tbuckley/cabot-search huggingface dataset:
Silvestrol exhibits significant in vivo and in vitro antileukemic activities and inhibits FLT3 and miR-155 expressions in acute myeloid leukemia
Authors: Houda Alachkar, Ramasamy Santhanam, Jason G Harb, David M Lucas, Joshua J Oaks, Christopher J Hickey, Li Pan, A Douglas Kinghorn, Michael A Caligiuri, Danilo Perrotti, John C Byrd, Ramiro Garzon, Michael R Grever, Guido Marcucci
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Activating mutations [internal tandem duplication (ITD)] or overexpression of the FMS-like tyrosine kinase receptor-3 ( FLT3 ) gene are associated with poor outcome in acute myeloid leukemia (AML) patients, underscoring the need for novel therapeutic approaches. The natural product silvestrol has potent antitumor activity in several malignancies, but its therapeutic impact on distinct molecular high-risk AML subsets remains to be fully investigated. We examined here the preclinical activity of silvestrol in FLT3 -ITD and FLT3 wild-type (wt) AML. Methods Silvestrol in vitro anti-leukemic activity was examined by colorimetric cell viability assay, colony-forming and flow cytometry assays assessing growth inhibition and apoptosis, respectively. Pharmacological activity of silvestrol on FLT3 mRNA translation, mRNA and protein expression was determined by RNA-immunoprecipitation, qRT-PCR and immunoblot analyses, respectively. Silvestrol in vivo efficacy was investigated using MV4-11 leukemia-engrafted mice. Results Silvestrol shows antileukemia activity at nanomolar concentrations both in FLT3 -wt overexpressing (THP-1) and FLT3 -ITD (MV4-11) expressing AML cell lines (IC 50 = 3.8 and 2.7 nM, respectively) and patients’ primary blasts [IC 50 = ~12 nM ( FLT3 -wt) and ~5 nM ( FLT3 -ITD)]. Silvestrol increased apoptosis (~4fold, P = 0.0001), and inhibited colony-formation (100%, P &lt; 0.0001) in primary blasts. Silvestrol efficiently inhibited FLT3 translation reducing FLT3 protein expression by 80–90% and decreased miR-155 levels (~60%), a frequently co-regulated onco-miR in FLT3 -ITD-positive AML. The median survival of silvestrol-treated vs vehicle-treated mice was 63 vs 29 days post-engraftment, respectively (P &lt; 0.0001). Conclusions Silvestrol exhibits significant in vivo and in vitro antileukemic activities in AML through a novel mechanism resulting in inhibition of FLT3 and miR-155 expression. These encouraging results warrant a rapid translation of silvestrol for clinical testing in AML.
Fever, hospitalization and healthcare utilization after research bronchoscopy
Authors: Elise Orvedal Leiten, Einar Marius Hjellestad Martinsen, Tomas Mikal Lind Eagan, Per Sigvald Bakke, Ingvild Haaland, Øistein Svanes, Gunnar Reksten Husebø, Rune Grønseth
Journal: European Respiratory Journal (2014)

Background and aims: Based on a study on airways inflammation and the respiratory microbiome, we aimed to investigate if bronchoscopy leads to fever, healthcare utilization or hospitalization in obstructive lung disease and control subjects.  Methods: From the ongoing Bergen Airways Microbiome Study 39 COPD patients (FEV 1  ≥ 17% of predicted values), 2 with asthma, and 33 controls were interviewed 1 week after bronchoscopy regarding fever and healthcare utilization (hospitalization, unscheduled visits to a doctor, antibiotic use). Bronchoscopy included collected protected specimen brushes in both lungs, and bronchoalveolar lavage (BAL) of the right middle lobe in all but 7 subjects. 50 subjects received conscious sedation with alfentanil. 24 subjects received only topical lidocaine.  Results: 31 women and 43 men, aged 35 to 81 years were examined. The post bronchoscopy fever rate was 41%, and was not related to healthcare utilization. 7 subjects received unscheduled medical care after the procedure, of these 1 was admitted for a bronchospasm (1 day), 2 for pneumonia (1 and 2 days), and one for 3 days for an unverified cerebral vascular incident. Case/control-status, sex, age, smoke, FEV 1 % of predicted, arterial PaO 2 , BAL yield, and conscious sedation were not associated with fever or healthcare utilization. A combination of low FEV 1 , exacerbation history and high symptom score did not predict outcomes in a logistic regression model.  Conclusion: Fever was a frequently reported side effect of bronchoscopy, but was not related to need of healthcare attention. Neither case/control status nor FEV 1  was related to healthcare utilization. Research bronchoscopy is safe in COPD, even with very low lung function.
Understanding the Heterogeneity in Volume Overload and Fluid Distribution in Decompensated Heart Failure Is Key to Optimal Volume Management
Authors: Wayne L. Miller, Brian P. Mullan
Journal: JACC Heart Failure (2014)

