tbuckley/cabot-search huggingface dataset:
Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.
Authors: T Zhou, J Cheng, P Yang, Z Wang, C Liu, X Su, H Bluethmann, J D Mountz
Journal: The Journal of Experimental Medicine (1996)

The Nur77/Nurr1 family of DNA binding proteins has been reported to be required for the signal transduction of CD3/T cell receptor (TCR)-mediated apoptosis in T cell hybridomas. To determine the role of this family of DNA-binding proteins in thymic clonal deletion, transgenic (Tg) mice bearing a dominant negative mutation were produced. The transgene consisted of a truncated Nur77 (deltaNur77) gene encoding the DNA-binding domain of Nur77 ligated to a TCR-beta enhancer resulting in early expression in thymocytes. Apoptosis of CD4+CD8+ thymocytes mediated by CD3/TCR signaling was greatly inhibited in the deltaNur77 Tg mice, compared with non-Tg littermates, after treatment with anti-CD3 or anti-TCR antibody in vivo and in vitro. Clonal deletion of self-reactive T cells was investigated in deltaNur77-Db/HY TCR-alpha/beta double Tg mice. There was a five-fold increase in the total number of thymocytes expressing self-reactive Db/HY TCR-alpha/beta in the deltaNur77-TCR-alpha/beta double Tg male mice. Deficient clonal deletion of self-reactive thymocytes was demonstrated by a 10-fold increase in the CD4+CD8+ thymocytes that expressed Tg TCR-alpha/beta. There was an eightfold increase in the CD8+, Db/HY TCR-alpha/beta T cells in the lymph nodes (LN) of delta Nur77-Db/HY TCR-alpha/beta double Tg compared with Db/HY TCR-alpha/beta Tg male mice. In spite of defective clonal deletion, the T cells expressing the Tg TCR were functionally anergic. In vivo analysis revealed increased activation and apoptosis of T cells associated with increased expression of Fas and Fas ligand in LN of deltaNur77-Db/HY TCR-alpha/beta double male mice. These results indicate that inhibition of Nur77/Nurr1 DNA binding in T cells leads to inefficient thymic clonal deletion, but T cell tolerance is maintained by Fas-dependent clonal deletion in LN and spleen.
Reply to M.L. Friedlander et al
Authors: Nicoletta Colombo
Journal: Journal of Clinical Oncology (2013)

In a recent letter, Friedlander et al discuss the role of symptom benefit in platinum-resistant or -refractory ovarian cancer. Qualityof-life (QoL) assessments are of extreme importance in this patient population and particularly in this setting of platinum-resistant, recurrent ovarian cancer. For this reason, evaluation of patient-reported symptoms and QoL by the Functional Assessment of Cancer TherapyOvary (FACT-O) and FACT-O Symptom Index were secondary objectives in the phase III study that compared patupilone with pegylated liposomal doxorubicin in this patient population, and the results were published online as supplementary material. As reported, these scores trended lower (suggesting a decrease in the QoL) in the patients in the patupilone arm compared with those in the pegylated liposomal doxorubicin arm. This result is intriguing in that patupilone produced a higher overall response rate compared with pegylated liposomal doxorubicin (15.5% v 7.9%). Thus, although one might expect a possible positive impact on disease-related symptoms, the converse was observed. This may be reflective of the relatively low response rate, which did not translate into an appreciable impact on QoL. Alternatively, the QoL may have been negatively affected by chemotherapyrelated symptoms, which may reflect the unique toxicity profile for patupilone compared with pegylated liposomal doxorubicin. A more in-depth assessment would be required to derive a more definitive conclusion, but as future trials measure and report QoL and symptom benefit assessments, these types of comparative analyses will become increasingly common. Nicoletta Colombo University of Milan-Bicocca and European Institute of Oncology, Milan, Italy
Training of Mental Health Professionals Through the Use of the "Bug in the Ear"
Authors: WILLIAM H. BOYLSTON, JUNE M. TUMA
Journal: American Journal of Psychiatry (1972)

The authors describe their experience with a training device through which a supervisor is able to give instructions to a beginning psychotherapist by using a transmitter broadcasting to a receiver placed in the therapist's ear. Instant communication with the trainee while the latter is working with a patient is thus possible. Advantages and disadvantages of the technique are outlined.
Fetal Heart Rate Response to Maternal Exertion
Authors: Robert W. Smith
Journal: JAMA (1988)

