tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera
Authors: Raffaele Landolfi, Roberto Marchioli, Jack Kutti, Heinz Gisslinger, Gianni Tognoni, Carlo Patrono, Tiziano Barbui
Journal: New England Journal of Medicine (2004)

The use of aspirin for the prevention of thrombotic complications in polycythemia vera is controversial.We enrolled 518 patients with polycythemia vera, no clear indication for aspirin treatment, and no contraindication to such treatment in a double-blind, placebo-controlled, randomized trial to assess the safety and efficacy of prophylaxis with low-dose aspirin (100 mg daily). The two primary end points were the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and the cumulative rate of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes. The mean duration of follow-up was about three years.Treatment with aspirin, as compared with placebo, reduced the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (relative risk, 0.41; 95 percent confidence interval, 0.15 to 1.15; P=0.09) and the risk of the combined end point of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95 percent confidence interval, 0.18 to 0.91; P=0.03). Overall mortality and cardiovascular mortality were not reduced significantly. The incidence of major bleeding episodes was not significantly increased in the aspirin group (relative risk, 1.62; 95 percent confidence interval, 0.27 to 9.71).Low-dose aspirin can safely prevent thrombotic complications in patients with polycythemia vera who have no contraindications to such treatment.
Chemokine Receptor 7, A New Player in Regulating Apoptosis of CD8+ T Cells in Cancer Patients
Authors: Giorgio Parmiani, Chiara Castelli, Licia Rivoltini
Journal: Clinical Cancer Research (2005)

One of the major issues of T cell–based cancer immunotherapy is the ability of growing tumors to impair the host immune system by acting at different steps of the immune response and on different immune cells. In fact, the tumor cytotoxic function of T cells can be blocked before their terminal
Inhibition of Hepatitis B Virus Replication during <i>Schistosoma mansoni</i> Infection in Transgenic Mice
Authors: Heike McClary, Rick Koch, Francis V. Chisari, Luca G. Guidotti
Journal: The Journal of Experimental Medicine (2000)

Although coinfection of hepatitis B virus (HBV) and Schistosoma mansoni is a frequent event in humans, little is known about the interactions between these two pathogens. S. mansoni infection induces T helper cell type 2 (Th2)–type cytokines in the liver of humans and mice. The intrahepatic induction of nitric oxide (NO) and Th1-type cytokines, such as interferon (IFN)-γ and IFN-α/β, inhibits HBV replication noncytopathically in the liver of transgenic mice. To examine whether S. mansoni infection and the accompanying induction of Th2-type cytokines could interfere with HBV replication in the liver, HBV transgenic mice were infected with S. mansoni. By 5 wk after infection, HBV replication disappeared concomitant with the intrahepatic induction of NO and Th1-type cytokines, and in the absence of Th2-type cytokines. By 6–8 wk after infection, HBV replication remained undetectable and this was associated with further induction of NO and Th1-type cytokines together with the appearance of Th2-type cytokines. The S. mansoni–dependent antiviral effect was partially blocked by genetically deleting IFN-γ, although it was unaffected by deletion of IFN-α/β. These results indicate that IFN-γ (probably via NO) mediates most of this antiviral activity and that Th2-type cytokines do not counteract the antiviral effect of IFN-γ. Similar events may suppress HBV replication during human S. mansoni infection.
Synthetic Lethality and Cancer Therapy: Lessons Learned from the Development of PARP Inhibitors
Authors: Christopher J. Lord, Andrew N.J. Tutt, Alan Ashworth
Journal: Annual Review of Medicine (2014)

