tbuckley/cabot-search huggingface dataset:
Suppressor-Cell Antibody in Systemic Lupus Erythematosus
Authors: Akira Sagawa, Nabih I. Abdou
Journal: Journal of Clinical Investigation (1979)

Circulating antibodies that could be responsible for the suppressor thymus-derived (T)-cell dysfunction in active systemic lupus erythematosus (SLE) were investigated. Sera from 14 active and inactive SLE patients were compared with a pool of 22 normal sera. All sera were adsorbed with a pool of normal platelets to exclude antihistocompatibility leukocyte antigen antibodies; with AB erythrocytes to exclude isohemagglutinins; and with a pool of normal bone marrow-derived (B) lymphocytes, monocytes, and neutrophils to deplete anti-B-cell antibodies, Fc-receptor antibodies, and antibodies directed against neutrophils or monocytes. Sera from active SLE patients were capable of inhibiting the activation of normal, blood lymphocytes by concanavalin A to become suppressor cells. The latter were assayed by coculturing the concanavalin A-activated cells with autologous lymphocytes, which were then activated with either phytohemagglutinin for proliferative response or with pokeweed mitogen for B-cell immunoglobulin (Ig) synthesis and secretion. Specific incorporation of cultures with phytohemagglutinin showed a value of 67±13 (mean±SD) for suppressor cells treated with adsorbed, active SLE sera. This value was significantly different (P < 0.001) from that of cells treated with the inactive SLE sera or with the pool of normal sera. Similar findings were seen with respect to the B-cell target parameters. Cytoplasmic Ig and IgG in supernates of cultures with pokeweed mitogen showed values of 17±5% and 717±134 ng/culture, respectively, for suppressor cells treated with the adsorbed, active SLE sera. This was significantly different from those treated with the inactive SLE sera or with the pool of normal sera. The antisuppressor-cell factor was shown to be IgG, complement independent, not cytotoxic, active at 37°C and at room temperature, but not at 4°C, and adsorbable with T cells.
Combined silencing of Ras and Jak/Stat inhibitors results in constitutive activation of Ras and Jak/Stat pathways in human hepatocellular carcinoma
Authors: Diego F. Calvisi, Sara Ladu, Alexis Gorden, Valentina M. Factor, Snorri S. Thorgeirsson
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2593 

Although a number of oncogenic events have been described to date, the molecular pathogenesis of human hepatocellular carcinoma (HCC) remains poorly understood. To better define the molecular mechanisms responsible for liver cancer development we have investigated the importance of Ras and Jak/Stat pathways in a collection of 10 normal livers, 80 HCCs and corresponding non-neoplastic surrounding livers. Strikingly, activation of Ras and Jak/Stat pathways was conspicuously enhanced in all HCCs when compared with non-neoplastic surrounding and normal livers regardless of HCC etiology or clinical outcome. We found that activation of the Ras pathway led to the induction of Ras-mediated proliferation and survival cascades (Akt, Raf, MEK, ERK, c-mos) with concomitant suppression of Ras pro-apoptotic signaling (MST1, caspase 3, p38 MAPK, and SAPK/JNK). Activation of the Jak/Stat pathway resulted in increased levels of phosphorylation at the Jak1, Jak2, and Tyk2 tyrosine kinases, Stat1, Stat3, and Stat 5 molecules as well as c-myc, cyclin D1 and 2, Mcl-1 and Bcl-xl target genes. Importantly, induction of Ras and Jak/Stat pathways in HCCs was paralleled by suppression of numerous Ras and Jak/Stat inhibitors, including RASSF1A, NORE1A, SOCS1, 2, 3, CIS, and SHP1. Subsequent analyses showed that suppression of Ras and Jak/Stat inhibitors in HCC was due to epigenetic (promoter hypermethylation) and genetic (loss of heterozygosity) mechanisms. Furthermore, treatment of HLF, Hep3B and Hep40 hepatoma cell lines with specific Ras and Jak/Stat inhibitors led to cell growth arrest mainly due to massive apoptosis. Taken together, these data clearly demonstrate the significance of Ras and Jak/Stat pathway activation in hepatocarcinogenesis and suggest that the use of Ras and Jak/Stat inhibitors as therapeutic modality for human liver cancer is justified.
Neurofibromatosis and oral contraceptive therapy [Answer to letter of Lawrence M. Nelson].
Authors: Proudfit Cm
Journal: JAMA (1980)

