tbuckley/cabot-search huggingface dataset:
Endogenous Hormone Levels, Mammographic Density, and Subsequent Risk of Breast Cancer in Postmenopausal Women
Authors: R. M. Tamimi, C. Byrne, G. A. Colditz, S. E. Hankinson
Journal: JNCI Journal of the National Cancer Institute (2007)

Mammographic density and circulating sex hormones are two well-confirmed predictors of breast cancer risk. Whether mammographic density reflects levels of endogenous sex hormones is unclear. We examined whether these predictors are independently associated with breast cancer risk in a prospective study. We conducted a nested case–control study within the Nurses' Health Study cohort of 253 case subjects with breast cancer and 520 control subjects. All participants were postmenopausal women who were not using postmenopausal hormones at the time of both blood collection and mammography. Plasma levels of estradiol, free estradiol, testosterone, and free testosterone were evaluated. Mammographic density was assessed by use of computer-assisted analysis of mammograms. Logistic regression models that were adjusted for matching variables and potential confounders were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Levels of circulating sex steroids and mammographic density were both statistically significantly and independently associated with breast cancer risk. The relative risk of breast cancer associated with mammographic density (RR for highest quartile compared with lowest quartile = 3.8, 95% CI = 2.2 to 6.6; Ptrend <.001) changed little when the analysis was adjusted for circulating estradiol (RR = 3.9, 95% CI = 2.2 to 6.9; Ptrend <.001) or circulating testosterone (RR = 4.1, 95% CI = 2.3 to 7.2; Ptrend <.001). Circulating levels of estradiol (RR = 2.4, 95% CI = 1.4 to 4.0) and of testosterone (RR = 2.0, 95% CI = 1.2 to 3.1) were both associated with breast cancer risk, before and after adjustment for mammographic density. In a joint analysis of mammographic density and plasma testosterone, the risk of breast cancer was highest in the highest tertiles of both relative to the lowest tertiles of both (RR = 6.0, 95% CI = 2.6 to 14.0). A similar pattern was observed in the joint analysis of estradiol and mammographic density (RR = 4.1, 95% CI = 1.7 to 9.8). Circulating sex steroid levels and mammographic density appear strongly and independently associated with the risk of breast cancer in postmenopausal women.
L1 Cell Adhesion Molecule Is a Novel Therapeutic Target in Intrahepatic Cholangiocarcinoma
Authors: Jeong-Ki Min, Jin-Man Kim, Shengjin Li, Jung Whoi Lee, Hyunho Yoon, Chun Jeih Ryu, Soung Hoo Jeon, Jae-Hyek Lee, Jin Young Kim, Hee Kwan Yoon, Young Kwan Lee, Bong-Hui Kim, Yeon Sung Son, Hong Seo Choi, Nam-Kyu Lim, Dae-Ghon Kim, Hyo Jeong Hong
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Intrahepatic cholangiocarcinoma (ICC), a highly malignant hepatobiliary cancer, has a poor prognosis and is refractory to conventional therapies. The aim of this study is to discover a novel molecular target for the treatment of ICC. Experimental Design: To discover novel cancer-associated membrane antigens expressed in ICC cells, we generated monoclonal antibodies (mAb) by immunizing mice with intact ICC cell lines and screened for those that bind to the plasma membrane of ICC cells but not to normal cells. The mAb A10-A3 was selected and its target antigen was identified as the L1 cell adhesion molecule. Expression of L1 in ICC was evaluated by immunohistochemical analysis of tumor samples from 42 ICC patients. The functional significance of L1 expression in the tumor progression of ICC was investigated by L1 suppression, L1 overexpression, and antibody treatment. Results: L1 was not expressed in normal hepatocytes and intrahepatic bile duct epithelium but highly expressed in 40.5% of ICC patients, remarkably at the invasive front of the tumors. Suppression of L1 with short hairpin RNA significantly decreased proliferation, migration, and invasion of ICC cells in vitro. Consistently, L1 overexpression in ICC cells enhanced proliferation, migration, invasion, and apoptosis resistance. In addition, L1 short hairpin RNA or anti-L1 mAb significantly reduced the tumor growth in nude mice bearing ICC xenograft. Conclusions: We identified that L1 is expressed in ICC. L1 plays an important role in the tumor progression of ICC by enhancing cell proliferation, migration, invasion, and survival. L1 may represent a novel therapeutic target for ICC. Clin Cancer Res; 16(14); 3571–80. ©2010 AACR.
Enhanced Killing of Melanoma Cells by Simultaneously Targeting Mcl-1 and NOXA
Authors: Jian-Zhong Qin, Hong Xin, Leonid A. Sitailo, Mitchell F. Denning, Brian J. Nickoloff
Journal: Cancer Research (2006)