The genetic concept of synthetic lethality, in which the combination or synthesis of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to cancer. Already there are promising indications, from clinical trials exploiting this concept by using poly(ADP-ribose) polymerase (PARP) inhibitors in patients with germline BRCA1 or BRCA2 gene mutations, that this approach could be beneficial. We discuss the biological rationale for BRCA-PARP synthetic lethality, how the synthetic lethal approach is being assessed in the clinic, and how mechanisms of resistance are starting to be dissected. Applying the synthetic lethal concept to target non-BRCA-mutant cancers also has clear potential, and we discuss how some of the principles learned in developing PARP inhibitors might also drive the development of additional genetic approaches.
Recruitment and expansion of dendritic cells in vivo potentiate the immunogenicity of plasmid DNA vaccines
Authors: Shawn M. Sumida, Paul F. McKay, Diana M. Truitt, Michael G. Kishko, Janelle C. Arthur, Michael S. Seaman, Shawn S. Jackson, Darci A. Gorgone, Michelle A. Lifton, Norman L. Letvin, Dan H. Barouch
Journal: Journal of Clinical Investigation (2004)

DCs are critical for priming adaptive immune responses to foreign antigens. However, the utility of harnessing these cells in vivo to optimize the immunogenicity of vaccines has not been fully explored. Here we investigate a novel vaccine approach that involves delivering synergistic signals that both recruit and expand DC populations at the site of antigen production. Intramuscular injection of an unadjuvanted HIV-1 envelope (env) DNA vaccine recruited few DCs to the injection site and elicited low-frequency, env-specific immune responses in mice. Coadministration of plasmids encoding the chemokine macrophage inflammatory protein-1α (MIP-1α) and the DC-specific growth factor fms-like tyrosine kinase 3 ligand with the DNA vaccine resulted in the recruitment, expansion, and activation of large numbers of DCs at the site of inoculation. Consistent with these findings, coadministration of these plasmid cytokines also markedly augmented DNA vaccine--–elicited cellular and humoral immune responses and increased protective efficacy against challenge with recombinant vaccinia virus. These data suggest that the availability of mature DCs at the site of inoculation is a critical rate-limiting factor for DNA vaccine immunogenicity. Synergistic recruitment and expansion of DCs in vivo may prove a practical strategy for overcoming this limitation and potentiating immune responses to vaccines as well as other immunotherapeutic strategies.
Changes in Alternative Splicing of Human and Mouse Genes Are Accompanied by Faster Evolution of Constitutive Exons
Authors: Brian P. Cusack, Kenneth H. Wolfe
Journal: Molecular Biology and Evolution (2005)

Alternative splicing is known to be an important source of protein sequence variation, but its evolutionary impact has not been explored in detail. Studying alternative splicing requires extensive sampling of the transcriptome, but new data sets based on expressed sequence tags aligned to chromosomes make it possible to study alternative splicing on a genome-wide scale. Although genes showing alternative splicing by exon skipping are conserved as compared to the genome as a whole, we find that genes where structural differences between human and mouse result in genome-specific alternatively spliced exons in one species show almost 60% greater nonsynonymous divergence in constitutive exons than genes where exon skipping is conserved. This effect is also seen for genes showing species-specific patterns of alternative splicing where gene structure is conserved. Our observations are not attributable to an inherent difference in rate of evolution between these two sets of proteins or to differences with respect to predictors of evolutionary rate such as expression level, tissue specificity, or genetic redundancy. Where genome-specific alternatively spliced exons are seen in mammals, the vast majority of skipped exons appear to be recent additions to gene structures. Furthermore, among genes with genome-specific alternatively spliced exons, the degree of nonsynonymous divergence in constitutive sequence is a function of the frequency of incorporation of these alternative exons into transcripts. These results suggest that alterations in alternative splicing pattern can have knock-on effects in terms of accelerated sequence evolution in constant regions of the protein.
Re: All-Cause Mortality in Randomized Trials of Cancer Screening
Authors: T. R. Church, F. Ederer, J. S. Mandel
Journal: JNCI Journal of the National Cancer Institute (2002)

