tbuckley/cabot-search huggingface dataset:
TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness
Authors: Xiaoming Lyu, Weiyi Fang, Longmei Cai, Hang Zheng, Yanfen Ye, Lan Zhang, Jinbang li, Hong Peng, William C S Cho, Ena Wang, Francesco M Marincola, Kaitai Yao, Hongbing Cai, Jiliang Li, Xin Li
Journal: Molecular Cancer (2014)

MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown. We firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation. TGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC. The present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.
Does Kidney Infection Cause Renal Failure?
Authors: C M Kunin
Journal: Annual Review of Medicine (1985)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
And then came the microelectrode
Authors: B Hoffman
Journal: Cardiovascular Research (2002)

It is difficult to fully appreciate the contributions made by the microelectrode to the understanding of cardiac electrophysiology without some idea of the prior state of the field. What was known about cardiac electrophysiology had been derived largely from studies of the electrocardiogram and cardiac electrogram and by the application of stimuli, usually electrical, to the heart. The voltage–time course of the atrial and ventricular action potentials had been revealed by the recording of monophasic potentials through suction electrodes or other means of registering injury potentials. The various phases of refractoriness had been defined by stimulation but this information usually was not related to the monophasic action potential. Evidence of the basic mechanisms underlying the observed phenomena was largely lacking. The major contributions to understanding the nature and mechanisms for arrhythmias and conduction disturbances resulted from precise measurements of the electrocardiogram and careful deductive reasoning. Early studies on in vitro preparations [1] had demonstrated reentrant excitation and identified an inexcitable barrier, unidirectional block and slow conduction as the necessary substrate for this arrhythmia. These abnormalities were attributed to a vaguely described depression of excitability. Some ectopic rhythms were ascribed to abnormal impulse generation and several theories as to mechanism were presented but largely without experimental justification. All in all one knew what was happening in the heart but without an understanding of why.

The ability to record the transmembrane potentials of cardiac muscle brought about a rapid and immense increase in understanding of the basis for normal and abnormal cardiac electrical activity. Intracellular electrodes had been employed to study giant nerve fibers [2] and permitted the brilliant experiments and deductions by Hodgkin, Huxley and Katz [3,4] among others. These experiments provided for the first time an understanding of the conductance changes and ionic currents causing the depolarization and repolarization shown … 

* Address for correspondence: 600 Gropetree Drive, Apt. 6 EM, Key Biscane, FL 33149, USA
No oncogenic mucosal human papillomaviruses in erosive vulval lichen planus
Authors: G. Kirtschig, A.A.T.P. Brink, R.J. Scheper, E.H. Jaspars
Journal: British Journal of Dermatology (2005)

Conflicts of interest: none declared. Sir, Erosive vulval lichen planus (LP) is a rare, difficult‐to‐treat inflammatory disease of unknown aetiology. One hypothesis is that a hypersensitivity reaction to a yet unidentified (intraepidermal) antigen may play a role. CD8+ lesional T cells are shown to be more cytotoxic against autologous lesional keratinocytes than clones isolated from nonlesional T‐cell lines; the possible antigen may be associated with major histocompatibility complex class I on lesional keratinocytes.1 In oral LP a hepatitis C‐specific T‐cell response is suggested; however, there is no hint to support this hypothesis for erosive vulval disease in Northern Europe.2 The malignant potential of erosive vulval LP is still a matter of debate. Our objective was to investigate the possibility of an (oncogenic) mucosal human papillomavirus (HPV) being involved in the aetiology and the possible premalignant character of erosive vulval LP. According to the study by Hørding et al., normal vulval skin does not normally harbour HPV DNA (types 6, 11, 16, 18, 33) in women aged 17–98 years (median 64).3 Furthermore, knowledge about the presence of HPV, a potential tumour promoter, in vulval erosive LP is relevant with regard to its treatment. Topical immunosuppressive therapy (tacrolimus or potent glucocorticosteroids) is usually needed, but would be contraindicated if (high‐risk) HPV were present.
Concentration-dependent phototoxicity in trimethylpsoralen bath psoralen ultraviolet A
Authors: E. Snellman, T. Rantanen
Journal: British Journal of Dermatology (2001)

