tbuckley/cabot-search huggingface dataset:
Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Type 1 Receptor Antagonist Therapy Is Associated with Prolonged Patient and Graft Survival after Renal Transplantation
Authors: Georg Heinze, Christa Mitterbauer, Heinz Regele, Reinhard Kramar, Wolfgang C. Winkelmayer, Gary C. Curhan, Rainer Oberbauer
Journal: Journal of the American Society of Nephrology (2006)

Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) reduce cardiovascular death in the general population, but data for renal transplant recipients remain elusive. Similarly, ACEI/ARB have been shown to reduce proteinuria, but data on graft survival are lacking. Therefore a retrospective open cohort study was conducted of 2031 patients who received their first renal allograft at the Medical University of Vienna between 1990 and 2003 and survived at least 3 mo. Patient and graft survival was compared between patients with versus without ACEI and/or ARB therapy. Data were analyzed with and without propensity score models for ACEI/ARB therapy. Medication and comorbidities were analyzed as time-dependent variables in the Cox regression analyses. Ten-year survival rates were 74% in the ACEI/ARB group but only 53% in the noACEI/ARB group (P < 0.001). The hazard ratio (HR) of ACEI/ARB use for mortality was 0.57 (95% confidence interval [CI] 0.40 to 0.81) compared with nonuse. Ten-year actual graft survival rate was 59% in ACEI/ARB patients but only 41% in nonusers (P = 0.002). The HR of actual graft failure for ACEI/ARB recipients was 0.55 (95% CI 0.43 to 0.70) compared with nonusers; the HR of functional graft survival was 0.56 (95% CI 0.40 to 0.78). Ten-year unadjusted functional graft survival rates were 76% among ACEI/ARB patients and 71% in noACEI/ARB recipients (P = 0.57). In summary, the use of ACEI/ARB therapy was associated with longer patient and graft survival after renal transplantation. More frequent use of these medications may reduce the high incidence of death and renal allograft failure in these patients.
Runx1–Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1
Authors: Wooseok Seo, Tomokatsu Ikawa, Hiroshi Kawamoto, Ichiro Taniuchi
Journal: The Journal of Experimental Medicine (2012)

Although Runx and Cbfβ transcription factor complexes are involved in the development of multiple hematopoietic lineages, their precise roles in early mouse B lymphocyte differentiation remain elusive. In this study, we examined mouse strains in which Runx1, Runx3, or Cbfβ were deleted in early B lineage progenitors by an mb1-cre transgene. Loss of Runx1, but not Runx3, caused a developmental block during early B lymphopoiesis, resulting in the lack of IgM+ B cells and reduced VH to DJH recombination. Expression of core transcription factors regulating early B cell development, such as E2A, Ebf1, and Pax5, was reduced in B cell precursors lacking Runx1. We detected binding of Runx1–Cbfβ complexes to the Ebf1 proximal promoter, and these Runx-binding motifs were essential to drive reporter gene expression. Runx1-deficient pro-B cells harbored excessive amounts of the repressive histone mark H3K27 trimethylation in the Ebf1 proximal promoter. Interestingly, retroviral transduction of Ebf1, but not Pax5, into Runx1-deficient progenitors restored not only development of B220+ cells that underwent VH to DJH rearrangement but also expression of B lineage signature genes. Collectively, these results demonstrate that Runx1–Cbfβ complexes are essential to facilitate B lineage specification, in part via epigenetic activation of the Ebf1 gene.
Flashbacks: Recurrent Intrusive Images After the Use of LSD
Authors: MARDI J. HOROWITZ
Journal: American Journal of Psychiatry (1969)

Flashbacks are returns of imagery for extended periods after the immediate effect of hallucinogens has worn off. The most symptomatic form is recurrent intrusions of the same frightening image into awareness, without volitional control. The author compares flashbacks with other clinical phenomena; he believes that psychotherapy is helpful, especially if there is a focus on the traumatic and screening aspects of the imagery.
Vascular Endothelial Growth Factor Receptor-3 and Focal Adhesion Kinase Bind and Suppress Apoptosis in Breast Cancer Cells
Authors: Christopher A. Garces, Elena V. Kurenova, Vita M. Golubovskaya, William G. Cance
Journal: Cancer Research (2006)

