity of the rat SERCA2 gene promoter. Diastolic [Ca2+]i in myocytes pacing at 1–2 Hz was dramatically increased by MKK6(Glu). NF-AT-dependent gene expression was activated by MKK6(Glu) and by pacing of contractions in a synergistic manner. Overexpression of SERCA2 mitigated the effects of MKK6(Glu) on [Ca2+]i and NF-AT. Conclusions: The MKK6(Glu)–p38 MAPK pathway prolongs the decay phase of the cardiac contractile calcium by downregulating SERCA2, increasing diastolic [Ca2+]i which activates NF-AT. The ability of SERCA2 over-expression to reduce NF-AT activity represents a potential novel therapeutic effect of SERCA2 that should be further considered in the development of cardiac gene therapy strategies.
A NEW COMBINED ELECTRO-CAUTERY INCISOR FOR THE BOTTINI OPERATION FOR PROSTATIC OBSTRUCTION.
Authors: HUGH H. YOUNG
Journal: JAMA (1902)

Although the electro-cautery operation was brought out by Bottini as far back as 1876, it was not generally adopted until 1897, when Freudenberg presented to the profession a greatly improved instrument, and followed it up by numerous convincing articles. During the past four years this operation has been performed very extensively, and we are now in a position to stop a moment, look over our results, and discuss the shortcomings of the operation, as well as its merits. Freudenberg's large collection of operated cases probably shows very accurately the value of the procedure. The statistics are as follows: 752 cases, in which the result was good in 86½ per cent., a failure in 7½ per cent., and the mortality between 4 and 6 per cent. These figures, if correct, undoubtedly show much better results than can be claimed for any other operative procedure. Castration, while peculiarly effective in a certain
Travelers' Immunizations-Reply
Authors: Charles R. McCance
Journal: JAMA (1990)

In Reply.—  Drs McKinney and Barnas identify a legitimate problem that has concerned the Travelers' Health Section, Division of Quarantine, Centers for Disease Control, for many years. The United States is signatory without reservation to the International Health Regulations as passed by the World Health Assembly of the United Nations. The Centers for Disease Control publishes and promotes the requirements as submitted to the World Assembly by member states. The suggestion that the Centers for Disease Control publish in the annual Health Information for International Travel the actual practice of other countries, in addition to the official requirement as reported to us by the World Health Organization, is unfortunately not feasible. One of the primary reasons is that the actual practices at the ports of entry may vary over time and with different personnel. The actual practices also may not be in accord with the country's explicit government policies.  On
The influence of preoperative use of ventricular assist devices on survival after heart transplantation: propensity score matched analysis
Authors: J. H Shuhaiber, K. Hur, R. Gibbons
Journal: BMJ (2010)

<b>Objective</b> To determine the influence of the preoperative placement of a left ventricular assist device on survival after heart transplantation. <b>Design</b> Prospective cohort study. <b>Setting</b> Organ sharing database with patient level data on heart transplants in the United States. <b>Participants</b> 2786 adults aged 18 or older in status 1A or 1B (highest priority for heart transplantation with either some form of ventricular assist device, intravenous inotrope, or life expectancy of less than seven days), based on the United Network for Organ Sharing Registry, 1996-2004. <b>Main outcome measure</b> Survival after heart transplantation in patients who did and did not receive a left ventricular assist device. <b>Results</b> The left ventricular assist device was not associated with decreased survival, even after the data were stratified by propensity score (the odds of being a treated patient). Inspection of the strata showed no difference in survival between patients who received the device and those who did not. The hazard ratios in strata 1 to 5 were 0.69, 1.37, 1.55, 0.75, and 1.19, respectively, and none was statistically significant. <b>Conclusion</b> Overall, survival after heart transplantation in patients who received a left ventricular assist device before transplantation was comparable to those who did not receive the device.
Police find range of drugs after trawling bins used by Tour de France cyclists
Authors: P. Benkimoun
Journal: BMJ (2009)

France’s antidoping agency has uncovered “a surprising therapeutic arsenal,” including two drugs that are not yet licensed, after scrutinising bins in the wake of the 2009 Tour de France.

Michel Rieu, the scientific adviser of the French Agency Against Doping (Agence Francaise de Lutte Contre le Dopage), said at a press conference on 7 October, “These are incongruous products in a milieu where people are supposed to be in good health.” 

Professor Rieu said that this “surprising therapeutic arsenal” had been reported to the World Anti-Doping Agency in July.

The agency said it suspected that some cyclists were using blood transfusions and two unlicensed substances.

