tbuckley/cabot-search huggingface dataset:
Mark Mulligan leads Emory swine flu vaccine trial
Authors: Brooke Grindlinger
Journal: Journal of Clinical Investigation (2009)

Mark Mulligan leads Emory swine flu vaccine trialFearing that the fall flu season in combination with the return of children to school could trigger a spike in swine flu cases, the National Institute of Allergy and Infectious Diseases has begun clinical trials of candidate vaccines against the pandemic influenza (H1N1) virus.The JCI spoke with Mark Mulligan (Figure 1), professor of medicine at Emory University School of Medicine and principal investigator at the Emory Vaccine Center's Vaccine and Treatment Evaluation Unit (VTEU), one of eight in a nationwide network of VTEUs where the trials will be conducted.JCI: The Emory Vaccine Center is experienced in developing candidate vaccines for HIV, malaria, and H5N1 avian influenza.So is this business as usual for your team?Mulligan: No, not by any means.These are extraordinary circumstances.We are in the midst of a public health emergency, and the sense of urgency to control this pandemic is greater than anything I've experienced in my career.JCI: What are the primary objectives of this trial?Mulligan: We hope to determine the strength (15 μg vs. 30 μg) and number of doses (one vs. two) of the vaccine required to stimulate an immune response likely to protect against H1N1 flu.We will evaluate vaccine safety and immunogenicity in five different age groups: 6 to 35 months, 3 to 9 years, 10 to 17 years, 18 to 64 years, and adults 65 years and older.We also hope to determine how best to give the H1N1 vaccine safely in combination with the seasonal flu vaccine and without reducing the immune response to either.JCI: Do you anticipate children, adults, and seniors responding differently to the vaccine?Mulligan: The influence of age has been very interesting in this pandemic.The burden of disease has been in children and young adults, while seniors have been mostly spared.Seniors may have had previous exposure to an H1N1-like virus that primed their immunological memory, providing a level of protection against H1N1.This could influence their response to vaccine; they may only require one dose.If true, this could be very important during the early stages of vaccine deployment if supply is limited.JCI: What have been some of the chal-
Iontophoretic transport of procainamide and d-sotalol into arrhythmogenic myocardium: Efficacy in ventricular tachycardia suppression
Authors: Boaz Avitall, John W. Hare, Gary L Zander, Cynthia S. Wilhelm, Mohammad R. Jazayeri, Patrick J. Tchou, Jasbir S. Sra, Paul J. Troup, Masood Akhtar
Journal: Journal of the American College of Cardiology (1991)
A Targetable GATA2-IGF2 Axis Confers Aggressiveness in Lethal Prostate Cancer
Authors: Samuel J. Vidal, Veronica Rodriguez-Bravo, S. Aidan Quinn, Ruth Rodriguez-Barrueco, Amaia Lujambio, Estrelania Williams, Xiaochen Sun, Janis de la Iglesia-Vicente, Albert Lee, Ben Readhead, Xintong Chen, Matthew Galsky, Berta Esteve, Daniel P. Petrylak, Joel T. Dudley, Raul Rabadan, Jose M. Silva, Yujin Hoshida, Scott W. Lowe, Carlos Cordon-Cardo, Josep Domingo-Domenech
Journal: Cancer Cell (2015)
Novel Transcriptional Targets of the SRY-HMG Box Transcription Factor SOX4 Link Its Expression to the Development of Small Cell Lung Cancer
Authors: Sandra D. Castillo, Ander Matheu, Niccolo Mariani, Julian Carretero, Fernando Lopez-Rios, Robin Lovell-Badge, Montse Sanchez-Cespedes
Journal: Cancer Research (2011)

The HMG box transcription factor SOX4 involved in neuronal development is amplified and overexpressed in a subset of lung cancers, suggesting that it may be a driver oncogene. In this study, we sought to develop this hypothesis including by defining targets of SOX4 that may mediate its involvement in lung cancer. Ablating SOX4 expression in SOX4-amplified lung cancer cells revealed a gene expression signature that included genes involved in neuronal development such as PCDHB, MYB, RBP1, and TEAD2. Direct recruitment of SOX4 to gene promoters was associated with their upregulation upon ectopic overexpression of SOX4. We confirmed upregulation of the SOX4 expression signature in a panel of primary lung tumors, validating their specific response by a comparison using embryonic fibroblasts from Sox4-deficient mice. Interestingly, we found that small cell lung cancer (SCLC), a subtype of lung cancer with neuroendocrine characteristics, was generally characterized by high levels of SOX2, SOX4, and SOX11 along with the SOX4-specific gene expression signature identified. Taken together, our findings identify a functional role for SOX genes in SCLC, particularly for SOX4 and several novel targets defined in this study.
Abstract IA11: New insights into DNA double-strand break responses
Authors: Michael B. Kastan
Journal: Cancer Research (2014)