Abstract By deciphering the dysregulation of apoptosis in melanoma cells, new treatment approaches exploiting aberrant control mechanisms regulating cell death can be envisioned. Among the Bcl-2 family, a BH3-only member, NOXA, functions in a specific mitochondrial-based cell death pathway when melanoma cells are exposed to a proteasome inhibitor (e.g., bortezomib). Some therapeutic agents, such as bortezomib, not only induce proapoptotic Bcl-2 family members and active conformational changes in Bak and Bax but also are associated with undesirable effects, including accumulation of antiapoptotic proteins, such as Mcl-1. To enhance the bortezomib-mediated killing of melanoma cells, the apoptotic pathway involving NOXA was further investigated, leading to identification of an important target (i.e., the labile Bcl-2 homologue Mcl-1 but not other survival proteins). To reduce Mcl-1 levels, melanoma cells were pretreated with several different agents, including Mcl-1 small interfering RNA (siRNA), UV light, or the purine nucleoside analogue fludarabine. By simultaneously triggering production of NOXA (using bortezomib) as well as reducing Mcl-1 levels (using siRNA, UV light, or fludarabine), significantly enhanced killing of melanoma cells was achieved. These results show binding interactions between distinct Bcl-2 family members, such as NOXA and Mcl-1, in melanoma cells, paving the way for novel and rational therapeutic combination strategies, which target guardians of the proapoptotic Bak- and Bax-mediated pathways, against this highly aggressive and often fatal malignancy. (Cancer Res 2006; 66(19): 9636-45)
Deciphering the Clinical Presentations, Pathogenesis, and Treatment of the Idiopathic Inflammatory Myopathies
Authors: Lisa G Rider, Frederick W Miller
Journal: JAMA (2011)

The idiopathic inflammatory myopathies or myositis syndromes (the most common forms are polymyositis, dermatomyositis, and inclusion body myositis) are systemic autoimmune diseases defined by chronic muscle weakness and inflammation of unknown etiology and result in significant morbidity and mortality. Research suggests that categorizing heterogeneous myositis syndromes into mutually exclusive and stable phenotypes by using clinical and immune response features is useful for predicting clinical signs and symptoms, associated genetic and environmental risk factors, and responses to therapy and prognosis. Knowledge of myositis phenotypes should enhance clinicians' ability to recognize and manage these rare disorders.
A cell-surface β-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma
Authors: Arihiro Aihara, Chiung-Kuei Huang, Mark J. Olsen, Qiushi Lin, Waihong Chung, Qi Tang, Xiaoqun Dong, Jack R. Wands
Journal: Hepatology (2014)

Hepatocellular carcinoma (HCC) has a poor prognosis as a result of widespread intra- and extrahepatic metastases. There is an urgent need to understand signaling cascades that promote disease progression. Aspartyl-(asparaginyl)-β-hydroxylase (ASPH) is a cell-surface enzyme that generates enhanced cell motility, migration, invasion, and metastatic spread in HCC. We hypothesize that inhibition of its enzymatic activity could have antitumor effects. Small molecule inhibitors (SMIs) were developed based on the crystal structure of the ASPH catalytic site followed by computer-assisted drug design. Candidate compounds were tested for inhibition of β-hydroxylase activity and selected for their capability to modulate cell proliferation, migration, invasion, and colony formation in vitro and to inhibit HCC tumor growth in vivo using orthotopic and subcutaneous murine models. The biological effects of SMIs on the Notch signaling cascade were evaluated. The SMI inhibitor, MO-I-1100, was selected because it reduced ASPH enzymatic activity by 80% and suppressed HCC cell migration, invasion, and anchorage-independent growth. Furthermore, substantial inhibition of HCC tumor growth and progression was observed in both animal models. The mechanism(s) for this antitumor effect was associated with reduced activation of Notch signaling both in vitro and in vivo . Conclusions : These studies suggest that the enzymatic activity of ASPH is important for hepatic oncogenesis. Reduced β-hydroxylase activity generated by the SMI MO-I-1100 leads to antitumor effects through inhibiting Notch signaling cascade in HCC. ASPH promotes the generation of an HCC malignant phenotype and represents an attractive molecular target for therapy of this fatal disease. (Hepatology 2014;60:1302–1313)
Endotoxemia and sepsis mortality reduction by non-anticoagulant–activated protein C
Authors: Edward J. Kerschen, José A. Fernandez, Brian C. Cooley, Xia V. Yang, Rashmi Sood, Laurent O. Mosnier, Francis J. Castellino, Nigel Mackman, John H. Griffin, Hartmut Weiler
Journal: The Journal of Experimental Medicine (2007)

