tbuckley/cabot-search huggingface dataset:
Abstract 12387: Association of CYP2C19 Polymorphism and Peripheral Endothelial Dysfunction With Clinical Outcome is More Important in Non-Chronic Kidney Disease (CKD) Than CKD Patients Following Coronary Stent Implantation
Authors: Noriaki Tabata, Seiji Hokimoto, Tomonori Akasaka, Yuichiro Arima, Koichi Kaikita, Kazuko Nakagawa, Hisao Ogawa
Journal: Circulation (2014)

Introduction: Chronic kidney disease (CKD) and CYP2C19 polymorphism are associated with increased risk of cardiovascular events following coronary stent implantation in patients with dual antiplatelet therapy. Endothelial dysfunction has recently been reported to correlate with adverse cardiovascular events in coronary heart disease. The aim of this study was to examine the differential impact of these factors on clinical outcome in patients with or without CKD.

Methods: We enrolled 556 consecutive patients after coronary stent implantation. All patients received aspirin (100mg/d) and clopidogrel (75mg/d for long-term treatment or a loading dose of 300mg). Patients were divided into two groups; CKD (n=230, male 70%), and non-CKD (n=326, male 72%) groups. CYP2C19 genotype and platelet reactivity by a light transmission aggregometry were examined, and high platelet reactivity was defined as above 5000 AU*min. Peripheral endothelial dysfunction was expressed as reactive hyperemia index (RHI) using reactive hyperemia peripheral arterial tonometry, and low RHI was defined as under the median value of RHI. Clinical events were evaluated according to non-CKD and CKD.

Results: There was no significance in the rate of CYP2C19 loss-of-function (LOF) allele carrier (64.6% versus 66.8%; P=0.65) and the rate of clinical outcome (12.9% versus 15.2%; P=0.456) between the non-CKD and CKD group, but the rate of high platelet reactivity was significantly more in the CKD group than in the non-CKD group (40.3% versus 29.2%; P=0.015). In the non-CKD group alone, the incidence of cardiovascular event was significantly higher in low RHI than high RHI patients (19.7% versus 7.7%; P=0.003). Multivariate analysis identified RHI (hazard ratio [HR]: 0.07; 95% confidence interval [CI]: 0.014 to 0.346; P=0.001) and CYP2C19 LOF carrier (HR: 2.669; 95% CI 1.207 to 5.903; P=0.015) as independent and significant predictors of cardiovascular events in the non-CKD group, but not in the CKD group.

Conclusions: Peripheral endothelial dysfunction and CYP2C19 polymorphism were independently associated with adverse cardiovascular events and were independent predictors of clinical outcome in non-CKD patients following coronary stent implantation.
Abstract 13616: Not Only the Degree of Epicardial Coronary Stenosis but Also Its Supply Area Affects Fractional Flow Reserve
Authors: Yasutsugu Shiono, Takashi Kubo, Hiroshi Aoki, Masahiro Takahata, Teruaki Wada, Yuichi Ozaki, Makoto Orii, Kunihiro Shimamura, Kohei Ishibashi, Takashi Yamano, Takashi Tanimoto, Yasushi Ino, Tomoyuki Yamaguchi, Kumiko Hirata, Toshio Imanishi, Takashi Akasaka
Journal: Circulation (2012)

Background: Fractional flow reserve (FFR) has been proposed as a clinical index to identify significant stenosis inducing reversible ischemia, and considered specific to epicardial coronary stenosi...
Safety and activity of blinatumomab for older patients (pts) with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) in two phase 2 studies.
Authors: Hagop M. Kantarjian, Anthony Selwyn Stein, Ralf C. Bargou, Carlos Grande, Richard A. Larson, Matthias Stelljes, Jonathan Eliot Benjamin, Catherine Jia, Max S. Topp
Journal: Journal of Clinical Oncology (2015)

