tbuckley/cabot-search huggingface dataset:
Abstract 3040: NANOG metabolically reprograms tumor-initiating stem-like cells in oxidative phosphorylation and fatty acid metabolism
Authors: Chia-Lin Chen, Dinesh Babu Uthaya Kumar, Vasu Punj, Jun Xu, Linda Sher, Sonja Hess, Keigo Machida
Journal: Cancer Research (2015)

Abstract Stem cell markers such as NANOG have been implicated in various cancers; however, the functional contribution of pluripotency transcription factor NANOG to cancer pathogenesis has remained unclear. Gene profiling, proteomics and metabolomics approaches were combined to identify the pathway(s) altered in tumors. Here, we show that Toll-like receptor 4 (TLR4) signaling phosphorylates E2F1 to transactivate NANOG via TAK1/TBK1. CD133+/CD49f+ TICs isolated from human HCC have tumorigenic activities dependent on TLR4 and NANOG. Down-regulation of Nanog significantly reduces tumor development in obesity-associated HCC mouse model. In the search for the NANOG-dependent mechanisms underlying growth of tumor-initiating stem-like cells (TICs), NANOG ChIP-seq identifies the genes associated with mitochondrial metabolic pathways. The specific pathways, which were examined: oxidative phosphorylation (OXPHOS) and fatty acid oxidation were identified as novel NANOG-mediated oncogenic pathways by NANOG ChIP-seq analysis and metabolomics. The causal roles of NANOG in mitochondrial metabolic reprogramming occurs through the inhibition of oxidative phosphorylation (OXPHOS) and levels of mitochondrial ROS and activation of fatty acid oxidation (FAO), which are required for both the self-renewal of TICs and their drug resistance. PPARδ physically interacts with NANOG. Restoration of OXPHOS and inhibition of FAO rendered TICs susceptible to drug. Our data showed that NANOG reprogramming of mitochondrial metabolism was responsible for human TIC oncogenicity and chemo-resistance. Together, NANOG-mediated metabolic reprogramming through dysregulation of mitochondrial functions generates TICs and drives tumorigenesis, providing insight into mechanisms of NANOG-mediated metabolic reprogramming and its roles in TIC oncogenic activity and chemo-resistance. NANOG suppresses OXPHOS and activates FAO, thus inhibiting OCR and ROS production, conferring a tumor chemoresistant state. These novel pathways are potential drug targets for the highly malignant TICs found in cancer patients. Reversal of NANOG-dependent effects on OXPHOS and FAO gene may offer a noteworthy strategy of countering therapeutic drug resistance associated with NANOG activation. Citation Format: Chia-Lin Chen, Dinesh Babu Uthaya Kumar, Vasu Punj, Jun Xu, Linda Sher, Sonja Hess, Keigo Machida. NANOG metabolically reprograms tumor-initiating stem-like cells in oxidative phosphorylation and fatty acid metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3040. doi:10.1158/1538-7445.AM2015-3040
The Association of Fatal Intracranial Hemorrhage and Blastic Crisis in Patients with Acute Leukemia
Authors: Richard D. Fritz, Claude E. Forkner, Emil J. Freireich, Emil Frei, Louis B. Thomas
Journal: New England Journal of Medicine (1959)

INTRACRANIAL bleeding is a common cause of death in acute leukemia.1 2 3 4 5 6 This often occurs as part of a generalized hemorrhagic diathesis, for which thrombocytopenia usually forms the essential background. This paper discusses another factor, —namely, rapidly rising numbers of abnormal leukocytes in the peripheral blood ("blastic crisis"), —which in a significant proportion of cases appears to be associated with massive intracranial hemorrhage. An abstract of this work has been presented previously.7 MethodsOne hundred patients with acute leukemia admitted consecutively to the National Cancer Institute between June, 1954, and March, 1957, were studied. All diagnoses of leukemia were confirmed by . . .
Challenges to Data Monitoring Committees When Regulatory Authorities Intervene
Authors: Karl Swedberg, Jeffrey S. Borer, Bertram Pitt, Stuart Pocock, Jean Rouleau
Journal: New England Journal of Medicine (2016)

