Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ringopened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic, study as part of a phase I study in patients with various types of soli

Особенности промышленного развития монофункциональных городов Донецкой области

Рассмотрены особенности промышленности моноотраслевых городов Донецкой области. Предлагаются мероприятия по решению проблем их социально-экономического развития.Розглянуто особливості промисловості моногалузевих міст Донецької області. Пропонуються заходи щодо вирішення проблем їх соціально-економічного розвитку.The paper describes the features of the industry in mono-branch cities of Donetsk region. The measures are offered to solve the problems concerning their socio-economic development

Protein versus DNA as a marker for peripheral blood mononuclear cell counting

Quantitative analysis of intracellular analytes requires an accurate and precise assay not only for the quantitation of the analytes, but also for the quantitation of the number of cells in which they were determined. In this technical note we compare protein and DNA as markers for the number of peripheral blood mononuclear cells (PBMCs) isolated from whole blood. The protein content of samples was highly influenced by red blood cell contamination and was, therefore, a less suitable marker. The DNA-based method was unaffected by red blood cell contamination and was finally validated over a range from 10 × 106 to 300 × 106 PBMCs/mL

IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women

Window studies are gaining traction to assess (molecular) changes in short timeframes. Decreased tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine therapy for breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women. Nonetheless, the marker is being used on this subpopulation. We compared pathologist assessed IHC-based Ki67 in samples from pre- and postmenopausal women in a neo-adjuvant, endocrine therapy focused trial (NCT00738777), randomized between tamoxifen, anastrozole, or fulvestrant. These results were compared with (1) IHC-based Ki67 scoring by AI, (2) mitotic figures, (3) mRNA-based Ki67, (4) five independent gene expression signatures capturing proliferation, and (5) blood levels for tamoxifen and its metabolites as well as estradiol. Upon tamoxifen, IHC-based Ki67 levels were decreased in both pre- and postmenopausal breast cancer patients, which was confirmed using mRNA-based cell proliferation markers. The magnitude of decrease of Ki67 IHC was smaller in pre- versus postmenopausal women. We found a direct relationship between post-treatment estradiol levels and the magnitude of the Ki67 decrease in tumors. These data suggest IHC-based Ki67 may be an appropriate biomarker for tamoxifen response in premenopausal breast cancer patients, but anti-proliferative effect size depends on estradiol levels.</p

Нейроендокринний супровід поліваріантних ефектів біоактивної води Нафтуся на рівень хронічного стресу у жінок з різним оваріальним статусом

Проанализированы изменения нейроэндокринных показателен, сопутствующие поливариантным эффектам биоактивной воды Нафтуся курорта Трускавец на уровень хронического стресса у женщин детородного возраста с различным овариальным статусом. Обнаружена значительная (R=0,59) каноническая корреляционная связь между динамикой нейро-гормонального индекса стресса, с одной стороны, и вегетативной реактивности, лютеинизирующего гормона, тиреотропного гормона, тироксина и прогестерона - с другой стороны.The changes in neuroendocrine parameters, concomitant multivariate effects of bioactive water Naftussya spa Truskavets to the level of chronic stress in women of childbearing age with different ovarian status. A significant (R=0,59) canonical correlation between the dynamics of the neuro-hormonal index of stress, on the one hand, and autonomic reactivity, luteinizing hormone, thyroid-stimulating hormone, thyroxine and progesterone - the other side

Histoire des syndicats de fonctionnaires et du mouvement social en Seine Maritime de 1944 à 1981

In 1944, the National Council of Resistance decides to rebuild a welfare state, in continuation of the Popular Front, that the second World War stops it. The trade unions reunified, in CGT (except CFTC) decide to sustain this program. The trade unions of civil servants from Seine-Maritime organize themselves to take part in this rebuild that they waited for it. What are their demands ? On What do they lean themselves to put them before ? What are their values for which they fight? Do they wait all from the state ? What is their idea of this welfare state ? At least, what means do they use to fight for it and bring it to progress ? Getting the recognition of their freedom union laws, which includes right striking, they agree civil servant status which turn out very protective against their adminstration and its hierarchy. They get too the management of Health Security by their mutual insurances which lead them, in Seine-Maritme, to build a powerful departemental mutual insurance. However, the division of world in two blocks, one liberal and one communist, goes through these trade unions and leads to the break away of 1947 That does not prevent the participation to strikes of 1953 wich they are be able to save their retirement. If they sustain general De Gaulle in his decolonization policy and against seditious generals, they clash him on his institutional, économic and social policy. The strike of 1968 is the culmination of it, throuhgout adjournements. But in order to restore the welfare state that they hope, they must sustain lefts’ candidate, François Mitterrand, in their electoral compaigns of 1974 and 1981, who wins in this last year, in spite of their differences and thanks to the Will of unity of their activists.En 1944, le Conseil national de la Résistance décide de reconstruire un Etat social dans la continuité du Front populaire, avant que le second conflit ne l’interrompe. Les syndicats ouvriers réunifiés dans la CGT (sauf la CFTC) décident de soutenir ce programme. Les syndicats de fonctionnaires de Seine-Maritime s’organisent pour participer à cette reconstruction qu’ils attendaient. Quels sont leurs revendications ? Sur quoi s’appuient-ils pour les mettre en avant ? Quels sont les valeurs qu’ils défendent ? Attendent-ils tout de l’Etat social ? Quelle est leur conception de cet Etat social ? Enfin, quels moyens utilisent-ils pour le défendre et le faire progresser ? Obtenant la reconnaissance de leur liberté syndicale qui comprend le droit de grève, ils acceptent un statut qui se révèle fort protecteur vis-à-vis de l’administration et de sa hiérarchie. Ils obtiennent aussi la gestion de la Sécurité sociale par leurs mutuelles qui les entraînent, en Seine-Maritime, à construire une mutualité départementale unifiée et puissante. Toutefois, la division du monde en deux blocs, un libéral et un communiste, traverse ces syndicats et aboutit à la scission de 1947. Cela n’empêche pas la participation aux grèves de 1953 qui leur permet de sauver leur retraite. S’ils soutiennent le général de Gaulle (1890-1970) dans sa politique de décolonisation et contre les généraux factieux, ils l’affrontent sur sa politique institutionnelle, économique et sociale. La grève de 1968 en est l’aboutissement, par-delà les remises en cause. Mais pour rétablir l’Etat social qu’ils souhaitent, il leur faut soutenir les campagnes électorales de 1974 et 1981 du candidat de la gauche, François Mitterrand (1916-1996), qui l’emporte en 1981, en dépit de leurs divergences et grâce à la volonté unitaire de leurs militants

POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients.

PURPOSE: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor. PATIENTS AND METHODS: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design. RESULTS: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients. CONCLUSIONS: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting

Intraductal cisplatin treatment in a BRCA-associated breast cancer mouse model attenuates tumor development but leads to systemic tumors in aged female mice

BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1-associated breast cancer may be local prophylactic treatment via the nipple. Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer. We show that ID cisplatin and PARP-inhibition can successfully ablate mammary epithelial cells, and this approach attenuated tumor onset in a mouse model of Brca1-associated breast cancer from 153 to 239 days. Long-term carcinogenicity studies in 150 syngeneic wild-type mice demonstrated that tumor incidence was increased in the ID treated mammary glands by 6.3% due to systemic exposure to cisplatin. Although this was only evident in aged mice (median age = 649 days), we conclude that ID cisplatin treatment only presents a safe and feasible local prevention option if systemic exposure to the chemotherapy used can be avoided