tbuckley/cabot-search huggingface dataset:
Occupational class and cause specific mortality in middle aged men in 11 European countries: comparison of population based studies Commentary: Unequal inequalities across Europe
Authors: A. E Kunst, F. Groenhof, J. P Mackenbach, E. W. G. o. S. I. i. Health, D. A Leon
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objectives:</b> To compare countries in western Europe with respect to class differences in mortality from specific causes of death and to assess the contributions these causes make to class differences in total mortality. <b>Design:</b> Comparison of cause of death in manual and non-manual classes, using data on mortality from national studies. <b>Setting:</b> Eleven western European countries in the period 1980-9. <b>Subjects:</b> Men aged 45–59 years at death. <b>Results:</b> A north-south gradient was observed: mortality from ischaemic heart disease was strongly related to occupational class in England and Wales, Ireland, Finland, Sweden, Norway, and Denmark, but not in France, Switzerland, and Mediterranean countries. In the latter countries, cancers other than lung cancer and gastrointestinal diseases made a large contribution to class differences in total mortality. Inequalities in lung cancer, cerebrovascular disease, and external causes of death also varied greatly between countries. <b>Conclusions:</b> These variations in cause specific mortality indicate large differences between countries in the contribution that disease specific risk factors like smoking and alcohol consumption make to socioeconomic inequalities in mortality. The mortality advantage of people in higher occupational classes is independent of the precise diseases and risk factors involved. <h3>Key messages</h3> Socioeconomic inequalities in total mortality among middle aged men are about equally large in most western European countries, with the exception of larger inequalities in France and Finland Inequalities in mortality from specific causes of death, and the contributions these causes make to inequalities in total mortality, vary between countries The contribution to inequalities in mortality of disease specific risk factors like smoking and alcohol consumption varies greatly between countries This variability imposes limits on the exchange of research findings and experiences with health policies between western European countries The similar size of inequalities in total mortality in most countries underlines the generalised ability of higher occupational classes to better avoid premature death
[F-18] FMISO PET hypoxia imaging in cervical cancer: Pretherapy uptake in predicting survival.
Authors: Joseph Rajendran, Janet O'Sullivan, Wui-Jin Koh, Ron Swensen, Lanell peterson, Jeffrey Scharnhorst, Kenneth Krohn
Journal: Cancer Research (2007)

5507  Objectives: Hypoxia has been recognized as a significant problem in cancer of the uterine cervix. The genetic instability and molecular changes secondary to hypoxic stress promote an aggressive tumor phenotype that imparts resistance to both radiotherapy and chemotherapy, resulting in poor patient outcome. PET imaging with [F-18] fluoromisonidazole (FMISO) takes advantage of increased tracer retention in hypoxic tissues and is a non-invasive method to characterize and quantify hypoxia in cancer. We report our early experience with FMISO PET as a predictor of survival in patients with cervical cancer. Methods: Eighteen patients with cancer of the uterine cervix were enrolled in an FMISO-PET imaging protocol through 2005. PET images were obtained 90 min following the injection of 0.1 mCi/Kg of FMISO. All patients had bladder catheterization with irrigation to reduce bladder uptake. Tissue to blood (T:B) FMISO ratio was calculated using venous blood samples obtained during the emission part of the scan and a cutoff T:B ratio of 1.2 was used to signify hypoxia. Hypoxic volume (HV) is the sum of all pixels with a T:B ratio â‰¥ 1.2 and is expressed in mL. These patients also had whole body FDG scans that enabled measurement of glucose metabolism (SUVmax). Survival was analyzed using Cox proportional hazard model for FMISO and FDG. Results: Clinical Stage I - 4; Stage II - 4 and Stage III - 10. Histopathology: 6 adenocarcinoma and 12 squamous cell carcinoma. There were 4 deaths, 5 progressions and 9 with NED during the period. The mean hypoxic volume (HV): 16 mL (0.4 -68.4) and the mean FMISO Tissue:Blood max: 1.9 (1.33 - 3.8). The mean FDG SUVmax: 15.5 (2.1 - 28.8). Hypoxic Volume (HV), Tumor to Blood ratio (T:Bmax) and FDG (SUVmax) were each assessed using univariate Cox proportional hazards regression to measure their significance in relation to overall survival and progression-free survival. HV was highly prognostic for both endpoints (p=0.036 and 0.025 respectively) but FDG was not (p= 0.79 and 0.76). Similarly, the survival analysis shows a significant role for ict survival with grea han FDG in these patients. Conclusions: FMISO PET is a useful and non-invasive way to characterize and quantify hypoxia in cervical cancer. In a small group of patents with cervical cancer, pre-therapy FMISO uptake is able to predict survival after therapy with confidence. (This study was supported by Seattle Cancer Consortium Pilot Grant and in part by NIH P01 CA42045).
The Opioid Epidemic: Crisis and Solutions
Authors: Phil Skolnick
Journal: The Annual Review of Pharmacology and Toxicology (2017)

The widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids have created what is commonly referred to as the opioid epidemic. The magnitude of this epidemic is startling: About 4% of the adult US population misuses prescription opioids, and in 2015, more than 33,000 deaths were attributable to overdose with licit and illicit opioids. Increasing the availability of medication-assisted treatments (such as buprenorphine and naltrexone), the use of abuse-deterrent formulations, and the adoption of US Centers for Disease Control and Prevention prescribing guidelines all constitute short-term approaches to quell this epidemic. However, with more than 125 million Americans suffering from either acute or chronic pain, the development of effective alternatives to opioids, enabled at least in part by a fuller understanding of the neurobiological bases of pain, offers the best long-term solution for controlling and ultimately eradicating this epidemic.
A novel surgical strategy for secondary hyperparathyroidism: Purge parathyroidectomy
Authors: Cheng-Xiang Shan, Nian-Cun Qiu, Si-Luo Zha, Miao-E Liu, Qiang Wang, Pei-Pei Zhu, Zhi-Peng Du, Chun-Yan Xia, Ming Qiu, Wei Zhang
Journal: International Journal of Surgery (2017)
Abstract 331: HCN Overexpression in Failing Heart Possibly Contributes to Ventricular Arrhythmias
Authors: Yoshihiro Kuwabara, Koichiro Kuwabara, Makoto Takano, Hideyuki Kinoshita, Yasuaki Nakagawa, Satoru Usami, Kazuhiro Nakao, Takeya Minami, Yuko Yamada, Chinatsu Yamada, Junko Shibata, Toshio Nishikimi, Shinji Yasuno, Kenji Ueshima, Kazuwa Nakao
Journal: Circulation Research (2012)

Accumulating evidence suggests increased ventricular expression of hyperpolarization-activated cation channels (HCNs) in hypertrophied and failing hearts contributes to the induction of arrhythmias. In this study, we addressed the capacity of HCNs blockade to prevent lethal arrhythmias associated with heart failure. Transgenic mice expressing a dominant-negative mutant of neuron-restrictive silencer factor in a cardiac-specific manner (dnNRSF-Tg) exhibited dilated cardiomyopathy and sudden arrythmic death with an increase in ventricular HCNs expression, which are potentially responsible for the observed lethal arrhythmias. Ivabradine (Iva), a specific HCN channel inhibitor, significantly improved the survival among dnNRSF-Tg mice. Though echocardiographic, hemodynamic, and histological analyses showed no significant difference between Iva and control, ECG telemetric monitoring showed the significant reduction of arrhythmias in dnNRSF-Tg mice treated with Iva (VT; Iva 19/h, control 92/h ; p&lt;0.05), suggesting that Iva improved the survival by preventing lethal arrhythmias. We also found that the transgenic mice overexpressing HCN2 specifically in the heart (HCN2-Tg) are susceptible to ventricular arrhythmias induced by chronic isoproterenol infusion. In isolated ventricular myocytes from HCN2-Tg, but not in those from wild type mice, isoproterenol induced abnormal spontaneous action potentials, which were suppressed with Iva. Our findings suggest that increased ventricular expression of HCN channels possibly contributes to the ventricular arrhythmias, and HCN channels blockade may represent a new and effective means of preventing sudden arrhythmic death in patients with heart failure.
Screening for Hepatitis B Virus Infection in Pregnancy: U.S. Preventive Services Task Force Reaffirmation Recommendation Statement
Journal: Annals of Internal Medicine (2009)