This study sought to quantitate total blood volume (TBV) in patients hospitalized for decompensated chronic heart failure (DCHF) and to determine the extent of volume overload, and the magnitude and distribution of blood volume and body water changes following diuretic therapy.The accurate assessment and management of volume overload in patients with DCHF remains problematic.TBV was measured by a radiolabeled-albumin dilution technique with intravascular volume, pre-to-post-diuretic therapy, evaluated at hospital admission and at discharge. Change in body weight in relation to quantitated TBV was used to determine interstitial volume contribution to total fluid loss.Twenty-six patients were prospectively evaluated. Two patients had normal TBV at admission. Twenty-four patients were hypervolemic with TBV (7.4 ± 1.6 liters) increased by +39 ± 22% (range, +9.5% to +107%) above the expected normal volume. With diuresis, TBV decreased marginally (+30 ± 16%). Body weight declined by 6.9 ± 5.2 kg, and fluid intake/fluid output was a net negative 8.4 ± 5.2 liters. Interstitial compartment fluid loss was calculated at 6.2 ± 4.0 liters, accounting for 85 ± 15% of the total fluid reduction.TBV analysis demonstrated a wide range in the extent of intravascular overload. Dismissal measurements revealed marginally reduced intravascular volume post-diuretic therapy despite large reductions in body weight. Mobilization of interstitial fluid to the intravascular compartment with diuresis accounted for this disparity. Intravascular volume, however, remained increased at dismissal. The extent, composition, and distribution of volume overload are highly variable in DCHF, and this variability needs to be taken into account in the approach to individualized therapy. TBV quantitation, particularly serial measurements, can facilitate informed volume management with respect to a goal of treating to euvolemia.
Implantable contraceptives for women
Authors: O. Meirik
Journal: Human Reproduction Update (2003)

Progestogen-only implantable contraceptives are used by increasing numbers of women worldwide. This review outlines the evidence accumulated on these methods to date. Reviews of toxicological evaluations, clinical trials, endocrinological, epidemiological and social science studies, as well as operations research and economic evaluation were undertaken in preparation for an Expert Consultation convened by the World Health Organization in 2001. At the meeting, these reviews were further evaluated and the research results summarized in this consensus paper. A large body of evidence demonstrates the high contraceptive effectiveness and safety of the 5-year levonorgestrel-releasing implants Norplant and Jadelle. Information on the 3-year etonogestrel-releasing implant Implanon is more limited, but suggests that this implant has a high contraceptive effectiveness and a satisfactory safety profile. Information available on levonorgestrel-releasing implants manufactured and approved in China suggests that their clinical performance is satisfactory, but was insufficient to allow their full safety assessment. For all implants, there is insufficient information on their use by women with medical conditions. Provision of contraceptive implants requires good quality family planning services and specific provider training.
Association of Serum Interleukin-7 Levels With the Development of Acute Graft-Versus-Host Disease
Authors: Robert M. Dean, Terry Fry, Crystal Mackall, Seth M. Steinberg, Fran Hakim, Daniel Fowler, Jeanne Odom, Jason Foley, Ronald Gress, Michael R. Bishop
Journal: Journal of Clinical Oncology (2008)