Activated protein C (APC) reduces mortality of severe sepsis patients but increases the risk of serious bleeding. APC exerts anticoagulant activity by proteolysis of factors Va/VIIIa. APC also exerts antiinflammatory and antiapoptotic effects and stabilizes endothelial barrier function by APC-initiated cell signaling that requires two receptors, endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR1). The relative importance of APC's various activities for efficacy in sepsis is unknown. We used protein engineering of mouse APC and genetically altered mice to clarify mechanisms for the efficacy of APC in mouse sepsis models. Mortality reduction in LPS-induced endotoxemia required the enzymatic active site of APC, EPCR, and PAR-1, highlighting a key role for APC's cytoprotective actions. A recombinant APC variant with normal signaling but &amp;lt;10% anticoagulant activity (5A-APC) was as effective as wild-type APC in reducing mortality after LPS challenge, and enhanced the survival of mice subjected to peritonitis induced by gram-positive or -negative bacteria or to polymicrobial peritoneal sepsis triggered by colon ascendens stent implantation. Thus, APC's efficacy in severe sepsis is predominantly based on EPCR- and PAR1-dependent cell signaling, and APC variants with normal cell signaling but reduced anticoagulant activities retain efficacy while reducing the risk of bleeding.
Effect of Melanoma on Immune Function in the Regional Lymph Node Basin
Authors: Benjamin Negin, David Panka, Wei Wang, Mustaqueem Siddiqui, Nicholas Tawa, John Mullen, Steven Tahan, Lucy Mandato, Adam Polivy, James Mier, Michael Atkins
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To determine if melanoma within the tumor microenvironment will result in immunosuppression within the draining lymph node as measured by down-regulation of T-cell receptor ζ (TCR ζ) expression. Experimental Design: Patients with clinical stage I to III melanoma undergoing wide local excision and sentinel lymph node biopsy or therapeutic lymph node dissection were consented to have a portion of their lymph node sampled. Lymph nodes were classified as macroscopically involved (TI), microscopically involved (MI), noninvolved with positive wide excision (NI+), or noninvolved with negative wide excision (NI−). Lymphocytes were stained using antibodies to TCR ζ and other immune cells and analyzed via flow cytometer. Reverse transcription-PCR was used to assess for mediators of immunosuppression. Results: Fifty patient lymph node samples (15 TI, 7 MI, 9 NI+, and 19 NI−) were evaluated. Increasing involvement of tumor in the lymph node was associated with decreasing TCR ζ chain expression (TI 56%, MI 76%, and NI− 89%). Differences between TI and MI (P = 0.005), TI and NI− (P = 0.0001), and MI and NI− (P = 0.019) were statistically significant. There was also a significant difference between TCR ζ chain expression of NI+ and NI− (73% versus 89%; P = 0.0016). A trend toward increased arginase expression in tumor-involved lymph nodes was detected by reverse transcription-PCR. Conclusions: Melanoma involvement of regional nodes is associated with loss of TCR ζ expression that is inversely related to tumor burden. Residual melanoma within the wide local excision specimen is associated with TCR ζ loss in noninvolved sentinel lymph nodes, suggesting that immune modulation precedes tumor spread.
Quantitative Adsorption of Antibody by the Isolated Heart and the Intensity of Cardiac Anaphylaxis
Authors: GEORGE A. FEIGEN, GERALD G. VUREK, WILLIAM S. IRVIN, JANICE K. PETERSON
Journal: Circulation Research (1961)