To the Editor.—  The recent investigation by Carpenter et al 1 has provided clinicians with additional information regarding exercise in pregnancy. Procedural technique may have affected the outcome, however.  Patients in the study were placed in a semirecumbent position for seven minutes after exercise. One wonders whether uterine pressure against the inferior vena cava might have contributed to the results obtained by the authors. It would be interesting to see data obtained with the patients in the left lateral decubitus position. Patients who suffer fetal bradycardia during labor often will respond to this maneuver. Should clinicians be advising their patients to assume the left lateral decubitus position after maximal exercise?  Maximum heart rate exercise should also be accomplished with the use of an upper body ergometer to ensure that the demonstrated effect is not due to leg exercise while using a bicycle. This study remains to be done before one
Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.
Authors: D E Vatner, S F Vatner, J Nejima, N Uemura, E E Susanni, T H Hintze, C J Homcy
Journal: Journal of Clinical Investigation (1989)

The goal of this study was to determine the mechanism of beta-adrenergic receptor desensitization after chronic elevation of circulating NE levels. Osmotic minipumps containing either NE or saline were implanted subcutaneously in dogs for 3-4 wk. Physiologic desensitization to isoproterenol was confirmed in conscious dogs, i.e., left ventricular dP/dt increased in response to isoproterenol (0.4 micrograms/kg per min) by 5,625 +/- 731 mmHg/s in control dogs with saline pumps, and significantly less, P less than 0.01, by 2,093 +/- 263 mmHg/s in dogs with NE pumps. Myocardial beta-adrenergic receptor density as determined with 125I-cyanopindolol binding was 49% higher (p less than 0.05) in the NE pump group. However, beta-adrenergic receptor agonist binding with isoproterenol demonstrated a significant shift into the low affinity state for the animals with NE pumps. Basal, GTP plus isoproterenol, 5'-guanylylimidodiphosphate, sodium fluoride, and forskolin-stimulated adenylate cyclase activity in the NE pump group were significantly depressed (P less than 0.05) by amounts ranging from 20 to 40%. The functional activity of the guanine nucleotide binding protein Gs was also reduced (P less than 0.05) in animals with NE pumps. Thus, the process of desensitization in response to chronic elevation of NE levels in intact, normal dogs does not involve a decrease in beta-adrenergic receptor density. Rather, it is characterized by reduced adenylate cyclase activation and uncoupling of the beta-adrenergic receptor in association with decreased activity of the GTP-coupling protein Gs.
When EGF is offside, magnesium is wasted
Authors: Shmuel Muallem, Orson W. Moe
Journal: Journal of Clinical Investigation (2007)

Our understanding of magnesium (Mg2+) regulation has recently been catapulted forward by the discovery of several disease loci for monogenic disorders of Mg2+ homeostasis. In this issue of the JCI, Groenestege et al. report that their study of a rare inherited Mg2+ wasting disorder in consanguineous kindred shows that EGF acts as an autocrine/paracrine magnesiotropic hormone (see the related article beginning on page 2260). EGF stimulates Mg2+ reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg2+ channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane. These authors show that a point mutation in pro-EGF retains EGF secretion to the apical but not the basolateral membrane, disrupting this cascade and causing renal Mg2+ wasting. This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology.
Long-Term Interleukin-6 Levels and Subsequent Risk of Coronary Heart Disease: Two New Prospective Studies and a Systematic Review
Authors: John Danesh, Stephen Kaptoge, Andrea G Mann, Nadeem Sarwar, Angela Wood, Sara B Angleman, Frances Wensley, Julian P. T Higgins, Lucy Lennon, Gudny Eiriksdottir, Ann Rumley, Peter H Whincup, Gordon D. O Lowe, Vilmundur Gudnason
Journal: PLoS Medicine (2008)

The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context.Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28-0.53, over 4 y, and 0.35, 95% CI 0.23-0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29-1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45-3.15) with long-term average ("usual") IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42-1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45-4.56] per 2 SD increase in usual [long-term average] IL-6 levels).Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6-mediated pathways to CHD.
Compassion in healthcare – lessons from a qualitative study of the end of life care of people with dementia
Authors: Jacqueline Crowther, Kenneth CM Wilson, Siobhan Horton, Mari Lloyd-Williams
Journal: Journal of the Royal Society of Medicine (2013)

Objectives A lack of compassion in UK healthcare settings has received much recent attention. This study explores the experiences of people with dementia in the last year of life and time surrounding death and how the presence and lack of compassion, kindness and humanity influenced the experience of care. Design Qualitative in-depth interviews with bereaved informal carers of people with dementia. Setting United Kingdom. Participants Forty bereaved carers – 31 women and nine men – with an age range of 18–86 years and from wide socioeconomic backgrounds participated. Main outcome measures Experiences of carers of care for person with dementia during last year of life. Results The interviews highlighted differences and challenges in care settings in providing compassionate, humanistic care and the impact of the care experienced by the person with dementia during the last year of life on informal carers during the bereavement period and beyond. Excellent examples of compassionate care were experienced alongside very poor and inhumane practices. Conclusion The concepts of compassion, kindness and humanity in dementia care are discussed within the paper. The ability to deliver care that is compassionate, kind and humanistic exists along a continuum across care settings – examples of excellent care sit alongside examples of very poor care and the reasons for this are explored together with discussion as to how health and social care staff can be trained and supported to deliver compassionate care.
COPD, diagrams and traditions: time to move on?
Authors: J. Vestbo
Journal: Thorax (2008)