During ATMOSPHERE, a trial comparing aliskiren, enalapril, or both for heart failure, two other trials suggested harm from aliskiren in patients with diabetes, and regulators stopped aliskiren in such patients in ATMOSPHERE. The data monitoring committee suggests that regulators should trust the DMC to ensure patient safety in a clinical trial. The trial sponsor (Novartis) and the regulatory agencies have responded in letters to the editor.
Clinical and biochemical features of depression in Parkinson's disease
Authors: R Mayeux, Y Stern, J B Williams, L Cote, A Frantz, I Dyrenfurth
Journal: American Journal of Psychiatry (1986)

Among 49 consecutive patients with Parkinson's disease, 40% were depressed according to DSM-III; they had major depression or dysthymic disorder accompanied by sleep disturbance, fatigue, psychomotor retardation, loss of self-esteem, and excessive guilt. During a 10-day dopamine-free period, lumbar puncture was performed to measure the metabolites of dopamine, serotonin, and norepinephrine. Patients were given an overnight dexamethasone suppression test, and the effects of thyrotropin-releasing hormone and L-dopa on plasma growth hormone and prolactin were examined. Level of CSF 5-hydroxyindoleacetic acid was lowest in parkinsonian patients with major depression and was related to psychomotor retardation and loss of self-esteem.
Treatment of Sideroblastic Anemia with Chloroquine
Authors: Bernard Drénou, Dominique Guyader, Bruno Turlin, Renée Fauchet
Journal: New England Journal of Medicine (1995)

To the Editor: The mainstay of treatment for sideroblastic anemia, a group of heterogeneous disorders1,2 involving a defect in heme synthesis,3 is transfusion. We describe a 19-year-old man with sideroblastic anemia who was successfully treated with chloroquine. The patient was referred to our institution in 1984 because of anemia. The white-cell count was 8.6×109 per liter, the platelet count 350×109 per liter, the hemoglobin level 5 g per deciliter, the mean cell volume 86 μm3, and the reticulocyte count 11×103 per liter. In the bone marrow, erythroid cellularity was normal, but there were 60 ringed sideroblasts per 100 . . .
FRI0409 Breast is best. Lifecourse influences on the development of knee osteophytes: The newcastle thousand families study
Authors: A. Abraham, K.D. Mann, M.S. Pearce, R.M. Francis, F. Birrell
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> There has been very little lifecourse research looking at the risk of osteoarthritis (OA). Several studies have demonstrated the association between adult risk factors such as obesity and higher bone mineral density with subsequent knee OA. <h3>Objectives</h3> We performed a lifecourse analysis of risk factors for knee OA (defined by osteophytes on ultrasound) acting at different stages of life, including early life factors, among members of the Newcastle Thousand Families birth cohort. <h3>Methods</h3> Potential risk factors for knee osteoarthritis (including birth weight, breast feeding data and socioeconomic status) have been collected prospectively in this birth cohort of subjects aged 63 (born in May-June 1947) and an a priori conceptual framework was developed. Subjects had both knees scanned by a trained musculoskeletal sonographer. Ultrasound protocols were derived from EULAR guidelines. The presence of knee osteophytes was assessed at the tibial and femoral sites, medially and laterally. These data were analysed in relation to a range of factors from across the lifecourse using logistic regression models. <h3>Results</h3> Among the 311 participants, the prevalence of knee osteophytes was 22%, 25% and 30% for right, left and "any" knee, respectively. While birth weight, exclusive breast feeding and social class at birth showed significant univariate associations with knee osteophytes, only exclusive breast feeding (among factors acting in early life) showed a significant association in the adjusted model (OR 0.81 per month; CI 0.68, 0.97; p=0.02). BMI (OR 1.11; CI 1.02, 1.20; p=0.01) and total hip bone mineral density at age 50 (OR 1.37 per 0.1 g/cm<sup>2</sup>; CI 1.06, 1.78; p=0.02) were the factors acting in adulthood that increased the risk of knee osteophytes at age 63. Serum fibrinogen levels at age 50 (a surrogate marker of inflammation) showed a borderline significant association in the multivariate model (OR 1.68 per g/L; CI 0.99, 2.85). The univariate effect of social class at birth on knee osteophytes was found to be mediated by its subsequent effect on breast feeding and total hip bone mineral density. <h3>Conclusions</h3> This is the first study to perform a lifecourse analysis of knee OA risk using prospectively collected data. While exclusive breast feeding is known to decrease risk of adult obesity and therefore of knee OA, this study suggests that exclusive breast feeding is an independent predictor of knee OA. The mechanism might be reduced burden of infection and inflammation through the lifecourse, a testable hypothesis. Systemic inflammation itself (as measured by serum fibrinogen at age 50) might be an independent predictor of knee osteophytes. <h3>Disclosure of Interest</h3> None Declared
Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions
Authors: Linda S. Zhang, Sean S. Davies
Journal: Genome Medicine (2016)