To support their argument that results of cancer screening trials based on disease-specific mortality are unreliable, Black et al. (1) compared the treatment effect measured by disease-specific mortality with the effect measured by all-cause mortality in 12 such trials. They found “major inconsistencies” between the two measures. We disagree with their interpretation and illustrate our reasons with results from the Min
Reciprocal CD4+ T-Cell Balance of Effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage
Authors: Kenichi Koyama, Hiroshi Kagamu, Satoru Miura, Toru Hiura, Takahiro Miyabayashi, Ryo Itoh, Hideyuki Kuriyama, Hiroshi Tanaka, Junta Tanaka, Hirohisa Yoshizawa, Koh Nakata, Fumitake Gejyo
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Small cell lung cancer (SCLC) possesses high tendency to disseminate. However, SCLC patients with paraneoplastic syndrome mediated by immunity against onconeural antigens remain in limited-stage disease (LD) without distant metastases. Cumulative evidence regulates that a balance between immune and regulatory T (Treg) cells determines the magnitude of immune responses to not only self-antigens but also tumor-associated antigens. The purpose of this study was to elucidate the immunologic balance induced in SCLC patients. Experimental Design: We analyzed T cells in the peripheral blood of 35 consecutive SCLC patients, 8 long-term survivors, and 19 healthy volunteers. Results: Purified CD4+ T cells with down-regulated expression of CD62L (CD62Llow) produced IFN-γ, interleukin (IL)-4, and IL-17, thus considered to be immune effector T cells (Teff). Significantly more Teff cell numbers were detected in LD-SCLC patients than that of extended-stage SCLC (ED-SCLC). By contrast, induction of CD62LhighCD25+ CD4+ Treg cells was significantly higher in ED-SCLC patients. Long-term survivors of SCLC maintained a high Teff to Treg cell ratio, whereas patients with recurrent disease exhibited a low Teff to Treg cell ratio. Teff cells in LD-SCLC patients included more IL-17–producing CD4+ T cells (Th17). Moreover, dendritic cells derived from CD14+ cells of LD-SCLC patients secreted more IL-23. Conclusion: These results show that CD4+ T-cell balance may be a biomarker that distinguishes ED-SCLC from LD-SCLC and predicts recurrence. This study also suggests the importance of inducing Teff cells, particularly Th17 cells, while eliminating Treg cells to control systemic dissemination of SCLC.
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial
Authors: Luca Gianni, Tadeusz Pienkowski, Young-Hyuck Im, Laslo Roman, Ling-Ming Tseng, Mei-Ching Liu, Ana Lluch, Elżbieta Staroslawska, Juan de la Haba-Rodriguez, Seock-Ah Im, Jose Luiz Pedrini, Brigitte Poirier, Paolo Morandi, Vladimir Semiglazov, Vichien Srimuninnimit, Giulia Bianchi, Tania Szado, Jayantha Ratnayake, Graham Ross, Pinuccia Valagussa
Journal: The Lancet Oncology (2011)
THE INTERACTION OF DONOR AND HOST LYMPHOID CELLS IN THE PATHOGENESIS OF RENAL CORTICAL DESTRUCTION INDUCED BY A LOCAL GRAFT VERSUS HOST REACTION
Authors: William L. Elkins
Journal: The Journal of Experimental Medicine (1966)

The graft versus host reaction (GVHR), which results from the injection of parental strain spleen cells beneath the kidney capsule of F1 hybrid rats, is transferable during its developmental phase into F1 hybrid hosts isogeneic with the primary host, but not into secondary hosts of the parental (donor) strain. Furthermore, the GVHR propagates but rarely in secondary hybrid hosts which are allogeneic with respect to the primary hosts, but which are also genetically tolerant of donor-type cells. These findings indicate that the donor cells not only initiate the GVHR but also maintain it by virtue of immunologically specific activity. Whole-body irradiation of (LBf)F1 and (LBN)F1 hosts 24 hours prior to the injection of parental (L) spleen cells results in inhibition of the subsequent GVHR to a degree commensurate with the radiation damage sustained by the lymphoid system of the host. Furthermore, propagation of transferred GVHRs did not occur if susceptible secondary hybrid hosts had been previously irradiated. These findings indicate that radiosensitive host cells play a continuing and essential role in the pathogenesis of the invasive-destructive lesion. It is concluded that the development of this lesion depends upon the continuous interaction of the specifically reactive donor-type cells with an immunologically non-specific population of host mononuclears.
Gonadotropin-Releasing Hormone Agonist for Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer
Authors: Zeev Blumenfeld
Journal: Journal of Clinical Oncology (2012)

