Prospective Multicenter Randomized Phase III Study of Weekly versus Standard Docetaxel (D2) for First-Line Treatment of Metastatic Breast Cancer

Purpose: Previous phase II studies have indicated a greatly reduced hematotoxicity of docetaxel-based regimens administered on weekly schedules. The present trial was initiated to randomly compare the toxicity and efficacy of weekly docetaxel versus its standard 3-weekly application. Methods: Patients previously untreated with chemotherapy for metastatic disease were recruited. Patients aged >60 years or with a Karnofsky Perfomance Status (KPS) of 60-80% were eligible for the D2 study. Patients were randomized to receive docetaxel either on a 3-weekly {[}75 mg/m(2) every 3 weeks (q3w)] or on a weekly (30 mg/m(2) on days 1, 8, and 15; q4w) schedule. Treatment was continued until a maximum of 8 cycles, unacceptable toxicity, or disease progression. All patients received standard corticosteroid prophylaxis. Results: Since statistical significance for the primary endpoint (toxicity) was achieved in the interim analysis, the study was closed according to the study protocol (102 of 162 patients). Compared to the standard arm, leukopenia >= grade 3 was a rare event in the weekly arm of the D2 study (per-patient analysis: 4.2% q1w vs. 51.9% q3w; p < 0.0001). No difference was observed between the 2 schedules regarding the occurrence of anemia or thrombocytopenia. With regard to non-hematological toxicity, there was a higher incidence of skin/nail and hepatological toxicity with the weekly schedule, whereas neurotoxicity was observed more often in the standard arm. The rate of omitted doses was significantly increased in the weekly arm (8.6% q1w vs. 0% q3w). The overall response rate was 22.9% in the weekly arm compared to 42.6% in the standard arm (p = 0.039). Time to progression was 5.4 (q1w) versus 6.3 (q3w) months (p = 0.91), and overall survival was 22.7 (q1w) versus 15.8 (q3w) months (p = 0.24). Conclusion: The present data support the feasibility of both weekly and 3-weekly application of docetaxel. As expected, severe leukopenia seems avoidable in weekly scheduled single-agent docetaxel and may serve as an important treatment option, particularly in elderly patients and patients with a reduced performance status. Copyright (C) 2011 S. Karger AG, Base

Prospective Multicenter Randomized Phase III Study of Weekly versus Standard Docetaxel plus Doxorubicin (D4) for First-Line Treatment of Metastatic Breast Cancer

Purpose: Previous phase II studies have indicated a greatly reduced hematotoxicity of docetaxel-based regimens administered on weekly schedules. The present trial was initiated to compare the toxicity and efficacy of weekly docetaxel versus its standard 3-weekly application in combination with doxorubicin. Methods: Patients previously untreated with chemotherapy for metastatic disease were recruited. Inclusion criteria were age = grade 3 was observed in the standard arm of the D4 study compared to the weekly schedule (per-patient analysis: 61.9% q3w vs. 65.1% q1w; p > 0.05). Grade 3 and grade 4 fever, diarrhea, and infections occurred more frequently in the standard arm, whereas neurotoxicity and skin/nail disorders were observed more frequently in the weekly arm. Except for fever, none of these differences reached a level of significance. Dose delays, dose reductions, and the rate of omitted doses were increased in the weekly arm. The overall response rate was 44.2% in the weekly arm compared to 52.4% in the standard arm (p = 0.52). Time to progression was 6.2 (q1w) versus 10.3 (q3w) months (p = 0.36), and overall survival was 20.5 (q1w) versus 28.7 (q3w) months (p = 0.98). Conclusion: The present data support the feasibility of both weekly and 3-weekly application of docetaxel in combination with doxorubicin. Nevertheless, given that leukopenia was similar in both arms and the efficacy parameters were at least numerically inferior with the weekly schedule, standard 3-weekly application seems to be preferable for patients requiring combination chemotherapy. Copyright (C) 2011 S. Karger AG, Base

Key Contributions by the Swiss Tropical and Public Health Institute Towards New and Better Drugs for Tropical Diseases

Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine, coupled with deeply rooted partnerships with institutions in low- and middle-income countries (LMICs), the Swiss Tropical and Public Health Institute (Swiss TPH) has been a key contributor in many drug research and development consortia involving academia, pharma and product development partnerships. Our know-how of the maintenance of parasites and their life-cycles in the laboratory, plus our strong ties to research centres and disease control programme managers in LMICs with access to field sites and laboratories, have enabled systems for drug efficacy testing in vitro and in vivo, clinical research, and modelling to support the experimental approaches. Thus, Swiss TPH has made fundamental contributions towards the development of new drugs – and the better use of old drugs – for neglected tropical diseases and infectious diseases of poverty, such as Buruli ulcer, Chagas disease, food-borne trematodiasis (e.g. clonorchiasis, fascioliasis and opisthorchiasis), human African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, soil-transmitted helminthiasis and tuberculosis. In this article, we show case the success stories of molecules to which Swiss TPH has made a substantial contribution regarding their use as anti-infective compounds with the ultimate aim to improve people’s health and well-being

