tbuckley/cabot-search huggingface dataset:
Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancer (NCI protocol 7156)
Authors: L. Chintala, R. Kurzrock, S. Fu, A. Naing, J. J. Wheler, S. L. Moulder, R. Newman, R. Gagel, S. Sebti, J. J. Wright, D. S. Hong
Journal: Journal of Clinical Oncology (2008)

3593 Background: The Ras and Raf kinases are intimately connected.Therefore, inhibiting both Ras (upstream) with a FTase inhibitor (tipifarnib) and B-Raf (downstream) with a Ras inhibitor(sorafenib) may confer synergistic antitumor effect. Moreover, sorafenib has been identified as a RET kinase inhibitor and the combination may also inhibit the RET/Ras/Raf/IKKB/NF-κB pathway. Methods: The trial was a conventional phase I 3+3 dose-escalation design. Each cycle consisted of 28 days of sorafenib and 21 days of tipifarnib.Correlative studies including PKs, optional FNA biopsies and PBMC samples pre and post cycle 1. PD analysis included FTase activity, western blots of downstream signaling of total and phosphorylated MEK1/2, ERK1/2 AKT and STAT3, and RET mutational sequencing of medullary thyroid (MTC) pts. Results: A total of 50 pts have been treated with 20 pts expanded at MTD.The most common drug related toxicities include rash,lymphopenia,& diarrhea.At dose level 4, 2/5 pts entered experienced a DLT of grade 3 rash,therefore the defined MTD is tipifarnib 100mg po BID, sorafenib 400mg qam,200mg qpm.Of the 37 evaluable pts,by RECIST,18 pts(49%) had SD for 4 months or longer.Several pts have had minor responses including papillary thyroid (N=4;20%,13%,19%,16% response)and MTC (N=2;17%,17% response).Two PRs were noted in MTC pts,one confirmed (N=2;44%,35% response). PK analysis showed similar profile for single agent sorafenib, however, tipifarnib plasma concentrations were lower than reported. Measured FTase activity in PBMCs showed little inhibition suggesting sorafenib may intefere with the ability of tipifarnib to inhibit FTase activity. Downstream proteins both total and phosphorylated MEK and ERK showed no changes. However, decrease in P-AKT and P-STAT3 was noted in some FNA samples. RET mutational analysis in 3 MTC pts who had minor response or PR all showed activating RET mutations. Conclusions: The MTD was determined to be tipifarnib at 100mg po BID, sorafenib at 400mg qam,200mg qpm.PK, PD analysis suggests that sorafenib may interfere with both plasma concentrations and FTase activity of tipifarnib. Activity in papillary thyroid and MTC pts warrant further exploration of this combination. No significant financial relationships to disclose.
Bupropion for Smoking Cessation in Patients Hospitalized With Acute Myocardial Infarction
Authors: Mark J. Eisenberg, Sonia M. Grandi, André Gervais, Jennifer O'Loughlin, Gilles Paradis, Stéphane Rinfret, Nizal Sarrafzadegan, Sat Sharma, Claude Lauzon, Rakesh Yadav, Louise Pilote
Journal: Journal of the American College of Cardiology (2013)
Hyperkalaemic cardiac arrest
Authors: M K Bresland, A R Bodenham
Journal: BMJ (1996)

Janet Lock and Dawn Gallagher are surprised that we mentioned the use of cardioselective P blockers.We did not wish to imply that patients with clear cut active asthma would be given ( blockers but rather wished to point out that many patients with little or no disease at all could be considered for treatment.Many patients are labelled as having asthma but do not in fact have the condition, and we considered our audience to be sufficiently sophisticated to take our point.With regard to methysergide, we mentioned ret- roperitoneal fibrosis to highlight a reasonably well appreciated clinical problem.With regard to
Abstract 3234: Patterns of Treatment of Patients with Atrial Fibrillation
Authors: Liza A Prudente, J. Michael Mangrum, Douglas E Lake, Yuping Xiao, John P DiMarco, Srijoy Mahapatra, John D Ferguson, J. Randall Moorman, J. Paul Mounsey
Journal: Circulation (2007)