Morbidity from acute graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic stem-cell transplantation (HSCT) to treat malignancy. Interleukin-7 (IL-7), the principal homeostatic cytokine for T cells, is required for acute GVHD in murine models. In contrast to inflammatory cytokines (eg, IL-2, tumor necrosis factor alpha), IL-7 has not been studied extensively in the clinical transplant setting relative to its relationship with acute GVHD.We evaluated the association of serum IL-7 levels with acute GVHD in 31 patients who were uniformly treated in a prospective clinical trial with reduced-intensity allogeneic HSCT from human leukocyte antigen-identical siblings. GVHD prophylaxis consisted of cyclosporine and methotrexate. Serum IL-7 levels and lymphocyte populations were determined at enrollment, the day of transplantation before the allograft infusion, and at specified intervals through 12 months post-transplantation.As expected, IL-7 levels were inversely correlated with T-cell populations (P < .00001). Acute GVHD was significantly associated with higher IL-7 levels at day +7 (P = .01) and day +14 (P = .00003) post-transplantation as well as with the allograft CD34(+) cell dose (P = .01). IL-7 levels at day +14 also correlated with the severity of acute GVHD (P < .0001). In logistic regression models, these factors were highly sensitive (up to 86%) and specific (100%) for classifying whether patients developed acute GVHD.These data support preclinical observations that IL-7 plays a critical role in inducing acute GVHD and provide a rational basis for novel approaches to prevent and treat acute GVHD through modulation of the IL-7 pathway.
Threshold for genetic testing in women with breast cancer needs to be determined
Authors: N. N. Basu, L. Barr, D. G. Evans, G. L. Ross
Journal: BMJ (2014)

US surveillance data describe a 150% increase in contralateral mastectomy in the past decade, so Metcalfe and colleagues’ study of survival in BRCA1 and BRCA2 mutation carriers undergoing contralateral mastectomy after breast cancer is timely.1 2 Since Angelina Jolie’s risk reducing surgery, clinicians often have to counsel patients asking for such procedures.

This study’s findings on survival benefit are similar to our own. …
The influence of age on the xylose absorption test
Authors: M. J. Kendall
Journal: Gut (1970)

Xylose absorption tests were performed on patients unselected except to exclude gastrointestinal or renal disease. The proportion of xylose excreted decreases with increasing age. Intravenous xylose tests suggest that this is due to a deterioration in renal function rather than to a reduction in intestinal absorption.
LOX-1, mtDNA damage, and NLRP3 inflammasome activation in macrophages: implications in atherogenesis
Authors: Z. Ding, S. Liu, X. Wang, Y. Dai, M. Khaidakov, X. Deng, Y. Fan, D. Xiang, J. L. Mehta
Journal: Cardiovascular Research (2014)

Lectin-like ox-LDL scavenger receptor-1 (LOX-1) and mitochondrial DNA (mtDNA) damage play a key role in a variety of cardiovascular diseases, including atherosclerosis, hypertension, and inflammation. We posited that damaged mtDNA could trigger autophagy and NLRP3 inflammasome activation, and LOX-1 may play a critical role in this process. In order to examine this hypothesis, cultured human THP-1 macrophages exposed to lipopolysaccharide (LPS) were applied to study the link between LOX-1, mtDNA damage, autophagy, and NLRP3 inflammasome expression. Our data showed that LPS markedly induced LOX-1 expression, reactive oxygen species (ROS) generation, autophagy, mtDNA damage, and NLRP3 inflammasome. LOX-1 inhibition with a binding antibody or siRNA inhibited ROS generation, autophagy and mtDNA damage, and a decreased expression of NLRP3 inflammasome. To study the LOX-1–NLRP3 inflammasome signalling, we performed studies using ROS inhibitors and an autophagy inducer, and found that both decreased the expression of NLRP3. On the other hand, autophagy inhibitor enhanced the expression of NLRP3 inflammasome. Knockdown of DNase II inhibited autophagy and NLRP3 inflammasome, providing further support for our hypothesis. Finally, we confirmed the relationship between LOX-1, ROS, mtDNA damage, autophagy, and NLRP3 inflammasome activation in primary macrophages. This study based on THP-1 macrophages and primary macrophages indicates that LOX-1-mediated autophagy and mtDNA damage play an essential role in NLRP3 inflammasome activation in inflammatory disease states.
Effects of hemoperfusion with polymyxin B-immobilized fibre on serum neopterin and soluble interleukin-2 receptor concentrations in patients with septic shock
Authors: T. Nakamura, I. Ebihara, N. Shimada, S. Suzuki, C. Ushiyama, H. Shoji, H. Koide
Journal: Journal of Infection (1998)
Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) Contributes to Interferon γ–Dependent Natural Killer Cell Protection from Tumor Metastasis
Authors: Mark J. Smyth, Erika Cretney, Kazuyoshi Takeda, Robert H. Wiltrout, Lisa M. Sedger, Nobuhiko Kayagaki, Hideo Yagita, Ko Okumura
Journal: The Journal of Experimental Medicine (2001)