7043 Background: Treatment options for older pts with R/R ALL are limited. Blinatumomab is a bispecific T-cell engager (BiTE) antibody construct that directs cytotoxic T cells to CD19-expressing B cells, and is approved in the US for treatment of Ph- R/R ALL. In two phase 2 adult studies of blinatumomab (Topp MS, et al. J Clin Oncol. 2014;32:4134-40; Topp MS, et al. Lancet Oncol. 2015;16:57-66), 69% and 43%, respectively, achieved complete response (CR) or CR with partial hematologic recovery (CRh*). We report pooled data for the combined subsets of older pts ( ≥ 65 yrs). Methods: Pts with R/R B-precursor ALL received open-label blinatumomab by continuous IV infusion (4 weeks on/2 weeks off). Pts achieving CR or CRh* after two cycles could receive three consolidation cycles. Response was assessed by bone marrow aspiration. CR required blasts < 5%, ANC > 1000/μL and platelets > 100,000/μL. CRh* required blasts < 5%, ANC > 500/μL and platelets > 50,000/μL. Minimal residual disease (MRD) was detected by ASO-PCR of Ig heavy chain loci. Results: 36 older pts (median age 70 yrs, range 65-79) received blinatumomab for a median (range) of 2 (1-6) cycles. 20 (56%) pts achieved best response of CR/CRh* within two cycles, including 14 (39%) CR and 6 (17%) CRh*. Among responders, 12 (60%) had complete MRD response and 4 other pts had detectable MRD but < 10-4. With median follow-up of 18.2 months, median (range) relapse-free survival for responders was 7.4 (1.0-34.0) months. With median follow-up of 29.4 months, overall survival was 5.5 (0.3-41.9) months. 10 (28%) pts were alive at last follow up; 6 in remission. 2 (10%) responders underwent allogeneic HSCT after blinatumomab. Treatment-emergent adverse events (AE) CTCAE grade ≥ 3 were reported for 31 (86%) pts, most commonly febrile neutropenia (22%) and neutropenia (19%). Neurologic AE occurred in 26 (72%) pts, including grade ≥ 3 events for 28%. 1 (3%) pt had grade ≥ 3 cytokine release syndrome. Of 7 fatal AEs, none were considered related to treatment. Conclusions: Older pts ( ≥ 65 yrs) with R/R ALL in two phase 2 studies of open-label blinatumomab had similar treatment responses and tolerability as pts in the overall study populations. Clinical trial information: NCT01209286 and NCT01466179.
Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post‐liver transplantation recurrence
Authors: Fred Poordad, Eugene R. Schiff, John M. Vierling, Charles Landis, Robert J. Fontana, Rong Yang, Fiona McPhee, Eric A. Hughes, Stephanie Noviello, Eugene S. Swenson
Journal: Hepatology (2016)

Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post-liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV genotypes. The open-label ALLY-1 study assessed the safety and efficacy of a 60-mg once-daily dosage of daclatasvir (pan-genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24-week follow-up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on-treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child-Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval [CI], 67.9%-92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child-Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%-99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment-related serious adverse events.The pan-genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post-liver transplantation recurrence or advanced cirrhosis.
Splitting and identification with the aggressor in assaultive borderline patients
Authors: K MacVicar
Journal: American Journal of Psychiatry (1978)

The author describes two borderline inpatients with assaultive behavior that was not controllable by medication. These patients use splitting to separate all-good and all-bad part representations, which hinders tolerance of ambivalence and control of aggression. Drive breakthroughs may reinforce their feelings of omnipotence. Interpreting episodes to the patient in this psychodynamic framework can aid their integration of self-representations and their ability to control aggression. Therapists and staff should resist the temptation to "give in" to such patients in order to forestall explosions.
Spontaneous Thymoma in an Inbred Strain of Rat 2
Authors: S.M. Hinsull, D. Bellamy
Journal: JNCI Journal of the National Cancer Institute (1977)