Mass spectrometry- and nuclear magnetic resonance-based metabolomic studies comparing diseased versus healthy individuals have shown that microbial metabolites are often the compounds most markedly altered in the disease state. Recent studies suggest that several of these metabolites that derive from microbial transformation of dietary components have significant effects on physiological processes such as gut and immune homeostasis, energy metabolism, vascular function, and neurological behavior. Here, we review several of the most intriguing diet-dependent metabolites that may impact host physiology and may therefore be appropriate targets for therapeutic interventions, such as short-chain fatty acids, trimethylamine N-oxide, tryptophan and tyrosine derivatives, and oxidized fatty acids. Such interventions will require modulating either bacterial species or the bacterial biosynthetic enzymes required to produce these metabolites, so we briefly describe the current understanding of the bacterial and enzymatic pathways involved in their biosynthesis and summarize their molecular mechanisms of action. We then discuss in more detail the impact of these metabolites on health and disease, and review current strategies to modulate levels of these metabolites to promote human health. We also suggest future studies that are needed to realize the full therapeutic potential of targeting the gut microbiota.
Art: Anatomy in the Gallery
Authors: Chloe Veltman
Journal: BMJ (2005)

A small, blue blanket sits upon a medical examination table, as if a child has mislaid it there. It looks soft, but feels surprisingly rough to the touch. Upon closer inspection, the blanket reveals itself to be crocheted not out of wool but from disposable hospital examination gowns.​gowns.




Figure 1



L J Douglas: Mixed Race #2, Terra Derma




The blanket is part of an interactive, multi-media installation entitled The Waiting Room, by Illinois-based artist Karen Jayne, currently on show at the International Museum of Surgical Science in Chicago alongside The Body... Re-imagined, a series of paintings that explore the skin's surface by Illinois painter L J Douglas. The Waiting Room and The Body... Re-imagined are part of the museum's ongoing Anatomy in the Gallery exhibition programme, which presents work by contemporary artists dealing with a range of medically related themes and which changes every two to three months.

The Waiting Room focuses on Jayne's relationship with her chronically ill child and the medical community that surrounds her. From Appointment, a tatty-looking side-table and chair, enmeshed in a web of shredded strands of old hospital records and doctors' prescriptions, to Waiting Room, an electrocardiogram embroidered on a white handmade paper-woven rug resting on a shelf supported by piles of glossy magazines, Jayne's emotionally explicit work conveys a sense of time passing slowly, endless waiting, and tolerant resignation regarding the process of illness and institutionalised care.​care.




Figure 2



Karen Jayne: detail from Waiting Room




Unlike Jayne's installation, which wears its heart on its sleeve, Douglas's paintings are, at least on the surface, clinical and unemotional. Abstract collages of tiny painted dots speckled with fragments of paper and other materials in mainly yellow, pink, and orange hues, Douglas's fantastical, detailed studies of human skin reveal their inner life only gradually. The canvases, with their overtones of pointillism and computer art, appear to shift depending on where you stand, transforming human skin into a landscape to be explored through detailed scientific observation.
Tonsillectomy History in Hodgkin's Disease
Authors: Sandra K. Johnson, Ralph E. Johnson
Journal: New England Journal of Medicine (1972)