TO THE EDITOR: Munster et al are to be congratulated for their prospective, randomized study. However, the conclusion may be inaccurate and biased by the premature ending of the correctly planned study. The study was targeted for 124 patients with a planned 5-year follow-up but was “stopped for futility after 49 patients were enrolled,” p533 with only 47 patients evaluable. For protocols in which 88% to 90% of patients resume regular menstruation within two years after chemotherapy, there is apparently little need for any intervention toward preservation of ovarian function. For such low gonadotoxic protocols, the number of patients needed to enroll onto each arm is much higher than 21 or 26. Indeed, the prestudy calculation required inclusion of 124 patients. Only in protocols resulting in more than 30% premature ovarian failure could a gonadotropin-releasing hormone agonist-a cotreatment result in a significant beneficial effect on fertility preservation, as detected by the prospective, randomized, multicenter phase III Gruppo Italiano Mammella study of 281 patients or by the prospective, randomized trial by Badawy et al. Last, but not least, all the methods for preservation of fertility despite gonadotoxic chemotherapy and/or radiotherapy are relevant to patients younger than age 40 years, and premature ovarian failure is defined as amenorrhea and high follicle-stimulating hormone levels in women younger than age 40 years. The ovarian reserve after this age is so low that the efficiency of fertility preservation is negligible or undetected. Given that the authors included patients “younger than 45 years of age,” p534 their results may be affected by the diminished ovarian reserve in women older than age 40 years. Indeed, the inclusion criteria of a follicle-stimulating hormone level of “less than 40 mIU/mL” p534 may include patients with low ovarian reserve and impending ovarian failure. We believe, therefore, that the conclusion should be rephrased in a more careful way, awaiting the publication of more accurate studies that are free of similar possible biases.
Multicentre phase II trial of bevacizumab combined with docetaxel–carboplatin for the neoadjuvant treatment of triple-negative breast cancer (KCSG BR-0905)
Authors: H.R. Kim, K.H. Jung, S.-A. Im, Y.-H. Im, S.Y. Kang, K.H. Park, S. Lee, S.-B. Kim, K.-H. Lee, J.S. Ahn, S.I. Kim, J.H. Sohn
Journal: Annals of Oncology (2013)
Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial
Authors: Nicole Sherry, William Hagopian, Johnny Ludvigsson, Sunil M Jain, Jack Wahlen, Robert J Ferry, Bruce Bode, Stephen Aronoff, Christopher Holland, David Carlin, Karen L King, Ronald L Wilder, Stanley Pillemer, Ezio Bonvini, Syd Johnson, Kathryn E Stein, Scott Koenig, Kevan C Herold, Anastasia G Daifotis
Journal: The Lancet (2011)
Preparedness of Internal Medicine and Family Practice Residents for Treating Common Conditions
Authors: Francine C. Wiest
Journal: JAMA (2002)

Although both internal medicine (IM) and family practice (FP) physicians frequently provide care for the same common adult conditions, IM and FP residency programs differ in their training emphases.To assess differences in IM and FP residents' self-perceived preparedness to diagnose and treat common adult medical conditions.Cross-sectional analysis of a national survey administered in the spring of 1998 to residents in their final year of residency at US academic health centers. A total of 279 IM residents in 25 programs and 326 FP residents in 75 programs responded to the survey.Residents' self-rated preparedness to diagnose and treat 4 inpatient conditions (acute myocardial infarction, diabetic ketoacidosis, acute asthma, and acute renal failure) and 8 outpatient conditions (diabetes, hypertension, low back pain, vaginitis, headache, depression, upper respiratory tract infection, and hyperlipidemia), controlling for resident sex, race/ethnicity, US medical school graduate status, intent to subspecialize, and estimates of exposure to patients in inpatient and outpatient settings.Internal medicine residents were more likely to report being very prepared for all 4 inpatient conditions (P< or =.001), while FP residents were more likely to report being very prepared for 5 of 8 outpatient conditions (P< or =.05). Differences between IM and FP residents persisted in multivariate analyses for all inpatient conditions and some outpatient conditions. Exposure to patients in inpatient and outpatient settings varied by specialty and was significantly associated with resident self-report of preparedness for a majority of conditions investigated.Internal medicine and FP residents report differences in preparedness to manage common adult conditions. These differences were consistent with the emphasis on an inpatient setting for IM residents and on office-based care for FP residents.
Interaction of Cytotoxic T Lymphocytes and Guinea Pig Ventricular Myocytes
Authors: Bella Felzen, Revital Lavy, Maria Garcia, Gideon Berke, Phyllis Gardner, Ofer Binah
Journal: Circulation Research (1996)