Thymomas that appear with high frequency in inbred WAB rats living into old age were examined. The spontaneous thymomas described were discrete, encapsulated bodies composed of lymphocytes and epithelial cells, with a predominance of lymphocytes. The rat neoplasms resembled the human thymomas, and their rate of incidence in older animals may suggest their use as models for the human condition.
Cisplatin + Vinorelbine Treatment of Recurrent or Metastatic Salivary Gland Malignancies (Rmsgm): a Final Report on 60 Cases
Authors: O. Ostellino, M. Garzaro, F. Pedani, M. Airoldi, E. Bellini, L. Raimondo, G. Pecorari
Journal: Annals of Oncology (2014)
Mitochondrial potassium homeostasis: a central player in cardioprotection
Authors: Rainer Schulz, Fabio Di Lisa
Journal: Cardiovascular Research (2016)

This editorial refers to ‘Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection’ by L. Testai et al. , pp. 40–50. 

Mitochondria play a central role in energy metabolism and ionic homeostasis through which they are involved in the initiation of or prevention from cell death. In particular, mitochondrial derangements contribute to cardiac diseases by decreasing ATP, altering intracellular Ca2+ homoeostasis and generating reactive oxygen species (ROS).1 Therefore, the maintenance of mitochondrial structure and function is crucial for cardioprotection, as especially characterized in the context of ischaemia/reperfusion injury.

Mitochondria convert the energy released from the flow of electrons along the respiratory chain into the electrogenic proton pumping across the inner mitochondrial membrane (IMM). The resulting electrochemical proton gradient or proton motive force (Δ p ) is the driving force for any energy-utilizing process occurring within mitochondria, including ATP synthesis. Both the electrical (Δψ) and the chemical (ΔpH) components of Δ p are involved in movements of anions and cations across the IMM. In particular, the very high Δψ (negative inside) drives the uptake of cations through mitochondrial channels that are nuclear encoded and imported via translocases located in the outer mitochondrial membrane and IMM.2 Although, in cardiac pathophysiology, …
ATPS-41DENDRITIC CELL BASED IMMUNOTHERAPY OF MALIGNANT GLIOMA VIA A NOVEL CD8α+ DC TARGETED ADENOVIRAL VECTOR
Authors: Julius W. Kim, J. Robert Kane, Jacob S. Young, Dou Yu, Jason Miska, Alan L. Chang, Aida Rashidi, Atique Ahmed, Irina Balyasnikova, Maciej S. Lesniak
Journal: Neuro-Oncology (2015)

The dismal clinical prognosis of glioblastoma multiforme (GBM) and severe lack of efficacious therapies demand the development of novel strategies that can directly translate to patient care. Given their role as nature's most potent antigen presenting cells, dendritic cells (DCs) have emerged as essential targets for anti-tumor vaccination over the past four decades. However, realities have thwarted the enthusiasm of DC vaccines: the lack of specific in vivo DC-targeted delivery vehicles and an inability to induce robust effector CD8 + T cell responses have led to an underwhelming anti-tumor T cell response. To surmount this major obstacle, we analyzed DC-induced T cell activation and showed that a CD8α+ DC subset is essential for priming robust CD8 + T cells responses. Based on this understanding, we engineered a CD8α + DC selective vector, Ad5scFv205FF by incorporating a single chain antibody against DEC205 which is selectively expressed in CD8α+ DC subset. After confirming the genetic engineering of the fiber modification via PCR and Western blot analysis, we analyzed the tropism of this novel DC targeted vehicle. This DC targeted Ad5scFv205FF vector lost its natural tropism (coxsackie and adenovirus receptor expressing cells) and gained a new, DC selective tropism. Furthermore, upon subcutaneous administration, Ad5scFv205FF infected an average of 90% of the CD8α+ DCs while a mere 4% of non-DCs (CD45 + /CD11c-) were infected by Ad5scFvDEC205FF-GFP. This work collectively represents a novel anti-glioma vaccination, enhanced by the in vivo selective delivery of the tumor antigen that will provide a platform for the evaluation and translation of highly promising glioma immunotherapy strategies.
The dangers of widespread nitric oxide screening for primary ciliary dyskinesia
Authors: Samuel A Collins, Laura Behan, Amanda Harris, Kerry Gove, Jane S Lucas
Journal: Thorax (2016)

