tbuckley/cabot-search huggingface dataset:
Abstract IA19: Intratumoral heterogeneity and drug response in high-grade serous carcinoma
Authors: James D. Brenton
Journal: Clinical Cancer Research (2013)

Abstract Our understanding of the molecular basis of epithelial ovarian cancer has changed dramatically over the past 10 years. We now recognise that different histological subtypes are fundamentally different diseases, based on recent discoveries identifying the cell-of-origin and key driver mutations for high-grade serous (HGSOC) and clear cell ovarian cancers. The major challenge for the development of personalized treatment for HGSOC is the extreme genomic heterogeneity between cases and additional intratumoural heterogeneity (ITH). We have previously shown that HGSOC is characterised by ubiquitous TP53 mutation and we have proposed that early loss of TP53 may be permissive for the development of a wide range of mutator phenotypes, which may contribute to platinum resistance and ITH. I will discuss our recent findings showing profound ITH in HGSOC and how tandem mutator phenotype may alter evolution in HGSOC. We have developed new methods to identify and quantify circulating tumour DNA in plasma samples from women with HGSOC. These methods provide highly specific biomarkers of response to treatment and can be used to track the emergence of resistant clonal populations. Application of these methods in a national study of relapsed ovarian cancer and in new clinical trials will provide critical clinical data to develop personalized treatment strategies for women with HGSOC. Citation Format: James D. Brenton. Intratumoral heterogeneity and drug response in high-grade serous carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA19.
1108-130 Granulocyte-colony stimulating factor mobilizes bone marrow stem cells and favorably alters cytokine profile in patients with advanced heart failure
Authors: Jacob Joseph, Asem Rimawi, Paulette Mehta, Michele Cottler-Fox, Anjan Sinha, Balkrishna Singh, Rebecca Pacheco, Eugene Smith, Jawahar L Mehta
Journal: Journal of the American College of Cardiology (2004)
Electrocardiographic findings in experimental myocarditis in DBA/2 mice: complete atrioventricular block in the acute stage, low voltage of the QRS complex in the subacute stage and arrhythmias in the chronic stage
Authors: Chiharu Kishimoto, Akira Matsumori, Minoru Ohmae, Nobuyoshi Tomioka, Chuichi Kawai
Journal: Journal of the American College of Cardiology (1984)
More foundation trusts are missing targets, finds regulator
Authors: G. Iacobucci
Journal: BMJ (2014)

The number of foundation trusts in England breaching the target for 85% of patients with cancer to start treatment within 62 days of being referred by a GP has more than quadrupled in the past year, new figures show.1

Some 18 trusts breached the target between October and December 2013, up from 12 in the previous quarter and from just four in the same quarter last year, said the health sector regulator Monitor.

The latest quarterly report from the regulator said that foundation trusts were generally coping with winter pressures, but it identified notable “challenges in some individual foundation trusts.” 

It found that 28 trusts …
Fas-mediated apoptosis in mouse hepatocytes involves the processing and activation of caspases
Authors: Richard A. Jones, Victoria L. Johnson, Neil R. Buck, Miloslav Dobrota, Richard H. Hinton, Sek C. Chow, George E. Kass
Journal: Hepatology (1998)

The mechanism of Fas antigen-induced hepatocyte apoptosis was investigated. Using a monoclonal antibody directed against the Fas antigen, apoptosis was induced in freshly isolated murine hepatocytes within 90 minutes of antibody addition as assessed by plasma membrane bleb formation, chromatin condensation, and DNA fragmentation. Pretreatment of the cells with the caspase inhibitors, N-acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-CHO), benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD-FMK), or Z-Asp-2,6-dichlorobenzoyloxymethylketone inhibited anti-Fas-mediated apoptosis. Likewise, the serine protease inhibitors, N-tosyl-L-phenyl chloromethyl ketone (TPCK) and 3,4-dichloroisocoumarin (DCI), prevented apoptosis, whereas N-tosyl-L-lysine chloromethyl ketone (TLCK), Ac-Leu-Leu-L-norleucinal, Ac-Leu-Leu-L-methional, and trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane were without effect. Examination of CED-3/caspase-3-related caspases revealed that pro-caspases-3 (CPP32) and -7 (Mch-3alpha) were rapidly processed after Fas antigen stimulation. Caspase-7 was further cleaved to form the catalytically active subunits. In contrast, the p17 subunit of caspase-3 was not detected, indicating slow formation or rapid degradation. The activation of CED-3-related caspases was further confirmed by an increase in the rate of Z-DEVD-7-amino-4-trifluoromethylcoumarin (Z-DEVD-AFC) hydrolysis that was sensitive to Ac-DEVD-CHO and was inhibited by pretreatment of the cells with TPCK but not by DCI. In contrast, no increase in the rates of hydrolysis of Z-YVAD-AFC, a substrate for caspase-1, was detected. Investigation of the in situ proteolytic cleavage of the CED-3 related caspases substrate, poly(ADP-ribose) polymerase, revealed that this protein was not degraded in hepatocytes undergoing Fas-mediated apoptosis. Taken together, our results show that processing of caspases, in particular, caspases-7 and -3, occurs during Fas-induced apoptosis of mouse hepatocytes and suggest a role of these proteases as well as serine protease(s) in the apoptotic response.
Setting budgets for general practice in the new NHS
Authors: P. C Smith
Journal: BMJ (1999)

