tbuckley/cabot-search huggingface dataset:
Abstract 1115: p32 is a downstream effector of c-Myc induced glutamine addiction
Authors: Valentina Fogal, Ying S. Chao, Sandra Pastorino, Lucia Wang, Pengfei Jian, Rajesh Mukthavaram, Matthew Gallagher, IlaSri B. Summitt, Santosh Kesari
Journal: Cancer Research (2012)

Abstract Genetic alterations of oncogenes and tumor suppressor genes are the main drivers not only of deregulated cell proliferation but also altered cancer cell metabolism. Compared with normal cells, malignant cells exhibit enhanced utilization of glucose and glutamine. As such, efforts to understand the molecular basis of the addiction to these two nutrients is likely to lead to the identification of new drug targets for the specific killing of cancer cells. A major player in tumor cell addiction to glutamine is the c-Myc oncogene. By stimulating the expression of glutamine transporters and glutaminase, this transcription factor promotes glutamine oxidation through the mitochondria. This rewiring of glutamine metabolism must be sustained by efficient mitochondrial function. The mitochondrial p32 protein was previously demonstrated to be critical in mitochondria metabolism by maintaining oxidative phosphorylation, yet the factors regulating its expression are not clear. Deregulated c-Myc is a frequent feature of gliomas and recent discoveries suggest the importance of metabolic alterations, in particular glutamine addiction, in the pathogenesis of these cancers. Interestingly, medulloblastoma can be clustered into six subgroups based on gene signature and the c-Myc amplified subgroup exhibits high p32 expression. In the present study, we hypothesized that p32 may be a downstream effector of c-Myc induced glutamine addiction. Using a c-Myc and estrogen receptor fusion protein construct in immortalized fibroblast, we demonstrated that p32 expression was up regulated upon c-Myc nuclear translocation. shRNA mediated stable knock-down of p32 in glioma cell lines and patient-derived tumor initiating cells impaired cell proliferation and tumorigenic potential in mouse models. Furthermore, attenuation of p32 expression reduced glioma cells sensitivity to glutamine deprivation and abrogated c-Myc induced glutamine consumption. Additional work is underway to determine whether c-Myc and p32 work in the same or parallel pathways to confer glutamine addiction on glioma cells and to establish the implications of this co-operation on tumor metabolism in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1115. doi:1538-7445.AM2012-1115
Mediastinoscopy and bronchial carcinoma: experience with 600 mediastinoscopies.
Authors: L K Lacquet, A Mertens, J V Kleef, C Jongerius
Journal: Thorax (1975)

Of 600 mediastinoscopies carried out from 1966 to 1973, 479 were performed to assess the operability of a pulmonary carcinoma. Of these, 206 (43%) were positive and 273 (57%) were negative. Of the 161 patients found positive during an initial period, 147 were refused operation; the remaining 14 were considered suitable candidates for operation, either because only one homolateral lymph node site was involved or because there was a concomitant osteoarthropathy. The tumour was irresectable in one of these 14 patients who died after 3-5 months; curative resection was possible in one and palliative resection in 12 patients. These 12 patients all died within a year. Of the 184 patients found negative during an initial period, 149 were treated by operation. The tumour proved irresectable in seven (5%), while curative resection was possible in 113 (76%) and palliative resection in 29 (19%) patients. Comparison with the period 1957-63, when in the same hospital resection was performed after a negative Daniels' (scalene node) biopsy, shows that the tumour was irresectable in 25 (20%) of the 124 patients with a negative biopsy, while curative resection was possible in 43 (35%) and palliative resection in 56 (45%) patients. During a second period, patients with a positive mediastinoscopy were in principle refused operation. Of 89 negative patients, 81 were treated by operation. No tumour was found to be irresectable; curative resection was possible in 63 (78%) and palliative resection in 18 (22%) patients. An operation for bronchial carcinoma was performed on 167 patients between September 1970 and September 1973 after a negative mediastinoscopy in 95, and without mediastinoscopy in 71 patients, either because of a peripheral tumour (70) or because of a tumour relapse after two years (1). The resection was palliative in 11% of the 71 cases, but in only one patient with a peripheral tumour could a mediastinoscopy have been positive. Finally, an operation was performed on one patient with a positive mediastinoscopy and a tumour relapse after six years. A survival study was made of the first 100 patients with pulmonary carcinoma, operated on between September 1970 and March 1972 and with a follow-up from a minumum of two years to a maximum of 3-5 years. The early mortality averaged 10% and was higher after pneumonectomy than after lobectomy. The late mortality was 16% after curative lobectomy, 38% after curative pneumonectomy, and 83% after palliative pneumonectomy. The survival after 2 to 3-5 years was 63%.
How much will Herceptin really cost?
Authors: Andrew Dillon, Peter Littlejohns
Journal: BMJ (2006)

