Zeitschriftenartikel: „VDA 6.3“

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Shin, Yong Sam, Byung Moon Kim, Se-Hyuk Kim, Sang Hyun Suh, Chang Woo Ryu, Jun Seok Koh, Dong Ik Kim und Dong Joon Kim. „Endovascular Treatment of Bilateral Intracranial Vertebral Artery Dissecting Aneurysms Presenting With Subarachnoid Hemorrhage“. Operative Neurosurgery 70, suppl_1 (25.07.2011): ons75—ons81. http://dx.doi.org/10.1227/neu.0b013e31822ed1f0.

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Abstract BACKGROUND: Optimal management of bilateral vertebral artery dissecting aneurysms (bi-VDAs) causing subarachnoid hemorrhage (SAH) remains unclear. OBJECTIVE: To investigate the treatment methods and outcomes of bi-VDA causing SAH. METHODS: Seven patients were treated endovascularly for bi-VDA causing SAH. Treatment methods and outcomes were evaluated retrospectively. RESULTS: Two patients were treated with 2 overlapping stents for both ruptured and unruptured VDAs, 2 with 2 overlapping stents and coiling for ruptured VDA and with conservative treatment for unruptured VDA, 1 with internal trapping (IT) for ruptured VDA and stent-assisted coiling for unruptured VDA, 1 with IT for ruptured VDA and 2 overlapping stents for unruptured VDA, and 1 with IT for ruptured VDA and a single stent for unruptured VDA. None had rebleeding during follow-up (range, 15-48 months). All patients had favorable outcomes (modified Rankin Scale score, 0-2). On follow-up angiography at 6 to 36 months, 9 treated and 2 untreated VDAs revealed stable or improved state, whereas 3 VDAs in 2 patients showed regrowth. Of the 3 recurring VDAs, 1 was initially treated with IT but recurred owing to retrograde flow to the ipsilateral posterior inferior cerebellar artery (PICA), the second was treated with single stent but enlarged, and the last was treated with 2 overlapping stents and coiling but recurred from the remnant sac harboring the PICA origin. All 3 recurred VDAs were retreated with coiling with or without stent insertion. CONCLUSION: Bilateral VDAs presenting with SAH were safely treated with endovascular methods. However, endovascular treatment may be limited for VDAs with PICA origin involvement.

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Prisk, G. K., A. R. Elliott, H. J. Guy, J. M. Kosonen und J. B. West. „Pulmonary gas exchange and its determinants during sustained microgravity on Spacelabs SLS-1 and SLS-2“. Journal of Applied Physiology 79, Nr. 4 (01.10.1995): 1290–98. http://dx.doi.org/10.1152/jappl.1995.79.4.1290.

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We measured resting pulmonary gas exchange in eight subjects exposed to 9 or 14 days of microgravity (microG) during two Spacelab flights. Compared with preflight standing measurements, microG resulted in a significant reduction in tidal volume (15%) but an increase in respiratory frequency (9%). The increased frequency was caused chiefly by a reduction in expiratory time (10%), with a smaller decrease in inspiratory time (4%). Anatomic dead space (VDa) in microG was between preflight standing and supine values, consistent with the known changes in functional residual capacity. Physiological dead space (VDB) decreased in microG, and alveolar dead space (VDB-VDa) was significantly less in microG than in preflight standing (-30%) or supine (-15%), consistent with a more uniform topographic distribution of blood flow. The net result was that, although total ventilation fell, alveolar ventilation was unchanged in microG compared with standing in normal gravity (1 G). Expired vital capacity was increased (6%) compared with standing but only after the first few days of exposure to microG. There were no significant changes in O2 uptake, CO2 output, or end-tidal PO2 in microG compared with standing in 1 G. End-tidal PCO2 was unchanged on the 9-day flight but increased by 4.5 Torr on the 14-day flight where the PCO2 of the spacecraft atmosphere increased by 1–3 Torr. Cardiogenic oscillations in expired O2 and CO2 demonstrated the presence of residual ventilation-perfusion ratio (VA/Q) inequality. In addition, the change in intrabreath VA/Q during phase III of a long expiration was the same in microG as in preflight standing, indicating persisting VA/Q inequality and suggesting that during this portion of a prolonged exhalation the inequality in 1 G was not predominantly on a gravitationally induced topographic basis. However, the changes in PCO2 and VA/Q at the end of expiration after airway closure were consistent with a more uniform topographic distribution of gas exchange.