<h3>Abstract</h3> Sexual systems are highly diverse and have profound consequences for population dynamics and resilience. Yet, little is known about how they evolved. Using phylogenetic Bayesian modelling and a sample of 4614 species, we show that gonochorism is the likely ancestral condition in teleost fish. While all hermaphroditic forms revert quickly to gonochorism, protogyny and simultaneous hermaphroditism are evolutionarily more stable than protandry. In line with theoretical expectations, simultaneous hermaphroditism does not evolve directly from gonochorism but can evolve slowly from sequential hermaphroditism, particularly protandry. We find support for the predictions from life history theory that protogynous, but not protandrous, species live longer than gonochoristic species and invest the least in male gonad mass. The distribution of teleosts’ sexual systems on the tree of life does not seem to reflect just adaptive predictions, suggesting that adaptations alone may not fully explain why some sexual forms evolve in some taxa but not others (Williams’ paradox). We propose that future studies should incorporate mating systems, spawning behaviours, and the diversity of sex determining mechanisms. Some of the latter might constrain the evolution of hermaphroditism, while the non-duality of the embryological origin of teleost gonads might explain why protogyny predominates over protandry in teleosts.
Illegitimate transcription. Application to the analysis of truncated transcripts of the dystrophin gene in nonmuscle cultured cells from Duchenne and Becker patients.
Authors: J Chelly, H Gilgenkrantz, J P Hugnot, G Hamard, M Lambert, D Récan, S Akli, M Cometto, A Kahn, J C Kaplan
Journal: Journal of Clinical Investigation (1991)

We have previously demonstrated that there is a low level of transcription of tissue-specific genes in every cell type. In this study, we have taken advantage of this phenomenon, called illegitimate transcription, to analyze the muscle-type dystrophin mRNA in easily accessible cells such as lymphoid cells, fibroblasts, and peripheral blood cells from Duchenne and Becker muscular dystrophies with known internal gene deletion. The results showed that, in the studied regions surrounding the deletions, processing of truncated transcripts is identical in specific (muscle tissue) and in nonspecific cells (lymphoid cells). In Becker cases with out-of-frame deletions, the already described alternatively spliced species found in muscle samples were also found in nonspecific cells. These results demonstrate that illegitimate transcripts are a bona fide version of tissue-specific mRNA, and that they represent a useful material to investigate the qualitative consequences of gene defects at the mRNA level.
P99Nrg1beta enhances glucose uptake in cardiomyocytes via mTOR, Src and Akt
Authors: L Pentassuglia, C Morandi, L Xu, S Lebboukh, M Brink
Journal: Cardiovascular Research (2014)

Background: Neuregulin (Nrg)1β is a growth factor that activates PI3K/Akt and Src/FAK via the ErbB2/ErbB4 receptors. Although it is currently in clinical trial to treat haert failure, it remains unclear which cellular mechanisms are responsible for its cardioprotective actions. Here we tested if Nrg1β regulates glucose uptake in cardiomyocytes and analyzed the underlying signaling mechanisms.
Toxicologic methods: controlled human exposures.
Authors: M J Utell, M W Frampton
Journal: Environmental Health Perspectives (2000)