How much will Herceptin really cost? Balancing local and national priorities is not newEditor-Herceptin for early stage breast cancer is a cost effective treatment, and it is right that the NHS should make it available.The challenge of funding new treatments and balancing local and national priorities is one the NHS has faced since its inception. 1 The process the National Institute for Health and Clinical Excellence (NICE) follows for evaluating new medicines is the most rigorous anywhere in the world, and local NHS organisations can have confidence that implementing our recommendations is an effective use of their resources.NICE's independent advisory committees do not rubber stamp decisions.They make them based on an objective and impartial interpretation of the evidence.Those who suggest otherwise should come forward with their evidence for doing so.It is wrong to suggest that a single recommendation from NICE will necessarily cause other services to be reduced and that these decisions are made by clinicians only.Many demands are made on available funds in any hospital at any one time and it is the responsibility of local NHS management, working with their clinical teams, to make the best use of these resources.This difficult job is made easier by NICE guidance and the support tools we offer, such as our commissioning guides and our forthcoming advice on shifting spending from less to more effective treatments.
Molecular aspects of persistent woodchuck hepatitis virus and hepatitis B virus infection and hepatocellular carcinoma
Authors: Charles E. Rogler, Okio Hino, Chun-Yeh Su
Journal: Hepatology (1987)

It seems evident that the development of fully malignant HCC is a multistage process with many variables. One possible mechanism by which many of these variables may interact is as follows. During chronic active hepatitis, viral DNA integration occurs randomly and at a low frequency in hepatocytes. Integration may be stimulated by the increased rate of hepatocyte cell division resulting from liver necrosis and regeneration during chronic disease. The presence of viral integrations in the cellular genome provides focal points for the generation of chromosomal aberrations. One pathway by which these aberrations may be generated involves rearrangement of integrated viral and cellular sequences following viral DNA integration. The rearrangements which occur may include deletion, translocation, transposition or amplification of specific viral and cellular DNA sequences. We and others have directly demonstrated that all of these events are associated with different HBV integrations. The presence of viral integrations in chromosomes may also, by some unknown mechanism, destabilize those chromosomes such that whole chromosomes fail to segregate and are lost from particular cells. Preliminary studies we have conducted using restriction fragment length polymorphisms have revealed the loss of Chromosome 11 alleles in several HCC, indicating that chromosome loss may be a common occurrence in HCC. Our studies with restriction fragment length polymorphisms support such a mechanism involving Chromosome 11 in HCC. Specific chromosomal aberrations associated with all HCCs have not yet been identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Public health is under threat from NHS reorganisation, expert warns
Authors: Claire Laurent
Journal: BMJ (2006)

Public heath services in England will be thrown into crisis if jobs in the specialty are cut in the latest round of reorganisation of the NHS, said Rod Griffiths, president of the faculty of public health at the Royal College of Physicians.

The crisis could result in incidents on the scale of the disaster at Stanley Royd Hospital in Wakefield in 1984, in which 19 people died of salmonella poisoning, or worse, he told the UK Health Protection Agency's annual conference in Warwick this week, referring to an article in last week's BMJ (2006;333:557).