There is evidence that neurofibromatosis may worsen or appear initially during pregnancy or during puberty.  The hormonal state is presumed the cause in these situations.  Since oral contraceptive (OC) therapy results in pharmacologic levels of estrogens and progestins the patient taking such medication is qualitatively if not exactly quantitatively similar to a pregnant woman with regard to hormonal milieu.  Many of the adverse effects of OCs are similar to metabolic effects observed during pregnancy.  Your reasonsing therefore seems to be on the right track.  However neurofibromatosis is probably not an absolute contraindication to OC therapy.  I am unaware of any reports of the results of OC therapy in women with neurofibromatosis.  Since there seems to be a reasonable theoretical chance of exacerbating this disease under conditions of increased estrogen and progestin levels another method of contraception would be preferable.  However the acceptability of other contraceptive methods must be taken into account for compliance is an important consideration.  Probably the risk from pregnancy is much greater than risks associated with OCs particularly since another contraceptive method could be substituted if it seems that the patients condition has worsened with OCs.  As in other situations where relative contraindications may exist the most appropriate contraceptive regimen is best selected after consideration of all pertinent factors by the physician and an informed patient.  (full text)
Quantitative gene expression by RT-PCR in classic and variant lobular carcinoma in ER+ breast cancer.
Authors: Joseph Michael Anderson, Carl N. Yoshizawa, Drew Watson, Vivian Tan, Helen Bailey, Athanasios C. Tsiatis, Steven Shak, Frederick L. Baehner
Journal: Journal of Clinical Oncology (2013)

11 Background: Classic lobular carcinoma is characterized by a distinctive morphology, loss of E-cadherin commonly due to mutation or deletion of CDH1 on chromosome 16q, and a variable clinical course. Variants (pleomorphic, solid and alveolar) with distinct morphologies and potential differences in outcome have been described (Rosen 2009). Herein we provide an 8-year update of the patterns of quantitative gene expression as measured by the 21 gene Oncotype DX assay observed between ductal NOS (DC) and classic and variant lobular carcinomas. Methods: All tumors analyzed in the Genomic Health laboratory from 6/1/04-5/31/12 were included. Central path used WHO criteria for classification of classic lobular (CL), solid and alveolar lobular (SAL), and pleomorphic lobular (PL) carcinomas. Quantitative expression of 16 cancer related genes was measured on a scale from 2 to 15 (relative to reference genes) where a 1 unit increment is associated with an ~2-fold change in expression. Descriptive statistics for RS &amp; individual genes [ER, PR, invasion gene group (IGG) and proliferation gene group (PGG)] among the subtypes were obtained. Comparisons of means among the subtypes were adjusted to control the overall error rate under any complete or partial null hypothesis. Results: DC accounted for 81.8% of 286,726 cases, CL 7.3%, SAL 0.4% and PL 0.4%. For all types a continuous range of RS was observed. DC had the greatest percentage of high risk RS followed by SAL, PL and CL. DC had the highest mean RS and PL and CL had the lowest RS. SAL had the highest mean ER expression and CL and PL had the lowest ER expression. These results may reflect a submission bias and are not population based. The proportion with ER+/PR- phenotype was slightly different among the subtypes: SAL (24.0%) and PL (19.4%) had a higher incidence compared to DC (14.1%) and CL (15.2%). SAL had the highest PGG expression; CL had the lowest. DC had the highest IGG; CL had the lowest. Conclusions: CL and the lobular carcinoma variants are characterized by differential patterns of gene expression. Outlier cases are not infrequent within each of the special subtypes in this large observational cohort. The variation in gene expression, noted by histologic subtype, will be presented in detail.
Abstract P180: Time to Screen for Medication Non-Adherence in Patients with Uncontrolled Hypertension? Comparing the Test Properties of Two Commonly Used Self-Report Adherence Questionnaires
Authors: Ian M Kronish, Benjamin Gallagher, Siqin Ye, Donald Edmondson
Journal: Circulation (2013)