The assessment of risk from exposure to environmental air pollutants is complex, and involves the disciplines of epidemiology, animal toxicology, and human inhalation studies. Controlled, quantitative studies of exposed humans help determine health-related effects that result from breathing the atmosphere. The major unique feature of the clinical study is the ability to select, control, and quantify pollutant exposures of subjects of known clinical status, and determine their effects under ideal experimental conditions. The choice of outcomes to be assessed in human clinical studies can be guided by both scientific and practical considerations, but the diversity of human responses and responsiveness must be considered. Subjects considered to be among the most susceptible include those with asthma, chronic obstructive lung disease, and cardiovascular disease. New experimental approaches include exposures to concentrated ambient air particles, diesel engine exhaust, combustion products from smoking machines, and experimental model particles. Future investigations of the health effects of air pollution will benefit from collaborative efforts among the disciplines of epidemiology, animal toxicology, and human clinical studies.
Randomised trial of self hypnosis for analgesia in labour.
Authors: R M Freeman, A J Macaulay, L Eve, G V Chamberlain, A V Bhat
Journal: BMJ (1986)

<h3>Objective</h3> Depression and anxiety are up to three times more prevalent in cardiac patients than the general population and are linked to increased risks of future cardiac events and mortality. Psychological interventions for cardiac patients vary in content and are often associated with weak outcomes. A recent treatment, metacognitive therapy (MCT) has been shown to be highly effective at treating psychological distress in mental health settings. This is the first study to explore qualitatively, cardiac rehabilitation (CR) patients’ experiences and understanding of group MCT with the aim of examining aspects of treatment that patients experienced as helpful. <h3>Methods</h3> In-depth qualitative interviews were conducted with 24 purposively sampled CR patients following group MCT. Data were analysed using thematic analysis. <h3>Results</h3> Two main themes were identified: (1) general therapy factors that were seen largely as beneficial, where patients highlighted interaction with other CR patients and CR staff delivery of treatment and their knowledge of cardiology; (2) group MCT-specific factors that were seen as beneficial encompassed patients’ understanding of the intervention and use of particular group MCT techniques. Most patients viewed MCT in a manner consistent with the metacognitive model. All the patients who completed group MCT were positive about it and described self-perceived changes in their thinking and well-being. A minority of patients gave specific reasons for not finding the treatment helpful. <h3>Conclusion</h3> CR patients with anxiety and depression symptoms valued specific group MCT techniques, the opportunity to learn about other patients, and the knowledge of CR staff. The data supports the transferability of treatment to a CR context and advantages that this might bring.
Food Consumption of Brussels Families in January, 1945
Authors: P. A. Bastenie, T. F. Macrae, G. A. Smart, S. Yudkin
Journal: BMJ (1945)

not severely disabled.The iodized oil was not removed at operation, and a further film taken before his discharge from hospital showed that the notched filling defect remained in the same position as before.Case III A housewife aged 44.First seen-July 20, 1944.Had had recurrent left sciatic pain for four years.Pain increased by coughing.Lasegue's sign present and left ankle-jerk diminished.No sensory loss or muscular wasting.C.S.F.: No cells; protein, 40 mg.per 100 c.cm.; W.R. negative.Myelography of the lumbar region showed a slight asymmetry of filling of the first sacral " axillary pouches," with less filling on the left side.No bony abnormality was seen and there was no narrowing of the disk spaces.Operation.-Sept.22. Laminectomy of L 4 and L 5. No evidence of disk protrusion on careful exploration of both disk spaces.No softening of disks found.Fine adhesions clearly seen on left first sacral root within the spinal canal.Tlhese were freed and the root mobilized.The patient made a rather slow recovery from her pain over three weeks and has remained free from pain since.
The role of ABCB1 transporter gene in breast cancer resistance.
Authors: R Vaclavikova, SH Nordgard, GA Alnaes, M Hubackova, I Hlavata, R Kodet, M Mrhalova, V Pecha, VN Kristensen, I Gut, P Soucek
Journal: Cancer Research (2009)