Professor Griffiths warned that …
OPERATIVE PROCEDURE ON THE EXCITING AND THE SYMPATHIZING EYE IN CASES OF SYMPATHETIC OPHTHALMIA.
Authors: JOHN E. WEEKS
Journal: JAMA (1905)

flex congestion caused by irritation of sensory nerves lasts for a considerable time, as it does in a sympathet¬ ically affected eye, it places the cells of the part in a con¬ dition of instability, lowers the vitality of the capillary walls, and offers facilities for the emigration of leuco¬ cytes, so that on slight provocation inflammation may be precipitated.In a word, they admit that, solely through the influence of the ciliary nerves, we may have in the sympathizing eye a condition which is just short of actual inflammation.At last, however, it would seem, the pathologists are willing to concede even more than this; to concede, in fact-if I rightly interpret the conclusions reached by Head and Campbell as a result of their carefully conducted investigations concerning the pathology of herpes zoster11-all that the advocates of the ciliary nerve theory of sympathetic ophthalmitis ever have claimed-that, without the intervention of bacteria or their products, inflammation may be set up in a dis¬ tant part in consequence of an irritation of sensory nerves in relation with this part.
Association of Lipoprotein Lipase Gene Variation with the Physiological Components of the Insulin-Resistance Syndrome in the Population of the San Luis Valley, Colorado
Authors: Young I Ahn, Robert E Ferrell, Richard F Hamman, M Ilyas Kamboh
Journal: Diabetes Care (1993)

OBJECTIVE To cross-sectionally evaluate the presence of clustering of the insulin-resistance syndrome components. Tests were conducted for association of the Hind III restriction site polymorphism at the lipoprotein lipase locus with clustering of the physiological components of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS DNA samples of 370 normoglycemic Hispanics and 520 normoglycemic non-Hispanic whites from the San Luis Valley, Colorado, were amplified by the polymerase chain reaction. Lipids and glucose were determined by the standard procedures. Cross-tabulation and χ2 analysis were used. RESULTS The insulin-resistance syndrome components (elevated fasting insulin, reduced high-density lipoprotein cholesterol, and elevated triglycerides) appeared together in individuals of this population sample more often than expected by chance. Individuals in the population with the (+/+) lipoprotein lipase-HindIII restriction of fragment-length polymorphism genotype were more likely to have elevated fasting insulin and triglycerides and a reduced high-density lipoproteincholesterol level than subjects with the (+/−) genotype (odds ratio = 2.3, 95% confidence interval 1.38–3.98). CONCLUSIONS As expected from the physiological function of lipoprotein lipase, the primary association of lipoprotein lipase genotypes is with triglyceride and high-density lipoprotein-cholesterol levels. This appears to be the first reported genetic association with the insulin-resistance syndrome and may reflect genotype specific differences in the regulation of lipoprotein lipase by insulin.
Devolution and the Health Service
Authors: T L Pilkington
Journal: BMJ (1978)

Methods to differentiate human pluripotent stem cells into kidney organoids were first introduced about 5 years ago, and since that time, the field has grown substantially. Protocols are producing increasingly complex three-dimensional structures, have been used to model human kidney disease, and have been adapted for high-throughput screening. Over this same time frame, technologies for massively parallel, single-cell RNA sequencing (scRNA-seq) have matured. Now, both of these powerful approaches are being combined to better understand how kidney organoids can be applied to the understanding of kidney development and disease. There are several reasons why this is a synergistic combination. Kidney organoids are complicated and contain many different cell types of variable maturity. scRNA-seq is an unbiased technology that can comprehensively categorize cell types, making it ideally suited to catalog all cell types present in organoids. These same characteristics also make scRNA-seq a powerful approach for quantitative comparisons between protocols, batches, and pluripotent cell lines as it becomes clear that reproducibility and quality can vary across all three variables. Lineage trajectories can be reconstructed using scRNA-seq data, enabling the rational adjustment of differentiation strategies to promote maturation of desired kidney cell types or inhibit differentiation of undesired off-target cell types. Here, we review the ways that scRNA-seq has been successfully applied in the organoid field and predict future applications for this powerful technique. We also review other developing single-cell technologies and discuss how they may be combined, using “multiomic” approaches, to improve our understanding of kidney organoid differentiation and usefulness in modeling development, disease, and toxicity testing.
Pathogenesis of Pneumococcal Infection
Authors: Elaine I. Tuomanen, Robert Austrian, H. Robert Masure
Journal: New England Journal of Medicine (1995)

