tbuckley/cabot-search huggingface dataset:
Mutation Rates and Mechanisms of Resistance to Etoposide Determined From Flucattion Analysis
Authors: J.-P. Jaffrezou, G. Chen, G. E. Duran, J.-S. Kuhl, B. I. Sikic
Journal: JNCI Journal of the National Cancer Institute (1994)

Background : The major known mechanisms of resistance to etoposide include altered expression of its target enzyme, topoisomerase II (Topo II), and the multidrug-resistant phenotypes encoded by the mdrl and MRP (multi-drug resistance-associated protein) genes. There is little information regarding the distribution, frequency, and origin of these mechanisms in cancer cells. Purpose : We performed fluctuation analysis experiments with the human sarcoma cell line, MES-SA, to assess 1) if selection or induction mechanisms are involved in resistance to etoposide, 2) mutation rates for cellular resistance to etoposide, and 3) the nature of the single-step selected surviving clones. Methods : Three groups of 10 flasks were seeded with more than 2000 cells each and allowed to grow to near confluence (approximately 3 × 10 6 cells per flask). After reseed-ing, each group received etoposide for 1 week at a final concentration of 0.5 [μ M (group A), 1.0 μ M (group B), and 5.0 μM (group C). Surviving colonies in each of the 30 populations were scored and individually harvested. Results : Mutation rates were estimated at 2.9 × 10 −6 (group A), 5.7 × 10 −7 (group B), and 1.7 × 10 −7 (group C) per cell generation. Of 61 propagated colonies, four of 26 from group A, five of 19 from group B, and none of 16 from group C were stably resistant. Analysis of variance supported the hypothesis of spontaneous mutations rather than induction, conferring etoposide resistance in groups A and B. Five of the stably resistant clones were cross-resistant to doxorubicin. Analysis by poly-merase chain reaction failed to detect the expression of the multidrug-resistant gene mdr1 messenger RNA (mRNA) in any of the clones. No increase in expression of the MRP gene was observed. However, a significant decrease in both Topo IIα and IIβ mRNA (30%–70%) was found in six of seven stably resistant and six of six unstably resistant mutants. Conclusions : Our study demonstrates that resistance to etoposide arises spontaneously, with most clones surviving either stochastically or through very labile mechanisms of resistance. The experimental design has derived a set of resistant mutants from a single-step selection. In those clones, decreased expression of Topo II is the predominant mechanism selected. Implications : These findings suggest that stable resistance to etoposide chemotherapy may be acquired by selection of spontaneously arising mutants rather than induction by drug exposure. The stably resistant clones may represent descendants from a single mutational event in each population.
Haemangiopericytoma of the stomach
Authors: G. N. Marangos
Journal: Gut (1965)

EDITORIAL SYNOPSIS The case is reported of a woman aged 40, from whom a haemangiopericytoma of the stomach was removed by partial gastrectomy.No metastases were found and the patient remains well 15 months after operation.The histological and clinical features of such gastric tumours are discussed.Whereas 21 % of histologically similar tumours arising in other parts of the body have proved malignant, no evidence of malignancy has been encountered among the small number of gastric haemangiopericytomata so far recorded.
Antibody to Thrombin Receptor Inhibits Neointimal Smooth Muscle Cell Accumulation Without Causing Inhibition of Platelet Aggregation or Altering Hemostatic Parameters After Angioplasty in Rat
Authors: Masahiro Takada, Hiroshi Tanaka, Toshie Yamada, Osamu Ito, Motoji Kogushi, Mamoru Yanagimachi, Takanori Kawamura, Takashi Musha, Fusayo Yoshida, Masashi Ito, Hiroko Kobayashi, Shinji Yoshitake, Isao Saito
Journal: Circulation Research (1998)