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Sekhon, H. S., und W. M. Thurlbeck. „Lung cytokinetics after exposure to hypobaria and/or hypoxia and undernutrition in growing rats“. Journal of Applied Physiology 79, Nr. 4 (01.10.1995): 1299–309. http://dx.doi.org/10.1152/jappl.1995.79.4.1299.

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We measured resting pulmonary gas exchange in eight subjects exposed to 9 or 14 days of microgravity (microG) during two Spacelab flights. Compared with preflight standing measurements, microG resulted in a significant reduction in tidal volume (15%) but an increase in respiratory frequency (9%). The increased frequency was caused chiefly by a reduction in expiratory time (10%), with a smaller decrease in inspiratory time (4%). Anatomic dead space (VDa) in microG was between preflight standing and supine values, consistent with the known changes in functional residual capacity. Physiological dead space (VDB) decreased in microG, and alveolar dead space (VDB-VDa) was significantly less in microG than in preflight standing (-30%) or supine (-15%), consistent with a more uniform topographic distribution of blood flow. The net result was that, although total ventilation fell, alveolar ventilation was unchanged in microG compared with standing in normal gravity (1 G). Expired vital capacity was increased (6%) compared with standing but only after the first few days of exposure to microG. There were no significant changes in O2 uptake, CO2 output, or end-tidal PO2 in microG compared with standing in 1 G. End-tidal PCO2 was unchanged on the 9-day flight but increased by 4.5 Torr on the 14-day flight where the PCO2 of the spacecraft atmosphere increased by 1–3 Torr. Cardiogenic oscillations in expired O2 and CO2 demonstrated the presence of residual ventilation-perfusion ratio (VA/Q) inequality. In addition, the change in intrabreath VA/Q during phase III of a long expiration was the same in microG as in preflight standing, indicating persisting VA/Q inequality and suggesting that during this portion of a prolonged exhalation the inequality in 1 G was not predominantly on a gravitationally induced topographic basis. However, the changes in PCO2 and VA/Q at the end of expiration after airway closure were consistent with a more uniform topographic distribution of gas exchange.

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Hutson, Thomas E., Long H. Dang, Richard C. Lauer, Alexander Starodub, Ralph J. Hauke, Theodore Logan, Kathryn A. Bylow et al. „Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group).“ Journal of Clinical Oncology 30, Nr. 5_suppl (10.02.2012): 373. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.373.

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373 Background: BNC105P is a Vascular Disruption Agent (VDA) that destabilizes tubulin polymers leading to selective damage of tumor vasculature, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. Preclinical investigations demonstrated that BNC105P is effective at selectively damaging the vasculature in primary and metastatic lesions. Furthermore, BNC105P monotherapy compared well with sunitinib in mice bearing kidney tumors. It follows that the combined use of this VDA with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6 and 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: In the clinic the BNC105P / everolimus combination was well tolerated and no DLTs were observed in any of the phase I patients. Toxicities deemed to be drug-related included single events of Grade 2 anemia, thrombocytopenia and mucositis. Of the 12 patients enrolled to the phase I, 7 remain on treatment. The medium number of cycles is 3 (range: 1–14) and 3 patients have been administered >6 cycles of treatment. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.

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Chebil, M., J. Soria, L. Chami, C. Massard, B. Benatsou, A. Roche, J. Armand und N. Lassau. „Interest of DCE-US with quantification to demonstrate the VDA effect on vascularization in patients with advanced solid tumors treated with AVE8062“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): e14522-e14522. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14522.