Abstract Repair of damaged DNA in cells is complicated by the necessity to repair the damage in the context of complex chromatin structures. Elucidation of molecular mechanisms of DNA repair in intact cells has been challenging. We developed a system that can rapidly induce DNA double strand breaks (DSBs) at defined endogenous sites in mammalian genomes and enables direct assessment of repair and monitoring of protein recruitment, egress, and modification at DSBs in viable cells. The tight regulation of the system also permits assessments of relative kinetics and dependencies of events associated with cellular responses to DNA breakage. Using chromatin immunoprecipitation, we found that nucleosomes are partially disassembled around DSBs during non-homologous end-joining repair in G1-arrested mammalian cells, characterized by a transient loss of the H2A/H2B histone dimer. Nucleolin, a protein with histone chaperone activity, interacts with RAD50 via its RGG domain and is rapidly recruited to DSBs in an MRE11-NBS1-RAD50 complex dependent manner. Down-regulation of nucleolin abrogates the nucleosome disruption, the recruitment of repair factors, and repair of the DSB, demonstrating for the first time the functional importance of nucleosome disruption in DSB repair and identifying a chromatin remodeling protein required for the process. Interestingly, the nucleosome disruption that occurs during DSB repair in cycling cells differs in that both H2A/H2B and H3/H4 histone dimers are removed. This complete nucleosome disruption is also dependent on nucleolin and is required for RPA recruitment to DSBs, a marker of DSB processing that is a requisite for homologous recombination repair. Since inhibition of nucleolin function blunts the DSB repair process, it has become a potential therapeutic target for radiosensitization of tumors. Similarly, small molecule inhibitors of PIKK kinases like ATM and DNA-PK have been developed and are potent radiosensitizers. The potential clinical use of such compounds will be discussed. Citation Format: Michael B. Kastan. New insights into DNA double-strand break responses. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA11. doi:10.1158/1538-7445.CANSUSC14-IA11
Clinical Lecture on a Case of Lead-Poisoning, Treated with Iodide of Potassium
Authors: H. Thompson
Journal: BMJ (1871)

fered from an attack of lead-colic, accompanied by inability to pass urine, and followed by slight loss of power in the arms and hands.During recovery from the above attack, he was seized with rheumatism and laid up for three months longer.Since that time he has never been thoroughly well.His principal ailments have been night-sweats, free perspiration by day on slight exertion, occasional violent pains in the forehead, frequent nausea after food, and gradual failure of strength in both arms and hands, especially on the right side.Four months before admission into the Middlesex Hospital he left off work, suffered for a while from habitual constipation, and, during the period mentioned, had three distinct attacks of colic.The first was accompanied by loss of power in the arms, which drooped and hung helplessly by his side.On admission, December 24th, there was marked drooping of both hands at the wrists, at the metacarpo-phalangeal joints, and at the two succeeding digital articulations.There was considerable wasting of all the muscles in the arm and fore-arm, most pronounced in the extensors
109. Expression of Porcine α(1–3)galactosyltransferase in Non-Human Primate Hematopoietic Progenitors Following Retroviral Mediated Gene Transfer
Authors: Lorenzo Benatuil, John Iacomini
Journal: Molecular Therapy (2005)

Background: We have previously shown in mice that expression of the enzyme |[alpha]|(1,3)galactosyltransferase (|[alpha]|GT), which synthesizes the epitope Gal|[alpha]|1-3Gal|[beta]|1-4GlcNAc-R (|[alpha]|Gal), in bone marrow (BM)-derived cells can be used to induce specific tolerance to |[alpha]|Gal. In order to move this approach into a pre-clinical non-human primate model, we examined the ability to transduce hematopoietic CD34+ progenitor cells from non-human primates and achieve expression of |[alpha]|GT in these cells.
Neurotransmitter modulation and supraspinal fatigue
Authors: B Roelands, M Klass, M Levenez, V Fontenelle, J Duchateau, R Meeusen
Journal: British Journal of Sports Medicine (2011)

