tbuckley/cabot-search huggingface dataset:
Haplotype-environment interactions regulating the human GSTP1 promoter
Authors: Stephane Cauchi, Weigo Han, Shalini V. Kumar, Simon D. Spivack
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

693 

Background: GSTP1-1 is a phase II enzyme playing an important role in the detoxification of oxidized carcinogens, including polycyclic aromatic hydrocarbons (PAH), as well as other compounds. Animal data suggest that the anticarcinogenesis effects of several candidate chemopreventive agents may operate through GSTP1 induction. Previous human studies suggest that there are wide inter-individual differences of GSTP1 expression that may be relevant to the development or biology of cancer. We explored the interaction of inter-individual sequence variation in the GSTP1 promoter and the effect of candidate phytochemicals in regulating GSTP1 expression. Methods: Individual SNPs and resulting haplotypes along 2 kb of the GSTP1 promoter were explored in PBMCs from 40 patients from a lung cancer case-control study. Ten previously-unreported polymorphisms found in the promoter with strong linkage disequilibrium were statistically evaluated, resulting in a frequency distribution of haplotypes. The three most frequently-observed haplotypes [HAP1 (43%), HAP2 (36%) and HAP3 (8%)] were then replicated using a site-directed mutagenesis strategy, placed into a luciferase reporter construct, transfected into normal human bronchial epithelial (NHBE) cells, and then treated with different concentrations of a panel of six plant-derived putative antioxidant compounds, cigarette smoke extract (CSE) and the oxidant hydrogen peroxide. Results: HAP3 had a significantly higher (1.8-fold) basal activity. This reporter was sensitive to increasing concentrations of sulforaphane, BITC and EGCG (but not the other phytochemical compounds); HAP3 promoter activity was decreased to the same levels as HAP2 and HAP1. To confirm this HAP 3 functionality, the native promoter regulating native mRNA transcript levels was examined in PBMCs and lung epithelial cells. Quantitative RNA-specific real-time RT-PCR experiments revealed that HAP3 is again associated with higher basal mRNA expression levels in unexposed cells, compared with the other two haplotypes [18-fold for homozygote (HAP3-HAP3), and 2-fold for heterozygotes (HAP3-HAP1, HAP3-HAP2)]. After exposure to sulforaphane, BITC or EGCG, HAP3-containing PBMCs return to basal GSTP1 mRNA expression levels. The same phenomenon was shown at the protein level for PBMCs [10-fold for homozygote (HAP3-HAP3), and 7-fold for heterozygotes (HAP3-HAP1, HAP3-HAP2) when unexposed cells] Perspectives: Further investigations on haplotype-specific responses to various combinations of CSE, hydrogen peroxide, and candidate antioxidant chemopreventive agents are underway to evaluate the actual impact on DNA damage. This study suggests the existence of vulnerable and protective promoter haplotypes for this anticarcinogenesis gene, and haplotype-specific interaction with individual chemopreventive agents.
Abstract 10992: Left Atrial Volume is Associated With the Intra-left Atrial Vortex Formation: Analysis With Phase-resolved Three-dimensional Cine Phase Contrast MRI (4D-Flow MRI)
Authors: Takeji Saitoh, Kenichiro Suwa, Yasuo Takehara, Makoto Sano, Mamoru Nobuhara, Masao Saotome, Tsuyoshi Urushida, Hideki Katoh, Hiroshi Satoh, Marcus Alley, Harumi Sakahara, Hideharu Hayashi
Journal: Circulation (2013)