Background: Atrial fibrillation (AF) is increasingly common, and a number of treatment options are available. Since trials such as AFFIRM show no mortality difference between rate or rhythm control strategies, we hypothesized that rate control would become more common with increased duration of AF. Methods: We evaluated history of treatment modalities in 1052 patients with AF referred to a dedicated AF center. 472 had AF for ≥ 5 years and 200 for ≥ 10 years. We recorded AF symptom burden, calculated as the product of frequency and duration of episodes, and treatment history from first AF episode using a database modeled on AHA-recommended key data elements. Results: The median (25th, 75th percentiles) AF duration was 4.5 (2, 9) years. The median symptom burden was 28% in the first year after symptoms started, and fluctuated from 10 to 15% thereafter. 37% had a CHADS2 score 0, 43% had score 1, and 20% had score ≥ 2. Anti-thrombotic use was near 40%. The Figure shows the spectrum of drug use. In the first year, rate control drugs (blue bars) were used 2.5 fold more commonly than AAD. Surprisingly, the use of anti-arrhythmic drugs (AAD) increased with duration of AF and after five years, they were nearly equal. 20% of patients had cardioversion in the first year, 3% in the second, and 1% or less for year 5 and after. 60% of all cardioversions were performed in the first year of symptoms. Conclusion: Cardioversion is more common during the first year of AF. In subsequent years, symptom burden falls and is relatively stable. AAD usage increases while rate control use remains constant. This suggests that physicians may continue to use AAD drugs to help control symptoms.
Abstract 9964: Vorapaxar, a Platelet Thrombin-Receptor Antagonist, in Medically Managed Patients with Non-ST-Segment Elevation Acute Coronary Syndrome: Results from the TRACER Trial
Authors: Claes Held, Pierluigi Tricoci, Zhen Huang, Frans Van de Werf, Harvey White, Paul Armstrong, Giuseppe Ambrosio, Philip Aylward, David Moliterno, Lars Wallentin, Edmond Chen, Aycan Erkan, Lixin Jiang, John Strony, Robert Harrington, Kenneth Mahaffey
Journal: Circulation (2012)

Purpose: This is a prespecified post-randomization subgroup analysis to evaluate efficacy and safety outcomes of vorapaxar in the TRACER trial in patients that were medically managed without revascularization procedures during index hospitalization. Methods: Vorapaxar, a novel platelet-protease-activated receptor-1 antagonist, was randomized with placebo in 12,944 patients with NSTE ACS. We explored the effect of vorapaxar vs placebo among medically managed patients at discharge (n=4194; 32.4 %) vs those undergoing revascularization (n=8750; 67.6%) from discharge to end of follow-up, with adjustments for baseline differences. Events rates are provided as 2-yr Kaplan-Meier estimates. Results: The medically managed patients were more likely to be older and female and have prior MI, prior CABG, and decreased renal function. The 2-yr event rate of the primary outcome (CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) was 16.9% with vorapaxar and 17.3% with placebo (HR 0.95; 95% CI 0.81-1.14), with no interaction between study drug and management strategy (p=0.63). The rate of the key secondary endpoint (CV death, MI, and stroke) was 13.9% with vorapaxar and 15.1% with placebo (HR 0.88; 95% CI 0.73-1.07), with no interaction (p=0.86). Lower MI rates were observed in medically managed patients treated with vorapaxar (9.3% vs 11.1% [HR 0.79; 95% CI 0.63-0.99). Vorapaxar significantly increased GUSTO moderate or severe bleeding in medically managed patients (HR 1.52; 95% CI 1.04-2.22) and in patients undergoing revascularization (HR 1.32; 95% CI 0.99-1.76). In the medical group, intracranial hemorrhage (ICH) occurred in 18 patients with vorapaxar and in 1 patient with placebo, whereas ICH occurred in 17 vorapaxar patients and 9 placebo patients treated with revascularization, with no significant interaction (p=0.056). Conclusion: In patients with NSTE ACS treated medically, the efficacy of vorapaxar was consistent with the main findings of the TRACER trial. Bleeding hazard with vorapaxar tended to be higher in medically treated patients, possibly due to patient selection factors.
Abstract 1463: Neuregulin-1 Promotes Embryonic Stem Cell Differentiation into the Cardiac Lineage in vitro
Authors: Maoyun Sun, Yun Bian, Anthony O. Caggiano, Xinhua Yan, James P. Morgan
Journal: Circulation (2008)