An important aspect of central fatigue is supraspinal fatigue, or fatigue originating from an insufficient output from the motor cortex. One possible underlying mechanism is that this reaction is evoked by changes in brain neurotransmitters such as dopamine (DA) and noradrenaline (NA). In the present study, we looked into the relation between supraspinal fatigue and changes in brain neurotransmitter concentrations before and after prolonged exercise. Ten well-trained male cyclists participated in this study. Subjects exercised in 18°C and performed 60 min at 55% Wmax followed by a time trial which required the subject to complete a work equal to 30 min at 75% Wmax as quickly as possible. Pharmacological interventions were placebo, methylphenidate (DA reuptake inhibitor) and reboxetine (NA reuptake inhibitor). Voluntary activation and corticospinal excitability changes were tested in the knee extensors using TMS and motor nerve electrical stimulation before and after the cycling exercise. Reaction time and attention were measured using the psychomotor vigilance test (PVT). NA administration decreased performance significantly (9%). This was accompanied by a significant reduction in voluntary activation. No differences were observed for DA reuptake inhibition. No changes in corticospinal excitability were observed. The PVT revealed that reaction time was negatively influenced by reboxetine. Higher NA concentrations in the brain enhance central fatigue. The reduction in both the voluntary activation and reaction time shows that this decrease in performance was centrally mediated.
Quantitative Measurements of Tumoral p95HER2 Protein Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab: Independent Validation of the p95HER2 Clinical Cutoff
Authors: Renata Duchnowska, Jeff Sperinde, Ahmed Chenna, Mojgan Haddad, Agnes Paquet, Yolanda Lie, Jodi M. Weidler, Weidong Huang, John Winslow, Tomasz Jankowski, Bogumiła Czartoryska-Arłukowicz, Piotr J. Wysocki, Małgorzata Foszczyńska-Kłoda, Barbara Radecka, Maria M. Litwiniuk, Jolanta Żok, Michał Wiśniewski, Dorota Zuziak, Wojciech Biernat, Jacek Jassem
Journal: Clinical Cancer Research (2014)

P95HER2 (p95) is a truncated form of the HER2, which lacks the trastuzumab-binding site and contains a hyperactive kinase domain. Previously, an optimal clinical cutoff of p95 expression for progression-free survival (PFS) and overall survival (OS) was defined using a quantitative VeraTag assay (Monogram Biosciences) in a training set of trastuzumab-treated metastatic breast cancer (MBC) patients.In the current study, the predictive value of the p95 VeraTag assay cutoff established in the training set was retrospectively validated for PFS and OS in an independent series of 240 trastuzumab-treated MBC patients from multiple institutions.In the subset of 190 tumors assessed as HER2-total (H2T)-positive using the quantitative HERmark assay (Monogram Biosciences), p95 VeraTag values above the predefined cutoff correlated with shorter PFS (HR = 1.43; P = 0.039) and shorter OS (HR = 1.94; P = 0.0055) where both outcomes were stratified by hormone receptor status and tumor grade. High p95 expression correlated with shorter PFS (HR = 2.41; P = 0.0003) and OS (HR = 2.57; P = 0.0025) in the hormone receptor-positive subgroup of patients (N = 78), but not in the hormone receptor-negative group. In contrast with the quantitative p95 VeraTag measurements, p95 immunohistochemical expression using the same antibody was not significantly correlated with outcomes.The consistency in the p95 VeraTag cutoff across different cohorts of patients with MBC treated with trastuzumab justifies additional studies using blinded analyses in larger series of patients.
Women need better information on routine mammography: Authors' reply
Authors: H. Thornton
Journal: BMJ (2003)

Editor—Responses to our paper identify the problems that underlie any attempt to produce honest, good quality information for healthy potential participants in routine mammography screening programmes. These hinge on the central question about the uncertainty of whether screening does more harm than good. Even so, current shortcomings in information provided are confirmed and identified, and constructive, practical suggestions for improvements offered.

In contrast to Peto and other researchers mentioned in our paper, Blanks and his colleagues claim to have teased out the different contributions to the reduction in breast cancer deaths.1 However, since population screening began in the United Kingdom, numerous factors have affected worldwide mortality trends in breast cancer,2 and systematic reviews of mammography have been published showing little or no reduction in mortality from good quality evidence.3 Sophisticated qualitative methodologies and instruments have also been developed that could helpfully assess a range of non-biomedical outcomes important to consumers.4

Marshall and Nottingham offer suggestions for practical improvements that could be implemented immediately. Patnick's concern to provide women with what they want so that it “is easy to understand,” rather than what they need to make a properly informed decision is somewhat patronising and does women a disservice. Sacrificing content to readability and presentation is unhelpful if you are to fulfil General Medical Council guidance that “you must ensure that anyone... can make a properly informed decision.”

