tbuckley/cabot-search huggingface dataset:
Cyclin D3 Compensates for the Loss of Cyclin D1 during ErbB2-Induced Mammary Tumor Initiation and Progression
Authors: Qian Zhang, Kazuhito Sakamoto, Chengbao Liu, Aleata A. Triplett, Wan-chi Lin, Hallgeir Rui, Kay-Uwe Wagner
Journal: Cancer Research (2011)

Cyclin D1 regulates cell proliferation and is a candidate molecular target for breast cancer therapy. This study addresses whether Cyclin D1 is indispensable for ErbB2-associated mammary tumor initiation and progression using a breast cancer model in which this cell-cycle regulator can be genetically ablated prior to or after neoplastic transformation. Deficiency in Cyclin D1 delayed tumor onset but did not prevent the occurrence of mammary cancer in mice overexpressing wild-type ErbB2. The lack of Cyclin D1 was associated with a compensatory upregulation of Cyclin D3, which explains why the targeted downregulation of Cyclin D1 in established mammary tumors had no effect on cancer cell proliferation. Cyclin D1 and D3 are overexpressed in human breast cancer cell lines and primary invasive breast cancers, and Cyclin D3 frequently exceeded the expression of Cyclin D1 in ErbB2-positive cases. The simultaneous inhibition of both cyclins in mammary tumor cells reduced cancer cell proliferation in vitro and decreased the tumor burden in vivo. Collectively, the results of this study suggest that only the combined inhibition of Cyclin D1 and D3 might be a suitable strategy for breast cancer prevention and therapy.
Trastuzumab-Related Cardiotoxicity Among Older Patients With Breast Cancer
Authors: Mariana Chavez-MacGregor, Ning Zhang, Thomas A. Buchholz, Yufeng Zhang, Jiangong Niu, Linda Elting, Benjamin D. Smith, Gabriel N. Hortobagyi, Sharon H. Giordano
Journal: Journal of Clinical Oncology (2013)

The use of trastuzumab in the adjuvant setting improves outcomes but is associated with cardiotoxicity manifested as congestive heart failure (CHF). The rates and risk factors associated with trastuzumab-related CHF among older patients are unknown.Breast cancer patients at least 66 years old with full Medicare coverage, diagnosed with stage I-III breast cancer between 2005 and 2009, and treated with chemotherapy were identified in the SEER-Medicare and in the Texas Cancer Registry-Medicare databases. The rates and risk factors associated with CHF were evaluated. Chemotherapy, trastuzumab use, comorbidities, and CHF were identified using International Classification of Diseases, version 9, and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics and Cox proportional hazards models.In total, 9,535 patients were included, of whom 2,203 (23.1%) received trastuzumab. Median age of the entire cohort was 71 years old. Among trastuzumab users, the rate of CHF was 29.4% compared with 18.9% in nontrastuzumab users (P < .001). Trastuzumab users were more likely to develop CHF than nontrastuzumab users (hazard ratio [HR], 1.95; 95% CI, 1.75 to 2.17). Among trastuzumab-treated patients, older age (age > 80 years; HR, 1.53; 95% CI, 1.16 to 2.10), coronary artery disease (HR, 1.82; 95% CI, 1.34 to 2.48), hypertension (HR, 1.24; 95% CI, 1.02 to 1.50), and weekly trastuzumab administration (HR, 1.33; 95% CI, 1.05 to 1.68) increased the risk of CHF.In this large cohort of older breast cancer patients, the rates of trastuzumb-related CHF are higher than those reported in clinical trials. Among patients treated with trastuzumab, those with cardiac comorbidities and older age may be at higher risk. Further studies need to confirm the role that the frequency of administration plays in the development of trastuzumab-related CHF.
Myeloid Cell Receptor LRP1/CD91 Regulates Monocyte Recruitment and Angiogenesis in Tumors
Authors: Nicole D. Staudt, Minji Jo, Jingjing Hu, Jeanne M. Bristow, Donald P. Pizzo, Alban Gaultier, Scott R. VandenBerg, Steven L. Gonias
Journal: Cancer Research (2013)

