tbuckley/cabot-search huggingface dataset:
Circulating endothelial cell (CEC) monitoring in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line bevacizumab (BEV)-based combination regimens: Results of the randomized phase II FNCLCC-ACCORD 13/0503 trial
Authors: F. Farace, J. Mendiboure, A. Adenis, E. Boucher, J. Pierga, T. Conroy, C. Montoto-Grillot, J. Pignon, M. Ducreux, D. Malka
Journal: Journal of Clinical Oncology (2009)

4071 Background: There is no validated biomarker to predict the efficacy of BEV, an anti-VEGF monoclonal antibody. Rare cell subpopulations such as CEC are good candidates. Methods: Pts with mCRC, aged 18–75 yrs, ECOG performance status (PS) 0–2, and no prior palliative chemotherapy were randomized to either BEV (5 mg/kg) + FOLFIRI every 2 weeks (arm A, 12 cycles) or BEV (7,5 mg/kg) + XELIRI every 3 weeks (arm B, 8 cycles). BEV was continued until disease progression [PD]. The primary endpoint was crude 6-month progression-free survival (PFS) rate. In consenting pts, CEC (CD45 - CD31 + CD146 + 7- amino-actinomycin - cells) were measured at baseline (Day [D]1, before treatment), D8, and at the end of cycle 1 (D15 or 22) in 1-mL whole blood by four-color flow cytometry according to a method we established previously (J Immunol Methods 2008). Results were correlated to pts’ characteristics and primary endpoint (Wilcoxon's, Fisher's, and trend tests). Results: From 03/06 to 01/08, we enrolled 145 pts (male, 56%; median age, 61 yrs; PS 0–1, 91%; number of metastatic sites [1/2/&gt;2], 45/48/8%). Pts with at least one CEC measurement (n=99; arm A, 51; arm B, 48) did not differ from the 46 other pts regarding sex, age, PS, and number of metastatic sites. Baseline CEC levels (n=97; median, 16/mL) were higher in PS 1–2 pts (n=42) than in PS 0 pts (n=55) (17 vs. 12/mL, p=0.02) (age, sex, number of metastatic sites: NS) and in pts with PD (n=17) than in pts with non- PD (n=80) at 6 months (30 vs. 15/mL, p=0.004). CEC levels were higher at the end of cycle 1 in the PD group (n=17) than in the non-PD group (n=74) (34 vs. 14/mL, p=0.01). The 6-month PFS rate varied from 0% to 32% in the 4 groups defined by baseline and end-of-cycle- 1 CEC values (cutoff: baseline median) (trend test, p=0.006) ( table ). Conclusions: Baseline and end-of-cycle-1 CEC levels may predict tumor control in patients with mCRC starting first-line BEV + chemotherapy. [Table: see text] [Table: see text]
Teacher and learner: Supervised and unsupervised learning in communities
Authors: Michael G. Shafto, Colleen M. Seifert
Journal: Behavioral and Brain Sciences (2015)

Abstract How far can teaching methods go to enhance learning? Optimal methods of teaching have been considered in research on supervised and unsupervised learning. Locally optimal methods are usually hybrids of teaching and self-directed approaches. The costs and benefits of specific methods have been shown to depend on the structure of the learning task, the learners, the teachers, and the environment.
Toxic-Shock Syndrome Associated with Diaphragm Use
Authors: L Hyde
Journal: New England Journal of Medicine (1981)