Primary ciliary dyskinesia (PCD) is underdiagnosed and requires complex testing at specialist diagnostic centres. Measurement of nasal nitric oxide (nNO) has good sensitivity and specificity screening for PCD, but is currently usually measured at PCD centres rather than prior to referral. Proposals to include NO testing for asthma diagnoses could widen access to PCD screening if nasal mode analysers are available. Data from 282 consecutive referrals to our PCD diagnostic centre (31 PCD positive) were used to model predictive values for nNO testing with varying pretest probability and showed that predictive values were good in the referral population, but extending screening to more general populations would result in excessive false positives that may overwhelm diagnostic services. Although nNO remains a useful test, a 'normal' result with classical clinical history should still be considered for further testing.
Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement
Authors: Luis Puente-Maestu, Paolo Palange, Richard Casaburi, Pierantonio Laveneziana, François Maltais, J. Alberto Neder, Denis E. O'Donnell, Paolo Onorati, Janos Porszasz, Roberto Rabinovich, Harry B. Rossiter, Sally Singh, Thierry Troosters, Susan Ward
Journal: European Respiratory Journal (2016)

This document reviews 1) the measurement properties of commonly used exercise tests in patients with chronic respiratory diseases and 2) published studies on their utilty and/or evaluation obtained from MEDLINE and Cochrane Library searches between 1990 and March 2015.Exercise tests are reliable and consistently responsive to rehabilitative and pharmacological interventions. Thresholds for clinically important changes in performance are available for several tests. In pulmonary arterial hypertension, the 6-min walk test (6MWT), peak oxygen uptake and ventilation/carbon dioxide output indices appear to be the variables most responsive to vasodilators. While bronchodilators do not always show clinically relevant effects in chronic obstructive pulmonary disease, high-intensity constant work-rate (endurance) tests (CWRET) are considerably more responsive than incremental exercise tests and 6MWTs. High-intensity CWRETs need to be standardised to reduce interindividual variability. Additional physiological information and responsiveness can be obtained from isotime measurements, particularly of inspiratory capacity and dyspnoea. Less evidence is available for the endurance shuttle walk test. Although the incremental shuttle walk test and 6MWT are reliable and less expensive than cardiopulmonary exercise testing, two repetitions are needed at baseline. All exercise tests are safe when recommended precautions are followed, with evidence suggesting that no test is safer than others.
Treating Triple-Negative Breast Cancer: Where Are We?
Authors: Aki Morikawa, Andrew D. Seidman
Journal: Journal of the National Comprehensive Cancer Network (2015)

Unlike estrogen receptor (ER)–positive and HER2-positive breast cancer, triple-negative breast cancer (TNBC) lacks a repertoire of targeted therapies. Hence, chemotherapy is the only available systemic option in current clinical practice. In general, survival of patients with TNBC is worse than that for those with ER-positive and HER2-positive breast cancer, especially for advanced-stage disease. Thus, a great unmet need exists. Conventional chemotherapeutic agents such as platinum-salts have been examined for specific benefit in TNBC; however, no one agent has yet been shown to offer a differential incremental benefit in metastatic TNBC. The hope is that ongoing research in targetable molecular pathways will lead to new therapeutic options for TNBC. Because these patients are likely to be increasingly subcategorized using potentially targetable molecular alterations, investigators will need to be mindful of the challenges in designing and conducting clinical trials in smaller subpopulations. The successful incorporation of targeted therapies in routine clinical practice for TNBC, which mirrors the success achieved by anti-HER2 and endocrine therapies, is awaited.
Selective Cytotoxicity of a Ricin A-Chain-Anti-Carcinoembryonic Antigen Antibody Conjugate for a Human Colon Adenocarcinoma Cell Line&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: T W Griffin, L R Haynes, J A DeMartino
Journal: JNCI Journal of the National Cancer Institute (1982)