Recruitment of monocytes into sites of inflammation is essential in the immune response. In cancer, recruited monocytes promote invasion, metastasis, and possibly angiogenesis. LDL receptor-related protein (LRP1) is an endocytic and cell-signaling receptor that regulates cell migration. In this study, we isografted PanO2 pancreatic carcinoma cells into mice in which LRP1 was deleted in myeloid lineage cells. Recruitment of monocytes into orthotopic and subcutaneous tumors was significantly increased in these mice, compared with control mice. LRP1-deficient bone marrow-derived macrophages (BMDM) expressed higher levels of multiple chemokines, including, most prominently, macrophage inflammatory protein-1α/CCL3, which is known to amplify inflammation. Increased levels of CCL3 were detected in LRP1-deficient tumor-associated macrophages (TAM), isolated from PanO2 tumors, and in RAW 264.7 macrophage-like cells in which LRP1 was silenced. LRP1-deficient BMDMs migrated more rapidly than LRP1-expressing cells in vitro. The difference in migration was reversed by CCL3-neutralizing antibody, by CCR5-neutralizing antibody, and by inhibiting NF-κB with JSH-23. Inhibiting NF-κB reversed the increase in CCL3 expression associated with LRP1 gene silencing in RAW 264.7 cells. Tumors formed in mice with LRP1-deficient myeloid cells showed increased angiogenesis. Although VEGF mRNA expression was not increased in LRP1-deficient TAMs, at the single-cell level, the increase in TAM density in tumors with LRP1-deficient myeloid cells may have allowed these TAMs to contribute an increased amount of VEGF to the tumor microenvironment. Our results show that macrophage density in tumors is correlated with cancer angiogenesis in a novel model system. Myeloid cell LRP1 may be an important regulator of cancer progression.
Infected left atrial mass within anatomically normal heart.
Authors: A D Malcolm, D M Chaput de Saintonge
Journal: Thorax (1975)

A case is presented with some features of subacute bacterial endocarditis and of left atrial myxoma. Operative removal of a 5x3 cm tumour lying above and attached to an anatomically normal mitral valve reversed a rapidly deteriorating clinical situation. Histologically the entire tumour appeared to be old thrombus, and Gram-positive cocci in its superficial strata corresponded with Streptococcus viridans previously isolated from blood cultures. Many features, including an eight-year history of intermittent neurological disturbances and recent increasing hypergammaglobulinaemia, accord with the diagnosis of atrial myxoma. However, the valvular attachment site, absence of any cardiac structural abnormality, and tumour histopathology with bacterial colonization of the tumour present a unique situation which is explored in the discussion.
Detecting Recent Positive Selection with High Accuracy and Reliability by Conditional Coalescent Tree
Authors: Minxian Wang, Xin Huang, Ran Li, Hongyang Xu, Li Jin, Yungang He
Journal: Molecular Biology and Evolution (2014)

Studies of natural selection, followed by functional validation, are shedding light on understanding of genetic mechanisms underlying human evolution and adaptation. Classic methods for detecting selection, such as the integrated haplotype score (iHS) and Fay and Wu's H statistic, are useful for candidate gene searching underlying positive selection. These methods, however, have limited capability to localize causal variants in selection target regions. In this study, we developed a novel method based on conditional coalescent tree to detect recent positive selection by counting unbalanced mutations on coalescent gene genealogies. Extensive simulation studies revealed that our method is more robust than many other approaches against biases due to various demographic effects, including population bottleneck, expansion, or stratification, while not sacrificing its power. Furthermore, our method demonstrated its superiority in localizing causal variants from massive linked genetic variants. The rate of successful localization was about 20–40% higher than that of other state-of-the-art methods on simulated data sets. On empirical data, validated functional causal variants of four well-known positive selected genes were all successfully localized by our method, such as ADH1B, MCM6, APOL1, and HBB. Finally, the computational efficiency of this new method was much higher than that of iHS implementations, that is, 24–66 times faster than the REHH package, and more than 10,000 times faster than the original iHS implementation. These magnitudes make our method suitable for applying on large sequencing data sets. Software can be downloaded from https://github.com/wavefancy/scct.
CD28 and T cell antigen receptor signal transduction coordinately regulate interleukin 2 gene expression in response to superantigen stimulation.
Authors: J D Fraser, M E Newton, A Weiss
Journal: The Journal of Experimental Medicine (1992)