Pierre Bordry, head of …
Abstract 4059: Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A.
Authors: Shinya Matsuzaki, Akiko Morimoto, Satoshi Serada, Takuhei Yokoyama, Toshihiro Kimura, Eiji Kobayashi, Yutaka Ueda, Kiyoshi Yoshino, Masami Fujita, Takayuki Enomoto, Tetsuji Naka, Tadashi Kimura
Journal: Cancer Research (2013)

Abstract Because platinum drugs are often used for the chemotherapy of human cancers, when platinum resistance occurs it is a major issue. We recently reported that enhanced expression of Annexin A4 (Anx A4) increases chemoresistance to Carboplatin via increased extracellular efflux of the drug. However, the precise mechanisms of that chemoresistance, and the relationship of Anx A4 to platinum resistance in vivo, remain unclear. In this report we investigate in vitro the mechanism of platinum resistance induced by Anx A4 in endometrial carcinoma cells (HEC1 cells) which normally have a low level of expression of Anx A4. Forced expression of Anx A4 in HEC1 cells resulted in chemoresistance to platinum drugs. In addition, we compared HEC1 control cells with Anx A4-overexpressing HEC1 cells when both were xenografted to mice, Anx A4-overexpressing xenografted mice presented with significantly greater chemoresistance to Cisplatin in vivo. By immunofluorescence analysis we found that exposure to platinum drugs induced relocation of Anx A4 from the cytoplasm to the cellular membrane, where it became co-localized with ATP7A, a copper transporter also well known to be a platinum effluxer. When the expression of ATP7A was suppressed by small interfering RNA in HEC1 control cells, they showed no change of chemosensitivity to platinum drugs. However, suppressed ATP7A in Anx A4 overexpressing platinum-resistant cells, they showed improved chemosensitivity to platinum drugs, to a level comparable of that of control cells. Our results indicate that enhanced expression of Anx A4 confers platinum resistance by promoting efflux of platinum drugs via ATP7A. Citation Format: Shinya Matsuzaki, Akiko Morimoto, Satoshi Serada, Takuhei Yokoyama, Toshihiro Kimura, Eiji Kobayashi, Yutaka Ueda, Kiyoshi Yoshino, Masami Fujita, Takayuki Enomoto, Tetsuji Naka, Tadashi Kimura. Annexin A4-conferred platinum resistance is mediated by the copper transporter ATP7A. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4059. doi:10.1158/1538-7445.AM2013-4059
Alemtuzumab as first-line therapy for B-cell chronic lymphocytic leukemia: long-term follow-up of clinical effects, infectious complications and risk of Richter transformation
Authors: C Karlsson, S Norin, E Kimby, B Sander, A Porwit MacDonald, B Nilsson, E Johansson, H Mellstedt, J Lundin, A Österborg
Journal: Leukemia (2006)
Abstract LB-239: ROCK1 inhibition reduces tumor collagen content in the KPC model for PDAC
Authors: Clifford J. Whatcott, Janine Lobello, Aprill Watanabe, Mario Sepulveda, Daniel D. Von Hoff, Haiyong Han
Journal: Cancer Research (2012)

Abstract ROCK1 is a multifunctional member of the AGC (protein kinase A/G/C) kinase family that has been implicated in the modulation of stress-fiber assembly, cell contraction, apoptosis, and in the migration and invasion of multiple cancer cell types. It has been reported that ROCK1 plays an important role in the activation and function of pancreatic stellate cells, including in the formation of desmoplasia in pancreatic ductal adenocarcinoma (PDAC)(Masamune, 2003, Br J Pharmacol, 140:1292). Desmoplasia and its effects are thought to contribute to poor drug delivery in PDAC treatment. We therefore hypothesized that ROCK1 inhibition may reduce desmoplasia and enhance drug efficacy in PDAC treatment. We previously reported that ROCK1 is overexpressed in human pancreatic tumor cells and amplified in a small subset of PDAC patient samples. In this study we report that the ROCK inhibitor, fasudil, reduced collagen mRNA levels by 3.9-fold in cultured pancreatic stellate cells derived from PDAC tissues treated at 100µM. We also observed a 3.0-fold reduction in collagen protein expression in co-cultured tumor and stellate cells at the same concentration of fasudil. Similar reductions were observed in immunofluorescence analysis of co-cultured tumor and stellate cells treated with fasudil. We next sought to determine if ROCK1 inhibition would result in a reduction in collagen expression in the the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model for PDAC. KPC mice were treated orally, b.i.d., with 100mg/kg fasudil and by i.p. with gemcitabine (q3dx4) at 80mg/kg. Tumors in KPC mice treated with the combination of fasudil and gemcitabine showed a marked reduction in overall tumor collagen content when compared to vehicle-treated mice as measured by a pentachrome staining. Histochemical analysis of tumors also showed reductions in the overall proliferation of the pancreatic stellate cell compartment. Ongoing efforts are being made to assess whether this treatment regimen may enhance gemcitabine efficacy in the KPC mice. These results indicate that ROCK1 is a potential therapeutic target in pancreatic cancer, and may provide an effective means to enhance current treatment regimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-239. doi:1538-7445.AM2012-LB-239
Abstract 2132: Deferoxamine and Deferasirox enhance anticancer effects of apoptosis in gastric cancer cells
Authors: Go Oun Oh, Myoung-Hee Kang, Han-Na Kang, Jung-Lim Kim, Jun-Suk Kim, Sang-Cheul Oh, Young-A Yoo Yoo, Seung-Young Lee Lee
Journal: Cancer Research (2011)