Abstract Focal adhesion kinase (FAK) and vascular endothelial growth factor receptor-3 (VEGFR-3) are protein tyrosine kinases that are overexpressed in human cancer and play an important role in survival signaling. In addition to its involvement with cell survival, VEGFR-3 is a primary factor in lymphatic angiogenesis. Because FAK function is regulated by its COOH terminus (FAK-CD), we used FAK-CD as a target to identify binding partners. We isolated a peptide from a phage library that bound to FAK-CD, specifically the focal adhesion targeting domain of FAK and was homologous to VEGFR-3, suggesting these two tyrosine kinases physically interact. We have also shown that VEGFR-3 is overexpressed in human breast tumors and cancer cell lines. For the first time, we have shown the physical association of FAK and VEGFR-3. The association between the NH2 terminus of VEGFR-3, containing the peptide identified by phage display, and the COOH terminus of FAK was detected by in vitro and in vivo binding studies. We then coupled a 12-amino-acid VEGFR-3 peptide, AV3, to a TAT cellular penetration sequence and showed that AV3 and not control-scrambled peptide caused specific displacement of FAK from the focal adhesions and affected colocalization of FAK and VEGFR-3. In addition, AV3 peptide decreased proliferation and caused cell detachment and apoptosis in breast cancer cell lines but not in normal breast cells. Thus, the FAK/VEGFR-3 interaction may have a potential use to develop novel molecular therapeutics to target the signaling between FAK and VEGFR-3 in human tumors. (Cancer Res 2006; 66(3): 1446-54)
Intrinsic and Extrinsic Control of Hemopoietic Stem Cell Numbers: Mapping of a Stem Cell Gene
Authors: Gerald de Haan, Gary Van Zant
Journal: The Journal of Experimental Medicine (1997)

We evaluated in vivo interactions between extrinsic (growth factor induced) and intrinsic (genetically determined) effectors of mouse primitive hemopoietic stem cell proliferation and numbers. Accordingly, stem cell frequency and cell cycle kinetics were assessed in eight strains of inbred mice using the cobblestone area–forming cell (CAFC) assay. A strong inverse correlation was observed between mouse lifespan and the number of autonomously cycling progenitors (CAFC day 7) in the femur. The population size of primitive stem cells (CAFC day 35) varied widely (up to sevenfold) among strains, unlike total CAFC day 7 numbers (cycling and quiescent), which were similar. Administration of the early acting cytokine flt-3 ligand to these strains resulted in activation of quiescent primitive stem cells exclusively in strains with high endogenous stem cell numbers (DBA and AKR), but was unrelated to strain-specific progenitor cell cycling. To map loci affecting stem cell frequency, we quantified stem cells in BXD recombinant inbred mice (offspring of C57BL/6 and DBA/2). The resulting strain distribution pattern showed high concordance with a marker that mapped to chromosome 18 (19 cM). Linkage with this genomic interval was associated with a likelihood of odds score of 3.3, surpassing the level required for significance. Interestingly, this segment, containing the EGR-1 gene, shows synteny with human chromosome 5q, a region strongly associated with various hematological malignancies. Our findings indicate that a gene mapping to this region is mutated in either C57BL/6 or DBA/2 (and possibly AKR) mice. These studies in apparently healthy mice may facilitate the identification of a gene implicated in human 5q-syndromes.
New Strategies in Kidney Cancer: Therapeutic Advances through Understanding the Molecular Basis of Response and Resistance
Authors: Brian I. Rini
Journal: Clinical Cancer Research (2010)

Abstract The emergence of viable therapeutic strategies in metastatic renal cell carcinoma has invigorated translational and clinical research in this disease. Building upon the clinical activity observed with inhibition of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, novel strategies are being investigated to extend existing clinical benefits. Preclinical study has identified potential molecular mechanisms of response and resistance, providing a rational basis for biomarker development as well as sequential and combination therapy strategies. Several treatment strategies have emerged that are in the early phases of clinical testing. Further clinical and translational research is needed to validate initial hypotheses and translate observations into novel treatment strategies. Clin Cancer Res; 16(5); 1348–54
High Plasma Levels and Effective Lymphatic Uptake of Docetaxel in an Orally Available Nanotransporter Formulation
Authors: Taher Nassar, Suha Attili-Qadri, Oshrat Harush-Frenkel, Shimon Farber, Shimon Lecht, Philip Lazarovici, Simon Benita
Journal: Cancer Research (2011)

Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-glycoprotein (P-gp) and more so to CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) which were embedded in entero-coated microparticles. An oral administration of the NC formulation elicited a higher absolute bioavailability than both a docetaxel solution (276%) and a free docetaxel NC formulation (400%) injected intravenously, a 5-mg/kg dose. The batches (B) I and II NC formulations elicited C(max) values that were 1,735% and 2,254%, respectively; higher than the C(max) value of the oral docetaxel solution combined with blank microparticles, a 10-mg/kg dose. No significant difference in AUC (area under curve) was observed between the batches. These unexpected results can be explained only if the pharmacokinetics of docetaxel had been modified. It was shown that NCs released from the microparticles penetrated the enterocytes, bypassing P-gp; apparently circumventing gut metabolism and accumulating within the lymphatic system from where both intact or biodegraded NCs and free docetaxel were progressively released into the circulation as plausibly supported by the fluorescent imaging results. Furthermore, the circulating docetaxel in plasma was unencapsulated and circulated either in free form or bound to albumin. Both free docetaxel NCs and microparticles exhibited in vitro efficacy on WRC 256 cells suggesting that the activity of docetaxel was not altered. This delivery concept has potential for clinical translation, perhaps allowing docetaxel chemotherapy to be switched from intravenous to oral delivery.
The Management of Cardiac Patients in Relation to Surgery
Authors: A. CARLTON ERNSTENE
Journal: Circulation (1951)

Skillful anesthesia and surgical operations do not significantly increase the demands upon the heart for work. Patients who have organic heart disease but who have been able to carry on normal daily activities without symptoms referable to the heart tolerate anesthesia and operation without difficulty provided that anoxia, hemorrhage and shock are avoided. Hypertension, cardiac enlargement, valvular disease other than advanced aortic stenosis, and electrocardiographic abnormalities, per se, do not increase surgical mortality or postoperative morbidity. When symptomatic myocardial insufficiency or evidence of congestive heart failure is present, a period of preoperativre treatment with rest, digitalis, sodium restriction and mercurial diuretics is advisable. Treatment should be as thorough as possible during the interval in which the operation can be safely delayed. With adequate management, patients who have had myocardial failure can be expected to tolerate aniesthesia and surgery satisfactorily. Postoperative complications, such as pneumonia, atelectasis, thromboembolic accidents and abdominal distention, are not well borne, however, and may be responsible for a return of cardiac decompensation. Patients who have auricular fibrillation or auricular flutter should be digitalized before operation even though there have been no symptoms of impaired myocardial reserve and regardless of the ventricular rate. Surgery should be avoided if possible in persons who have severe coronary disease, aortic stenosis, coronary ostial steniosis due to syphilitic aortitis, and high grade or complete auriculoventricular block complicated by the Stokes-Adams syndrome. Spinal anesthesia should not be employed in the presence of these conditions. The decision as to the exact type of operation to be performed is seldom influenced by the existence of organic heart disease. The presence of organic heart disease is only occasionally of more than secondary importance in determining the choice of the anesthetic agent to be given by inhalation. Cyclopropane, however, should not be used. Although unimportant disturbances of cardiac rhythm occur frequently during anesthesia and operation, serious complications such as ventricular tachycardia, standstill of the heart and ventricular fibrillation are uncommon. The treatment of these conditions has been discussed. Postoperative cardiac complications are not common and are seldom responsible for death of the patient. The greatest incidence occurs in patientswhohaveseverecoronaryarterydisease. The intravenous administration of fluids which contain sodium should be avoided during operation and the postoperative period unless their use is specifically indicated.
Effects of Ionizing Radiation on Self-Renewal and Pluripotency of Human Embryonic Stem Cells
Authors: Kitchener D. Wilson, Ning Sun, Mei Huang, Wendy Y. Zhang, Andrew S. Lee, Zongjin Li, Shan X. Wang, Joseph C. Wu
Journal: Cancer Research (2010)