Activation of an immune response requires intercellular contact between T lymphocytes and antigen-presenting cells (APC). Interaction of the T cell antigen receptor (TCR) with antigen in the context of major histocompatibility molecules mediates signal transduction, but T cell activation appears to require the induction of a second costimulatory signal transduction pathway. Recent studies suggest that interaction of CD28 with B7 on APC might deliver such a costimulatory signal. To investigate the role of CD28 signal transduction during APC-dependent T cell activation, we have used Staphylococcal enterotoxins (SEs) presented by a B7-positive APC. We used anti-B7 monoclonal antibodies and a mutant interleukin 2 (IL-2) promoter construct, unresponsive to CD28-generated signals, in transient transfection assays to examine the contribution of the CD28-B7 interaction to IL-2 gene activation. These studies indicate that the CD28-regulated signal transduction pathway is activated during SE stimulation of T cells and plays an important role in SE induction of IL-2 gene expression through its influence upon the CD28-responsive element contained within the IL-2 gene promoter. This effect is particularly profound in the activation of the IL-2 gene in peripheral blood T cells.
Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia
Authors: Kerstin Kampa-Schittenhelm, Michael Heinrich, Figen Akmut, Katharina Rasp, Barbara Illing, Hartmut Döhner, Konstanze Döhner, Marcus Schittenhelm
Journal: Molecular Cancer (2013)

Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. In acute leukemia, the AKT pathway is frequently activated, however mutations in the PI3K/AKT pathway are uncommon. In some cases, constitutive AKT activation can be linked to gain-of-function tyrosine kinase (TK) mutations upstream of the PI3K/AKT pathway. Inhibitors of the PI3K/AKT pathway are attractive candidates for cancer drug development, but so far clinical efficacy of PI3K inhibitors against various neoplasms has been moderate. Furthermore, specific MTORC1 inhibitors, acting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We now evaluated the antitumor efficacy of NVP-BGT226, a novel dual pan-PI3K and MTORC1/2 inhibitor, in acute leukemia. Native leukemia blasts were stained to analyze for AKT phosphorylation levels on a flow cytometer. Efficacy of NVP-BGT226 in comparison to a second dual inhibitor, NVP-BEZ235, was determined with regard to cellular proliferation, autophagy, cell cycle regulation and induction of apoptosis in in vitro and ex vivo cellular assays as well as on the protein level. An isogenic AKT-autoactivated Ba/F3 model, different human leukemia cell lines as well as native leukemia patient blasts were studied. Isobologram analyses were set up to calculate for (super) additive or antagonistic effects of two agents. We show, that phosphorylation of AKT is frequently augmented in acute leukemia. NVP-BGT226 as well as NVP-BEZ235 profoundly and globally suppress AKT signaling pathways, which translates into potent antiproliferative effects. Furthermore, NVP-BGT226 has potent proapoptotic effects in vitro as well as in ex vivo native blasts. Surprisingly and in contrast, NVP-BEZ235 leads to a profound G1/G0 arrest preventing significant induction of apoptosis. Combination with TK inhibitors, which are currently been tested in the treatment of acute leukemia subtypes, overcomes cell cycle arrest and results in (super)additive proapoptotic effects for NVP-BGT226 – but also for NVP-BEZ235. Importantly, mononuclear donor cells show lower phospho-AKT expression levels and consequently, relative insensitivity towards dual PI3K-MTORC1/2 inhibition. Our data suggest a favorable antileukemic profile for NVP-BGT226 compared to NVP-BEZ235 – which provides a strong rationale for clinical evaluation of the dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.
The effect of addition of calcipotriol ointment (50 mug/g) to acitretin therapy in psoriasis
Authors: None Van DE Kerkhof, None Cambazard, None Hutchinson, None Haneke, None Wong, None Souteyrand, None Damstra, None Combemale, None Neumann, None Chalmers, None Olsen, None Revuz
Journal: British Journal of Dermatology (1998)