Background:  The intra-left atrial (LA) blood flow from pulmonary veins (PVs) to the left ventricle (LV) changes under various conditions and may contribute to global cardiac function and thrombogenesis. 4D-Flow MRI can visualize velocity vectors of intra-cardiac blood flow. We aimed to examine the characteristics of intra-LA flow dynamics and factors that affect it using 4D-Flow MRI.   Methods:  Thirty two patients with and without organic heart diseases (59±14 years) underwent 4D-Flow MRI with routine cardiac MRI, and trans-thoracic echocardiography (TTE). Four planes were set to traverse each exit of PVs, and the intra-LA velocity vectors from each PV were post-processed to delineate streamline images during a cardiac cycle. The flow direction from each PV into LA was also analyzed.   Results:  (1) The streamline images revealed the intra-LA vortex formation in 20 patients but did not in 12 patients. The representative images are shown in Figure. All the vortices showed characteristic counter-clockwise flow patterns when viewed from the cranial side. The streamlines from the right PVs lengthened predominantly toward the vortex and partly toward LV, whereas those from the left PVs joined the vortex periphery or retained near the LA wall (arrows). (2) The LV end-diastolic volume (LVEDV), end-systolic volume (LVESV) in cine-CMR and LA volume in TTE were less in patients with vortex than in those without vortex (LVEDV: 104±34 ml vs. 155±67 ml, LVESV: 46±28 ml vs. 88±59 ml, and LA volume: 37±13 ml vs. 59±16 ml, respectively, means±SD, p   Conclusions:  Streamline images derived from 4D-Flow MRI can clearly depict the intra-LA vortex formation. The vortex formation was dependent on the LA volume, but not on the flow direction from PVs.
Abstract P164: Seasonal patterns of mortality from cardiovascular diseases in Panama.
Authors: Jorge A Motta, Carlos Gordon, Beatriz Gomez, Eva Castillo, Hugo Herrera-Ballesteros
Journal: Circulation (2012)

Seasonal patterns of cardiovascular (CV) mortality have been reported in many regions of the world, but mostly in temperate zones. These cycles and seasonal patterns of mortality have been identified by looking at mortality rate series over extended periods of time and by filtering its stochastic components. The reasons for these variations have been attributed to multiple causes. Empirical observations by health care worker have suggested that in Panama there are seasonal changes of CV disease mortality but this phenomenon had not been studied. The speculation is that this may be related to variation in the incidence of respiratory diseases, weather changes or to population activity patterns associated with holidays. Our hypothesis for this study is that in Panama mortality related to CV disease has a seasonal pattern. We compiled from the National Registry of Mortality all deaths that occurred in the country from cardiovascular diseases (n=36,145) and diabetes (n=7,076) for the years 2001–2009. A monthly time series of mortality was calculated and its components were decomposed utilizing moving averages. Elements, like cycle, seasonal occurrence and stochastic components, were separated. We also developed a seasonal index of mortality for these diseases. For the same years, we performed a similar analysis for all deaths attributed to cancer and external causes. Analysis of these mortality series revealed seasonal cycles for total cardiovascular mortality and diabetes mortality. Death from cancer and external causes also showed seasonal cycles. CV mortality and diabetes mortality peaked at the beginning of the third trimester of the year and were lowest during the first trimester. For the month of July, the CV mortality seasonal index showed a score of 108, and an average number of CV deaths of 364. The lowest seasonal index score for CV mortality was 87 in February, with an average number of CV deaths of 296. The cycles observed for cancer and deaths from external causes did not match the cycles observed for CV diseases and diabetes. We conclude that there is a seasonal pattern of CV mortality in Panama. The drivers of these cyclical changes of CV mortality have not yet been identified, but we are evaluating the relationship of acute respiratory illnesses, population activity patterns and weather changes to these seasonal mortality variations.
A memorable patient: Our duty lasts until the end of life
Authors: K. Khan
Journal: BMJ (1999)