Introduction: One major cause of uncontrolled hypertension is poor medication adherence. Yet, clinicians are poor at judging adherence and the gold standard for measuring medication adherence - electronic monitoring - is rarely available in clinic settings. Self-report adherence questionnaires, by contrast, are free, simple to administer, and may be useful for screening. Hypothesis: To compare the test properties of the Morisky Medication Adherence Questionnaire (MMAQ) and the Visual Analog Scale (VAS) for diagnosing non-adherence in patients with uncontrolled hypertension, using electronic pillbox monitoring as the gold standard. Methods: Thus far, 48 patients with uncontrolled hypertension [BP ≥140/90 mmHg (or ≥130/80 mmHg if diabetic) on 2 serial clinic visits] have been enrolled during visits to a hospital-based primary care practice. Patients are asked to take up to 4 of their BP medications from a 4-bin electronic pillbox (MedSignals) that records the date and time each bin is opened. At the next visit, patients complete the MMAQ, comprised of 8 brief questions that assess pill-taking behavior. The MMAQ is scored from 0 to 8; 8 signifies perfect adherence. Patients also complete the VAS by marking an “X” on a line from 0% to 100% to indicate how often they took each of their BP medications. Sensitivity, specificity, and negative likelihood ratio (NLR) were assessed for each test. The gold standard for adherence was ≥ 80% adherence averaged across each of the electronically monitored medications. Results: Mean age is 62 years (range 34 [[Unable to Display Character: &amp;#8211;]] 83), 70% women, 62% Hispanic, 52% Black, and 50% with diabetes. Mean BP at enrollment was 160/88 mmHg. Patients were prescribed a mean (SD) of 2.6 (0.9) BP medications. Adherence was monitored for 41 +/- 23 days. Mean adherence by electronic monitoring was 78% (range 13%-100%); 42% were adherent (≥ 80%) by the gold standard. Using a cutpoint of 7.5 (67% of the sample were below this cutpoint), the MMAQ has a sensitivity of 94% and specificity of 54%, corresponding to a NLR of 0.10 (95%CI 0.01 to 0.67). Using a cutpoint of 80% (only 11% of the sample below this cutpoint), the VAS has a sensitivity of 28%, specificity of 67%, and a NLR of 0.72. Conclusions: The MMAQ, but not the VAS, is a sensitive tool for screening for non-adherence in patients with uncontrolled hypertension and may be useful for excluding medication non-adherence as the cause of uncontrolled hypertension for a large proportion of patients.
Diagnostic delay in young women with breast cancer: A population-based analysis.
Authors: May Lynn Quan, Janice Austin, Nadine Lam, Rob Quinn
Journal: Journal of Clinical Oncology (2014)

92 Background: Breast cancer in young women is aggressive. Delays in diagnosis and treatment may contribute to the worse outcomes observed in the treatment of breast cancer in young women. The purpose of this study is to determine if there was diagnostic delay for women ≤ 35 with breast cancer in Alberta. Methods: We conducted a population based analysis of all women ≤ 35 treated for breast cancer between 2007 and 2010. Patient demographics, diagnostic modality, and time to treatment (surgery and radiation) were abstracted. “Diagnostic” and “treatment” delay were defined as ≥ 90 days from first imaging to pathologic diagnosis and pathologic diagnosis to surgery. Results: One hundred and one patient charts were identified in the Alberta Cancer Registry and reviewed. Mean age at diagnosis was 31.6 (± 3.3) years. Initial imaging modality was mammogram and ultrasound in 49.5% and 46.5% of women. The median time from imaging to pathologic diagnosis was 6 days (range 0-502). Of these, 11 (10.1%) women experienced diagnostic delay, with a median delay of 131 days (range 95-502). The stage at diagnosis was not significantly different for women with and without diagnostic delay (p = 0.47). For women with diagnostic delay, the initial imaging findings were most often reported as likely benign or recommended only follow up imaging. Mean time from diagnosis to surgery was 25 (± 14) days. Of patients undergoing surgery, 25 (24.8%) had breast conserving surgery. Radiation therapy occurred at a median of 48 (range 25-204) days post operatively or post chemotherapy. Conclusions: Ten percent of women ≤ 35 with breast cancer experienced a diagnostic delay. Diagnostic delay most often occurred due to initial imaging reports of benign or negative findings. Further studies are required to determine the impact of diagnostic delay on patient outcomes.
Abstract #4399: Role of eotaxin-1 signaling in ovarian cancer
Authors: Vera Levina, Brian Nolan, Adele Marrangoni, Jeffrey Marks, Elieser Gorelik, Anna Lokshin
Journal: Cancer Research (2009)