An antibody was raised in rabbits against SFFLRNPSEDTFEQF peptide, which is an NH2-terminal peptide of the thrombin-cleaved rat thrombin receptor. In vitro, the antibody inhibited rat smooth muscle cell proliferation but had no effect on rat platelet aggregation or clotting time. These data indicate that the antibody is a specific blocker of the thrombin receptor-signaling pathway in rat smooth muscle cells but does not work as a blocker in rat platelets, suggesting the existence of a second thrombin receptor in the platelets. Using an in vivo balloon catheter-induced injury model in rats, we examined the effect of the anti-rat thrombin receptor IgG on intimal smooth muscle cell accumulation 2 weeks after angioplasty. Analysis of the ratio of intimal to medial cross-sectional areas showed that injection of immune IgG resulted in 43.7% and 53.1% reduction (P<0.01) of neointimal smooth muscle cell accumulation compared with saline and nonimmune IgG treatment, respectively. Moreover, the injection of immune IgG caused a significant decrease of thrombin receptor mRNA expression and also 40.5% and 43.0% decreases (P<0.01) of the proliferating cell nuclear antigen (PCNA) index in the intima compared with the PCNA index after saline and nonimmune IgG treatment, respectively. The suppression of the PCNA index was also observed in the immune IgG-treated group at an early stage after angioplasty. These results suggest that thrombin receptor activation is involved in the proliferation and accumulation of neointimal smooth muscle cells induced by balloon injury.
Phase I Safety and Pharmacodynamic of Inecalcitol, a Novel VDR Agonist with Docetaxel in Metastatic Castration-Resistant Prostate Cancer Patients
Authors: Jacques Medioni, Gael Deplanque, Jean-Marc Ferrero, Tristan Maurina, Jean-Michel P. Rodier, Eric Raymond, Jorge Allyon, Gerard Maruani, Pascal Houillier, Sarah Mackenzie, Stephanie Renaux, Jean-Francois Dufour-Lamartinie, Reza Elaidi, Celine Lerest, Stephane Oudard
Journal: Clinical Cancer Research (2014)

We conducted a phase I multicenter trial in naïve metastatic castrate-resistant prostate cancer patients with escalating inecalcitol dosages, combined with docetaxel-based chemotherapy. Inecalcitol is a novel vitamin D receptor agonist with higher antiproliferative effects and a 100-fold lower hypercalcemic activity than calcitriol.Safety and efficacy were evaluated in groups of three to six patients receiving inecalcitol during a 21-day cycle in combination with docetaxel (75 mg/m2 every 3 weeks) and oral prednisone (5 mg twice a day) up to six cycles. Primary endpoint was dose-limiting toxicity (DLT) defined as grade 3 hypercalcemia within the first cycle. Efficacy endpoint was ≥30% PSA decline within 3 months.Eight dose levels (40-8,000 μg) were evaluated in 54 patients. DLT occurred in two of four patients receiving 8,000 μg/day after one and two weeks of inecalcitol. Calcemia normalized a few days after interruption of inecalcitol. Two other patients reached grade 2, and the dose level was reduced to 4,000 μg. After dose reduction, calcemia remained within normal range and grade 1 hypercalcemia. The maximum tolerated dose was 4,000 μg daily. Respectively, 85% and 76% of the patients had ≥30% PSA decline within 3 months and ≥50% PSA decline at any time during the study. Median time to PSA progression was 169 days.High antiproliferative daily inecalcitol dose has been safely used in combination with docetaxel and shows encouraging PSA response (≥30% PSA response: 85%; ≥50% PSA response: 76%). A randomized phase II study is planned.
Does Money Make Bioethics go ‘Round?
Authors: Raymond G. De Vries, Carla C. Keirns
Journal: The American Journal of Bioethics (2008)

Money is the stuff of life; it is the medium of exchange that we use to buy food, clothes, warmth in the winter, cool in the summer, and the fuel that moves us around the planet. Of course money makes the world go ‘round, but does it, Sharp and his colleagues (2008) want to know, make bioethics go ‘round? We all agree that there are things money cannot buy – happiness, love, contentment – but are there things money can, but should not, buy? How about health care? Citizens in the countries of the developed world (with one notable exception) have decided that while the market may work
The effects of PCB exposure and fish consumption on endogenous hormones.
Authors: V Persky, M Turyk, H A Anderson, L P Hanrahan, C Falk, D N Steenport, R Chatterton, S Freels
Journal: Environmental Health Perspectives (2001)