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is expressed by in vitro activated natural killer (NK) cells, but the relevance of this observation to the biological function of NK cells has been unclear. Herein, we have demonstrated the in vivo induction of mouse TRAIL expression on various tissue NK cells and correlated NK cell activation with TRAIL-mediated antimetastatic function in vivo. Expression of TRAIL was only constitutive on a subset of liver NK cells, and innate NK cell control of Renca carcinoma hepatic metastases in the liver was partially TRAIL dependent. Administration of therapeutic doses of interleukin (IL)-12, a powerful inducer of interferon (IFN)-γ production by NK cells and NKT cells, upregulated TRAIL expression on liver, spleen, and lung NK cells, and IL-12 suppressed metastases in both liver and lung in a TRAIL-dependent fashion. By contrast, α-galactosylceramide (α-GalCer), a powerful inducer of NKT cell IFN-γ and IL-4 secretion, suppressed both liver and lung metastases but only stimulated NK cell TRAIL-mediated function in the liver. TRAIL expression was not detected on NK cells from IFN-γ–deficient mice and TRAIL-mediated antimetastatic effects of IL-12 and α-GalCer were strictly IFN-γ dependent. These results indicated that TRAIL induction on NK cells plays a critical role in IFN-γ–mediated antimetastatic effects of IL-12 and α-GalCer.
Invasion of Human Breast Cancer Cells <i>In vivo</i> Requires Both Paracrine and Autocrine Loops Involving the Colony-Stimulating Factor-1 Receptor
Authors: Antonia Patsialou, Jeffrey Wyckoff, Yarong Wang, Sumanta Goswami, E. Richard Stanley, John S. Condeelis
Journal: Cancer Research (2009)

Colony-stimulating factor-1 (CSF-1) and its receptor (CSF-1R) have been implicated in the pathogenesis and progression of various types of cancer, including breast cancer. This is based on high levels of circulating CSF-1 in patient sera with aggressive disease and increased CSF-1R staining in the tumor tissues. However, there have been no direct in vivo studies to determine whether a CSF-1 autocrine signaling loop functions in human breast cancer cells in vivo and whether it contributes to invasion. Recently, in mouse and rat models, it has been shown that invasion and metastasis are driven by an epidermal growth factor (EGF)/CSF-1 paracrine loop between tumor cells and host macrophages. In this macrophage-dependent invasion, tumor cells secrete CSF-1 and sense EGF, whereas the macrophages secrete EGF and sense CSF-1. Here, we test the hypothesis that in human breast tumors, the expression of both the CSF-1 ligand and its receptor in tumor cells leads to a CSF-1/CSF-1R autocrine loop which contributes to the aggressive phenotype of human breast tumors. Using MDA-MB-231 cell-derived mammary tumors in severe combined immunodeficiency mice, we show here for the first time in vivo that invasion in a human mammary tumor model is dependent on both paracrine signaling with host macrophages as well as autocrine signaling involving the tumor cells themselves. In particular, we show that the autocrine contribution to invasion is specifically amplified in vivo through a tumor microenvironment-induced upregulation of CSF-1R expression via the transforming growth factor-beta1.
The Morris Fishbein Fellowship in Medical Journalism
Authors: M. THERESE SOUTHGATE
Journal: JAMA (1982)

Morris Fishbein, MD, died in 1976 at the age of 87. For 37 years, from 1913 until his retirement in 1949, he had been a member of the editorial staff ofThe Journal, serving as its editor for the last 25 of those years. During that same period, the number of specialty journals grew from two to ten, and the Association also began publication of a popular health magazine entitled Hygeia . In addition, Dr Fishbein was a prolific writer of books, including his well-known Medical Writing: The Technic and the Art , which went into four editions. After his retirement, he was to have longer than a quarter of a century more devoted to medical writing and editing. In the end, he had 27 books to his credit as either an author or coauthor, and he was the editor of 16 others. He also wrote a newspaper column for many years
Why does allergic contact dermatitis exist?
Authors: J.P. McFadden, P. Puangpet, D.A. Basketter, R.J. Dearman, I. Kimber
Journal: British Journal of Dermatology (2013)