Purpose: Tumor cell growth and migration can be directly regulated by chemokines. In the present study the association of CCL11 with ovarian cancer has been investigated. Experimental design and results: Circulating levels of CCL11 in sera of patients with ovarian cancer were significantly lower than those in healthy women or women with breast, lung, liver, pancreatic or colon cancers. Cultured ovarian carcinoma cells absorbed soluble CCL11 indicating that absorption by tumor cells could be responsible for the observed reduction of serum level of CCL11 in ovarian cancer. Ovarian tumors express CCL11 and its cognate receptors, CCR2, CCR3, and CCR5, thus forming a regulatory loop. CCR3 was predominantly expressed in paraffin-embedded tumor sections from ovarian cancer patients. CCL11 potently stimulated proliferation and migration/invasion of ovarian carcinoma cell lines. The growth stimulatory effects of CCL11 were likely associated with activation of ERK1/2, MEK-1, and STAT3 phosphoproteins and with increased production of multiple cytokines, growth and angiogenic factors. Inhibition of CCL11 autocrine loop by the combination of neutralizing antibodies against the ligand and its receptors dramatically inhibited proliferation of ovarian carcinoma cells. Inhibition of CCL11 signaling also significantly increased sensitivity to cisplatin in these cells. We conclude that CCL11 signaling plays an important role in proliferation and invasion of ovarian carcinoma cells and CCL11 could be targeted for therapy in ovarian cancer.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4399.
Abstract 400: Calcium Responsive Element Binding Protein CREB Molecular Network is Differentially Enriched during Rejection and Quiescence in Heart Transplant Recipients.
Authors: Mario C Deng, Martin Cadeiras, Wei Keat Lim, Manuel Bayern, Anshu Sinha, Jianfeng Li, Helen M Baron, Steven Rosenberg, Russell Dedrick, Tod Klingler, Charles C Marboe, Nicole Suciu-Foca, Andrea Califano
Journal: Circulation (2006)

Background: Genomics and computational biology provide powerful tools to identify specific regulatory genes and modules that are potential targets for designing interventions for allograft rejectio...
Abstract 9243: Comparison of the 2006 and 2010 Appropriate Use Criteria for CT Coronary Angiography in an Academic Medical Center
Authors: Ethany Cullen, Shivani Aggarwal, Brian Goss, Philip Araoz, Raymond Gibbons
Journal: Circulation (2011)

Purpose: We previously analyzed the 2006 appropriateness criteria for cardiac computed tomography (CT) and found 42% of our patients were not classifiable, suggesting the criteria were difficult to apply clinically. These criteria were revised in 2010. The purpose of our study is to compare the new 2010 appropriate use criteria to the original 2006 criteria to determine if the 2010 criteria were more applicable. Materials and Methods: In a previous study we applied the 2006 appropriateness criteria to 251 patients that underwent cardiac CT from June 1 to December 31, 2007. Each patient was assigned an indication from the 2006 appropriate use criteria by two observers, classifying patients as appropriate, inappropriate, uncertain, or nonclassifiable. A third observer settled disagreements. This process was applied to the same 251 patients using the 2010 criteria. The data from the previous study using the 2006 criteria was compared to the data obtained using the 2010 criteria to determine changes in the number of nonclassifiable, appropriate, inappropriate, and uncertain exams. These results were then analyzed using Bowker's test of symmetry. Observer agreement was calculated using the kappa statistic. Results: 115 patients (46%) were not classifiable using the 2006 criteria. When the 2010 criteria were applied, the number of not classifiable patients decreased to 40 (16%), with the plurality, 41 (16%), of the not classifiable patients moving to inappropriate. In 2006, 69 (27%) were classified as appropriate, 25 (10%) were uncertain, 42 (17%) inappropriate. In 2010, the appropriate increased to 84 (33%), uncertain increased to 40 (16%), and inappropriate increased to 87 (35%). Bowker's test of symmetry demonstrated a statistically significant change with a p&lt;0.001. Agreement between the two observers assigning patients to classification groups also improved with a kappa of 0.55 using the 2010 criteria compared to kappa of 0.31 in 2006. Conclusion: The number of not classifiable patients decreased using the 2010 criteria and the interobserver agreement improved, suggesting they are more applicable and complete than the 2006 criteria. This decrease in not classifiable patients came primarily from an increase in the number of inappropriate indications.
Microfabricated natural killer cells: Selective in vitro cytotoxicity of EGFR-expressing tumor cells by micrometer size porous silicon particles loaded with a cytolysin and targeted by surface-grafted EGF
Authors: Francis J. Martin, Kristie Melnik, Michael H. Cohen, Arfaan Rampersaud, Anthony A. Boiarski
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