Of 174 patients recently treated for Hodgkin's disease, a history of tonsillectomy was obtained in 52 per cent. Except for a low rate of tonsillectomy in younger patients, statistically significant variations from the overall rate were absent when tonsillectomy was correlated with other features such as sex, extent of disease, presence versus absence of constitutional symptoms, primary site of involvement and histologic subclassification. A comparison of patients and matched siblings did not reveal a difference in tonsillectomy rate although a number of patients with intact tonsils had healthy matched siblings with a history of tonsillectomy. The review failed to demonstrate a relation between tonsillectomy and the clinical features of Hodgkin's disease and did not support the hypothesis that prior tonsillectomy increases susceptibility to this disease by removal of a "lymphoid barrier." Also of interest were two sibling pairs without tonsillectomy in whom Hodgkin's disease developed coincidentally within a span of one year despite separate residences.
Acquired loss of p53 induces blastic transformation in p210bcr/abl-expressing hematopoietic cells: a transgenic study for blast crisis of human CML
Authors: Hiroaki Honda, Toshikazu Ushijima, Kuniko Wakazono, Hideaki Oda, Yuji Tanaka, Shin-ichi Aizawa, Takatoshi Ishikawa, Yoshio Yazaki, Hisamaru Hirai
Journal: Blood (2000)
P143 Associations between quadriceps isokinetic endurance and exercise test parameters in COPD patients
Authors: TJ Hargreaves, JP Fuld, KP Sylvester
Journal: Thorax (2015)

<h3>Background</h3> Skeletal muscle dysfunction is a clinically relevant extra-pulmonary manifestation of COPD.<sup>1</sup> While muscle strength is undoubtedly important in functional performance, the ability to perform extended physical activity is also dependent upon muscular endurance. While previous studies have shown a correlation between quadriceps endurance and exercise test performance,<sup>2</sup> we wished to investigate the same correlation across a wider range of functional outcomes. In addition, we have previously explored the clinical meaning of a “distance-desaturation product” in field tests and data have indicated increased clinical value of the measure. We hypothesised, therefore, that measures of skeletal muscle isokinetic endurance might add clinical value to measures of strength, especially in day-to-day or submaximal activities. <h3>Methods</h3> A prospective cohort of 11 patients with COPD (age median 66, range 58–79; FEV<sub>1</sub> median 0.81 L, range 0.68–1.41 L) was studied. We compared all 11 patients’ performance in functional tests (6-minute walk test (6MWT), incremental CPET, endurance CPET, and activity data) with the following measures of isokinetic quadriceps function: Endurance (the peak torque of voluntary quadriceps contraction after 40 maximal reps, as a fraction of initial peak torque). A putative “strength-endurance product” (SEP), as a novel measure to better reflect the overall functional performance of the musculature. <h3>Results</h3> Somewhat surprisingly, isokinetic quadriceps endurance was not significantly associated with any parameter across all 4 exercise tests. Furthermore, combining strength and endurance in the SEP yielded only a minor improvement: only resting energy expenditure was significantly correlated (p &lt; 0.05). <h3>Discussion</h3> Understandably it appears that quadriceps endurance is a poor predictor of performance in exercise tests, however limited added value of a combined “SEP” was evident. The clinical meaning of endurance measures remain unclear. <h3>References</h3> 1 Van’t Hul A, Harlaar J, Gosselink R, <i>et al</i>. Quadriceps muscle endurance in patients with chronic obstructive pulmonary disease. <i>Muscle Nerve</i> 2009;<b>29</b>(2):267–74 2 Vilaro J, Rabinovich R, Gonzalez-deSuso JM, <i>et al</i>. Clinical assessment of peripheral muscle function in patients with chronic obstructive pulmonary disease. <i>Am J Phys Med Rehabil</i>. 2009;<b>88</b>(1):39–46
Evidence for the Superiority of Immunosuppressive Drugs and Prednisone over Prednisone Alone in Lupus Nephritis
Authors: David T. Felson, Jennifer Anderson
Journal: New England Journal of Medicine (1984)