A case report is presented of toxic shock syndrome associated wtih diaphragm use. The patient, an 18-year old white woman, gravida 1, para 1, was in good health prior to the reported episode. She had a low transverse cesarean section for fetal distress 3 months prior to admission and had not yet resumed menstruation. 48 hours prior to admission, after unprotected intercourse, she developed a vaginal discharge requiring the use of a pad. 12 hours later she used a diaphragm, left it in place overnight, and failed to remove it the next morning. During the day pelvic and lumbar pain developed, followed by vomiting and a fever as high as 103 degrees Farenheit. That evening, 12 hours before admission, the diaphragm was removed with drainage of copious purulent discharge. The edges of the diaphragm and the discharge were blood streaked. She also developed a diffuse macular blanching rash, sparing only the circumoral region. At the time of admission the following morning her blood pressure was 60/0mmHg; pulse, 180 beats/minute; and temperature, 102 degrees Farenheit. Significant physical findings included the rash, conjunctivitis, a pharyngeal infection, and a lack of adenopathy. Pelvic examination showed a vaginal discharge, a very tender, slightly enlarged warm uterus, and normal adnexa. Cultures of the vaginal discharge were positive for Staphylococcus aureus, resistant to penicillin and ampicillin, and sensitive to methicillin, cephalothin, erythromycin, colistin, chloramphenicol, tetracycline, sulfisoxazole, and aminoglycoside antibiotics. The white blood count rose from 11,000/mm on admission to a high of 13,000/mm with a left shift the next day. The patient received 1.2 million units of intravenous penicillin every 4 hours, 80 mg of gentamicin every 8 hours, and 300 mg of clindamycin every 6 hours, as well as fluid replacement of 2 g of methylprednisolone followed by 1 g every 6 hours. The shock, fever, and rash resolved in the following 48 hours. 2 days after admission there was circumoral exfoliation. The discharge and electrolyte and renal abnormalities cleared in 3 days. Laboratory abnormalities corrected in 24-48 hours except for liver function tests. After 8 days in the hospital, the patient was discharged on 500 mg of cloxacillin every 6 hours. This particular case is unusual because it began with development of a vaginal discharge without vaginal obstruction, developed during a 24-hour period when a diaphragm was in place, and was not associated with menstruation. Whether the discharge represented staphylococcal infection is unknown, but the diaphragm certainly seems to have contributed to the course of events.
α-Enolase–binding peptide enhances drug delivery efficiency and therapeutic efficacy against colorectal cancer
Authors: Chien-Hsun Wu, Yi-Huei Kuo, Ruey-Long Hong, Han-Chung Wu
Journal: Science Translational Medicine (2015)

α-Enolase–targeted lipid nanoparticles containing chemotherapeutic drugs are effective for the treatment of colorectal cancer.
Left ventricular hypertrophy in hypertrophic cardiomyopathy
Authors: Jeffrey S. Borer
Journal: Journal of the American College of Cardiology (2004)

Left ventricular myocardial hypertrophy (LVH) occurs in many conditions, usually, it is thought, as a secondary or “compensatory” response to abnormal pressure or volume loading and to stimuli, as yet incompletely understood, resulting from deficiencies in cardiac performance [(1)][1]. These
Clinical academics’ postdoctoral career development
Authors: Veronica Ranieri, Helen Barratt, Naomi Fulop, Geraint Rees
Journal: BMJ (2015)

Could be helped by mentoring, improving the work environment, and better access to funding

Over the past 20 years commentators have warned of an impending crisis in academic medicine resulting from a failure to attract and retain medically qualified, clinical researchers.1 2 In 2005, in response to these challenges, the UK government established an integrated academic training pathway to generate a “pipeline” of world class future clinical academics. This pathway, overseen by the National Institute for Health Research, encourages junior doctors with an interest in research to advance from an academic clinical fellowship, and after completion of a PhD, to clinical lectureship.3 Each step along this path is competitively awarded and provides a formal structure in which trainees receive protected research time alongside their clinical training. However, whether this pathway boosts our supply of clinical academics has yet to be assessed.

Recent exit data for clinical PhD graduates from two of the largest funding bodies in the UK, the Wellcome Trust and Cancer Research UK, suggest that about …
Re: Parsa et al.: Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation (Ophthalmology 2015;122:439-42)
Authors: Matthew S.J. Katz, Bert M. Glaser, Barrett Katz
Journal: Ophthalmology (2015)
Coming full circle Membrane potential, sarcolemmal calcium influx and excitation–contraction coupling in heart muscle
Authors: I Hobai
Journal: Cardiovascular Research (1999)

In heart muscle, strong evidence shows that excitation-contraction coupling involves Ca-induced Ca-release. However, under some conditions, single heart cells show Ca release and contraction which is not correlated with Ca entry via the Ca channel, suggesting a second Ca-independent release mechanism. Similar observations were made in early, pioneering studies using voltage-clamped multi-cellular preparations. We review the influence that experimental preparations and conditions have had on excitation-contraction coupling theory over the last 20 years.
Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges
Authors: Aiwu Cheng, Ying Yang, Ye Zhou, Chinmoyee Maharana, Daoyuan Lu, Wei Peng, Yong Liu, Ruiqian Wan, Krisztina Marosi, Magdalena Misiak, Vilhelm A. Bohr, Mark P. Mattson
Journal: Cell Metabolism (2015)
Is liberal bias universal? An international perspective on social psychologists
Authors: Michal Bilewicz, Aleksandra Cichocka, Paulina Górska, Zsolt Péter Szabó
Journal: Behavioral and Brain Sciences (2015)