MHC class I chain-related protein A shedding in chronic HIV-1 infection is associated with profound NK cell dysfunction

Natural killer (NK) cells play a critical role in host defense against viral infections. However chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cells, that poorly control viral replication. The underlying mechanisms for this NK cell mediated dysfunction are not understood. Certain tumors evade NK cell mediated detection by dampening NK cell activity through the downregulation of NKG2D, via the release of soluble NKG2D-ligands, resulting in a potent suppression of NK cell function. Here we show that chronic HIV-1 infection is associated with a specific defect in NKG2D-mediated NK cell activation, due to reduced expression and transcription of NKG2D. Reduced NKG2D expression was associated with elevated levels of the soluble form of the NKG2D-ligand, MICA, in patient sera, likely released by HIV+CD4+ T cells. Thus, like tumors, HIV-1 may indirectly suppress NK cell recognition of HIV-1-infected CD4+ T cells by enhancing NKG2D-ligand secretion into the serum resulting in a profound impairment of NK cell function

Mice with targeted disruption of the fatty acid transport protein 4 (Fatp 4, Slc27a4) gene show features of lethal restrictive dermopathy

The fatty acid transport protein family is a group of evolutionarily conserved proteins that are involved in the cellular uptake and metabolism of long and very long chain fatty acids. However, little is known about their respective physiological roles. To analyze the functional significance of fatty acid transport protein 4 (Fatp4, Slc27a4), we generated mice with a targeted disruption of the Fatp4 gene. Fatp4-null mice displayed features of a neonatally lethal restrictive dermopathy. Their skin was characterized by hyperproliferative hyperkeratosis with a disturbed epidermal barrier, a flat dermal–epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis. The rigid skin consistency resulted in an altered body shape with facial dysmorphia, generalized joint flexion contractures, and impaired movement including suckling and breathing deficiencies. Lipid analysis demonstrated a disturbed fatty acid composition of epidermal ceramides, in particular a decrease in the C26:0 and C26:0-OH fatty acid substitutes. These findings reveal a previously unknown, essential function of Fatp4 in the formation of the epidermal barrier

Проектирование автономного быстровозводимого защитного гидротехнического сооружения для местности с периодическими затоплениями

В данной выпускной квалификационной работе был проведен анализ паводковой ситуации за 20 лет. Рассмотрены инженерно-технические и организационные мероприятия по защите населения от наводнения. Исследованы современные типы быстровозводимых водоналивных дамб. Разработан проект быстровозводимого гидротехнического сооружения.In this final qualification work the analysis of a flood situation for 20 years was carried out. Technical and organizational actions for protection of the population against a flood are considered. The modern types of pre-fabricated water filling dams are investigated. The project of the pre-fabricated hydraulic engineering construction is develope

Biological Effects of Antiprotons Are Antiprotons a Candidate for Cancer Therapy?

2009 Status Report of AD-4 Experimen

Molecular Epidemiology of the HIV Epidemic in Three German Metropolitan Regions - Cologne/Bonn, Munich and Hannover, 1999-2016

Using HIV sequence data to characterize clusters of HIV transmission may provide insight into the epidemic. Phylogenetic and network analyses were performed to infer putative relationships between HIV-1 partial pol sequences from 2,774 individuals receiving care in three German regions between 1999-2016. The regions have in common that they host some of the largest annual festivals in Europe (Carnival and Oktoberfest). Putative links with sequences (n = 150,396) from the Los Alamos HIV Sequence database were evaluated. A total of 595/2,774 (21.4%) sequences linked with at least one other sequence, forming 184 transmission clusters. Clustering individuals were significantly more likely to be younger, male, and report sex with men as their main risk factor (p < 0.001 each). Most clusters (77.2%) consisted exclusively of men;41 (28.9%) of these included men reporting sex with women. Thirty-two clusters (17.4%) contained sequences from more than one region;clustering men were significantly more likely to be in a position bridging regional HIV epidemics than clustering women (p = 0.027). We found 236 clusters linking 547 sequences from our sample with sequences from the Los Alamos database (n = 1407;31% from other German centres). These results highlight the pitfalls of focusing HIV prevention efforts on specific risk groups or specific locales

DIFFUSE JUVENILE SYSTEMIC SCLEROSIS PATIENTS SHOW DISTINCT ORGAN INVOLVEMENT, ANTIBODY PATTERN AND HAVE SIGNIFICANTLY MORE SEVERE DISEASE IN THE LARGEST JSSC COHORT OF THE WORLD. RESULTS FROM THE JUVENILE SCLERODERMA INCEPTION COHORT

Peer reviewe