Description: Reaffirmation of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for hepatitis B virus hepatitis B virus infection in pregnancy. Methods: The USPSTF performed a brief literature update, including a search for new and substantial evidence on the benefits and harms of screening pregnant women for hepatitis B virus infection. Finding: The net benefit of screening continues to be well established. Recommendation: Screen for hepatitis B virus infection in pregnant women at their first prenatal visit. (Grade A recommendation.)
Philip Michael John Tombleson
Authors: Mike Tombleson
Journal: BMJ (2017)

Philip Michael John Tombleson always maintained that he gained his medical school placing by virtue of his ability to play the double bass. He was promptly ejected from the orchestra after starting at Guy’s. After qualifying he moved to Brighton and considered a career in anaesthetics, but a practice became vacant in Ditchling, where he moved and fell in love with both general practice and the village. He was a dedicated GP to the small community for the following 36 years. He was the much loved, quintessential village doctor with an open door policy …
Multicenter randomized Phase II study of AZD1775 plus chemotherapy versus chemotherapy alone in patients with platinum-resistant TP53-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Authors: Kathleen N. Moore, D. Scott McMeekin, Erika Paige Hamilton, Donald K Strickland, Suzanne Fields Jones, Dawn Michelle Stults, Naomi Laing, David R. Spigel, Howard A. Burris
Journal: Journal of Clinical Oncology (2015)

TPS5608 Background: WEE1 is DNA damage cell-cycle checkpoint protein that inactivates cyclin-dependent kinase 1 (CDC2) and is overexpressed in a variety of malignancies. Pts with deficient p53 expression rely on the WEE1 kinase to arrest cell-cycle progression at the G2 checkpoint for DNA repair. AZD1775, a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase, is being developed for the treatment of advanced solid tumors with TP53-mutated malignancies. Inhibition of WEE1 allows CDC2 phosphorylation and subsequent cell-cycle progression despite DNA damage. This G2 checkpoint abrogation thus sensitizes cells to cytotoxic agents. Preliminary efficacy data have been promising when AZD1775 is used in combination with chemotherapy. In this randomized, phase II trial in pts with platinum-resistant, TP53-mutated cancers, AZD1775 will be added to a standard chemotherapy regimens (paclitaxel, gemcitabine, or carboplatin), with the goal of improving efficacy when compared to chemotherapy alone. The primary endpoints are response rate (Part 1), and progression-free survival (Part 2). Methods: In Part 1, up to 69 pts will be randomized to receive AZD1775 plus paclitaxel, gemcitabine or carboplatin (Arm A: AZD1775 175 mg PO BID Days 1, 2, 8,9,15, and 16 plus gemcitabine 1000 mg/m2 IV Days 1, 8, and 15; Arm B: AZD1775, 5 doses of 225 mg PO BID Days 1-3, 8-10, and 15-17 plus paclitaxel 80 mg/m2 IV Days 1, 8, and 15; Arm C: AZD1775, 5 doses of 225 mg PO BID Days 1-3 plus carboplatin AUC 5 IV Day 1). In Part 2, up to 108 pts will be randomized 1:1 to the most efficacious AZD1775/chemotherapy combination identified in Part 1, or chemotherapy alone. Pts will be restaged every 2 cycles and continue treatment until disease progression or unacceptable toxicity. Key eligibility includes: platinum-resistant TP53-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer, measurable disease per RECIST v 1.1, ECOG PS 0 or 1, QTc < 470 msec, and no known CNS disease. Tumor samples will be collected for evaluation of specific biomarkers. Clinical trial information: NCT02272790.
Abstract 150: S-nitrosylation Of Thioredoxin1 At Cysteine 73 Promotes Trans-nitrosylation, Autophagy And Cell Survival During Glucose Deprivation.
Authors: Narayani Nagarajan, Sebastiano Sciarretta, Junichi Sadoshima
Journal: Circulation Research (2014)