Participants, methods, and resultsAn outbreak was investigated in a small village in Switzerland.All children (ages 5-13) were included in the cohort.Information on immunisation status was obtained from vaccine certificates.The person who investigated the cases of mumps was blinded with regard to the vaccination status.A case was defined if mumps virus was isolated on culture, if a doctor confirmed the diagnosis, or if the typical clinical picture was described in a sibling of a patient with confirmed disease.The absence of IgG antibodies to mumps virus served as confirmation of full susceptibility to mumps in non-vaccinated children without clinical signs of the disease.The cohort comprised 165 children.All questionnaires sent to their parents were returned and evaluated (response rate 100%).All immunised children had received their immunisation before the age of 2 years, almost half with the Rubini strain (table).Sixty six cases of epidemic parotitis occurred, resulting in an overall attack rate of 40%.Altogether 11(16%) children had parotid enlargement without fever; only one case (vaccinated with the Rubini strain) had a complicated course that required hospital admission.The attack rate was similar in unvaccinated children (63%) and children vaccinated with the Rubini strain (67%) but significantly lower in those vaccinated with the Jeryl-Lynn (14%) or the Urabe strain (8%) (table ).When the attack rate for the two currently available vaccine strains was compared the relative risk of developing mumps was 4.8-fold greater (95% confidence interval 2.1 to 11.1) in children vaccinated with the Rubini compared with the Jeryl-Lynn strain.The low vaccine efficacy of the Rubini strain was observed throughout all age groups.In contrast, cases of mumps in children vaccinated with the Jeryl-Lynn or Urabe strains occurred only at the age of 8 or older.In the three vaccine categories no difference in the severity of mumps was observed.
Tezacitabine induces programmed cell death in human colon cancer cells
Authors: Pietro Taverna, Payman Amiri, Dragana Jekic-Mcmullen, Jeff Dove, Mina Aikawa, Barbara Hibner
Journal: Cancer Research (2004)

2974   The anticancer nucleoside analogue Tezacitabine (2’-deoxy-2’-fluoromethylene cytidine; FMdC)is characterized by a dual mechanism of action. FMdC is an irreversible inhibitor of Ribonucleotide Reductase (RNR) and a DNA chain terminator. The cell metabolites of FMdC are the diphosphate, active in RNR inhibition, and the triphosphate, a substrate for DNA pol alpha that interferes with further DNA synthesis. FMdC has been shown to be a potent anticancer compound in a variety of human tumor cell lines and xenografts, and is now in Phase I/II clinical trials as monotherapy or in combination with other chemotherapeutic agents. Previous studies (Zhou et al., Molec. Pharmac. 2002) demonstrated that FMdC induces cell cycle arrest and apoptosis in leukemia cell lines. We investigated the cellular responses to FMdC in HCT116 human colon carcinoma cells. Using a clonogenic assay as measure of cell survival following drug treatment, we observed an evident time-dependency of FMdC-induced cell killing on HCT116 cells (IC50 decreased ∼ 3-fold when the exposure time was increased from 24 to 48 hours). Similarly, FMdC induced in a time-dependent fashion Caspases 3-7 in HCT116 cells, suggesting that the observed cytotoxicity is the result of a cascade of programmed cell death events. Since FMdC is being used clinically in combination with other chemotherapy drugs, like fluoropyrimidines, we also investigated how FMdC can modulate the mechanisms involved in sensitivity or resistance to 5-fluoro-2’-deoxyuridine (FUdR) in human colon cancer cells. We found that FMdC-induced potentiation of FUdR cell killing in HCT116 cells can be explained by a significant increase in Caspase 3-7 activation after 24 hours exposure to FUdR. Our data suggest that FMdC can be a strong modulator of cell responses to clinically used anticancer agents like fluoropyrimidines and may overcome possible mechanisms of resistance to DNA-interacting drugs.
Abstract P3-05-21: Investigation into the oncogenic potential of the androgen receptor in aromatase inhibitor resistant breast cancer
Authors: Leonie Young, Laura Creevey, Azlena Ali, Arnold DK Hill, Marie McIlroy
Journal: Cancer Research (2015)