Infiltrating cytotoxic T lymphocytes (CTLs) are important immune effectors that damage the myocardium during heart transplant rejection as well as in cardiomyopathy and Chagas' heart disease. We have previously shown that in an in vitro model of murine-derived peritoneal exudate CTL (PEL)-guinea pig ventricular myocyte interaction, PEL induced in conjugated myocytes reduction of resting membrane potential and action potential (AP) amplitude, shortening of AP duration, delayed afterdepolarizations (DADs), and myocyte contracture and destruction. Since these findings indicated that cytotoxicity was largely caused by [Ca2+]i overload, in the present study we tested the hypothesis that blocking the L-type Ca2+ current (ICa,L) in the myocyte will eliminate the trigger for Ca2+ release from intracellular stores and will reduce [Ca2+]i overload and subsequent myocyte deterioration. CoCl2 (3 mmol/L) prevented PEL-induced AP changes, induction of DADs, and myocyte destruction. Since verapamil (2 mumol/L) was ineffective, indicating that the CoCl2 protection was not due to block of ICa,L, we tested whether the different action of these Ca2+ channel blockers was due to their differential effect on the PEL's K+ current (IK), previously shown to participate in lymphocyte activation and cytotoxicity. In agreement with their protective efficacy, CoCl2 but not verapamil blocked IK in PELs, suggesting that this is the mechanism for the protection provided by CoCl2. To support this notion, we tested the effect of the scorpion-derived peptide margatoxin (10 nmol/L), a specific K+ channel blocker in lymphocytes, on PEL-myocyte interaction and on PEL's IK; margatoxin prevented PEL-induced cytotoxicity and also blocked IK in PEL. Based on these findings, an alternative modality for attenuating CTL-induced lymphocytotoxicity is proposed.
BILE FISTULAS AND RELATED ABNORMALITIES
Authors: W. B. Hawkins, G. H. Whipple
Journal: The Journal of Experimental Medicine (1935)

A clearer understanding of the various abnormalities which may develop in relation to the experimental or clinical bile fistula will be of value to the laboratory worker as well as to the physician and surgeon. A better comprehension of these diseased conditions will make for a saner analysis of the great mass of experimental data relating to the various types of bile fistula. Too frequently in the literature the bile fistula material is used to debate a physiological state whereas in reality the animal is in a pathological condition. It is possible but not easy to keep a bile fistula dog in a normal state for months or years if proper attention is given to the diet and physical state. The most significant abnormalities are—intestinal disturbances, spontaneous bleeding, osteoporosis, cholelithiasis and duodenal ulcer. Three types of bile fistula were used in our experiments and each one has its advantages and disadvantages. Intestinal intoxication is best controlled by diet, by whole bile or bile salts or combinations of dog and ox bile. Spontaneous bleeding seems to be due to the loss of something by way of the bile and this can be prevented by bile feeding. The blood deficiency appears to be a lack of prothrombin. Osteoporosis appears inevitably after many months if bile is excluded from the intestine. This state is related to the lack of absorption of vitamin D. It is of some interest that liver feeding will prevent it. Duodenal ulcers and cholelithiasis are common in bile fistula dogs and absolute control or prevention is not easy. It may be restated that bile secretion into the intestine is necessary for normal health and even for actual continuation of life beyond a few months' period. Some of these experimental data should be of value to physicians and surgeons in the care and study of human fistula cases and should emphasize the necessity of prompt dietary control.