Thioredoxin-1 (Trx1) is a key antioxidant protein that is known to play a protective role in the heart during oxidative stress mainly through its oxidoreductase activity. Trx1 can be S-nitrosylated and, in turn, can trans-nitrosylate other proteins. However, the role of Trx1-dependent S-nitrosylation in cardiomyocytes (CMs) is not known. Here, we investigated the role of Trx1-mediated protein S-nitrosylation in the regulation of CM survival in response to stress. Using the biotin-switch assay, we found that wild-type Trx1 (Trx1WT) was S-nitrosylated, whereas the extent of S-nitrosylation was attenuated in Trx1C73S, suggesting that Trx1 is S-nitrosylated at Cys73. Also, we observed that the redox activity of Trx1 was intact in the Trx1C73S mutant. Overall protein S-nitrosylation in rat neonatal CMs was increased in response to 4 hrs of glucose deprivation (GD). Using biotin-switch assay and immunocytochemistry (fluorescent staining of s-nitrosylated cysteines), we observed that overexpression of Trx1WT increased, whereas short-hairpin RNA-mediated knockdown of Trx1 (shTrx1) or overexpression of Trx1C73S decreased, total protein S-nitrosylation in response to GD. These results suggest that Trx1Cys73 plays a key role in the regulation of protein S-nitrosylation in CMs during GD. Overexpression of Trx1 increased CM survival after 24 hrs of GD (Trx1WT vs. LacZ: propidium iodide assay, 0.5 ± 0.08-fold, p&lt;0.01). Conversely, shTrx1 or overexpression of Trx1C73S increased cell death during GD (Trx1C73S vs. LacZ: 1.7 ± 0.034-fold, p&lt;0.05). Autophagy is a pro-survival mechanism during GD. Therefore, we tested the effect of Trx1 on autophagy. After 4 hrs of GD, knockdown of Trx1 or overexpression of Trx1C73S decreased autophagy compared to control cells (LC3-II/LC3-I, 0.7-fold; autophagosomes, 0.83 ± 0.16-fold; autolysosomes, 0.62 ± 0.13-fold, p&lt;0.005). Taken altogether, our results suggest that Trx1 promotes autophagy during GD through a trans-nitrosylation dependent mechanism. S-nitrosylation of Trx1 at Cys73 is associated with an overall increase in protein S-nitrosylation in CMs and promotes autophagy and thus, cell survival during GD.
Abstract 321: Deletion Of The Translational Repressors Eukaryotic Translation Initiation Factor 4e Binding Proteins 1 And 2 Protects Against Pressure Overload Induced Heart Failure
Authors: zhongbing lu, Xinli Hu, Yimin Huang, Xin Xu, Ping zhang, Mark Peterson, Vitaly A Polunovsky, Nahum Sonenberg, Robert. J Bache, Peter B Bitterman, Yingjie Chen
Journal: Circulation Research (2013)