The study of Streptococcus pneumoniae has led to many insights into the pathogenesis of bacterial infections. The importance of the polysaccharide capsule of the organism in determining its virulence was indicated by studies of the protective role of anticapsular antibodies.13 Of comparable importance was the observation that noncapsulated pneumococci caused progressive disease in rabbits with agranulocytosis, demonstrating thereby the pathogenic properties of the pneumococcal soma.4 Investigation of the pathologic events in pneumococcal infection led to the discovery of DNA,2,3 the development of the first bacterial polysaccharide vaccine,5 and insights into the mechanism of action of penicillin,6 antibiotic tolerance, . . .
Prevalence of an abnormal ankle-brachial index in patients with primary antiphospholipid syndrome: preliminary data
Authors: M A Baron
Journal: Annals of the Rheumatic Diseases (2004)

To evaluate the prevalence of abnormal ankle-brachial indexes (ABIs), their relationship with other cardiovascular risk factors and/or the presence of antiphospholipid antibodies (aPL), and the clinical use of the ABI in patients with primary antiphospholipid syndrome (primary APS).An 8 MHz Doppler probe was used in the arms and legs to assess the ABI in 43 patients with primary APS (mean (SD) age 40.2 (7.9) years) and 49 healthy subjects (aged 41.0 (11.7)) matched for age and sex. Data on traditional cardiovascular risk factors, such as hypertension, hypercholesterolaemia, presence of diabetes mellitus, nephrotic syndrome or renal failure, smoking, and other variables, were collected at that time for all subjects. A ratio of the highest blood pressure from the posterior tibial or pedal arteries of each leg to the highest blood pressure from the brachial arteries <1.00 was considered abnormal.Abnormal ABIs were found in 8/43 (19%) patients with primary APS and 2/49 (4%) controls (p = 0.026). No correlation between abnormal ABI and traditional cardiovascular risk factors nor with the presence of aPL was found.Abnormal ABIs are more common in primary APS than in healthy controls, possibly indicating a subclinical atherosclerotic process in these patients.
Causes, consequences, and reversal of immune system aging
Authors: Encarnacion Montecino-Rodriguez, Beata Berent-Maoz, Kenneth Dorshkind
Journal: Journal of Clinical Investigation (2013)

The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.
Effect of acidosis on contraction of microvascular smooth muscle by alpha 1- and alpha 2-adrenoceptors. Implications for neural and metabolic regulation.
Authors: K M McGillivray-Anderson, J E Faber
Journal: Circulation Research (1990)

Our previous studies have identified that adrenergic regulation of large arterioles and venules in skeletal muscle uses both postjunctional alpha 1- and alpha 2-adrenoceptors, whereas terminal arterioles appear to be subserved primarily by alpha 2-receptors. Adrenergic constriction of terminal arterioles is known to be particularly susceptible to inhibition by increased tissue metabolic rate. The purpose of this study was to examine the influence of tissue acidosis on alpha 1- and alpha 2-adrenoceptor constriction of skeletal muscle microvessels to determine if this differential receptor distribution might have significance in neural-metabolic interactions. Intravital microscopy of rat cremaster skeletal muscle was used to obtain concentration-response curves (diameter changes) of large distributing arterioles (mean diameter, 100 microns), small precapillary arterioles (20 microns), and capacitance venules (150 microns) for addition to the tissue bath of alpha-adrenergic agonists during normal pH (7.4) and during tissue bath acidosis (pH 7.1) produced by increasing bath PCO2. The following alpha-agonists were used: phenylephrine (alpha 1), B-HT 933 (alpha 2), and norepinephrine (mixed alpha 1/alpha 2). Acidosis had no effect on baseline diameter of the three vessel types, indicating a lack of effect on "intrinsic tone." Acidosis also had no effect on large microvessel sensitivity to phenylephrine but markedly reduced responses to B-HT 933. Acidosis had no effect on large arteriolar and venular sensitivity to norepinephrine but markedly decreased (x300) small precapillary arteriolar sensitivity. These data suggest that 1) alpha 2- but not alpha 1-adrenoceptor-mediated constriction of microvessels may be selectively sensitive to modest reductions in tissue pH, and 2) the prevalence of alpha 2-receptors on terminal arterioles and the marked sensitivity of alpha 2 constriction to tissue acidosis may contribute to the particular susceptibility of neural constriction at this level of the microcirculation to metabolic inhibition.
ALTERATIONS IN SUBCUTANEOUS SMALL ARTERY WALL STRUCTURE CORRELATE WITH DIASTOLIC PARAMETERS IN PATIENTS WITH METABOLIC SYNDROME
Authors: Kaivan Khavandi, Matthew Luckie, Reza Aghamohammadzadeh, Ali Khavandi, Aliya Mastan, Adam Greenstein, Rayaz Malik, Rajdeep Khattar, Anthony M. Heagerty
Journal: Journal of the American College of Cardiology (2011)
Doctors should abandon ties and avoid nose rings
Authors: R. Dobson
Journal: BMJ (2003)