640 

Microfabrication (MEMS) techniques are adapted to create micrometer sized, disk-shaped drug delivery particles out of porous silicon dioxide (Cohen, Melnik et al, Biomedical Microdivices 5; 253-259, 2003). Particles are 2-5 μm in diameter, about 1 μm thick, the average volume is 20 μm3 and >50% of this volume is occupied by 6-7 nm diameter pores. Particles are silianized at 70°C for 4 hours to introduce SH- groups onto the particle surface. Mouse epidermal growth factor (EGF) is chemically modified (RT for 4 hr) with sulfo-SMCC (Pierce) to create a thiol-reactive derivative. The thiol-bearing particles and purified thiol-reactive EGF are incubated at RT for a few hours and washed by repeated pelleting. Approximately 120fg (about 10,000 molecules) of EGF is grafted to each particle using this procedure. The particles are dried, an equal volume of a saturated solution of the cytolysin melittin (2.5 mg/mL) is added and the particles are re-dried under reduced pressure for 24 hours. About 2.5 pg of melittin is loaded into each particle, and approximately half is released within 1 hour when particles are resuspended in excess buffer (0.0001 to 0.1 pg is sufficient to kill an individual cell). Swiss 3T3 cells and A431 cells, known to express EGFR, were used as target cell populations, while CHO cells which do not express the receptor were used as a negative control. Particles (1x106) and target or control cells (1 x 106) are mixed at a 1:1 ratio and allowed to interact for 1 hour. Cells are washed and then labeled fluorescently with dyes specific for each cell type membrane and a DNA vital stain is used to show dead/dying cells. Results obtained from flow cytometry indicate that 3.5% of CHO cells were killed in the presence of the highest concentration of particles, while 95% of the Swiss cells and 75% of the A431 cells are killed in the presence of that same concentration of particles. All experiments are carried out in serum supplemented media so that any melittin that escaped the particles would be inactivated and not harm surrounding, untargeted cell populations. Controls including treatment of Swiss 3T3 with non-EGF bearing, drug-loaded particles and drug-loaded non-EGF-bearing particles show less than 5% cytotoxicity. Future plans include in vivo experiments aimed at demonstrating an anti-tumor response to this novel particle drug delivery system. This work was supported by NCI contract N01-CO-17043.
Pro-life (Fas/FasL) and Pro-death (HGF/c-Met) receptor/ligand system interactions regulates invasion in vitro.
Authors: Snezana Ivanova, Peter McCullough, Rachel Fung, David Peck, Ara Darzi
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2077 

Introduction: Tumor metastasis is the limiting factor in successful treatment for a wide range of malignancies. Selective targeting of individual molecular pathways provides partial treatment benefit.

The Fas/ FasL system, widely investigated for its pro-apoptotic effects, has been indicated to correlate with tumor progression. Hepatocyte growth factor (HGF) through its receptor c-Met has been shown to enhance the invasive capacity of cancer cells via tyrosine kinase-dependent intracellular signalling pathways. The authors hypothesize that cross-talk between these two receptor/ligand systems and their signalling pathways can regulate proteases essential for tumor invasion and augment metastatic potential.

Methods: A human pancreatic ( PSN-1) and colon cancer (SW1222/ SW620) cancer cell lines were used. Quantitative analysis for presence of Fas/FasL and c-Met by Flow cytometry and qualitative images by fluorescence cytology were obtained. Assays were repeated in response to HGF, TNF-α, IL-6 and IL-8. Inhibition of signaling pathways was investigated by incorporating the potent tyrosine kinase inhibitors Wortmannin and Ly 294002. Fas and c-Met expression in response to Fas ligation was also determined by flow cytometry. HGF production in response to Fas ligation and the pro-inflamatory cytokines was determined by ELISA. Cell supernatants from control and CH-11/HGF treated cells were subjected to substrate zymography for MMP-2/MMP-9 expression. Densitometric analysis was done by Scion image software. The ability of CH-11 treated cells to invade through matrigel treated 8.0μm Transwell filters was analyzed by colorimetric MTS assay and by direct staining of the filters. Transcription factor Nf-kappaB and AP-1,activation was detected by EMSA. ANOVA analysis of variance was the statistical method employed.

Results: Fas and c-Met were constitutively expressed in all cell lines as detected by FACS and confirmed by Fluorescence microscopy. Whilst c-Met was upregulated Fas expression was downregulated in response to cytokines. HGF induced an autocrine upregulation of c-Met. Tyrosine kinase blockade attenuated that response. Protease production in response to HGF and Fas-L was enhanced. The stimulation of Fas with agonist resulted in: Significant dose dependent upregulation (p<0.05) of MMP2/MMP-9; Activation of transcription factors Nf-kappaB and Ap-1; and increased invasiveness.

Conclusions: Our results provide evidence that the invasive capacity of the HGF/c-Met system is strongly influenced by Fas/Fas-L. We have shown a clear interaction between the two receptor/ ligand systems

that may be critical in determining the metastatic potential of a range of gastrointestinal carcinomas. Further research in this direction may identify appropriate therapeutic targets.

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