Prospective screening participants first need to know what their risk of getting the disease is, and their risk of dying of it, and the chances of undergoing invasive investigations as a result of attending screening. These and other facts are important if women are to go on to consider whether the harms and benefits of screening are worthwhile for them. Published decision aids are already available5: we suggest they be fed quickly into a new leaflet from the NHS Breast Cancer Programme.
Molecular Mechanisms of Cocaine Addiction
Authors: A I Leshner
Journal: New England Journal of Medicine (1996)

Effective medication for the treatment of cocaine overdose and addiction is a major unmet need of worldwide importance. In contrast to heroin, for which there are effective medications to treat both overdose (naloxone) and addiction (methadone), there are no pharmacologic treatments for any aspect of cocaine addiction. Recent discoveries indicating that an anti-cocaine medication is actually within reach are cause for great optimism. This work is defining specific molecular targets against which such a medication might be directed.A recent study by Giros et al.1 affirms the central importance of the dopamine-reuptake transporter in the behavioral and biochemical action of . . .
Adénopathies tuberculeuses péri-pancréatiques: apport diagnostique de l'écho-endoscopie (EE) avec ponction
Authors: C Stefanescu, A Aubert, P Hammel, A Couvelard, L Noussair, MP Vullierme, D O'Toole, F Maire, AL Pelletier, V Rebours, P Lévy, P Ruszniewski
Journal: Endoscopy (2008)

Introduction: L'atteinte tuberculeuse des ganglions péri-pancréatiques est rare et de présentation clinique variée. Le diagnostic de certitude est difficile car les examens biologiques et d'imagerie sont non spécifiques. Le diagnostic nécessite un recueil de matériel biopsique ganglionnaire pour une étude histologique et bactériologique. Le but de ce travail rétrospectif était d'étudier les performances de l'EE avec ponction dans cette indication.
"Golden Pill" award remains unfilled for the fourth year running
Authors: Z. Kmietowicz
Journal: BMJ (2012)

The annual awards ceremony of the non-profit and fiercely independent French journal Prescrire in Paris at the end of January must have been a bit of a subdued and extremely short affair. No new drugs or new indications for established drugs reviewed in 2011 impressed the editorial team sufficiently to grab any of the top three categories. 

The “Golden Pill” award for a major …
Points: Alcohol and violence
Authors: M Carew--McColl, T F Beattie, J W Gerrard
Journal: BMJ (1987)

and informed approach to long term catheterisation and are eager to support further research into specific aspects of catheter management.Two short booklets are available from Bard Limited for patients and those responsible for their care, and further information will be gladly given to any doctor heeding Mr Kinder's call.
End of an ERA: Lessons from Negative Clinical Trials in Idiopathic Pulmonary Fibrosis
Authors: Paul W. Noble, Luca Richeldi, Naftali Kaminski
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Comment on BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. [American Journal of Respiratory and Critical Care Medicine, 2011]
Uptake of synthetic Low Density Lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy
Authors: Peixun Zhou, Sophia Hatziieremia, Moira A. Elliott, Linda Scobie, Claire Crossan, Alison M. Michie, Tessa L. Holyoake, Gavin W. Halbert, Heather G. Jørgensen
Journal: Journal of Controlled Release (2010)
Increase in myocardial oxygen consumption indexes by exercise training at onset of ischemia in patients with coronary artery disease.
Authors: L J Laslett, L Paumer, E A Amsterdam
Journal: Circulation (1985)