Previous studies have suggested that exposure to polychlorinated biphenyls (PCBs) may alter thyroid function, but data on effects of PCB exposure on other endogenous hormones has been lacking. The current study is ancillary to a larger investigation of the effects of Great Lakes fish consumption on PCBs and reproductive function. In the current study we examine associations of PCBs, 1,1-bis (4-chlorophenyl)-2,2-dichloroethene (DDE), and fish consumption with thyroid and steroid hormones in 178 men and PCBs, DDE, and fish consumption with thyroid hormones in 51 women from the original study. Serum PCB level and consumption of Great Lakes fish are associated with significantly lower levels of thyroxine (T(4)) and free thyroxine index (FTI) in women and with significantly lower levels of T(4) in men. Fish consumption, but not PCB level, is significantly and inversely associated with triiodothyronine (T(3)) in men. Results for thyroid-stimulating hormone (TSH) are inconsistent. Among men, there are significant inverse associations of both PCB and fish consumption with sex hormone-binding globulin (SHBG)-bound testosterone, but no association with SHBG or free testosterone. There are no significant overall associations of PCB, DDE, or fish consumption with estrone sulfate, follicle-stimulating hormone, luteinizing hormone, or dehydroepiandrosterone sulfate. The results of this study are consistent with previous studies showing effects of fish consumption and PCB exposure on thyroid hormones and suggest that PCBs may also decrease steroid binding to SHBG. Elucidation of specific mechanisms must await future investigations.
Myocardial oxygen supply/demand ratio in aortic stenosis: Hemodynamic and echocardiographic evaluation of patients with and without angina pectoris
Authors: Robert Nadell, Nicholas L. DePace, Jian-Fang Ren, A-Hamid Hakki, Abdulmassih S. Iskandrian, Joel Morganroth
Journal: Journal of the American College of Cardiology (1983)
Abstract 2253: Left Atrial Appendage Function And Clinical Outcome After Electrical Isolation Of Left Atrial Appendage In Patients Undergoing Atrial Fibrillation Ablation
Authors: Roland R Tilz, Boris Schmidt, Shyam Divakara Menon, K R Chun, Alexander Fuernkranz, Andreas Metzner, Buelent Koektuerk, Melanie Konstantinidou, Thomas Zerm, Rainer Malesius, Carsten Schneider, Matthias Antz, Karl Heinz Kuck, Feifan Ouyang
Journal: Circulation (2008)

Electrical isolation of left atrial appendage (LAA) can occur during extensive left atrial (LA) ablation for AF. However, the long-term outcome after electrical isolation is unknown. In this study, we evaluated the echocardiographic LAA function and the clinical outcome after electrical isolation of LAA in this patient cohort.18 consecutive pts (8 male, 64±9 years, LA diameter 45±11mm) were included in this study. Before the 1st procedure, there were 4 pts with paroxysmal AF and 14 pts with long-lasting persistent AF. LAA isolation occurred during the 1st ablation procedure in 1 pt, during the 2nd procedure in 5 pts, during the 3d procedure in 7 pts during the 4th procedure in 4 pts and during the 5th procedure in one pt. Isolation of the LAA was identified by dissociation of electrical activity in the LAA from the LA or by electrical silence in the LAA. After ablation, oral anticoagulation was continued with a target INR of 2–3. LAA function was assessed prior to and 3 months after the procedure by TEE Doppler. LAA flow velocity (LAAFV; filling and emptying), LA diameter, spontaneous echo contrast (SEC) and incidence of LAA thrombus were assessed. LA diameter did not change significantly after LAA isolation (44,6±11 vs 44,5±11cm/s). After LAA isolation, LAAFV (filling) was normal (>50cm/s) in 3 pts, impaired (25
Evolution of the donor T-cell repertoire in recipients in the second decade after allogeneic stem cell transplantation
Authors: Robert Quan Le, J. Joseph Melenhorst, Minoo Battiwalla, Brenna Hill, Sarfraz Memon, Bipin N. Savani, Aarthi Shenoy, Nancy F. Hensel, Eleftheria K. Koklanaris, Keyvan Keyvanfar, Frances T. Hakim, Daniel C. Douek, A. John Barrett
Journal: Blood (2011)
Abstract 4975: Api6/AIM/SPα/CD5L overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma
Authors: Hong Du, Yuan Li, Peng Qu, Lingyan Wu, Beilin Li, Cong Yan
Journal: Cancer Research (2012)