The skin immune system's propensity to produce allergic contact dermatitis (ACD) to harmless chemicals, while otherwise being an efficient defence system, represents a dermatological paradox. We postulate that a major role in signalling in ACD is played by Toll-like receptor (TLR)2 and TLR4, and arises from their activation by extracellular danger-associated molecular patterns (DAMPs). Ligand activation of TLR4/2 results in the expression of interleukins (ILs) IL-1β, IL-6, IL-12, IL-18 and IL-23, tumour necrosis factor-α and interferon-α. These cytokines promote acquisition of sensitization, and facilitate elicitation of contact allergy via multiple mechanisms, including the recruitment of CD4+ Th1 and Th17 cells. As Th1 cells secrete large amounts of DAMPs, a DAMP immune circuit (positive-feedback loop) is created. This is an important driver of skin sensitization and skin inflammation. Pathogenic extracellular bacteria, but not commensal bacteria, produce pathogen-associated molecular pattern molecules, which stimulate the expression of Th1- and Th17-promoting cytokines via TLR2 and TLR4. This also induces an immune circuit. The ability of the skin immune system to activate host defence mechanisms and to distinguish between pathogenic bacteria and commensals provides an explanation for why skin sensitization and ACD develop, as they are processes that rely on the same biological pathways. These pathways may also shed light on the pathogenesis of chronic pustular inflammatory dermatoses (e.g. acne vulgaris). The existence of safety signals from commensal bacteria, which prevent initiation of these pathways, may provide opportunities for novel therapeutic approaches to the treatment of inflammatory skin diseases.
Zero tolerance: the future of head injury in sports
Authors: Mark Aubry, Jiří Dvořák, Paul McCrory, Willem Meeuwisse, Martin Raftery, Allen Sills, Lars Engebretsen
Journal: British Journal of Sports Medicine (2013)

Concussion is a common type of brain injury caused by impact forces to the head following intentional or unintentional collisions. All sports, whether they are team sports (eg, football, rugby and ice hockey), or individual sports (eg, horse riding, skiing or boxing) have finite risk of a concussion injury, which should be reduced as much as possible if the potential for long-term problems is to be avoided. Concussion must be recognised quickly and treated appropriately; however, the most important aspect of medical management is the timing of the return to play decision. The team physician is commonly under pressure from the team, the coach or the administration to get the athlete back in the game, particularly in high-profile sports. The physician has to take the ultimate responsibility for the decision on when the athlete can safely return to play or not.

The main objective for the 4th International Concussion Consensus Conference held in November 2012 in Zurich, Switzerland at the home of Federation International de Football Association (FIFA), was to …
An Adolescent With Nonsuicidal Self-Injury: A Case and Discussion of Neurobiological Research on Emotion Regulation
Authors: Kathryn R. Cullen, Melinda K. Westlund, Lori L. LaRiviere, Bonnie Klimes-Dougan
Journal: American Journal of Psychiatry (2013)

The management of nonsuicidal self-injurious behavior is a common focus of clinical care, particularly in the treatment of adolescents and young adults. Increased recognition of this problem has led to proposed criteria for future study in DSM-5, which may be beneficial in advancing the field. Clinical care may be fruitfully informed by an understanding of the neurodevelopmental underpinnings of this behavior. The authors discuss the current status of neurobiological research related to nonsuicidal self-injury with a focus on the key dimension of emotion regulation. A case is presented to illustrate the critical points. Preliminary empirical evidence suggests disturbances in neurobiological systems relevant to emotion regulation. Disturbances involve engagement of limbic brain regions and frontal regulatory brain regions that may evolve over time. Additionally, disturbances are observed in serotonin and physiological response systems relevant to emotion regulation. Treatment with serotonin reuptake inhibitors may be most beneficial in combination with dialectical behavioral therapy to address safety, build self-soothing strategies to enhance emotion regulation, and reduce interpersonal sensitivity. Delineation of the neurobiological markers that reflect successful treatment response will help in the identification of new avenues for research and the development of personalized treatments for adolescents with nonsuicidal self-injury.