Abstract Based on our comparison of political orientation and research interests of social psychologists in capitalist Western countries versus post-Communist Eastern European countries, we suggest that Duarte and colleagues' claim of liberal bias in the field seems American-centric. We propose an alternative account of political biases which focuses on the academic tendency to explain attitudes of lower status groups.
Time to first antibiotic and mortality in adults hospitalised with community-acquired pneumonia: a matched-propensity analysis
Authors: Priya Daniel, Chamira Rodrigo, Tricia M Mckeever, Mark Woodhead, Sally Welham, Wei Shen Lim
Journal: Thorax (2015)

A matched-propensity analysis of national data from the British Thoracic Society community-acquired pneumonia audit was conducted (n=13 725). Overall, time to first antibiotic (TFA) was ≤4 h in 63%. Adjusted 30-day inpatient (IP) mortality was lower for adults with TFA ≤4 h compared with TFA >4 h (adjusted OR 0.84, 95% CI 0.74 to 0.94; p=0.003). Increasing TFA was associated with greater OR of 30-day IP mortality (p value for trend=0.001), but no TFA threshold was evident. Although we found an association between TFA and mortality, we cannot say whether this is causal or whether TFA might just be a quality measure for overall or other processes of care.
Usefulness of daily physical activity for monitoring therapeutic response in COPD
Authors: Osamu Hataji, Masahiro Naito, Esteban Gabazza, Osamu Taguchi
Journal: European Respiratory Journal (2013)

The level of physical activity during routine daily life is being recognized as an important parameter to assess therapy response in COPD patients. Markers of physical activity have been shown to correlate with mortality and with the number of hospitalizations and exacerbations of disease. Previous studies have shown data validating the use of accelerometers for objectively assessing the physical activity in COPD patients. We used a new type of accelerometer that can be easily carry while performing daily routine activities to assess therapy response in COPD patients. Twenty three stable COPD patients that consulted in our institution were enrolled in the present study. The diagnosis of COPD was done according to the criteria of American Thoracic Society. Informed consent was obtained from all subjects before entry. To assess the clinical value of physical activity to monitor therapeutic response, the patients were asked to carry an uniaxial accelerometry sensor fixed to their belts for 4 weeks before therapy; the patients were then asked to carry again the device for 4 weeks during treatment with a long-acting β2-agonist (indacaterol) by inhalation. The number of steps, the time in seconds of moderate or more degree of activity and the energy expenditure were significantly increased after treatment compared to before treatment in all COPD patients. Also, the metabolic equivalent of task was significantly enhanced after treatment with the long-acting β2-agonist compared to data before treatment. In conclusion, the results of this clinical investigation suggest the usefulness of measuring the daily physical activity for the assessment of therapeutic response in patients with COPD.
Pathogenesis of Marek's Disease in Chicks With and Without Maternal Antibody
Authors: L. N. Payne, M. Rennie
Journal: JNCI Journal of the National Cancer Institute (1973)

The pathogenesis of Marek's disease (MD) in chicks with maternal antibody (AP) or without antibody (AN) was studied up to 35 days after infection. MD virus antigens, detected by fluorescent antibody tests, and lymphoid proliferation were more frequent in the tissues of AN chicks than in those of AP chicks. In AN chicks, lymphoid proliferation was preceded by a phase of reticulum cell hyperplasia in the bursa, thymus', and spleen, 5–7 days after infection and showing abundant viral antigen, cytolysis, intranuclear inclusion bodies, and infiltration by granulocytes, macrophages, and lymphocytes. This phase appeared to represent an Inflammatory response to viral antigen and cellular degeneration and was accompanied by lymphoid regression in the bursa and thymus. These changes were absent or markedly suppressed in AP chicks. The acute phase was followed by a recovery phase from 7–21 days after infection, in which viral antigen disappeared from the lymphoid organs, lymphocyte populations in the bursa and thymus tended to return to normal, and areas of reticulum cell hyperplasia disappeared or were replaced by lymphoid tissue. Lymphoid proliferation leading to lymphoma formation and nerve infiltration commenced during the recovery phase; at the end of the experimental period, a second phase of viral antigen production occurred in the bursa and, less regul,arly, in the thymus and spleen; it was accompanied by lymphoid regression in the bursa and thymus.
VB6-845: recombinant engineering of an Ep-CAM-specific Fab antibody for optimal delivery of de-immunized bouganin (de-bouganin)
Authors: Jeannick Cizeau, Denis Bosc, Joycelyn Entwistle, Nick Glover, Glen MacDonald
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