The non-proportional Venn diagram explaining the components of chronic obstructive pulmonary disease (COPD) has been a graphical “COPD evergreen” along the Fletcher-Peto curve ever since it was proposed by Snider.1 The diagram has very much been intended as a way of visualising the concepts behind the processes contributing to COPD, but over the last few years there has been a growing interest in quantifying the various components of the diagram.2 3 These studies have used registered administrative diagnoses or self-reported diagnoses with the possibilities that errors in diagnostic labelling may have introduced significant bias. In this issue of Thorax Marsh et al 4 present a proportional Venn diagram based on clinical data, pulmonary function measurements and CT findings from an ongoing population study in New Zealand ( see page 761 ).

Marsh et al found that asthma was a significant cause of COPD in their general population sample; 55% of patients with COPD fulfilled their criteria for asthma whereas 30% had questionnaire-derived chronic bronchitis and 32% had emphysema defined by CT or reduced transfer factor. The overwhelming—and somewhat surprising—impact of asthma on COPD is not substantially different from that found in the previous studies;2 3 nevertheless, it challenges our traditional views and deserves attention. In addition, a significant proportion of patients with COPD were never smokers (36% overall, ranging from 13% among COPD patients with emphysema to 38% among COPD patients with asthma).

The quick …
Effect of Lapatinib on the Outgrowth of Metastatic Breast Cancer Cells to the Brain
Authors: B. Gril, D. Palmieri, J. L. Bronder, J. M. Herring, E. Vega-Valle, L. Feigenbaum, D. J. Liewehr, S. M. Steinberg, M. J. Merino, S. D. Rubin, P. S. Steeg
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundThe brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis.
Mini symposium. New aspects of spermatogenesis. Expression of mitochondrial marker proteins during spermatogenesis
Authors: A Meinhardt, B Wilhelm, J Seitz
Journal: Human Reproduction Update (1999)

Spermatogenesis is a highly complex, hormonally regulated cytodifferentiation process finally leading to the production of spermatozoa. In addition to other events germ cell differentiation is characterized by a gradual structural modification of many organelles including mitochondria which plays a unique role. The morphological and functional development of germ cell mitochondria is a reflection of the permanent change in the testicular microenvironment which occurs when the germ cells are slowly moving from the base of the seminiferous epithelium to the lumen. Concomitant with the structural changes, several mitochondrial proteins are known to be expressed and synthesized during distinct phases of the organelle's development. This review pays particular attention to these transiently expressed mitochondrial proteins such as hsp60, Lon protease, sulphydryl oxidase and cytochrome ct. Furthermore, the biological function of this stepwise gene activation during mitochondrial and germ cell development is discussed. Keywords: chaperones/Lon protease/mitochondria/spermatogenesis/sulphydryl oxidase
Single dose primaquine for clearance of Plasmodium falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised, controlled, double-blind, dose-ranging trial
Authors: Alice C Eziefula, Teun Bousema, Shunmay Yeung, Moses Kamya, Asiphas Owaraganise, Grace Gabagaya, John Bradley, Lynn Grignard, Kjerstin H W Lanke, Humphrey Wanzira, Arthur Mpimbaza, Samuel Nsobya, Nicholas J White, Emily L Webb, Sarah G Staedke, Chris Drakeley
Journal: The Lancet Infectious Diseases (2013)
Myocardial mechanical, biochemical, and structural alterations induced by chronic ethanol ingestion in rats.
Authors: J M Capasso, P Li, G Guideri, A Malhotra, R Cortese, P Anversa
Journal: Circulation Research (1992)