The necktie, that traditional symbol of male medical authority, is under threat. Pressure is mounting for doctors to either pin their ties back to stop the spread of infection from flapping tie ends or get rid of them altogether.

Junior doctors are this week being asked to back a resolution saying that there is no longer a reason for doctors to wear ties while at work and while seeing patients.

Wearing a tie may enhance patients' satisfaction and confidence, say critics, but a dangling tie also substantially …
The Poor Quality of Early Evaluations of MRI
Authors: James W. Reinig
Journal: JAMA (1988)

To the Editor.—  Before a new technology can be assesed, it must first be described. Twenty-six of the 54 articles evaluated by Cooper et al 1 were the first or second description in this literature of a given organ, part of the body, or disease. Clearly, these were preliminary works, meant to describe possible applications of magnetic resonance imaging (MRI), not to critically assess it. Indeed, the first clinical MRI unit was not installed in the United States until November 1982, 2 almost three years into the 4 1/2-year period covered by this study.  It is naive for the authors to believe that this group of articles (published from 1980 to 1984) would be the appropriate collection to evaluate whether MRI imaging had been compared in a statistically significant manner with established imaging techniques. In the early 1980s, MRI was a largely investigational procedure being studied only in a few
Treatment of Diabetes Mellitus
Authors: W. Oakley
Journal: BMJ (1959)

It is about 35 years since Banting and Best discovered insulin, and, in spite of a vast amount of research, the exact mode of action of this hormone is still unknown. The structure of the insulin molecule has been brilliantly demonstrated by Sanger and his colleagues (Ryle et al., 1955), who showed that insulin is a protein with a molecular weight of 6,000 or multiples thereof. Each molecule consists of two polypeptide chains held together by -S-Slinkages derived from the amino-acid cystine. The A chain is made up of 21 amino-acid residues and the B chain of 30. It is convenient to consider first the actions of insulin and then the effects of such actions, as the former are
Advanced Exercises in Diagnostic Radiology--Rheumatic Disorders
Authors: I. Watt
Journal: Annals of the Rheumatic Diseases (1989)

This is a practical manual and deserves the place it has achieved in American medicine.From a conventional rheumatological point of view the chapters on rheumatic and connective tissue diseases offer a straightforward approach to the most important factors in treatment.There is a good and succinct account of the advantages and snags of rest, aspirin treatment, the use of splints, metatarsal bars, and all the currently used drug regimens.Reiter's syndrome, Sjogren's syndrome, and the cutaneous complications of connective tissue diseases are well dis-
Pakistan starts HIV treatment programme
Authors: Ashfaq Yusufzai
Journal: BMJ (2006)

Authorities in Pakistan have begun a three year antiretroviral treatment programme, for which drugs are being imported from India. Four treatment centres have been set up—in Islamabad, Peshawar, Lahore, and Karachi. The programme aims to provide treatment to 8000 infected people at the five centres. It will only be available to patients at public sector hospitals.

So far, about 100 patients have been registered at all the …