Ricin A-chain, the toxic subunit of the potent plant toxin ricin, has been isolated by affinity chromatography and conjugated via a disulfide linkage to affinity-purified goat anti-carcinoembryonic antigen (CEA) antibody. Such conjugates retained the integrity of their antibody-combining site, as demonstrated by the ability to displace 125I-labeled anti-CEA antibody bound to CEA-positive cell lines. In addition, such conjugates retained A-chain activity, producing inhibition of [14C]leucine incorporation into a CEA-negative G-361 human melanoma cell line at concentrations similar to those of unconjugated A-chain. However, these conjugates were 40 times as potent in the inhibiton of [14C]leucine incorporation in the CEA-bearing WiDr human adenocarcinoma cell line as A-chain alone or as an unreacted mixture of A-chain and specific antibody. Such toxicity could be blocked by preincubation of the conjugate with fluid-phase CEA. Complete inhibition of [14C]leucine incorporation as well as inhibition of cellular proliferation by the conjugate was seen at 50 nM concentration. Conjugates that combine the determinant specificity of an antibody with the toxicity of ricin A-chain may show promise as selective cytotoxins for cells bearing CEA.
Biochemical Relapse After Primary Treatment for Prostate Cancer: Studies on Natural History and Therapeutic Considerations
Authors: Eli Rosenbaum, Alan Partin, Mario A. Eisenberger
Journal: Journal of the National Comprehensive Cancer Network (2004)

After local treatment, a substantial proportion of patients with prostate cancer present with rising prostate specific antigen (PSA) serum levels as the only indication of disease activity. Evolving data derived from large databases that were predominantly retrospectively evaluated show that the natural history of these patients is quite variable. Various clinical and pathologic parameters have been shown to predict for the probability of development of distant metastasis, including the surgical Gleason score, time of PSA relapse after primary treatment, and PSA doubling time (PSADT). The PSADT appears to be the most important predictor of development of distant metastasis and prostate cancer-specific mortality. At present, no data support a standard management approach for these patients, and clinical trials pose a major challenge in view of the methodologic complexities involved. Patients and treating physicians should make major efforts to participate in clinical trials in this patient population.
Endoscopic management with multiple plastic stents of anastomotic biliary stricture following liver transplantation: long-term results
Authors: Andrea Tringali, Federico Barbaro, Margherita Pizzicannella, Ivo Boškoski, Pietro Familiari, Vincenzo Perri, Giovanni Gigante, Graziano Onder, Cesare Hassan, Raffaella Lionetti, Giuseppe Ettorre, Guido Costamagna
Journal: Endoscopy (2016)

Anastomotic biliary stricture (ABS) is the most common biliary complication after orthotopic liver transplantation (OLT) and can be successfully managed endoscopically. The long-term results of a protocol using placement of multiple plastic stents to treat ABS following OLT were analyzed.All patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) for OLT-related biliary complications at our Endoscopy Unit between July 1994 and March 2012 were retrospectively identified from the ERCP database. Patients with an ABS treated with an increasing number of plastic stents were included in the study. Follow-up after stent removal was obtained by telephone contact with the patient and/or referring physician and by liver function tests (LFTs) evaluation.56 patients, treated with an increasing number of plastic stents until resolution of the stricture, were included. Five patients were then excluded (unrelated death during treatment, n = 3; incomplete treatment because of poor compliance, n = 2), and 51/56 patients reached study end points and were included in the analysis. Resolution of ABS was obtained in 50/51 patients; 1 patient required hepaticojejunostomy because of failure to pass the stricture with the guidewire (per protocol resolution, 98 %). Mean duration of endoscopic treatment was 11.5 months, with a median 4 ERCPs per patient. Immediate ERCP-related adverse events occurred in 3/56 patients (5.4 %). After a median follow-up of 5.8 years from stent removal, 3/50 patients (6 %) had recurrence of ABS. These 3 patients were successfully treated again endoscopically and are asymptomatic after a further median follow-up of 5.6 years.At long-term follow-up, endoscopic treatment with multiple plastic stents of ABS following OLT appeared to be effective in most patients. Stricture recurrence is rare and can be successfully treated again endoscopically.