Long-term use of topical trimethylpsoralen (TMP) psoralen bath plus ultraviolet A (bath PUVA) is considered safe with regard to the risk of skin cancer. However, the potential for severe phototoxicity limits its use.To study the effect of dilution of the TMP bath on the minimal phototoxic dose (MPD).Fifteen volunteers participated in the study. The MPD tests were performed for three TMP concentrations: 0.33 mg L-1, 0.1 mg L-1 and 0.033 mg L-1 at 2-week intervals. Geometric UVA dose series increasing by a factor of radical2 were used for the testing on the previously unexposed buttock skin. The MPD72 h was assessed at 72 h from the bath.For the highest TMP concentration of 0.33 mg L-1, the median MPD72 h was 0.14 J cm-2 (95% confidence interval (CI), 0.10-0.14 J cm-2). For the diluted TMP bath concentration of 0.1 mg L-1, the median MPD72 h increased to 0.29 J cm-2 (95% CI, 0.2-0.41 J cm-2) and for 0.033 mg L-1 to 0.81 J cm-2 (95% CI, 0.57-1.15 J cm-2), respectively. Thus, diluting the labelled concentration of 0.33 mg L-1 1 : 10 increased the median MPD72 h 5.6-fold.With regard to the safety and practicality of the TMP bath PUVA, the lower concentrations of TMP may be of clinical importance, and this needs to be validated in future controlled clinical trials.
Routine Thrombectomy in Percutaneous Coronary Intervention for Acute ST-Segment–Elevation Myocardial Infarction
Authors: Anne Kaltoft, Morten Bøttcher, Søren Steen Nielsen, Hans-Henrik Tilsted Hansen, Christian Terkelsen, Michael Mæng, Jens Kristensen, Leif Thuesen, Lars Romer Krusell, Steen Dalby Kristensen, Henning Rud Andersen, Jens Flensted Lassen, Klaus Rasmussen, Michael Rehling, Torsten Toftegaard Nielsen, Hans Erik Bøtker
Journal: Circulation (2006)

Distal embolization during primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction may result in reduced myocardial perfusion, infarct extension, and impaired prognosis.In a prospective randomized trial, we studied the effect of routine thrombectomy in 215 patients with ST-segment-elevation myocardial infarction lasting <12 hours undergoing primary PCI. Patients were randomized to thrombectomy pretreatment or standard PCI. The primary end point was myocardial salvage measured by sestamibi SPECT, calculated as the difference between area at risk and final infarct size determined after 30 days (percent). Secondary end points included final infarct size, ST-segment resolution, and troponin T release. Baseline variables, including ST-segment elevation and area at risk, were similar. Salvage was not statistically different in the thrombectomy and control groups (median, 13% [interquartile range, 9% to 21%] and 18% [interquartile range, 7% to 25%]; P=0.12), but 24 patients in the thrombectomy group and 12 patients in the control group did not have an early SPECT scan, mainly because of poor general or cardiac condition (P=0.04). In the thrombectomy group, final infarct size was increased (median, 15%; [interquartile range, 4% to 25%] versus 8% [interquartile range, 2% to 18%]; P=0.004).Thrombectomy performed as routine therapy in primary PCI for ST-elevation myocardial infarction does not increase myocardial salvage. The study suggests a possible deleterious effect of thrombectomy, resulting in an increased final infarct size, and does not support the use of thrombectomy in unselected primary PCI patients.
The Anatomy of Medical Research
Authors: Hamilton Moses, David H. M. Matheson, Sarah Cairns-Smith, Benjamin P. George, Chase Palisch, E. Ray Dorsey
Journal: JAMA (2015)