Our previous studies demonstrated that transplantation of embryonic stem cell (ESCs) derived cardiomyocytes improved the cardiac function in myocardial infarction injured mice. However, significant challenges remain to be solved, such as how to produce sufficient amount and mature differentiated cardiomyocytes for the therapy. Neuregulin-1 (NRG-1) is essential for the development of the heart. Here, we tested whether NRG-1 could promote the differentiation of ESCs into cardiomyocytes. Differentiation of murine ESCs was induced by the hanging-drop method. NRG-1 was added at different points of ESC differentiation. The expression of cardiac specific genes, as well as NRG-1 and its erbB receptors were measured by quantitative RT-PCR and Western blot analysis. Our results showed that during the course of hanging-drop induced ESC differentiation, the mRNA level of cardiac-specific structure proteins cardiac troponin T (cTNT), cardiac troponin I (cTNI), myosin light chain 2a (MLC2a) and alpha-sarcomeric actin was elevated. The mRNA level of cardiac transcription factors NKX2.5 and GATA4 was also increased. In addition, beating EBs first appeared on day7 and about 90% of beating EBs was observed on day12. Further, the mRNA level of NRG-1α and NRG-1β, and both mRNA and protein levels of erbB receptors were elevated during the differentiation of ESCs. When NRG-1 was added during a certain developmental window, the mRNA level of cTNT, MLC2a and MEF2c, as well as the protein level of cTNT, CXN40, a marker for cardiac conduction system, and transcriptional factors NKX2.5, GATA4 were increased in NRG-1 treated ESCs compared to untreated cells. These results demonstrated that NRG-erbB signaling was activated during the course of hang-drop induced ESC differentiation; NRG-1 treatment further promoted ESC differentiation into the cardiac lineage in vitro. Our results suggest that NRG-1 might be used to produce more and/or more mature ESC derived cardiomyocytes for the treatment of cardiovascular diseases in the clinical setting.
让社区医生迷惑的"感冒"病人
Authors: 张永林, 陈文芳, 王文夫
Journal: BMJ (2011)

2010年4月23日,一位社区医生送来一位让其备感迷惑的感冒病人,通过病人自述和社区医生的介绍,我们了解到病人的发病及诊治过程.随着病人的病情不断变化,社区医生的诊断在不断修改,治疗效果却越来越差,这让社区医生感到束手无策.患者的临床经过如下。
Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation
Authors: Marc Lúcia, Sergi Luque, Elena Crespo, Edoardo Melilli, Josep M. Cruzado, Jaume Martorell, Marta Jarque, Salvador Gil-Vernet, Anna Manonelles, Josep M. Grinyó, Oriol Bestard
Journal: Kidney International (2015)
Abstract 188: Arterial Oxygen Saturation May Be the Limiting Factor for O2 Delivery During Compression-Only CPR
Authors: Qian Li, Hovig Chitilian, Yanhong Liu, Robert M Kacmarek, Yandong Jiang
Journal: Circulation (2011)

Background Previous studies show that there is no difference in outcomes between bystander conventional and chest-compression-only (CCO) CPR. However, several points need to be addressed: 1) the eq...
Abstract 4652: Incidence and Mode of AF Termination During Substrate Ablation of AF Guided Solely by Complex Fractionated Atrial Electrograms Mapping
Authors: Naoya Oketani, Evan Lockwood, Koonlawee Nademanee
Journal: Circulation (2008)

One of the key end points of catheter ablation of atrial fibrillation (AF) substrate guided by complex fractionated atrial electrograms (CFAE) mapping is termination of sustained AF. But controversy exists as to how effective CAFÉ ablation is in AF termination especially in chronic AF. Thus, we carried out the following study to determine incidence and mode of AF termination including electrogram characteristics at the successful site. Methods: Our study included 616 consecutive patients (pts); 206 (33%) were paroxysmal (PAF) and 410 (67%) chronic (CAF), who underwent CFAE ablation from Jan 2006 to Dec 2007. The recordings of electrograms at baseline, during AF termination and cycle length changes were analyzed blindly off-line; the sites of successful termination were then associated with the detailed grid of 44 regions of both atria and coronary sinus (CS). Results: Of the 616 Pts, AF could be terminated in 203 (99 %) of PAF (64 pts [31%] with Ibutilide [Ib] ), 80% in CAF (283 pts [69%] with Ib); the remaining 20% of the chronic AF Pts required cardioversion. The termination sites were located 76% in LA, 11% in CS, and 13% in RA. The common areas of the termination are at the upper septum at the anterior aspect of the right pulmonary veins (PVs), proximal CS, posterior aspects of the left PV antrums, the ridge of LA appendage, and postero-septum of RA. AF organized and changed to atrial flutter (Afl) in 121 pts (35%), while 342 pts (65%) of the patients remained in AF with a significant increase (164 to 247 msec) in cycle length before termination. There are 3 distinct electrogram characteristics at the successful sites of tachycardia termination; 1) low voltage CFAE which the shortest cycle length in relation to the rest of the atria (42%); 2) mid-diastolic and fractionated potentials in patients whose AF converted to Afl (45%) and 3) a very low voltage fractionated potentials with the highest amplitude of the potentials was ≤ 0.06 mV (0.044 ± 0.011 mV), commonly found at the previous ablation sites (13%). Conclusion: Substrate ablation guided by CFAE mapping successfully terminate AF in the majority of Pts. Knowledge of specific areas that have predilection to be sites of termination and electrogram characteristics may be helpful to achieve AF termination.
A CD4-Independent Interaction of Human Immunodeficiency Virus-1 gp120 With CXCR4 Induces Their Cointernalization, Cell Signaling, and T-Cell Chemotaxis
Authors: Dorothée Missé, Martine Cerutti, Nelly Noraz, Patrick Jourdan, Jean Favero, Gérard Devauchelle, Hans Yssel, Naomi Taylor, Francisco Veas
Journal: Blood (1999)
Transplatin, a cisplatin trans-isomer, may enhance the anticancer effect of 5-fluorouracil.
Authors: B Nakata, S Yamagata, I Kanehara, T Shirasaka, K Hirakawa
Journal: Journal of experimental & clinical cancer research (2006)