The present experiments show that the adsorption of antibodies to the guinea pig heart can be achieved by perfusing the heart with rabbit antiovalbumin solutions. The amount of radioactive antibody remaining on the tissue is a definite function of the concentration of antibody in the bulk phase instilled into the coronary circulation. When the antibody-loaded organ is challenged with ovalbumin, the efflux rate of antibody is increased; it is also increased in response to such nonspecific agents as histamine and epinephrine. Since the output rate is not affected when the heart fails to react to rechallenge with antigen, the release of antibody may be entirely dependent upon the mechanical response. The maximal amount.it of histamine-like material that can be produced by the heart undergoing anaphylaxis was found to be 1 x 10 -s moles/Gm./min., estimated as histamine; the minimal amount of antibody necessary to release this quantity was calculated to be 0.343 µg. of specific antiovalbumin/100 mg. of heart. This load can be achieved by perfusing the heart with an antibody solution containing 30 µg. of specific γ-globulin. Perfusion with an antibody solution containing 50 µg./ml. showed the amount of histamine subsequently liberated by the same dose of ovalbumin to be reduced by 50 per cent. The rate and amplitude of contraction were increased to the same absolute values in all cases in which either ovalbumin or histamine was employed to set off the reaction, suggesting that the release of active material at even the low sensitizing doses of antibody used exceeded the ceiling of the physiological response. The decrease in coronary flow was inversely related to the dose of sensitizing antibody and bore little relation to the changes in this parameter induced by the subsequent administration of histamine.
Improved Fecal DNA Test for Colorectal Cancer Screening
Authors: Steven H. Itzkowitz, Lina Jandorf, Randall Brand, Linda Rabeneck, Paul C. Schroy, Stephen Sontag, David Johnson, Joel Skoletsky, Kris Durkee, Sanford Markowitz, Anthony Shuber
Journal: Clinical Gastroenterology and Hepatology (2006)
A Bench to Bedside View of Uremic Toxins
Authors: Raymond Vanholder, Ulrich Baurmeister, Philippe Brunet, Gerald Cohen, Griet Glorieux, Joachim Jankowski
Journal: Journal of the American Society of Nephrology (2008)

Reviewing the current picture of uremic toxicity reveals its complexity. Focusing on cardiovascular damage as a model of uremic effects resulting in substantial morbidity and mortality, most molecules with potential to affect the function of a variety of cell types within the vascular system are difficult to remove by dialysis. Examples are the larger middle molecular weight molecules and protein-bound molecules. Recent clinical studies suggest that enhancing the removal of these compounds is beneficial for survival. Future therapeutic options are discussed, including improved removal of toxins and the search for pharmacologic strategies blocking responsible pathophysiologic pathways.
ERS/WHO Tuberculosis Consilium assistance in extensively drug-resistant tuberculosis
Authors: Alkesh Kumar Khurana, Deepak Aggarwal
Journal: European Respiratory Journal (2014)

We read with interest the article by Esposito et al. [1], whereby they emphasised the role of the European Respiratory Society (ERS)/World Health Organization (WHO) Tuberculosis (TB) Consilium [2–4] in the management of an extensively drug-resistant (XDR)-TB case. The creation of this e-platform brings together many brains and aims at improving treatment outcome. However, a few points in this regard need to be addressed. ERS/WHO TB Consilium is a timely step aimed to improve management of highly fatal drug-resistant TB <http://ow.ly/Cc7gw>
THE TRANSFORMATION IN VITRO OF R PNEUMOCOCCI INTO S FORMS OF DIFFERENT SPECIFIC TYPES BY THE USE OF FILTERED PNEUMOCOCCUS EXTRACTS
Authors: J. Lionel Alloway
Journal: The Journal of Experimental Medicine (1932)

1. Avirulent R pneumococci derived from S forms of a specific type may be changed by growth in broth containing anti-R serum and a heated, filtered extract of S pneumococci of a different type, into virulent S organisms identical in type with the bacteria extracted. This has been accomplished in the case of R strains derived from Type II pneumococci, employing extracts prepared from Type III and Type I S forms. 2. The constituents of the extract supply an activating stimulus of a specific nature in that the R pneumococci acquire the capacity of elaborating the capsular material peculiar to the organisms extracted.
Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver
Authors: Yvonne Meier, Christiane Pauli-Magnus, Ulrich M. Zanger, Kathrin Klein, Elke Schaeffeler, Andreas K. Nussler, Natascha Nussler, Michel Eichelbaum, Peter J. Meier, Bruno Stieger
Journal: Hepatology (2006)