Medical research is a prerequisite of clinical advances, while health service research supports improved delivery, access, and cost. Few previous analyses have compared the United States with other developed countries.To quantify total public and private investment and personnel (economic inputs) and to evaluate resulting patents, publications, drug and device approvals, and value created (economic outputs).Publicly available data from 1994 to 2012 were compiled showing trends in US and international research funding, productivity, and disease burden by source and industry type. Patents and publications (1981-2011) were evaluated using citation rates and impact factors.(1) Reduced science investment: Total US funding increased 6% per year (1994-2004), but rate of growth declined to 0.8% per year (2004-2012), reaching $117 billion (4.5%) of total health care expenditures. Private sources increased from 46% (1994) to 58% (2012). Industry reduced early-stage research, favoring medical devices, bioengineered drugs, and late-stage clinical trials, particularly for cancer and rare diseases. National Insitutes of Health allocations correlate imperfectly with disease burden, with cancer and HIV/AIDS receiving disproportionate support. (2) Underfunding of service innovation: Health services research receives $5.0 billion (0.3% of total health care expenditures) or only 1/20th of science funding. Private insurers ranked last (0.04% of revenue) and health systems 19th (0.1% of revenue) among 22 industries in their investment in innovation. An increment of $8 billion to $15 billion yearly would occur if service firms were to reach median research and development funding. (3) Globalization: US government research funding declined from 57% (2004) to 50% (2012) of the global total, as did that of US companies (50% to 41%), with the total US (public plus private) share of global research funding declining from 57% to 44%. Asia, particularly China, tripled investment from $2.6 billion (2004) to $9.7 billion (2012) preferentially for education and personnel. The US share of life science patents declined from 57% (1981) to 51% (2011), as did those considered most valuable, from 73% (1981) to 59% (2011).New investment is required if the clinical value of past scientific discoveries and opportunities to improve care are to be fully realized. Sources could include repatriation of foreign capital, new innovation bonds, administrative savings, patent pools, and public-private risk sharing collaborations. Given international trends, the United States will relinquish its historical international lead in the next decade unless such measures are undertaken.
Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study
Authors: B. Van Calster, K. Van Hoorde, L. Valentin, A. C. Testa, D. Fischerova, C. Van Holsbeke, L. Savelli, D. Franchi, E. Epstein, J. Kaijser, V. Van Belle, A. Czekierdowski, S. Guerriero, R. Fruscio, C. Lanzani, F. Scala, T. Bourne, D. Timmerman
Journal: BMJ (2014)

<b>Objectives</b> To develop a risk prediction model to preoperatively discriminate between benign, borderline, stage I invasive, stage II-IV invasive, and secondary metastatic ovarian tumours. <b>Design</b> Observational diagnostic study using prospectively collected clinical and ultrasound data. <b>Setting</b> 24 ultrasound centres in 10 countries. <b>Participants</b> Women with an ovarian (including para-ovarian and tubal) mass and who underwent a standardised ultrasound examination before surgery. The model was developed on 3506 patients recruited between 1999 and 2007, temporally validated on 2403 patients recruited between 2009 and 2012, and then updated on all 5909 patients. <b>Main outcome measures</b> Histological classification and surgical staging of the mass. <b>Results</b> The Assessment of Different NEoplasias in the adneXa (ADNEX) model contains three clinical and six ultrasound predictors: age, serum CA-125 level, type of centre (oncology centres <i>v</i> other hospitals), maximum diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites. The area under the receiver operating characteristic curve (AUC) for the classic discrimination between benign and malignant tumours was 0.94 (0.93 to 0.95) on temporal validation. The AUC was 0.85 for benign versus borderline, 0.92 for benign versus stage I cancer, 0.99 for benign versus stage II-IV cancer, and 0.95 for benign versus secondary metastatic. AUCs between malignant subtypes varied between 0.71 and 0.95, with an AUC of 0.75 for borderline versus stage I cancer and 0.82 for stage II-IV versus secondary metastatic. Calibration curves showed that the estimated risks were accurate. <b>Conclusions</b> The ADNEX model discriminates well between benign and malignant tumours and offers fair to excellent discrimination between four types of ovarian malignancy. The use of ADNEX has the potential to improve triage and management decisions and so reduce morbidity and mortality associated with adnexal pathology.
Phase II Trial of PS-341 in Patients With Renal Cell Cancer: A University of Chicago Phase II Consortium Study
Authors: Nancy B. Davis, David A. Taber, Rafat H. Ansari, Christopher W. Ryan, Christopher George, Everett E. Vokes, Nicholas J. Vogelzang, Walter M. Stadler
Journal: Journal of Clinical Oncology (2003)