It has been unclear whether exercise training of patients with coronary artery disease increases the level of myocardial oxygen consumption, as indicated by heart rate and double product of heart rate and systolic blood pressure, at which electrocardiographic evidence of myocardial ischemia develops. To assess this question we evaluated the experience of 10 patients with coronary artery disease who underwent a modest-level exercise training program for 6 months. All of these subjects had achieved a training effect, had developed electrocardiographic evidence of ischemia during initial exercise testing, had not increased the amount of cardiac medication taken, and had not been taking digoxin. After completion of the training period, the mean heart rate at which electrocardiographic evidence of ischemia developed increased from 107 +/- 19 to 119 +/- 23 beats/min (p less than .05) and the mean double product increased from 166 +/- 18 to 209 +/- 51 X 10(2) mm Hg X beats/min (p less than .05). Eight of the 10 patients demonstrated an increase in heart rate at onset of ischemia (p less than .02), and seven of the eight in whom double product could be assessed manifested an increase in this parameter at onset of ischemia (p less than .05). Thus the rate of myocardial oxygen consumption at which myocardial ischemia develops, as indirectly assessed by heart rate and double product, can be favorably altered by 6 months of moderate-level exercise training.
The Long-Term Follow-Up of Malignant Hypertension
Authors: Dera Kinsey
Journal: JAMA (1962)

In a 25-year study of 251 patients with malignant hypertension, the survival rate of 160 patients who were treated by the lumbodorsal splanchnicectomy was approximately the same as that of the patients, treated with the newer antihypertensive drugs for the first 4 years of observaion. Thereafter, the survival rate of medically treated patients, reported recently in several selected studies, dropped noticeably and was less at the end of 5 years than the survival rate of the surgically treated patients at the end of 10 years. Although the use of antihypertensive drugs has prolonged the survival of malignant hypertensive patients, studies will have to be extended over a longer period of time before valid comparisons can be made between the results of drug therapy and the results of surgical treatment.
Letter by Stocker and Maghzal Regarding Article, “Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in Humans”
Authors: Roland Stocker, Ghassan J. Maghzal
Journal: Circulation (2014)

As recognized in the accompanying editorial, 2 it remains controversial whether oxidative stress and the resulting oxidative damage are a cause or a consequence of atherosclerosis.The overall disappointing outcome of prospective clinical trials of antioxidants has led to a lively debate on whether the oxidative modification hypothesis has been adequately tested. 3In addition, modified versions of the original hypothesis have been formulated, including the notion that increased reactive oxygen species (ROS) resulting from mitochondrial dysfunction cause atherogenesis.To test this hypothesis, Yu et al 1 used mice deficient for mitochondrial polymerase-γ proofreading activity and apolipoprotein E (polG -/-/ ApoE -/-), together with the novel probe MitoB, to determine mitochondrial hydrogen peroxide (H 2 O 2 ). 4 The authors interpret their data as suggestive of mitochondrial dysfunction and mitochondrial DNA defects promoting atherosclerosis independently of ROS.Similarly, the editorial 2 concludes that the concept of "mitochondrial DNA damage and oxidative stress leading to atherosclerosis may need to be revised."We wish to briefly comment on the data presented and associated interpretations. 1,2irst, assessment of ROS at sites where atherosclerosis develops in polG -/-/ApoE -/-and ApoE -/-mice was limited to the analysis of MitoB and its oxidized form, MitoP, in the aorta.Contrary to the
PROGNOSTIC VALUE OF TISSUE DOPPLER IMAGING AND NT-PRO-BNP IN ASYMPTOMATIC AORTIC STENOSIS
Authors: Miquel Gomez, Mercedes Cladellas, Lluis Molina, Aleyska Ramirez, Joan Vila, Cristina Roqueta, Hector Sanz, Jordi Bruguera
Journal: Journal of the American College of Cardiology (2011)
Complications of Corticotropin Therapy in Multiple Sclerosis
Authors: Leo J. Cass
Journal: JAMA (1966)

Indications for corticotropin therapy for multiple sclerosis, are steadily progressive disease or exacerbations lasting six months without remission. Definite contraindications are diabetes, psychosis, tuberculosis or other serious infection, severe hypertension, and active ulcers. Relative contraindications include prediabetic state, past ulcers, slight hypertension or osteoporosis, severe neurosis or depression. Successful management is possible in these cases, however. Serious complications in 47 cases during intensive treatment were psychoses, five; ulcers, three; septicemia, two; pathological fracture, one; adrenal exhaustion, one. Corticotropin therapy was discontinued in five patients because of psychoses, three; perforated ulcers, two. There was one death from septicemia. Serious complications in 41 cases during maintenance treatment (maximum four years) were osteoporosis, two; adrenal exhaustion, three; steroid diabetes, one; septicemia, one; ulcers, two. Corticotropin therapy was discontinued in three patients because of osteoporosis, one; septicemia, one; perforated ulcer, one. There was one death from steroid diabetes.