Abstract Chronic inflammation is an important contributor to the development of lung cancers, one of the most common malignancies worldwide, but the underlying molecular mechanisms of inflammation that specifically cue cancer risk remains poorly understood. We have previously found that blocking neutral lipid metabolism in lysosomal acid lipase knock-out mice (lal-/-) leads to severe tissue inflammation and diseases in multiple organs, including the lung. In an effort to identify downstream target genes of LAL to promote lung inflammation, Affymetrix GeneChip microarray analysis were performed and identified apoptosis inhibitor 6 (Api6, AIM, Sp-alpha, CD5L) as one of top increased expression gene (70 folds in the lal-/- lung). This aberrant up-regulation of Api6 occurs primarily in alveolar type II (AT II) epithelial cells of lal-/- mice and this up-regulation of Api6 can be reduced by treatment of ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) in lal-/- mice. To determine the functional role of Api6 in AT II epithelial cells, an epithelial-specific CCSP-rtTA/(TetO)7-CMV-Api6 bitransgenic mouse model has been generated. Here we report that Api6 is a pro-inflammatory and oncogenic molecule. Api6 overexpression inhibited apoptosis and activated oncogenic signaling in AT II lung epithelial cells, inducing emphysema and adenocarcinoma. Additionally, Api6 overexpression in AT II cells increased the concentrations of pro-inflammatory cytokines/chemokines in bronchoalveolar lavage fluid and serum, which promote expansion of myeloid derived suppressor cells (MDSCs) in the lung and blood but not in bone marrow or spleen. Lung MDSCs suppressed T cell proliferation and activity in vitro and reduced levels of T cells in vivo following doxycycline treatment to activate Api6. Together, our findings establish that Api6 promotes lung tumorigenesis by blocking a mechanism of epithelial apoptosis that would normally support immunosurveillance. In humans, expression of the Api6 gene is up-regulated in chronic obstructive pulmonary disease (COPD, the major phenotype is emphysema) and lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4975. doi:1538-7445.AM2012-4975
Abstract 5302: Overcoming cancer immune evasion in lung carcinoma using EGFR-TKI (Gefitinib)
Authors: Ryosuke Satomi, Katsuhiko Naoki, Tomonori Yaguchi, Hiroyuki Yasuda, Sohei Nakayama, Satoshi Yoda, Hideki Terai, Shinnosuke Ikemura, Takashi Sato, Kenzo Soejima, Akitoshi Ishizaka, Yutaka Kawakami
Journal: Cancer Research (2010)