Abstract The heterogenous nature of breast cancer, exemplified by a wide range of subtype classifications, has been well documented. The identification of the novel molecular apocrine breast tumours (ER-, PR-ve, HER2-ve, AR+), with a gene expression profile reflective of ER+ luminal breast cancer, has led to the proposition of an alternative role for the androgen receptor as a pseudo ER. This proposition was borne out of global expression profiling and AR recruitment of molecular apocrine cells, demonstrating that more than 50% of AR binding to the genome mirrors the pattern of ER binding suggesting that in the absence of ER, AR can mimic ER in its DNA binding capabilities. Aromatase Inhibitor (AI) therapy is the gold standard first line therapy for postmenopausal breast cancer. AIs function by abrogating the activity of the enzyme Cyp 19 (aromatase), which is responsible for converting circulating androgens to estrogen. By preventing this conversion step, this eradicates the main steroid driving breast cancer growth and in turn results in a more androgenic environment. We hypothesise that AR may also act as a pseudo ER in our AI resistant (MCF7-letrozole resistant) cells. Preliminary data demonstrates that AR is recruited to some but not all classical ER target genes as well as some AR target genes in MCF7-LetR cells, therefore highlighting the potential of AR to act as an oncogene in this setting. Analysis of AR protein expression also demonstrates higher levels of AR in AI resistant cells versus sensitive cells. In the evaluation of the responsiveness of a range of breast cancer cell lines to the AR antagonist Bicalutamide, it was noted that our AI resistant cells demonstrated responsiveness to Bicalutamide treatment. RNA sequencing experiments following AR knockdown in AI resistant cells also provide crucial information as to the key genes differentially regulated by AR. Given that resistance to AI therapy is an emerging clinical issue, further elucidation of the potential mechanisms of AI resistance and potential AR targets is highly warranted. Citation Format: Leonie Young, Laura Creevey, Azlena Ali, Arnold DK Hill, Marie McIlroy. Investigation into the oncogenic potential of the androgen receptor in aromatase inhibitor resistant breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-21.
Phorbol ester, ultraviolet light and oxidative stress induced inflammation and up-regulation of pro-inflammatory cytokines in mouse ears
Authors: Mou-Tuan Huang, Yue Liu, Chi-Tang Ho, Robert Rosen
Journal: Cancer Research (2004)

1757   12-O-Tetradecanoylphorbol-13-acetate (TPA), ultraviolet light (UV) and benzoyl peroxide (oxidative stress) can activate the innate immune response in the mouse ear model and induce inflammation and increase the expression of pro-inflammatory cytokines, interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) in ears of CD-1 mice. A single topical application of TPA (0.2 –2 nmol) to the ears of CD-1 mice induced a dose- and time-dependant ear edema and formation of over-expression of pro-inflammatory cytokines, IL-1 beta and IL-6 in the ears. Both ears of CD-1 mice were treated topically with acetone or TPA (0.8 –1.0 nmol) in acetone once a day for 4 days. The mice were sacrificed at 6 hours after the last dose of TPA. This treatment induced ear inflammation, over-expression of IL-1 beta and IL-6 as well as increased formation of the arachidonic acid metabolites PGE2 and LTB4 in a dose-dependant manner. Topical application of benzoyl peroxide (2 mg) or irradiation with UV light (180 mJ/cm2) to CD-1 mice once a day for 4 days induced ear inflammation and increased over-expression of IL-1 beta and IL-6 in ears. Topical application of antioxidant nutraceuticals (-)-epigallocatechin gallate (EGCG), theaflavin, theaflavin-3, 3′-digallate, curcumin, or caffeic acid phenethyl ester at 20 –30 min before topical application of TPA (0.8 –1.0 nmol) once a day for 4 days inhibited TPA-induced inflammation, over-expression of IL-1 beta and IL-6 as well as the formation of PGE2 and LTB4 in mouse ears (Supported by the NJ State Commission on Science and Technology).
Phase lb study of LEE011 and BYL719 in combination with letrozole in estrogen receptor-positive, HER2-negative breast cancer (ER+, HER2− BC).
Authors: Pamela N. Munster, Erika Paige Hamilton, Catherine Franklin, Suraj Bhansali, Kitty Wan, Becker Hewes, Dejan Juric
Journal: Journal of Clinical Oncology (2014)