683 

Tumor-targeting immunotoxins are composed of the variable regions of an antibody linked to a bacterial, fungal or plant toxin. Although several trials have shown promising clinical benefits, the induction of a human anti-toxin antibody response (HATA) is still a major limitation to achieving therapeutic success. At Viventia, VB5-845, a Fab version of an anti-EpCAM scFv antibody, was genetically linked to a de-immunized form of bouganin (de-bouganin), a potent, plant-derived, type I ribosome-inactivating protein (RIP), to create the antibody-toxin construct VB6-845. To determine the optimal antibody-de-bouganin orientation, several forms of a dicistronic expression unit were generated, expressed and tested for potency. In each case, the dicistronic unit was cloned into the pING3302 vector under the control of the arabinose-inducible araBAD promoter and transformed in E104 E.coli . Upon induction, the presence of the PelB leader sequence directed the secretion of the Fab-de-bouganin fusion protein into the culture supernatant. Two of several constructs tested comprised a pelB leader sequence adjacent to either the VH-CH or VL-CL domains linked to de-bouganin by a protease-sensitive linker. Immediately following was the second unit comprising either, pelB-VL-CL or the pelB-VH-CH domain as well as an N-terminal histidine affinity tag. For constructs where de-bouganin was re-positioned to the N-terminal end, Western-blot analysis showed no detectable product and only C-terminal linked de-bouganin yielded an intact soluble protein. Similarly, the addition of a second de-bouganin domain in the molecule with the optimal orientation did not yield product. A competition assay with Proxinium™, a scFv version of VB6-845, but containing a variant of Pseudomonas exotoxin A, demonstrated that the Ep-CAM specificity of VB6-845 was unaltered when engineered into a Fab format. In addition, cell-free and MTS assays demonstrated that de-bouganin retained its potency when conjugated to the Fab fragment. Using Ep-CAM positive cell lines, CAL-27 and OVCAR-3, the IC50 of VB6-845 was 1 to 2 nM. The development of VB6-845, comprising a tumor-targeting antibody fragment linked to de-immunized bouganin should permit repeat systemic administration of this drug and hence offer a greater clinical benefit.
Phase I study of SIR-sphere plus sorafenib as first-line treatment in patients with nonresectable hepatocellular carcinoma: The Asia-Pacific Hepatocellular Carcinoma Trials Group protocol 05 (AHCC05)
Authors: P. K. Chow, D. Poon, S. Choo, H. Lai, A. Goh, T. Lim, R. Lo, K. Tay, S. B. Tan, K. Soo
Journal: Journal of Clinical Oncology (2009)

e15538 Background: Sorafenib has been shown to significantly prolong survival in patients with nonresectable hepatocellular carcinoma (HCC) without however significant tumour regression. The addition of radio-ablative therapy could confer additional survival benefit. This phase I trial was carried out to ascertain the toxicities and safety of this combination and was designed as a prelude to a phase II trial. Methods: Eligible patients were administered SIR-sphere (max dose 3 GBq) and subsequently given Sorafenib therapy (400mg bd) either 14 days (Cohort 1: first 3 patients) or 11 days (Cohort 2: subsequent patients) later. Assessment was carried out for 30 days after commencement of Sorafenib. Results: 10 patients were recruited into this phase I trial. The second patient became ineligible for sorafenib therapy after SIR-sphere due to pulmonary bleeding not related to radio-therapy and was excluded from assessment. The characteristics of the patients are in the Table. At the end of the study period, there was no adverse events (AE) of grade 3 or 4 for Cohort 1 and 3 for Cohort 2. The only serious adverse event (SAE) recorded was from Cohort 2. Conclusions: Starting sorafenib 14 days after SIR-sphere therapy is associated fewer AEs and SAEs. The phase II trial has commenced withsorafenib starting 14 days after SIR-sphere. [Table: see text] [Table: see text]
Richter's syndrome: a report on 39 patients.
Authors: L E Robertson, W Pugh, S O'Brien, H Kantarjian, C Hirsch-Ginsberg, A Cork, P McLaughlin, F Cabanillas, M J Keating
Journal: Journal of Clinical Oncology (1993)