Abstract Clinical studies for immunotherapy targeting various types of carcinoma, including lung carcinoma, are currently underway, yet the clinical effectiveness of these therapies is very limited. Recent findings demonstrate that cancer immune evasion is a major contributing factor to this problem. Cancer cells produce a variety of immunosuppressive molecules that inhibit the host cell's immune response, leading to conditions such as cachexia that decrease patients’ quality of life. EGFR mutations in lung carcinoma are known to lead to processes characteristic of malignancies, such as cell cycle progression, metastasis, and angiogenesis. Based on these observations, we tested the hypothesis that EGFR activation leads to immune evasion by cancer cells via the production of various immunosuppressive molecules. In this study, 6 lung adenocarcinoma cell lines were used, namely A549, RELF-LC-OK, PC-9, HCC-827, NCI-H1650, and NCI-H1975. We demonstrate that these cells secrete immunosuppressive cytokines such as IL-6, TGF-beta and VEGF, which inhibit the maturation of dendritic cells and prevent them to activate T cells. Then, we show that Gefitinib administration at sub-lethal concentration inhibits the production of immunosuppressive cytokines in EGFR-TKI sensitive PC-9 and HCC-827 cells those with EGFR mutations as well as in EGFR-TKI resistant NCI-H1650 cells that have an EGFR mutation but lack the PTEN gene. While, cytokine production is not inhibited by Gefitinib in A549 and RELF-LC-OK cells with wild type EGFR genes and NCI-H1975 cells that have both EGFR-TKI sensitive and resisitant mutations. Additionally, EGFR-TKI administration in PC-9, HCC827, and NCI-H1650 cells restores dendritic cell function, which was initially reduced by the supernatant of tumor cells. These results show that lung adenocaricinoma harboring EGFR mutations evade immune response through secreteting immunosuppressive agents and that the immune response is restored by Gefitinib administration. Thus, the combination of Gefitinib and immunotherapy may have synergistic effect and will be a promising treatment of lung cancer patients harboring EGFR mutation, including certain population of EGFR-TKI resistant cases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5302.
Treatment of Septic Abortion
Authors: C. W. F. Burnett
Journal: BMJ (1952)

The correct management of patients suffering from septic abortion presents a gynaecological problem which still awaits an agreed solution; the main controversy lies between the interventionist school, who advise immediate evacuation of retained products of conception from the uterus in most cases, and the non-interventionists,who postpone operation until later in the course of the illness and avoid it altogether if they possibly can. Although this problem has been deprived of much of its urgency by the advent of powerful antibiotic drugs which. produce good results when used in conjunction with either form of treatment, it is still desirable to determine which method will the better curtail the patient's illness, with the least possibility of subsequent ill-health and infertility. As a contribution towards this decision, the results of the treatment received by 267 consecutive cases of septic abortion admitted to the West Middlesex Hospital during the five years 1946-50, inclusive, have been analysed and are here presented for consideration.
Patients in England are given green light to buy drugs privately alongside NHS care
Authors: Z. Kmietowicz
Journal: BMJ (2008)

Patients in England will be able to top up their treatment with drugs bought privately and yet continue to receive NHS care, provided that they have their top-up treatment administered in a non-NHS setting, the health secretary announced this week.

The change in rules on top-up drugs, which has immediate effect, is part of a package of 14 recommendations made by Mike Richards, England’s national clinical director for cancer, in his review of copayments, all of which the government has accepted.

Taken together the new plans will reduce the number of people seeking private drug treatment from the estimated 5000 patients a year currently to a few hundred people, predicted Professor Richards.

New guidance, which is being sent to all trusts and commissioners in England, says that patients may pay for additional private healthcare while continuing to receive care from the NHS but that there should be no risk of the NHS subsidising their private care. Patients who opt to buy drugs privately will need to pay for any predictable related costs, such as antiemetic drugs, heart scans, and pharmacy and nursing costs, although any unpredictable costs, such as from side effects of drugs, will be covered by the NHS.

The health secretary, Alan Johnson, asked Professor Richards in June to review the rule after …
Helping patients with strokes.
Authors: O G Owen
Journal: BMJ (1981)

In Britain the incidence of cerebral infarction and haemorrhage (strokes) in the total population is two new cases per 1000. In the elderly population? those aged from 65 to 74?it rises to around 20 and in the over 75s is as high as 45. At least 30% of patients who suffer a stroke will be dead in a month. Of the survivors, only one third will recover sufficiently to be fully independent. Many victims are left with a devastating hemiplegia, some will also be aphasie, and the risk of further stroke is high. Within three to five years after the stroke, half the survivors will be dead also (though not necessarily of a further stroke). Around 75% of patients with acute strokes are admitted to hospital and of these about 40% are discharged home?the remainder requiring residential care for their rehabilitation. With motivation and the help of good nursing, physiotherapy, and family support, most survivors will recover sufficient motor function in their affected side to be able to walk