Assembly of the translation initiation machinery is negatively regulated by the eukaryotic translation initiation factor 4E binding proteins, which sequester the mRNA cap-binding protein eIF4E, thus preventing assembly of an intact initiation complex. However, the role of translational control on the development of congestive heart failure (CHF) has not been systematically examined. Here we perturbed translational control in mice by knockout of both 4E binding protein 1 (Eif4ebp1) and 2 (Eif4ebp2) (designated as Eif4ebp1/2 double knockout) to study its impact on left ventricular hypertrophy and CHF resulting from transverse aortic constriction. Eif4ebp1/2 double knockout caused a modest increase in left ventricular mass under basal conditions. However, following transverse aortic constriction, Eif4ebp1/2 double knockout profoundly attenuated the development of CHF and its attendant mortality. Examination of candidate genes involved in the mechanism revealed increased expression of transcription factors for genes governing energy metabolism and mitochondrial biogenesis with corresponding increases in the expression of their target genes. Our data indicate that removing physiological restraints on translation initiation exerts a profound cardiac protective effect against pressure overload induced CHF, suggesting that method(s) to disrupt the function of the 4E binding proteins may be a novel therapeutic approach for preventing or treating CHF.
Candidate Gene Polymorphisms and Their Association with TCD Velocities in Children with Sickle Cell Disease.
Authors: Abdullah Kutlar, Donald Brambilla, Betsy Clair, Anne Haghighat, Sule Bakanay, Gaye Adams, Ferdane Kutlar, Virgil McKie, Beatrice Files, Gerald Woods, Melanie Kirby, Elliott Vichinsky, Clark Brown, Charles Scher, Robert Adams
Journal: Blood (2007)
Abstract 18782: Knockout of Type VI Collagen Preserves Mitochondrial Structure and Function Following Myocardial Infarction
Authors: J G Meszaros, Daniel J Luther, Spencer R Andrei, Holly C Cappelli, Ravi K Adapala, Roslin J Thoppil, Hemal Patel, Ingrid R Niesman, Patrick T Kang, Paolo Bonaldo, Yong-Renn Chen, Charles K Thodeti, William M Chilian
Journal: Circulation (2013)

Cardiac remodeling is a dynamic process that is accelerated after myocardial infarction (MI). Types I and III collagen, both fibrillar collagens, have been the focus of the remodeling and repair literature. We have recently uncovered a potentially novel role for non-fibrillar type VI collagen (Col6) in post-MI repair and global LV function. We reported that Col6 null (Col6-/-) mice are protected from ischemic injury as evidenced by significantly reduced infarct sizes and preserved systolic function. Interestingly, the Col6-/- mouse, originally developed as a model for a skeletal muscle dystrophy known as Bethlem Myopathy, allowed for the discovery that type VI collagen mutations or knockout led to mitochondrial dysfunction and skeletal myocyte apoptosis with aging. Our hypothesis that altered mitochondrial structure and function in the myocardium of Col6-/- mice is the mechanistic basis of the paradoxical protection from ischemic injury. To investigate the potential mitochondrial mechanism(s) responsible for the cardioprotection in Col6-/- mice, we began by using transmission electron microscopy (TEM) to assess mitochondrial morphology. Mitochondria from uninjured Col6-/- LV tissue had similar morphology as WT. Mitochondrial morphology at 3 days post-MI indicates that WT and Col6-/- mitochondria are compromised. However, TEMs of Col6-/- hearts 14 days post-MI show longer chains of intrerfibrillar mitochondria, whereas swollen, isolated mitochondria were apparent in WT. Interestingly, we observed a 3.0 vs. 1.7-fold increase (WT vs. and Col6-/- mice, respectively) in the fission protein Drp1 specifically in the infarcted zones at 24 hours post injury. We next measured O2 consumption 24 hours post-MI using isolated mitochondria from both phenotypes, discovering a reduced coupling of oxidative phosphorylation (44.5 ± 4.7% reduction in respiratory control index; RCI) in Col6-/- mice compared to WT controls. However, the RCI of the infarcted region in Col6-/- 24 hours post-MI hearts did not significantly decline compared to WT. Together, these data indicate that Col6-/- mice have preserved mitochondrial morphology and respiration following MI and may be a mechanism underlying the unexpected cardioprotection from MI injury in Col6-/- mice.
Abstract 20334: Dysregulation in Metabolic and Angiogenic Pathways Are Associated Defective Right Ventricular Adaptation in Fischer Rats With Severe Pulmonary Arterial Hypertension
Authors: Colin M Suen, Ketul R Chaudhary, Yupu Deng, Anli Yang, Baohua Jiang, Duncan J Stewart
Journal: Circulation (2016)