533 Background: Postmenopausal women with advanced ER+ BC are usually treated with aromatase inhibitors (AIs) as first-line therapy but resistance eventually develops. Dysregulation of the PI3K pathway and cyclin D kinases 4 and 6 (CDK4/6) has been implicated in resistance to endocrine therapy. LEE011 (a selective CDK4/6 inhibitor) and BYL719 (an α-selective PI3K inhibitor) demonstrate clinical activity in ER+ BC as single agents. In ER+ BC xenograft models, LEE011 has demonstrated enhanced antitumor activity when combined with BYL719 and letrozole versus each agent alone, suggesting this combination may optimize treatment in ER+ BC. In the ongoing Phase Ib part of this study (NCT01872260), two doublet combinations, LEE011 + letrozole (Arm 1) and BYL719 + letrozole (Arm 2), and the triplet combination of LEE011 + BYL719 + letrozole (Arm 3), are explored in patients with ER+ BC. Methods: Postmenopausal women with locally advanced/metastatic ER+, HER2− BC not amenable to curative treatment by surgery/radiotherapy receive escalating doses of oral LEE011 QD (3-wks on/1-wk off) or BYL719 QD (continuous) and a fixed dose of letrozole QD (2.5 mg, continuous) in 28-day cycles. The primary objective is to estimate the MTD and/or RP2D of each combination by assessing DLTs in Cycle 1 using an adaptive Bayesian Logistic Regression Model (BLRM) guided by the escalation with overdose control (EWOC) principle. Secondary objectives include safety, PK and preliminary efficacy assessments. Results: As of Jan 31, 2014, 6 patients have been treated in Arm 1 (LEE011 600 mg + letrozole), and 1 DLT (G4 neutropenia) has been reported. Five patients have started treatment in Arm 2 (BYL719 300 mg + letrozole). Preliminary PK data are consistent with that for the respective single agents, with no evidence of drug–drug interactions. Conclusions: AIs are recommended as first-line endocrine therapy in postmenopausal patients with advanced ER+, HER2− BC, but most patients develop resistance. This is the first trial evaluating an AI in combination with a PI3K and CDK4/6 inhibitor in ER+, HER2− BC. Phase II will compare the preliminary antitumor activity of the doublets vs. triplet combinations. Clinical trial information: NCT01872260.
Long-Term Results of Balloon Catheter Dilation for Benign Gastric Outlet Stenosis
Authors: J Solt, J Bajor, M Szabó, O P Horváth
Journal: Endoscopy (2003)

In 1981, the authors introduced balloon catheter dilation for postoperative gastric outlet stenosis and later for peptic, corrosive and postvagotomy gastric outlet stenosis. This retrospective study evaluates the effectiveness, safety and outcome of balloon catheter dilation in these various indications.Between September 1981 and September 2001, 177 balloon catheter dilation procedures were carried out in 72 patients with benign stenoses. Double-lumen or single-lumen balloon catheters with a mean diameter of 18 mm (range 12-25 mm) were used. Endoscopic check-up examinations were carried out 1-3 weeks later, and then after three, six and 12 months, or if symptoms returned. The mean follow-up period for patients who did not undergo surgery was 98 months (range 12-240 months).Symptomatic relief was obtained immediately in 80 % and after 3 months or more in 70% of the patients. The mean diameter of the stenoses was 6 mm (2.0-9.5 mm) before dilation and 16 mm (10-20 mm) afterwards. Gastric retention was observed in 49 patients (68%) before dilation and in 19 patients (26.4%) afterward. Sixteen patients had recurrent stenosis 1-18 months after the first dilation. All of the 18 postoperative strictures, 21 (70%) of the 30 peptic stenoses, six (35%) of the 17 patients with corrosive strictures, and five of the six patients with postvagotomy functional stenosis were successfully treated with dilation. Pyloric perforation occurred in two cases, and arterial hemorrhage was observed in one case after dilation.Balloon catheter dilation is an important and effective diagnostic and therapeutic method; depending on the causative factor, it can make surgery unnecessary in nearly 70% of patients with benign gastric outlet stenosis.
Abstract 1697: Role of the Posterior Left Atrial Septo-Pulmonary Bundle in Wavebreak Formation During Atrial Fibrillation by Pulmonary Veins Impulses
Authors: Matthew Klos, Sharon Zlochiver, Sergey Mironov, Damian Sanchez-Quintana, Jose Jalife, Omer Berenfeld, Jerome Kalifa
Journal: Circulation (2006)

It is well known that foci in the pulmonary veins (PVs) act as triggers and the posterior left atrium (PLA) is a substrate for atrial fibrillation (AF). However, the role played by the complex anat...
AC133 Antigen Expression Is Not Restricted to Acute Myeloid Leukemia Blasts But Is Also Found on Acute Lymphoid Leukemia Blasts and on a Subset of CD34+ B-Cell Precursors
Authors: Hans-Jörg Bühring, Martina Seiffert, Anke Marxer, Burkhard Weiß Christoph Faul, Lothar Kanz, Wolfram Brugger
Journal: Blood (1999)