Our purpose was to find out whether the addition of calcipotriol ointment (50 micrograms/g) to systemic treatment with acitretin produces additional therapeutic effects and thereby an acitretin-sparing effect, and further to investigate the safety and tolerability of this combination. A multicentre, randomized, double-blind placebo-controlled study was designed. Patients were randomized to receive calcipotriol or placebo. All patients were treated with a starting dose of 20 mg acitretin per day and doses were adjusted at 2-weekly intervals with increments of 10 mg per day up to a maximum of 70 mg per day. The dose requirement for acitretin, clinical signs and adverse events were recorded. Seventy-six patients were randomized to treatment with calcipotriol 50 micrograms/g ointment twice daily and 59 patients to treatment with the vehicle only twice daily. Clearance or marked improvement was achieved by 67% of the patients in the calcipotriol group and by 41% of the patients in the placebo group (P = 0.006). Calcipotriol treatment proved to have a statistically significant additional effect to acitretin on the Psoriasis Area and Severity Index, redness, thickness and scaliness as compared with placebo. Clearance or marked improvement was achieved with a statistically significantly lower cumulative dose of acitretin by the patients in the calcipotriol group as compared with the placebo group. The number of patients reporting adverse events was pronounced and largely related to acitretin. No significant differences were observed between the two treatment groups with respect to adverse events. Laboratory assessments were essentially normal. The addition of calcipotriol ointment to acitretin treatment contributes to the efficacy, reduces the cumulative dose of acitretin to reach marked improvement or clearance, and is well-tolerated and safe.
MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells
Authors: Jaehak Oh, Nan Wu, Günther Baravalle, Benjamin Cohn, Jessica Ma, Bryan Lo, Ira Mellman, Satoshi Ishido, Mark Anderson, Jeoung-Sook Shin
Journal: The Journal of Experimental Medicine (2013)

Membrane-associated RING-CH1 (MARCH1) is an E3 ubiquitin ligase that mediates ubiquitination of MHCII in dendritic cells (DCs). MARCH1-mediated MHCII ubiquitination in DCs is known to regulate MHCII surface expression, thereby controlling DC-mediated T cell activation in vitro. However, its role at steady state or in vivo is not clearly understood. Here, we show that MARCH1 deficiency resulted in a substantial reduction in the number of thymus-derived regulatory T cells (T reg cells) in mice. A specific ablation of MHCII ubiquitination also significantly reduced the number of thymic T reg cells. Indeed, DCs deficient in MARCH1 or MHCII ubiquitination both failed to generate antigen-specific T reg cells in vivo and in vitro, although both exhibited an increased capacity for antigen presentation in parallel with the increased surface MHCII. Thus, MARCH1-mediated MHCII ubiquitination in DCs is required for proper production of naturally occurring T reg cells, suggesting a role in balancing immunogenic and regulatory T cell development.
WHO's budgetary allocations and burden of disease: a comparative analysis
Authors: David Stuckler, Lawrence King, Helen Robinson, Martin McKee
Journal: The Lancet (2008)

BackgroundMinisters of health, donor agencies, philanthropists, and international agencies will meet at Bamako, Mali, in November, 2008, to review global priorities for health research. These individuals and organisations previously set health priorities for WHO, either through its regular budget or extra-budgetary funds. We asked what insights can be gained as to their priorities from previous decisions within the context of WHO.MethodsWe compared the WHO biennial budgetary allocations with the burden of disease from 1994–95 to 2008–09. We obtained data from publicly available WHO sources and examined whether WHO allocations varied with the burden of disease (defined by death and disability-adjusted life years) by comparing two WHO regions—Western Pacific and Africa—that are at differing stages of epidemiological transition. We further assessed whether the allocations differed on the basis of the source of funds (assessed and voluntary contributions) and the mechanism for deciding how funds were spent.FindingsWe noted that WHO budget allocations were heavily skewed toward infectious diseases. In 2006–07, WHO allocated 87% of its total budget to infectious diseases, 12% to non-communicable diseases, and less than 1% to injuries and violence. We recorded a similar distribution of funding in Africa, where nearly three-quarters of mortality is from infectious disease, and in Western Pacific, where three-quarters of mortality is from non-communicable disease. In both regions, injuries received only 1% of total resources. The skew towards infectious diseases was substantially greater for the WHO extra-budget, which is allocated by donors and has risen greatly in recent years, than for the WHO regular budget, which is decided on by member states through democratic mechanisms and has been held at zero nominal growth.InterpretationDecision makers at Bamako should consider the implications of the present misalignment of global health priorities and disease burden for health research worldwide. Funds allocated by external donors substantially differ from those allocated by WHO member states. The meeting at Bamako provides an opportunity to consider how this disparity might be addressed.FundingNone.
Pre- and postjunctional inhibitory effects of fenspiride on guinea-pig bronchi
Authors: V Girard, E Naline, O Crambes, M Malbezin, RE Malmstrom, JM Lundberg, C Advenier
Journal: European Respiratory Journal (1997)