Introduction: Fischer rats exhibit a very high mortality in the SU5416 (SU)/ chronic hypoxia (CH) model of severe pulmonary arterial hypertension (PAH) compared to Sprague Dawley (SD) rats, despite...
Detecting HPV integration and amplification by molecular combing: Applications for cervical cancer.
Authors: Pierre Walrafen, John Herrick, Chiara Conti, Jun Komatsu, Aaron Bensimon
Journal: Clinical Cancer Research (2007)

B3  Human papillomavirus (HPV) genital infection is very common, with one or more subtypes of HPV. In most cases, viral DNA can no longer be detected after some time, revealing the transient character of infection. However, in some cases, tied to some so-called “high-risk” HPV subtypes, infection is persistent and leads to cervical intraepithelial neoplasia (CIN) and potentially to cancerous transformation. Nearly all cases of cervical cancer involve infection with a high-risk HPV.  Cervical cancer is one of the most common cancers among women, and can be readily treated if diagnosed at early stage. Current routine screening involves cytological detection of abnormalities (Pap smear). Abnormal results are confirmed through histology on a biopsy and sometimes detection of high-risk HPV DNA. However, given the high rates of spontaneous clearance of the virus and regression of CIN, tests based either on detection of high-risk HPV DNA or on histological analysis of cervical cells have a low predictive value for the evolution towards cancer.  Molecular combing allows high resolution analysis of large regions of genomic DNA at a single molecule level. A surface-treated coverslip is dipped in a solution of high molecular weight (>1Mb) DNA, then pulled out of the solution vertically. The motion of the meniscus stretches the DNA molecules and aligns them vertically. Hundreds of genomes are thus immobilized on a single slide. Hybridization allows direct visualization and physical cartography over tens of megabases and at kilobase-resolution. In addition, pre-labelling of nascent DNA with modified nucleotides on cells in S-phase allows precise assessment of DNA replication kinetics in a given region or throughout the whole genome.  We have applied Molecular combing to the study of HPV integration and its consequences on the host genome. We recently established a link between the integration profile (site and fragment size) of HPV, amplification of myc family genes, and aggressiveness in several cervical cancer cell lines. We now show an analysis of the replication dynamics in the amplicon. The replication pattern (origin spacing and fork progression) was highly perturbed in the amplicon compared with other regions of the genome. Strikingly, replication origins fired from both viral sequences and co-amplified genomic sequences. This may explain the genomic instability associated with HPV integration and further supports a link between integration profile and tumor aggressiveness.  Because integration of HPV is reported to be a critical event in the cancerous transformation of cervical cells, and because we hold a sensitive and sharp tool for the detection of integrated HPV and assessment of integration profile and oncogene amplification, we intend to initiate a larger-scale study in order to develop a clinically relevant cancer prediction and tumor staging tool.
The Best of Times
Authors: Johanna T. Dwyer
Journal: Annual Review of Nutrition (2017)

I came of age as a nutrition scientist during the best of times-years that spanned a rapidly changing world of food and nutrition science, politics, and policy that greatly broadened the specialty and its influence on public affairs. I followed the conventional route in academe, working my way up the academic ladder in Boston from a base first in a school of public health and later in a teaching hospital and medical school, interspersed with stints in Washington, DC. Thus I tell a tale of two cities. Those were the best of times because nutrition science and policy converged and led to important policies and programs that shaped the field for the next 50 years.