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e14522 Background: To determine the optimal time for the assessment of the perfusion in patients receiving AVE8062 (Vascular Disrupting Agent) at different doses combined with a fixed dose of cisplatin and then to correlate these results with the tumor response. Methods: Patients (pts) with advanced solid tumors, treated with AVE8062 (from 11.5 to 30 mg/m2) in combination with 75 mg/m2 cisplatin given every 3 weeks, were prospectively followed by DCE-US. DCE-US was performed before treatment, at 3 time points (0, 6 and 24 hours (h)) on Day 1 of the first (C1) and second cycle (C2), then every 2 cycles thereafter. Contrast uptake was acquired using VRI perfusion software after SonoVue bolus injection. Time-Intensity Curves (TIC) were determined using linear raw- data from CHI-Q (Toshiba) software. Peak Intensity (PI) representing the blood volume was calculated from automatic modeling of TIC. CT-scans performed before treatment and every 2 cycles were reviewed and tumor response assessed (RECIST). Results: A total of 96 DCE-US were performed in 13 pts, 11 of whom had data for both cycle 1 and cycle 2. Among these 11 patients, 8 presented with a dramatic decrease of PI and 3 with an increase of PI. At cycle 1, mean change from baseline in PI was -36% at 6h and -47% at 24h after AVE8062 infusion. Greater decreases were observed at cycle 2, -70% at 6 h and 78% at 24 h. No pt had a clinical response, but by cycle 2, the 8 pts with a decrease in PI at 24h went on to have stable disease as best response; 3 pts with increased PI 24h after their second treatment all had disease progression as best response. Conclusions: The best timing to observe the effect of AVE8062 on the PI seems to be 24 hours after drug administration at cycle 2. These preliminary results suggest that 24 hr PI at cycle 2 could be useful for determining pts who are more likely to have disease progression as best response to AVE8062. If confirmed, the assessment of PI variation may predict the clinical response to AVE8062. Further studies are needed to assess the possible predictive value of DCE-US on duration of progression-free survival. No significant financial relationships to disclose.

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Desai, J., S. Wong, G. Chong, D. Bibby, A. Leske, G. Kremmidiotis, M. Rosen und D. Rischin. „Phase I, pharmacokinetic, and pharmacodynamic evaluation of BNC105P, a novel anticancer agent that is both a vascular disrupting agent (VDA) and an inhibitor of cancer cell proliferation“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): e14512-e14512. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14512.

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e14512 Background: BNC105P is a novel anticancer agent that inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly becomes the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells compared to quiescent endothelial cells. Methods: BNC105P (2.1 to 18.9 mg/m2) was given IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors (ECOG 0–2) and adequate organ function. The objectives were to determine safety, tolerability, MTD and pharmacokinetics (PK). A pharmacodynamic response was evaluated using DCE-MRI with two baseline and two post dose assessments (3–6, 24 h). DLTs were determined during the first 21 days. Results: 9 pts (7 M; 2 F), median age 60 years have been enrolled with one pt each at 2.1 and 4.2 mg/m2. At 8.4 mg/m2, one pt experienced Grade 2 (Gr 2) mucositis and a switch to a ‘3+3’ design occurred. No DLTs have been observed in 3 pts at 12.6 mg/m2 and 1 pt at 18.9 mg/m2. Notable toxicity includes one episode of Gr 1 febrile episode possibly related to infusion, two episodes of Gr 1 fatigue and one Gr 1 rash. PK data of BNC105 indicates a linear increase in plasma AUC levels (Table) and plasma half life of < 0.5 h. Best observed responses were SD in 2/9 pts including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2). At doses ≥ 8.4 mg/m2, DCE-MRI images indicate changes in tumor perfusion post-dose. Two pts at 12.6 mg/m2 had a decrease in Ktrans values of 6 and 15 % compared to baseline. Conclusions: Pharmacodynamically active doses have been achieved with plasma drug levels correlating with active preclinical plasma exposure. To date, no excess toxicity has been observed at doses up to 18.9 mg/m2. [Table: see text] [Table: see text]

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Ricart, A. D., M. Cooney, J. Sarantopoulos, J. Brell, K. W. Locke, R. E. Gammans, G. Medina, A. Zambito, A. W. Tolcher und S. C. Remick. „A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MN-029, a novel vascular disrupting agent (VDA), in patients (pts) with advanced solid tumors“. Journal of Clinical Oncology 24, Nr. 18_suppl (20.06.2006): 3096. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3096.