Abstract Abstract #4158 Background: Cellular multidrug resistance (MDR) to anticancer drugs remains one of the primary causes of suboptimal outcomes in cancer therapy. ATP-binding cassette (ABC) transporters belong to a family of transporter proteins that contribute to drug resistance via ATP-dependent drug efflux pumps. The aim of this study was to assess the role and clinical impact of ABCB1 and other ABC transporter-related genetic factors in development of MDR.&amp;#x2028; Material and Methods: Expression profile of ABC transporter genes (ABCB1, ABCC1/2, ABCG2) was evaluated in 90 breast cancer patients. Gene expression was quantified in samples from tumor and non-tumor breast tissues by real-time PCR. In addition, seven ABCB1 polymorphisms (SNPs) were analyzed using Nanogen electronic microarrays and compared with High Resolution Melting Analysis. Determination of associations between: 1/ expression of ABC transporters, 2/ genetic variability and 3/ haplotype pattern of ABCB1 on one side and clinico-pathological features including survival of patients on the other side was performed.&amp;#x2028; Results: ABC transporters were expressed in majority of cases. Striking inter-individual variability in their expression was found. ABCB1 was down-regulated in 79.5% of all tumors, while opposite was observed for ABCC1/2 expression. Similar expression profiles were found in patients treated by neoadjuvant and adjuvant chemotherapy. Patients with high ABCB1 expression treated with P-gp substrates anthracyclines or taxane containing regimens had significantly shorter disease-free survival than those treated by other regimens (P = 0.031). In genetic variation studies, high frequencies of variant alleles in ABCB1 exon12 (C1236T, qT=38.3), exon21 (G2677T/A, qT=40.0) and exon26 (C3435T, qT=54.0) were observed. Individuals with variant alleles in exons12 and 26 had significantly lower ABCB1 expression in their tumors than patients with normal genotype. These two SNPs also correlated with estrogen receptor status of patients (P=0.011 and P=0.051 respectively).&amp;#x2028; Conclusions: ABCB1 SNPs may affect function of protein by influencing the expression level and modify breast cancer prognosis. Especially, SNPs in exons 12 and 26 influenced ABCB1 expression and seem to be good candidates for cancer association studies. The observed association of ABCB1 SNPs with estrogen receptor status of patients warrants further research based on extended haplotype analysis. Moreover, high expression of ABCB1 in tumor tissue is considered to be an increased risk of failure of anthracycline or taxane-based chemotherapy. This work was supported by grants IGA 9426-3 and GACR 305/07/P347. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4158.
The DSM‐5: Classification and criteria changes
Authors: Darrel A. Regier, Emily A. Kuhl, David J. Kupfer
Journal: World Psychiatry (2013)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) marks the first significant revision of the publication since the DSM‐IV in 1994. Changes to the DSM were largely informed by advancements in neuroscience, clinical and public health need, and identified problems with the classification system and criteria put forth in the DSM‐IV. Much of the decision‐making was also driven by a desire to ensure better alignment with the International Classification of Diseases and its upcoming 11th edition (ICD‐11). In this paper, we describe select revisions in the DSM‐5, with an emphasis on changes projected to have the greatest clinical impact and those that demonstrate efforts to enhance international compatibility, including integration of cultural context with diagnostic criteria and changes that facilitate DSM‐ICD harmonization. It is anticipated that this collaborative spirit between the American Psychiatric Association (APA) and the World Health Organization (WHO) will continue as the DSM‐5 is updated further, bringing the field of psychiatry even closer to a singular, cohesive nosology.
Brain abscess presenting as an intracranial gas shadow.
Authors: K C Lee, J P McCann, D P Nicholls
Journal: BMJ (1987)

A brain abscess may present as a gas shadow in a plain skull radiograph.' Owing to the rarity of this feature its importance may not be recognised,2 which may lead to delay in diagnosis of a surgically correctable condition.The following case highlights the problem. Case reportA previously well 77 year old man was seen by his general practitioner for the sudden onset ofconfusion; he was found by his wife reading a newspaper upside down.There was no preceding history of deafness or ear discharge.FIG 1-Lateral skull radiograph of patient presenting with abrupt onset of confusion showing lucent area in temporal region.(Presence of air-fluid interface more evident when radiograph viewed in brow up position (as originally taken).)No definite abnormality was detected, and it was assumed that he had suffered a cerebrovascular accident.No specific treatment was given.He remained confused and complaining of headaches and one week later was found collapsed at home.
Abstract 009: Microclinic Social Network Lifestyle Intervention for Weight Loss and Obesity Management: A 10-Month Randomized Controlled Trial
Authors: Eric L Ding, Marta R Prescott, Kathleen T Watson, Nancy Bui, Leila Makarechi, Daniel E Zoughbie
Journal: Circulation (2013)