Transplatin (TDDP), a trans-isomer of cisplatin (CDDP), is well known to have faint cytotoxicity because its geometric structure allows less adduct formation with DNA than does CDDP. However, TDDP might have the potential to enhance the anticancer effect of 5-fluorouracil (5-FU) as well as CDDP. In this study, five gastric cancer cell lines were used. Cells were treated with 5-FU, TDDP, TDDP+5-FU, CDDP, and CDDP+5-FU, for 72 hrs. Synergistic effects between TDDP and 5-FU were observed in OCUM-2MD3, OCUM-2M, and OCUM-11, though they were not observed in MKN-45 or MKN-28. The cell lines in which synergistic effects were observed between TDDP and 5-FU were the same ones in which synergistic effects are shown between CDDP and 5-FU. The cell lines without synergism between 5-FU +TDDP/CDDP had lower thymidylate synthase (TS) activities than those with synergism, suggesting TS might be attributable to the synergistic mechanism. TDDP alone, compared to CDDP alone, gave rather low cytotoxicity for these cell lines. In conclusion, TDDP might be a clinically useful modulator of 5-FU.
Abstract 2137: Bicuspid Aortic Valve, Aortic Dissection And Sudden Death In The Young: Just A Matter Of Ascending Aorta Diameters?
Authors: Cristina Basso, Stefano Nistri, Stefania Rizzo, Aierkeen Abudureheman, Gaetano Thiene
Journal: Circulation (2007)

Background. Although bicuspid aortic valve (BAV) may remain silent during life, it can announce dramatically with aortic dissection and sudden death. The aim of the study was to determine the aortic diameters and histopathologic background in young people with BAV and aortic dissection. Design. Among 449 cardiovascular sudden deaths in the young (&lt;35 years), 15 (3.3%), mean age 27±6.6, 14 M/1F, had a mechanical cardiac arrest due to aortic dissection (type I: 7, type II: 6, type III: 2): 6 had isolated BAV, 2 BAV associated with coarctation, 2 Marfan syndrome, 1 coarctation, 1 pregnancy, 1 hypertension and 2 were idiopathic. Ten young BAV patients who died suddenly without aortic dissection and 10 sex and age-matched controls were considered for comparison. Aortic root was measured at 4 levels (A1, annulus; A2, sinuses of Valsalva, A3, supraaortic ridge and A4, proximal ascending aorta). Histopathologic evaluation of the aortic tunica media was performed to assess elastic fragmentation, disarray, medial necrosis, proteoglycans deposits and fibrosis. Results. Aortic diameter values in dissected BAV vs normal BAV vs controls were: A1, 30.7±2.0 vs 27.4±2.3 (p=0.05) vs 26.3±1.6 (p&lt;0.001); A2, 35.0±5.2 vs 28.9±1.8 (p=0.01) vs 27.3±1.5 (p=0.003); A3, 32.5±5.8 vs 26.7±2.5 (p=0.03) vs 24.5±1.5 (p=0.003); and A4, 38.7±7.0 vs 26.6±3.4 (p=0.002) vs 23.9±1.8 (p&lt;0.001). Aortic diameters were significantly higher in Marfan patients (A1, 34.4±2.7; A2, 44.9±4.0; A3, 45.8±5.4; A4, 46.4±1.9). When comparing BAVs with and without dissection, higher scores of medial necrosis (1.2±0.4 vs 0.2±0.5, p=0.01), elastic fragmentation (2.4±0.5 vs 0.7±0.5, p=0.001) and fibrosis (1.6±0.5 vs 0.2±0.5, p=0.004) were found. Moreover, when comparing dissected BAVs and Marfan patients, similar structural abnormalities were found except lower medial necrosis (1.2±0.4 vs 2±0.0, p=0.002). Conclusions. Aortic root diameters are lower in dissected BAV than Marfan patients. However, structural abnormalities of the tunica media in terms of elastic fragmentation and fibrosis are similar. Imaging techniques able to assess not only a progressive increase of aortic diameters, but also abnormal aortic elasticity and stiffness are warranted to indentify patients at risk of aortic dissection.
Abstract 21651: X-Linked Inhibitor of Apoptosis Protein (XIAP)-Mediated Attenuation of Apoptosis Using a Novel Cardiac Enhanced Adeno-Associated Viral Vector
Authors: Valentino Piacentino, Michael Bolanos, Jacob Schroder, Emily Messina, Edward Jones, Ava Krol, Nenad Bursac, Gayathri Devi, Lan Mao, R. Jude Samulski, Carmelo Milano, Dawn Bowles
Journal: Circulation (2010)