Purpose Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. Patients and Methods PS-341 1.5 mg/m 2 was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m 2 ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. Results Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P = .07 and .11, respectively). Conclusion Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.
Clinical experience of lymphangioleiomyomatosis in the UK
Authors: S R Johnson
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Lymphangioleiomyomatosis is a rare lung disease that affects only women. No controlled trials of management have been performed and, until such data are available, management must be based on clinical experience. This study provides data on the natural history of lymphangioleiomyomatosis in the UK and compares this with experience from other centres. <h3>METHODS</h3> We tried to identify all cases of lymphangioleiomyomatosis in the UK over a five year period by contacting all chest physicians. Cases were confirmed by lung biopsy or history and high resolution computed tomographic (CT) scanning. Details of disease and management were obtained from hospital notes. <h3>RESULTS</h3> The 50 patients who fitted the diagnostic criteria for lymphangioleiomyomatosis had a median age at onset of 35 years (range 22–50). Five presented when postmenopausal (four taking hormone replacement therapy). Pneumothorax and dyspnoea were the most common presenting features. Extrapulmonary presentations included renal angiomyolipomas (3) and lymphangiomyomas (2). Only half the patients were assessed for renal angiomyolipoma and six were identified. Thirty patients had had one or more pneumothoraces, of which two thirds recurred if treated conservatively. Chylous effusions occurred in 11 patients, five requiring surgery. Pregnancy was uncommon once the diagnosis was made (n=7), but was associated with an increase in complications. Half the patients were taking a β agonist and many showed a bronchodilator response in the laboratory. Thirty six patients had received hormone treatment. <h3>CONCLUSIONS</h3> Our UK five year period prevalence was one per 1.1 million population. Since prophylactic interventions are sometimes indicated for renal angiomyolipoma, these data suggest that screening for angiomyolipoma, ideally by CT scanning, may be underused. Patients need to be aware of the increase in complications associated with pregnancy. Recurrence rate of pneumothorax was high in those not treated surgically. Hormone treatment was used variably and controlled trials are needed to determine their role and the optimum duration and dose.
Shared Health Governance: The Potential Danger of Oppressive “Healthism”
Authors: Stacy M. Carter, Vikki Ann Entwistle, Kirsten McCaffery, Lucie Rychetnik
Journal: The American Journal of Bioethics (2011)

We share an interest in public health and in the capabilities approach developed by Amartya Sen, Martha Nussbaum, and others (Comim, Qizilbash, and Alkire 2008; Sen 2009; Nussbaum 1999), so were cu...
Errors in RNA-Seq quantification affect genes of relevance to human disease
Authors: Christelle Robert, Mick Watson
Journal: Genome biology (2015)

RNA-Seq has emerged as the standard for measuring gene expression and is an important technique often used in studies of human disease. Gene expression quantification involves comparison of the sequenced reads to a known genomic or transcriptomic reference. The accuracy of that quantification relies on there being enough unique information in the reads to enable bioinformatics tools to accurately assign the reads to the correct gene. We apply 12 common methods to estimate gene expression from RNA-Seq data and show that there are hundreds of genes whose expression is underestimated by one or more of those methods. Many of these genes have been implicated in human disease, and we describe their roles. We go on to propose a two-stage analysis of RNA-Seq data in which multi-mapped or ambiguous reads can instead be uniquely assigned to groups of genes. We apply this method to a recently published mouse cancer study, and demonstrate that we can extract relevant biological signal from data that would otherwise have been discarded. For hundreds of genes in the human genome, RNA-Seq is unable to measure expression accurately. These genes are enriched for gene families, and many of them have been implicated in human disease. We show that it is possible to use data that may otherwise have been discarded to measure group-level expression, and that such data contains biologically relevant information.
Respiratory and haemodynamic effects of the prone position at two different levels of PEEP in a canine acute lung injury model
Authors: C‐m Lim, Y Koh, J.y Chin, J.s Lee, S.d Lee, W.s Kim, D.s Kim, W.d Kim
Journal: European Respiratory Journal (1999)

This study was designed to examine whether the oxygenation response in the prone position differs in magnitude depending on the level of positive end-expiratory pressure (PEEP) applied in the supine position, and whether cardiac output (CO) increases in the prone position. In seven supine dogs, acute lung injury was established by saline lavage (arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2) 17.8+/-9.6 kPa (134+/-72 mmHg)), and inflection point (Pflex) of the respiratory system was measured (6.6+/-1.4 cmH2O). Pa,O2/FI,O2 and CO of the supine and prone positions were obtained under the application of low PEEP and then under optimal PEEP (2 cmH2O below and above Pflex, respectively). The net increase in Pa,O2/FI,O2 by prone positioning was greater at low PEEP (27.3+/-12.0 kPa (205+/-90 mmHg)) than at optimal PEEP (4.4+/-13.0 kPa (33+/-98 mmHg)) (p=0.006). CO decreased significantly with optimal PEEP in the supine position (2.4+/-0.5 versus 3.1+/-0.4 L x min(-1) at baseline, p<0.001), and increased to 3.4+/-0.6 and 3.6+/-0.7 L x min(-1) in the prone position at 5 min and 30 min, respectively (both p=0.018). When the dogs were turned supine at optimal PEEP, CO again decreased (2.4+/-0.5 L x min(-1), p<0.001). In conclusion, the prone position augmented the effect of relatively low positive end-expiratory pressure on oxygenation, and attenuated the haemodynamic impairment of relatively high positive end-expiratory pressure in a canine acute lung injury model.