Fenspiride is a drug with potential benefits in the treatment of obstructive airways disease. It has antibronchoconstriction and anti-inflammatory properties. The aim of this study was to investigate the effect of this drug on the contractions induced in the guinea-pig isolated main bronchus and perfused lung by electrical field stimulation (EFS) or exogenously added agents. Bronchi were stimulated transmurally in the presence of indomethacin 10(-6) M and propranolol 10(-6) M, and isometric tension was measured. In the perfused lung model calcitonin gene-related peptide (CGRP) release was determined in the perfusate fractions as a measure of neuropeptide production. Two successive contractile responses were observed: a rapid cholinergic contraction, followed by a long-lasting contraction due to local release of neuropeptides from C-fibre endings. Fenspiride (10(-6) to 10(-4) M) inhibited the nonadrenergic, noncholinergic (NANC) component of the contraction of the guinea-pig isolated main bronchus induced by EFS. Fenspiride significantly affected contractions induced by exogenously added substance P or [Nle10]-NKA(4-10) only at concentrations higher than 10(-3) M. In the guinea-pig perfused lung, fenspiride inhibited low pH- but not capsaicin-evoked release of CGRP. At higher concentrations (10(-4) M to 3x10(-4) M) fenspiride exhibited a significant inhibitory effect both on the cholinergic component of contractile response induced by EFS in the guinea-pig isolated main bronchus and on exogenously added acetylcholine. In conclusion, the result of this study suggests that fenspiride, in moderate concentrations, reduces the release of neuropeptides, including tachykinins, from sensory nerve endings at a prejunctional level. At higher concentrations, postjunctional actions on bronchial smooth muscle are also present.
ASSOCIATION OF ADMISSION HYPERGLYCEMIA WITH IMPAIRED CORONARY FLOW VELOCITY PATTERN AND LEFT VENTRICULAR REMODELING IN PATIENTS WITH ACUTE ANTERIOR MYOCARDIAL INFARCTION
Authors: Yoshimori An, Atsushi Yamamuro, Shuichiro Kaji, Makoto Kinoshita, Natsuhiko Ehara, Atsushi Kobori, Takeshi Kitai, Kitae Kim, Tomoko Tani, Toru Kita, Yutaka Furukawa
Journal: Journal of the American College of Cardiology (2010)
NHS chief admits to errors in costing of pay reform
Authors: Adrian O'Dowd
Journal: BMJ (2006)

The government miscalculated the full cost of the pay reforms in the NHS, its chief executive admitted to MPs this week.

Mr Nicholson was giving evidence to the House of Commons Committee of Public Accounts as part of its one-off inquiry into the National Audit Office and Audit Commission report Financial Management in the NHS , which was published in June.

“As far as the department is concerned we could be better at costing some of our policies,” he said. “There are some examples …
Subspecialization of Cxcr5+ T Cells
Authors: Chang H. Kim, Lusijah S. Rott, Ian Clark-Lewis, Daniel J. Campbell, Lijun Wu, Eugene C. Butcher
Journal: The Journal of Experimental Medicine (2001)

The T helper (Th) cell pool is composed of specialized cells with heterogeneous effector functions. Apart from Th1 and 2 cells, CXCR5+ T cells have been suggested to be another type of effector T cell specialized for B cell help. We show here that CXCR5+ T cells are heterogeneous, and we identify subsets of CXCR5+ CD4 T cells that differ in function and microenvironmental localization in secondary lymphoid tissues. CD57+CXCR5 T cells, hereafter termed germinal center Th (GC-Th) cells, are localized only in GCs, lack CCR7, and are highly responsive to the follicular chemokine B lymphocyte chemoattractant but not to the T cell zone EBI1-ligand chemokine. Importantly, GC-Th cells are much more efficient than CD57-CXCR5+ T cells or CXCR5- T cells in inducing antibody production from B cells. Consistent with their function, GC-Th cells produce elevated levels of interleukin 10 upon stimulation which, with other cytokines and costimulatory molecules, may help confer their B cell helper activity. Our results demonstrate that CXCR5+ T cells are functionally heterogeneous and that the GC-Th cells, a small subset of CXCR5+ T cells, are the key helpers for B cell differentiation and antibody production in lymphoid tissues.