Human embryonic stem cells (hESC) present a novel platform for in vitro investigation of the early embryonic cellular response to ionizing radiation. Thus far, no study has analyzed the genome-wide transcriptional response to ionizing radiation in hESCs, nor has any study assessed their ability to form teratomas, the definitive test of pluripotency. In this study, we use microarrays to analyze the global gene expression changes in hESCs after low-dose (0.4 Gy), medium-dose (2 Gy), and high-dose (4 Gy) irradiation. We identify genes and pathways at each radiation dose that are involved in cell death, p53 signaling, cell cycling, cancer, embryonic and organ development, and others. Using Gene Set Enrichment Analysis, we also show that the expression of a comprehensive set of core embryonic transcription factors is not altered by radiation at any dose. Transplantation of irradiated hESCs to immune-deficient mice results in teratoma formation from hESCs irradiated at all doses, definitive proof of pluripotency. Further, using a bioluminescence imaging technique, we have found that irradiation causes hESCs to initially die after transplantation, but the surviving cells quickly recover by 2 weeks to levels similar to control. To conclude, we show that similar to somatic cells, irradiated hESCs suffer significant death and apoptosis after irradiation. However, they continue to remain pluripotent and are able to form all three embryonic germ layers. Studies such as this will help define the limits for radiation exposure for pregnant women and also radiotracer reporter probes for tracking cellular regenerative therapies.
Prophylaxis against malaria for travellers from the United Kingdom. Malaria Reference Laboratory and the Ross Institute.
Authors: D Bradley
Journal: BMJ (1993)

To provide revised guidance on malaria prevention for the medical advisers of travellers from the United Kingdom going overseas to malarious areas, a committee of those most involved in giving advice and with specialist expertise in the United Kingdom agreed a policy document. There is a need for all travellers to be aware of the risk of malaria and to take measures to avoid being bitten by anopheline mosquitos, especially at night. Chemoprophylaxis is recommended also for most malarious areas. In view of the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and proguanil, mefloquine is added to the list of recommended drugs for more areas than in the past, and is the preferred chemoprophylactic for east and central Africa. Chloroquine with proguanil continues to be widely appropriate. Detailed recommendations are given for each country. Travellers out of reach of prompt medical assistance are advised to carry treatment doses of a standby drug: halofantrine, Fansidar, or quinine. The need for full compliance with any regimen is emphasised. No prophylaxis is totally effective. Malaria must be considered in the differential diagnosis of any fever in someone who has visited an endemic area within the past year.
BCG re-vaccination
Authors: P GRIME
Journal: Thorax (2001)

COPD exacerbationsWe read with interest the paper by Cotton and associates 1 on early discharge for patients with exacerbations of chronic obstructive pulmonary disease and the accompanying editorial by Killen and Ellis. 2 In both publications the 1991 study of our RespiCare home care programme was referenced, 3 and both asserted that our programme was not cost eVective.In fact, our study reached the opposite conclusion-namely, that the Respi-Care programme was shown to be cost eVective.Actual direct care charges in US dollars were used in our calculations of both pre-programme and on-programme costs.Additionally, administrative costs of operating RespiCare were added into the onprogramme costs.Our findings showed that, while hospitalisation costs substantially decreased during the programme, home care costs increased.However, the decrease in hospital costs more than oVset the subsequent increase in home care costs, with a total cost savings of $328 US dollars per patient per month or $3956 per year being realised for those on the RespiCare programme.Although the emphasis of the work was on improvements in clinical outcome, the cost savings were a significant and important aspect of our study.I hope this clarifies any misunderstanding created by the recent articles.
Campylobacter jejuni capsular genotypes are related to Guillain–Barré syndrome
Authors: A.P. Heikema, Z. Islam, D. Horst-Kreft, R. Huizinga, B.C. Jacobs, J.A. Wagenaar, F. Poly, P. Guerry, A. van Belkum, C.T. Parker, H.P. Endtz
Journal: Clinical Microbiology and Infection (2015)
Prognostic and Predictive Gene Signature for Adjuvant Chemotherapy in Resected Non–Small-Cell Lung Cancer
Authors: Chang-Qi Zhu, Keyue Ding, Dan Strumpf, Barbara A. Weir, Matthew Meyerson, Nathan Pennell, Roman K. Thomas, Katsuhiko Naoki, Christine Ladd-Acosta, Ni Liu, Melania Pintilie, Sandy Der, Lesley Seymour, Igor Jurisica, Frances A. Shepherd, Ming-Sound Tsao
Journal: Journal of Clinical Oncology (2010)