Abstract Deferoxamine(DFO) and Deferasirox(DFRA) is an iron chelating agent that has been used extensively to treat acute iron detoxification and chronically iron overloaded patients. Recent reports have been shown that iron chelators induce anti-proliferative effect in multiple leukemia cells. However, their roles and the underlying mechanism in anti-tumorigenic function of solid tumor, especially gastric cancer, are not yet known. In this work, we evaluated the anti-tumorigenic action of these two iron chelating agent with gastric cancer cell line, and investigated their apoptosis-inducing effects as the potential mechanism in this process. The results show that both of them induce the growth inhibitory effects in both dose- and time-dependent fashion in gastric cancer cell line AGS and SNU-638. Cell cycle analysis by FACS indicated that both DFO/DFRA-treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of gastric cancer cells to DFO/DFRA also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. The results by multiple in vitro experimental model, showed that DFO /DFRA induce these gastric cancer cells to undergo apoptosis with a release of cytichrome C from mitochondria, the activation of caspase-3/9, the cleavage of PARP, the cleavage of anti-apoptotic protein Bcl-2, together with the accumulation of pro-apoptotic protein Bax and Bim. Furthermore, knock-down of Bax and Bim expression by RNA interference virtually eliminated DFO/DFRA-induced apoptosis. Importantly, inhibition of JNK kinase activity demonstrated that DFO/DFRA-induced apoptotic pathway was regulated by the JNK signaling cascade In conclusion, this finding indicates that iron-chelating agent, DFO and DFRA, promotes apoptosis of gastric cancer cells by sequential activation of the JNK signaling pathway followed by the up-regulation of intrinsic pathway of Bax/Bim-caspase 3/9. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2132. doi:10.1158/1538-7445.AM2011-2132
Prevention of Bacterial Endocarditis
Authors: Sam C. Colachis
Journal: JAMA (1991)

To the Editor.—  Dajani et al 1 provide excellent recommendations for prophylaxis against bacterial endocarditis for dental and surgical procedures in patients at risk.  I was concerned to find that urethral catheterization was listed among surgical procedures, not because catheterization is a potential risk for transient bacteremia, but because so many individuals with neurogenic bladder dysfunction are treated with intermittent catheterization. Multiple medical conditions and traumatic events result in neurogenic bladder dysfunction. Of the over 200 000 persons with spinal injuries living in the United States, it is estimated that 6% to 8% are treated with long-term intermittent catheterization. 2 Studies have shown that a significant number of these individuals' bladders are colonized with bacterial organisms, many of which are highly resistant to antibiotics and some of which are known to cause endocarditis (eg, Enterococcus species, Staphylococcus species). The levels of organisms from catheterized urine samples in asymptomatic individuals can
Efficacy and Safety of Inhaled Insulin (Exubera) Compared With Subcutaneous Insulin Therapy in Patients With Type 1 Diabetes
Authors: Teresa Quattrin, André Bélanger, Nancy J.V. Bohannon, Sherwyn L. Schwartz
Journal: Diabetes Care (2004)

OBJECTIVE—The aim of this study was to determine whether premeal pulmonary delivery of rapid-acting, dry-powder insulin (Exubera) plus Ultralente could provide glycemic control comparable to a conventional insulin regimen in type 1 diabetes. RESEARCH DESIGN AND METHODS—Three hundred thirty-five subjects were randomly assigned to receive either premeal inhaled insulin plus bedtime Ultralente or two to three injections of regular and NPH insulin for 24 weeks. The primary end point was a change in HbA1c. RESULTS—Mean decreases in HbA1c values were comparable for inhaled (8.1–7.9%) and conventional groups (8.1–7.7%) (adjusted treatment group difference 0.16% [95% CI −0.01 to 0.32]). There were greater reductions for inhaled versus conventional regimen in fasting and postprandial plasma glucose (adjusted mean change differences −25.17 and −30.28 mg/dl, respectively [95% CI −43.39 to −6.95 and −54.58 to −5.97, respectively]). Hypoglycemia (events/subject month) was lower for the inhaled (8.6) versus the conventional (9.0) group (risk ratio, 0.96 [95% CI 0.93–0.99]). In subjects receiving inhaled insulin, increased insulin antibody levels were observed, but there were no associated clinical or laboratory changes. Adverse events were comparable between groups. Mild to moderate cough was more frequent in the inhaled insulin group (27 vs. 5%) but decreased during the treatment. Pulmonary function tests were not different between the groups except for a greater decrease in carbon monoxide diffusing capacity in the inhaled insulin group. Treatment satisfaction was greater in the inhaled than in the conventional group. CONCLUSIONS—Inhaled insulin is effective, well tolerated, and well accepted in patients with type 1 diabetes and provides glycemic control comparable to that with a conventional insulin regimen.