BACKGROUND: Lifestyle behaviors and health conditions, such as obesity, smoking, and alcohol use, are observed to contagiously propagate in social networks. However, to date, such effects have only...
Amyloidosis-associated delayed postpolypectomy bleeding
Authors: L. Filik, S. Koklu, B. Cakal
Journal: Endoscopy (2009)

We read with great interest the article by Sawhney et al. about the risk factors for delayed postpolypectomy bleeding [1]. They concluded in their case–control study that greater polyp diameter was associated with increased risk of postpolypectomy bleeding. Herein, we report a delayed gastrointestinal bleeding after polypectomy.
Lipoprotein(a) in Android Obesity and NIDDM
Authors: Nicola Wassef, Gloria Sidhom, Zakareya El-Khayat, Mohamed El-Kholy
Journal: Diabetes Care (1997)

OBJECTIVE To assess the level of serum lipoprotein(a) [Lp(a)] in nonobese and obese NIDDM subjects with android body distribution. RESEARCH DESIGN AND METHODS Serum Lp(a) levels were measured in 30 long-standing NIDDM patients (duration of diabetes 12.5 ± 3 years, mean ± SD), with 15 of the patients being obese of android distribution (BMI &amp;gt; 30 kg/m2 and waist-to-hip ratio &amp;gt; 0.8). In addition, there were 15 android obese nondiabetic subjects and 10 healthy subjects serving as the control group. RESULTS All groups of patients in this study (diabetic, obese, and obese diabetic) showed significantly higher levels of Lp(a) than the healthy control group. Lp(a) concentrations were significantly higher in NIDDM patients with android type of obesity than in nondiabetic androids (24.1 ± 5.6 vs. 14.8 ± 2.4 mg/dl, P &amp;lt; 0.001). Significantly greater levels of Lp(a) were found in nonobese subjects with diabetes when compared with obese subjects without diabetes (22.3 ± 4.1 vs. 14.8 ± 2.4 mg/dl, P &amp;lt; 0.001). Furthermore, Lp(a) serum concentrations were not dependent on the degree of glycemic control (controlled NIDDM 23.6 ± 5.0 vs. uncontrolled NIDDM 21.4 ± 2.7 mg/dl, NS), but were much greater in subjects with diabetes complicated by vascular disease (complicated 26.3 ± 5.0 vs. uncomplicated 20.5 ± 2.7 mg/dl, P &amp;lt; 0.001). No correlation was found between Lp(a) and other lipid parameters in this study. CONCLUSIONS Lp(a) levels are significantly elevated in both android-obese and nonobese NIDDM patients regardless of the degree of glycemic control. Lp(a) is an independent risk factor showing greater elevations in those subjects complicated with diabetic vascular diseases.
When I use a word: Triage
Authors: D. Carvel
Journal: BMJ (2000)

Since my days as an accident and emergency senior house officer I had believed (and perhaps I was taught) erroneously that triage was the process of dividing war or other casualties into three broad groups. These groups, I thought, were the dead and dying; the salvable; and the walking or less seriously wounded. The tri-, as I later discovered, is nothing to do with three—that is, tripartite.

The word triage was coined in the 18th century from the French trier: to pick, to choose, or to sort. Gare de triage is the French for a marshalling yard.1 My English dictionary defines triage as “the action of sorting (casualties, etc) according to priority.”2 There is no quantification of categories; in fact ABC of Major Trauma lists five: immediate, urgent, minor, palliative, dead.3 There is no suggestion that this is “quinage.”

Medline cites 751 papers and letters since 1960 containing triage in the title. It seems that there is increasing breadth of usage and use of the verb rather than the noun form, but it is still restricted to the emergency situation. Newer types of triage include mental health, cardiology, obstetrics, and nurse triage.

1   New Cassell's French Dictionary. New York: Cassell's, 1968. 2   The New Collins Concise English Dictionary. Glasgow: Collins, 1982. 3   ABC of Major Trauma. London: BMJ Publications, 1992.
What Physicians Know
Authors: S J Tanenbaum
Journal: New England Journal of Medicine (1993)

It has become a truism that not only does the United States spend more money on health care than do other industrialized nations, but also a substantial portion of this sum is wasted on unproved or ineffective diagnosis and therapy. Not surprisingly, then, outcomes research -- that is, the rigorous determination of what works in medical care and what does not -- figures prominently in proposals for health care reform. Outcomes research, by informing the content of policy positions, payment rules, and practice guidelines, presumably both solves the problems of quality and cost that beset the health care system and . . .