In an effort to clarify the role of immunosuppressive drugs in the management of lupus nephritis, we pooled data from all published clinical trials in which patients had been randomly assigned to receive either prednisone alone or prednisone plus cyclophosphamide or azathioprine. The pooled analysis showed that patients receiving immunosuppressive drugs had less renal deterioration (P = 0.006), were less likely to have end-stage renal disease (P = 0.023), and were less likely to die from kidney disease (P = 0.024) than patients receiving steroids alone. There were no significant differences with respect to deaths from nonrenal causes or overall mortality. When cyclophosphamide and azathioprine were considered separately, both were associated with a 40 per cent reduction in the rates of adverse renal outcomes, although because the treatment groups were smaller, many of these differences were not statistically significant. A power analysis showed that a study of 100 high-risk patients (development of renal insufficiency in 50 per cent) would be needed to prove that an immunosuppressive agent is 50 per cent superior to steroids alone in preventing renal deterioration. We conclude that immunosuppressive drugs and steroids together are more effective than steroids alone in treating lupus nephritis and that published trials have reached false negative conclusions because of small sample sizes. (N Engl J Med 1984; 311:1528–33.)
Seroconversion to Antibodies against Kaposi's Sarcoma–Associated Herpesvirus–Related Latent Nuclear Antigens before the Development of Kaposi's Sarcoma
Authors: Shou-Jiang Gao, Lawrence Kingsley, Donald R. Hoover, Thomas J. Spira, Charles R. Rinaldo, Alfred Saah, John Phair, Roger Detels, Preston Parry, Yuan Chang, Patrick S. Moore
Journal: New England Journal of Medicine (1996)

If Kaposi's sarcoma–associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma, serologic evidence of infection should be present in patients before the disease develops.
A Comparative Study of the Effect of Transfusion of Fresh and Preserved Whole Blood on Bleeding in Patients with Acute Leukemia
Authors: Emil J. Freireich, Paul J. Schmidt, Marvin A. Schneiderman, Emil Frei
Journal: New England Journal of Medicine (1959)

GROSS bleeding is a frequent and major complication in patients with acute leukemia. The etiology of this bleeding is closely related to thrombocytopenia,1 although other coagulation abnormalities have been identified in a few patients.2 With the development of plastic and other nonwettable surfaces, the transfusion of viable platelets that circulate for five to seven days was demonstrated.3 , 4 These studies also showed that clinical hemorrhage could be interrupted if circulating platelet levels were sufficiently increased by platelet transfusion. Because of the time-consuming manipulations necessary for preparing platelet concentrates and because of the difficulty in obtaining large numbers of immediately available donors, . . .
FEC 60 adjuvant chemotherapy (AdCT) in breast cancer (BC) patients (Pts): 10-year follow-up results
Authors: F. Moura Silva, C. Tosello, M. T. Laloni, C. M. Andrade, A. Bertozzi, P. Vernaglia, F. M. Correa, R. P. Moraes, J. S. Goes
Journal: Journal of Clinical Oncology (2006)

10725 Background: To evaluate the efficacy of the Epirubicin as a part of the FEC60 AdCT in operable BrC patients in a Brazilian single-center. Methods: We verified retrospectively our experience with FEC 60 as AdCT in pre and postmenopausal, node positive and negative, pathologic stage I, II and III patients with BrC. Pts were submitted after surgery to receive Fluorouracil 600 mg/m 2 , Epirubicin 60 mg/m 2 and Cyclophosphamide 600 mg/m 2 every 28 days for 6 cycles. Pts who were ER+ and/or PR+ received Tamoxifen (TMX) 20 mg/day for 5 years after AdCT. Radiotherapy was also offered at the end of AdCT if indicated. All patients were evaluated in terms of 10 year (y) Disease Free Survival (DFS) and Overall Survival (OS). The most common toxicities (acute and chronic) and metastatic sites will also be reported. Results: Between July 1983 and December 1995 a total of 752 patients (ranging from 22 to 77 years old - median 47.7) were encountered and all of them were evaluated to 10 year (y) DFS and OS. Approximately 61% of these patients received adjuvant TMX. Pts in premenopausal and postmenopausal represented 62.5% and 37.5% respectively. 72 (11%) pts had pathological stage I; 353 (46%) pts had stage II and 327 (43%) had stage III. The 10y DFS was 70%, 46% and 19% for stage I, II and III respectively. The 10y OS after a minimal follow-up of 122.98 months was 74%, 48% and 20% for stage I, II and III respectively. Conclusions: Our results demonstrated that FEC 60 regimen is active and well tolerated in the adjuvant treatment for BrC pts. We had about 89% of stage II and III pts and in this population FEC60 regimen add benefit. Nevertheless, the randomized studies indicate that the greatest anticancer effect of Epirubicin requires doses ranging from 75 to 120 mg/m 2 , but due to economic reasons (we integrate the brazilian public healthy system) we could not offer dosages greater than 60 mg/m 2 . FEC 60 was feasible and offered reasonable results in our population in terms of 10y DFS and OS. No significant financial relationships to disclose.