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3096 Background: MN-029 is a novel VDA that binds reversibly to the colchicine-binding site on tubulin and inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor endothelial cells (EC). Disruption of the tumor EC cytoskeleton ultimately leads to a temporary reduction in tumor blood flow. Methods: MN-029 is administered IV as a 10–20 min infusion, at 3-wk intervals in pts with advanced cancer. The study has followed an accelerated titration design, with intrapatient dose escalation. PD effects on tumor blood flow are evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 28 pts were enrolled (13M/15F), median age 56 (range 35 - 76) and tumor types: colorectal (5), renal (5), hepatocellular (3), ovarian (2), melanoma (2), soft tissue sarcoma (2), carcinoid (2) and others (7). A total of 110 cycles of MN-029 were given, median 3/pt (range 1–20), over 9 dose levels (4, 8, 16, 24, 36, 54, 80, 120 and 180 mg/m2). Escalation proceeded until an initial dose-limiting toxicity (DLT) was observed in 1 pt in the 180 mg/m2 cohort, consisting of a reversible episode (3 hours post dose) of acute coronary ischemia (without sequelae and with preservation of myocardial function) probably due to coronary vasospasm. Therefore, this cohort was expanded to 6 pts, with no further DLTs observed. Common mild to moderate toxicities included nausea, vomiting (which appears dose-related), hypotension, fatigue and diarrhea. There was no significant myelotoxicity, stomatitis or alopecia. Seven pts had stable disease after 3 cycles, including 2 pts with carcinoid tumor (+21 cycles and +17 cycles). PK data generally indicated dose-related increases in Cmax and AUC values, although substantial inter-patient variability was observed. Tumor blood flow reduction assessed by DCE-MRI was recorded at 120 and 180 mg/m2, but not at 80 mg/m2. Conclusions: MN-029 produced reductions in tumor blood flow at doses that were well tolerated. Accrual continues at 225 mg/m2. [Supported in part by grants from MediciNova, Inc. and M01 RR-000080] [Table: see text]

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Lam, T. C., N. G. Shrive und C. B. Frank. „Variations in Rupture Site and Surface Strains at Failure in the Maturing Rabbit Medial Collateral Ligament“. Journal of Biomechanical Engineering 117, Nr. 4 (01.11.1995): 455–61. http://dx.doi.org/10.1115/1.2794207.

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The relationship between the pattern of surface strain and the site of failure in maturing rabbit ligaments was studied in vitro. Bone-medial collateral ligament (MCL)-bone complexes of 24 female New Zealand White rabbits at 3, 6, 9 and 12 months of age (n = 6 rabbits, 12 MCLs per group) were tested in tension to failure. A video dimension analysis (VDA) system was used to map the surface strain at failure across the width and along the length of the medial side of each MCL during testing. Results showed that the highest strains were consistently located at the femoral insertion decreasing towards the midsubstance, with the highest strain occurring in the anterior portion of the MCL immediately adjacent to the femoral insertion. Strains of the complex at failure increased with rabbit maturation. The strain distribution however, did not change dramatically, even though the locations of MCL failure changed from exclusively tibial avulsion in the three month old rabbits to predominantly midsubstance failures in the 12 month old rabbits. In the six month old rabbits, there was a particular dissociation with all MCLs failing near the tibial insertion while femoral strains were apparently the highest. These results suggest two possibilities beyond that of some unknown artifacts of optical strain measurement. First, since failure sites rarely correlated with areas of maximum surface strain in this study, it seems possible that higher strains could exist deeper in the tissue, particularly at the bone-ligament interface of the tibial insertion in immature animals and somewhere within the midsubstance of the MCL in the adult. Secondly, it is possible that the ligament material may be heterogeneous.