Interindividual variability in hepatic canalicular transporter expression might predispose to the development of hepatic disorders such as acquired forms of intrahepatic cholestasis. We therefore investigated expression patterns of bile salt export pump (BSEP, ABCB11 ), multidrug resistance protein 3 (MDR3, ABCB4 ), multidrug resistance associated protein 2 (MRP2, ABCC2 ) and multidrug resistance protein 1 (MDR1, ABCB1) in healthy liver tissue of a white population. Protein expression levels were correlated with specific single nucleotide polymorphisms (SNPs) in the corresponding transporter genes. Hepatic protein expression levels from 110 individuals undergoing liver resection were assessed by Western blot analysis of liver plasma membranes enriched in canalicular marker enzymes. Each individual was genotyped for the following synonymous (s) and nonsynonymous (ns) SNPs: ABCB11: (ns:1457T&gt;C and 2155A&gt;G), ABCB4: (ns:3826A&gt;G) and ABCC2 (ns:1286G&gt;A,3600T&gt;A and 4581G&gt;A) and ABCB1 (ns:2677G&gt;T/A and s:3435C&gt;T). Transporter expression followed unimodal distribution. However, of all tested individuals 30% exhibited a high expression and 32% a low or very low expression phenotype for at least one of the four investigated transport proteins. Transporter expression levels did not correlate with age, sex, underlying liver disease, or presurgery medication. However, low BSEP expression was associated with the 1457C-allele in ABCB11 ( P = .167) and high MRP2 expression was significantly correlated with the 3600A and 4581A ABCC2 variants ( P = .006). In conclusion , the results demonstrate a considerable interindividual variability of canalicular transporter expression in normal liver. Furthermore, data suggest a polymorphic transporter expression pattern, which might constitute a risk factor for the development of acquired forms of cholestatic liver diseases. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html)
FastME 2.0: A Comprehensive, Accurate, and Fast Distance-Based Phylogeny Inference Program: Table 1.
Authors: Vincent Lefort, Richard Desper, Olivier Gascuel
Journal: Molecular Biology and Evolution (2015)

FastME provides distance algorithms to infer phylogenies. FastME is based on balanced minimum evolution, which is the very principle of Neighbor Joining (NJ). FastME improves over NJ by performing topological moves using fast, sophisticated algorithms. The first version of FastME only included Nearest Neighbor Interchange. The new 2.0 version also includes Subtree Pruning and Regrafting, while remaining as fast as NJ and providing a number of facilities: Distance estimation for DNA and proteins with various models and options, bootstrapping, and parallel computations. FastME is available using several interfaces: Command-line (to be integrated in pipelines), PHYLIP-like, and a Web server (http://www.atgc-montpellier.fr/fastme/).
Sex-Specific Associations of Gestational Glucose Tolerance With Childhood Body Composition
Authors: Nolwenn Regnault, Matthew W. Gillman, Sheryl L. Rifas-Shiman, Emma Eggleston, Emily Oken
Journal: Diabetes Care (2013)

OBJECTIVE To examine the associations of maternal gestational glucose tolerance with offspring body composition in late childhood. RESEARCH DESIGN AND METHODS Among 958 women in the prebirth cohort Project Viva, glucose tolerance was assessed in the second trimester by nonfasting 50-g 1-h glucose challenge test (GCT), followed if abnormal by fasting 100-g 3-h oral glucose tolerance test (OGTT). We categorized women as normoglycemic (83.3%) if GCT was ≤140 mg/dL, isolated hyperglycemia (9.1%) if GCT was abnormal but OGTT normal, intermediate glucose intolerance (IGI) (3.3%) if there was one abnormal value on OGTT, or gestational diabetes mellitus (GDM) (4.5%) if there were two or more abnormal OGTT values. Using multivariable linear regression, we examined adjusted associations of glucose tolerance with offspring overall (N = 958) and central (N = 760) adiposity and body composition using dual X-ray absorptiometry (DXA) measured at the school-age visit (95 ± 10 months). RESULTS Compared with that in the male offspring of normoglycemic mothers, DXA fat mass was higher in male offspring of GDM mothers (1.89 kg [95% CI 0.33–3.45]) but not in male offspring of mothers with IGI (0.06 kg [−1.45 to 1.57]). DXA trunk-to-peripheral fat mass, a measure of central adiposity, was also somewhat higher in male offspring of GDM mothers (0.04 [−0.01 to 0.09]). In girls, DXA fat mass was higher in offspring of mothers with IGI (2.23 kg [0.12–4.34]) but not GDM (−1.25 kg [−3.13 to 0.63]). We showed no association of gestational glucose tolerance with DXA lean mass. CONCLUSIONS In this study, only male offspring of GDM mothers manifested increased adiposity, whereas only female offspring of mothers with IGI did so. Sex differences in glycemic sensitivity may explain these findings.