To determine the effects of moderate ethanol consumption on the mechanical, biochemical, and structural characteristics of the heart, myocardial mechanical performance, contractile protein enzyme activity, and the number and size of myocytes were measured in male Fischer 344 rats after the ingestion of 30% oral ethanol. Papillary muscles removed from the left ventricle were greater in length, weight, and cross-sectional area than the corresponding muscles from the right side. However, no differences were found between control and ethanol-treated myocardium when either the left or right side was compared separately. Chronic ethanol ingestion resulted in an increase in resting tension in left ventricular muscles, with no alteration in peak developed tension. Moreover, time to peak tension was significantly prolonged, whereas a depression was observed in the peak rate of isometric tension development. Isotonically, left muscles from ethanol-treated rats revealed a prolongation of time to peak shortening and a marked depression in the velocity of shortening at physiological loads. No changes were noted in muscles from the right ventricle. Contractile protein enzyme activity revealed no differences in myofibrillar Mg(2+)-ATPase activity in right and left ventricular myocardium between control and ethanol-treated rats in the presence of EGTA. However, at physiological activating levels of calcium, an upward shift of the myofibrillar Mg(2+)-ATPase activity-calcium curve occurred in left myocardium, whereas a depression in this relation was seen in the right ventricle. As a result of chronic ethanol intake, a decrease was noted in the volume percent of myocardium occupied by myocytes, and that myocyte cell volume per nucleus was found to remain essentially constant throughout the various layers of the ventricular wall. Importantly, a 14% significant decrease in the total number of myocyte nuclei was demonstrated in the left ventricular myocardium of rats on chronic ethanol consumption. Thus, chronic but moderate alcohol ingestion resulted in depressed contractile performance, alterations in myofibrillar Mg(2+)-ATPase activity, and myocyte loss. These events may serve to function as preliminary indicators of the onset of heart failure of alcoholic origin in this animal model.
BATF2 Deficiency Promotes Progression in Human Colorectal Cancer via Activation of HGF/MET Signaling: A Potential Rationale for Combining MET Inhibitors with IFNs
Authors: Zebing Liu, Ping Wei, Yu Yang, Wenli Cui, Bing Cao, Cong Tan, Baohua Yu, Rui Bi, Kaiqin Xia, Weixiang Chen, Yiqin Wang, Youyuan Zhang, Xiang Du, Xiaoyan Zhou
Journal: Clinical Cancer Research (2015)

Abstract Purpose: BATF2, a novel IFN-stimulated gene, inhibits tumor cell proliferation, invasion, and migration. The objectives of this study were to determine how BATF2 expression is associated with colorectal cancer progression and patient outcome, to investigate how BATF2 overexpression inhibits hepatocyte growth factor (HGF)/MET signaling, and to elucidate the rationale for combining MET inhibitors with IFN. Experimental Design: BATF2 expression in colorectal cancer tissues was determined and correlated with colorectal cancer patient prognosis. Cultured colorectal cancer cells were used to investigate the effects of BATF2 overexpression on the malignant phenotype of colorectal cancer cells and HGF/MET signaling. Tumor xenograft models were used to validate the effects of BATF2 on colorectal cancer xenograft growth and assess the efficacy of the combination of MET inhibitors with IFNs in colorectal cancer. Results: In colorectal cancer tissues, BATF2 was found to be significantly downregulated, and its expression negatively correlated with MET expression. Decreased BATF2 expression was associated with progression and shorter patient survival in colorectal cancer. BATF2 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in colorectal cancer cells, as well as dramatically blunted tumor xenograft growth. In addition, MET inhibitors in combination with IFNβ produced synergistic cytotoxicity both in vitro and in vivo. Conclusions: Together, these novel findings suggest that BATF2, a tumor suppressor gene, is a potent negative regulator of HGF/MET signaling in colorectal cancer and may serve as a prognostic tumor marker. Furthermore, these results provide a rationale for combining MET inhibitors with IFNs in preclinical trials. Clin Cancer Res; 21(7); 1752–63. ©2015 AACR.
Detection of fluoroquinolone resistance associated mutations in Mycobacterium tuberculosis by use of sequencing and TaqMan probes
Authors: Veronika Slizen, Aksana Zalutskaya, Larisa Surkova
Journal: European Respiratory Journal (2012)

Mutations conferring resistance of MBT to fluoroquinolones occur in two short discrete segments of gyrA and gyrB genes. The nature of the amino acids at positions 88, 90 and 94 in gyrA plays a crucial role in the acquired resistance to quinolones. The aim of investigations is to evaluate the method of real time PCR with dual TaqMan probes for rapid detection of MBT resistance to fluorquinolones.  Methods. Resistance to ofloxacin of MBT was determined by reference technique, gyrA genes were amplified and autosequenced. The real-time PCR with dual TaqMan probes was developed to detect mutations in triplets 90, 94 of the gyrA gene.  Results. The gyrA codons 90, 91, 94 were reported to be the most frequently mutated codons worldwide, the same tendency was registered in Belarus: point mutations were predominately localized at codons 90 and 94 and rarer - 91. Mutations occurred at codon 90 resulted in Ala→Val replacements, at triplet 94 – Asp→Gly or Asp→Asn, at codon 91 - Ser→Pro. The designed dual TaqMan probes for real-time PCR allowed detecting mutations in triplets 90, 94 of gyrA gene. Samples with mutations were characterized by above-threshold florescence on JOE-channel and subthreshold florescence on FAM-channel, while samples without mutations displayed above-threshold florescence on FAM-channel and subthreshold florescence on JOE-channel. The results obtained by real-time PCR with dual TaqMan probes showed high level of coincidence with sequencing data (94%).  Conclusion. The dominant mutations in 90, 94 triplets gyrA can be rapidly and effectively detected by PCR with dual-probe TaqMan probes.