PURPOSE The incidence, clinical features, laboratory findings, and treatment results of 39 patients with Richter's syndrome (RS) are reported. PATIENTS AND METHODS Thirty-nine of 1,374 patients with chronic lymphocytic leukemia (CLL) developed RS. RESULTS Features associated with RS included systemic symptoms (59%), progressive lymphadenopathy (64%), extranodal involvement (41%), elevation of lactate dehydrogenase (LDH; 82%), and a monoclonal gammopathy (44%). Analysis of the CLL karyotype showed no specific chromosomal abnormality that conferred increased risk; however, multiple abnormalities were common. Patients at all Rai stages and in complete response (CR) were at risk, including three CR patients with no residual disease at the level of detection by dual-parameter flow cytometry or restriction analysis for immunoglobulin (Ig) gene rearrangements. The incidence was not higher in patients who had received prior fludarabine or chlorodeoxyadenosine. The median survival duration was only 5 months, despite multiagent therapy. Patients who responded had prolonged survival durations (P &lt; .001). Three of eight patients who survived more than 1 year had a de novo presentation of both CLL and large-cell lymphoma (LCL). Comparison of surface light-chain analysis from both low- and high-grade components demonstrated isotypic light-chain expression in 12 of 15 patients. Ig heavy- and light-chain gene rearrangement analysis showed identical rearrangement patterns in five of five patients. CONCLUSION The clinical, laboratory, and survival characteristics of our RS patients were similar to those reported in earlier studies. Ig gene rearrangement and light-chain isotype analysis support a common origin for CLL and LCL. Despite progress in the treatment of CLL, the development of LCL remains a serious complication and continued surveillance in all CLL patients is warranted.
Novel role of platelet endothelial cell adhesion molecule-1 (PECAM-1) in facilitating TGF-beta-mediated inhibition of T cell function
Authors: Debra Newman, Tamara Adams, Vidhyalakshmi Arumugam, Theresa Bluemn, Guoping Fu, Matthew Riese
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Transforming Growth Factor β (TGFb) is an immunosuppressive cytokine that inhibits pro-inflammatory functions of T cells, and is a major contributor to abrogating TH1 and cytotoxic T cell activity against tumors. While canonical signal transduction through effector Smads has been
Long-Term Nationwide Follow-Up Study of Simple Congenital Heart Disease Diagnosed in Otherwise Healthy Children
Authors: Jørgen Videbæk, Henning Bækgaard Laursen, Morten Olsen, Dan Eik Høfsten, Søren Paaske Johnsen
Journal: Circulation (2015)

Background— Systematic follow-up is currently not recommended for patients with simple congenital heart disease; however, only a few data exist on the long-term prognosis of simple congenital heart disease. Methods and Results— We undertook a nationwide follow-up study of a cohort of 1241 simple congenital heart disease patients, diagnosed from 1963 through 1973, in otherwise healthy children and alive at 15 years of age. We identified 10 age- and sex-matched general population controls per patient. We followed the study population through Danish public registries from the age of 15 years up to January 1, 2013 with respect to mortality, cause of death, morbidity, and medical follow-up. The patients were followed for a total of 58 422 patient-years and had a median age at the end of follow-up of 47.4 years (interquartile range, 43.5–50.9). Mortality was increased compared with the general population, both overall (adjusted hazard ratio [aHR],1.9; 95% confidence interval [CI], 1.5–2.4)] and for patients (79%) without medical follow-up (aHR, 1.7; 95% CI, 1.3–2.2). The most common cause of death (40%) was sudden unexpected death (aHR, 4.3; 95% CI, 2.9–6.5). The incidence of critical cardiac morbidity was 3.9 per 1000 patient-years with the most frequent events being an adult (re)operation and hospitalization for heart failure or ventricular tachyarrhythmia. This corresponded to an aHR of 5.7 (95% CI, 4.6–6.9) when compared with the general population. Conclusions— Patients diagnosed with simple congenital heart disease in the 1960s have substantially increased long-term mortality and cardiac morbidity compared with the general population. Further studies on the effectiveness of systematic medical follow-up programs appear warranted.
DRB1*11 allele expression and HER2 pre-existing immunity may predict benefit in breast cancer patients vaccinated with the HER2 modified AE37 peptide vaccine
Authors: Eleftheria A Anastasopoulou, Panagiotis Tzonis, Sotirios P Fortis, Louisa Mahaira, Christoforos Vaxevanis, Alexandros Ardavanis, Elizabeth A Mittendorf, George E Peoples, Constantin N Baxevanis, Michael Papamichail, Sonia A Perez
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Identification of immune biomarkers indicating potential clinical benefit from immunotherapies may contribute to the selection of the right patient for the right therapy. We have recently reported that HLA-DRB1*11 and HLA-A*24 alleles might serve as predictive factors for