Background: Measurements of anti-apoptotic proteins, such as XIAP, in non-failing (NF) & failing (F) left ventricular (LV) samples have been inconsistent & complicate the development of anti-apopto...
Abstract 12255: The Prevalence and Comorbidity of Nonspecific Troponin Elevation Detected by Highly Sensitive Assay in Patients with Acute Chest Pain
Authors: Masaaki Konishi, Hiroyuki Suzuki, Kozo Okada, Yasushi Matsuzawa, Katsutaka Hashiba, Kenichirou Saka, Nobuhiko Maejima, Noriaki Iwahashi, Mitsuaki Endo, Kengo Tsukahara, Kiyoshi Hibi, Toshiaki Ebina, Kazuo Kimura, Satoshi Umemura
Journal: Circulation (2011)

Background: Cardiac troponin is considered as a specific marker for the diagnosis of acute myocardial infarction (AMI) and latest generation of sensitive troponin assays have improved sensitivity f...
The role of the brain in perception
Authors: Paul Bach-y-Rita, Steven J. Hasse
Journal: Behavioral and Brain Sciences (2001)

The recent interest of cognitive- and neuro-scientists in the topic of consciousness (and the dissatisfaction with the present state of knowledge) has revealed deep conceptual differences with Humanists, who have dealt with issues of consciousness for centuries. O'Regan &amp; Noë have attempted (unsuccessfully) to bridge those differences.
Prognosis of sub-types of cancer of unknown primary (CUP) compared to metastatic cancer
Authors: J. F. Bishop, E. Tracey, P. Glass, P. Jelfs, D. Roder
Journal: Journal of Clinical Oncology (2007)

21010 Background: The aim is to study the clinical characteristics and outcomes of a complete cohort of presentations of Cancer of Unknown Primary (CUP) compared with patients presenting with metastatic cancer of known primary site. Methods: All persons diagnosed with cancer in New South Wales, Australia, from 1980 to 2004 were studied using a population based cancer registry. Patients classified as CUP were documented, compared to those with initial metastatic presentations of a known primary, for the same period. Results: There were 65,239 histologically or cytologically confirmed metastatic cancers presented. Of these 46,435 (77%) were metastatic with a known primary site and 13,280 (22%) were CUP. The median survival (ms) of all patients presenting with CUP was 3 months compared with 7 months for metastatic cancers of known primary site (p&lt;0.0001). Patients with CUP with adenocarcinoma had significantly worse prognosis compared to metastatic adenocarcinoma of known primary site. However patients with squamous cell CUP had a significantly better outcome (ms 12 months) than metastatic squamous histology with a known primary site (ms 5 months, p&lt;0.0001) with 31% of squamous cell CUP alive at 6 years. For those with CUP and adenocarcinoma the risk of dying was 80% greater compared to those with a known primary and adenocarcinoma (HR 1.8 95%CI 1.7–1.8). For those with CUP and squamous cell carcinoma the risk of dying was 50 % less (HR 0.49 95%CI 0.46–0.53). CUP with small cell, (HR 0.77 95%CI 0.71–0.85) and undifferentiated histology (HR 0.84, 95%CI 0.76–0.93) after controlling for sex and age, had a significantly better prognosis than other metastatic cancers. Germ cell CUP represented only 0.2% of all CUP presentations. Conclusions: CUP is a heterogeneous classification of cancer with a poorer prognosis overall when compared to metastatic cancer of known primary site especially if adenocarcinoma. However, squamous cell and small cell CUP had a better prognosis suggesting a need for specific and more focused treatment. Lack of trends for less CUP presentations compared to reducing metastatic cancer over this 24 year period suggests that CUP is in part a distinct clinico-pathological entity rather than a missed primary diagnosis. No significant financial relationships to disclose.