The JBR.10 trial demonstrated benefit from adjuvant cisplatin/vinorelbine (ACT) in early-stage non-small-cell lung cancer (NSCLC). We hypothesized that expression profiling may identify stage-independent subgroups who might benefit from ACT.Gene expression profiling was conducted on mRNA from 133 frozen JBR.10 tumor samples (62 observation [OBS], 71 ACT). The minimum gene set that was selected for the greatest separation of good and poor prognosis patient subgroups in OBS patients was identified. The prognostic value of this gene signature was tested in four independent published microarray data sets and by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR).A 15-gene signature separated OBS patients into high-risk and low-risk subgroups with significantly different survival (hazard ratio [HR], 15.02; 95% CI, 5.12 to 44.04; P < .001; stage I HR, 13.31; P < .001; stage II HR, 13.47; P < .001). The prognostic effect was verified in the same 62 OBS patients where gene expression was assessed by qPCR. Furthermore, it was validated consistently in four separate microarray data sets (total 356 stage IB to II patients without adjuvant treatment) and additional JBR.10 OBS patients by qPCR (n = 19). The signature was also predictive of improved survival after ACT in JBR.10 high-risk patients (HR, 0.33; 95% CI, 0.17 to 0.63; P = .0005), but not in low-risk patients (HR, 3.67; 95% CI, 1.22 to 11.06; P = .0133; interaction P < .001). Significant interaction between risk groups and ACT was verified by qPCR.This 15-gene expression signature is an independent prognostic marker in early-stage, completely resected NSCLC, and to our knowledge, is the first signature that has demonstrated the potential to select patients with stage IB to II NSCLC most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine.
Predictors of target lesion revascularization in diabetic patients treated with Palmaz-Schatz stents
Authors: A. Abizaid, G.S. Mintz, B. Otjaca, K.M. Kent, L.F. Satler, A.D. Pichard, H. Wu, R. Mehran, T. Bucher, J.J. Popma, M.B. Leon
Journal: Journal of the American College of Cardiology (1998)
Respiratory mechanics after heart-lung and bilateral lung transplantation
Authors: R. A. Chacon, P. A. Corris, J. H. Dark, G. J. Gibson
Journal: Thorax (1997)

The factors determining respiratory mechanics following heart-lung transplantation (HLT) and bilateral lung transplantation (BLT) are incompletely understood.The dynamic and static lung volumes of 15 patients after HLT (n = 6) and BLT (n = 9) with no evidence of obliterative bronchiolitis were analysed to assess the factors which determine lung volumes following transplantation. Post-transplantation total lung capacity (TLCpost) was compared with the size of the recipient's lungs (TLCpre), the predicted capacity of the thorax of the recipient (TLCpred), and the predicted size of the donor's lungs (TLCdon). In addition, the post-transplantation respiratory mechanics were investigated by measuring the static pressure-volume (PV) curve of the lungs and the maximum respiratory pressures in a subgroup of nine patients (four HLT, five BLT).TLCpost was closely related to TLCpred in both groups and showed no correlation with TLCpre. The mean (95% CI) TLCpost was 102.5 (90.2 to 115)% predicted for the recipient in the HLT group and 109 (97.6 to 120)% predicted for the recipient in the BLT group. Despite the near normal TLC, residual volume (RV) and functional residual capacity (FRC) remained increased after transplantation in both groups. These abnormalities were not attributable to either airflow obstruction or expiratory muscle weakness. On average, lung compliance expressed in terms of the shape constant of the static pressure-volume curve of the lungs was mildly reduced in both groups compared with values predicted for the recipient.These results suggest that at high lung volumes the chest wall adapts to the size of transplanted lungs, while at lower volumes the increase in FRC and RV might be due to a persistent change in the static pressure-volume curve of the chest wall.
Genetic Determinants of Sudden Cardiac Death
Authors: Peter A. Noseworthy, Christopher Newton-Cheh
Journal: Circulation (2008)

S udden cardiac death (SCD) is the final common end point of multiple disease processes.It results from a complex interplay of structural, metabolic, and genetic determinants.Although epidemiological risk factors such as age, prior myocardial infarction, and low ejection fraction are well established, this syndrome also has a strong genetic component.An understanding of the genetic contributions to risk could add substantially to the prediction and prevention of SCD.In this review, we explore the epidemiology, heritability, and allelic architecture of SCD and provide a detailed overview of the genetics of inherited electrophysiological and structural heart diseases that are potent risk factors for SCD. Mechanisms of Arrhythmic SCDMost often, SCD occurs in patients with underlying ischemic heart disease that predisposes to either ventricular tachycardia From the Cardiology Division (P.A.