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Rischin, Danny, Daniela Matei, Jeffrey C. Goh, Michelle Margaret Vaughan, Philip James Beale, Meaghan Elizabeth Tenney, Julie Martyn et al. „A phase I/II study of the vascular disrupting agent BNC105P in combination with gemcitabine-carboplatin in partially platinum-sensitive ovarian cancer patients in first or second relapse: An international collaborative group trial of ANZGOG and HOG.“ Journal of Clinical Oncology 31, Nr. 15_suppl (20.05.2013): TPS5612. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps5612.

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TPS5612 Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia, and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m2) and gemcitabine (800-1000 mg/m2) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N = 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (<6 months vs 6 months or more), and first relapse vs. second relapse. Biomarker (tissue and blood-borne) sampling and PK analysis will also be undertaken. Clinical trial information: NCT01624493.

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Libutti, Steven K., Lowell Brian Anthony, David J. Chaplin und Julie Ann Sosa. „A phase II study of combretastatin A4-phosphate (CA4P) in the treatment of well-differentiated, low- to intermediate-grade, unresectable, recurrent, or metastatic pancreatic, or GI neuroendocrine tumors/carcinoid (GI-NETs/PNETs) with elevated biomarkers.“ Journal of Clinical Oncology 35, Nr. 4_suppl (01.02.2017): 432. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.432.

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432 Background: GI-NETs/PNETs are highly vascular tumors. CA4P, a vascular disrupting agent (VDA), occludes tumor vasculature resulting in ischemic necrosis. Pre-clinical studies of CA4P have shown activity in GI-NETs/PNETs. Methods: OX4218s is a phase II, single-arm, open-label study (NCT02132468) of CA4P in patients (pts) with GI-NETs/PNETs with elevated biomarkers who relapsed during or after standard-of-care treatment. Pts received CA4P 60 mg/m2 IV on days 1, 8, and 15 of a 21-day cycle for 3 cycles. Primary endpoint was change in biomarkers from baseline. Secondary endpoints were safety, tolerability, symptoms, and QOL. Exploratory endpoints were ORR (RECIST 1.1). Pts achieving biomarker or symptom response were eligible for a rollover study. Results: 18 pts were enrolled; 7 subsequently entered the rollover study. Pts were on average aged 58 years, white (89%), male (50%) with ECOG status of 0-1. The majority (94%) had well-differentiated disease (GI-NETS 78%) and received prior Tx (94%). There were no meaningful changes in biomarkers. Eleven (61%) pts had stable disease (SD) and 1 (6%) had a partial response (PR). In the rollover study, 5 (71%) had SD, and 1 had SD for 14 cycles prior to progression (PD). 77% of pts had treatment-related AEs. Key grade 3-5 AEs (> 10%): anemia, abdominal pain, fatigue, hypertension, ALT and AST increases, with 1 grade 5 carcinoid syndrome. Conclusions: The primary endpoint was not met. However, the number of pts entering the rollover study and ORR suggest that CA4P conferred some activity and was generally safe and well tolerated. These findings suggest that due to their inherent variability, tumor biomarkers may not be an ideal endpoint for this population. Clinical trial information: NCT02132468. [Table: see text]

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Surman, Sherri L., Rhiannon R. Penkert, Robert E. Sealy, Bart G. Jones, Tony N. Marion, Peter Vogel und Julia L. Hurwitz. „Consequences of Vitamin A Deficiency: Immunoglobulin Dysregulation, Squamous Cell Metaplasia, Infectious Disease, and Death“. International Journal of Molecular Sciences 21, Nr. 15 (04.08.2020): 5570. http://dx.doi.org/10.3390/ijms21155570.

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Vitamin A is an important regulator of immune protection, but it is often overlooked in studies of infectious disease. Vitamin A binds an array of nuclear receptors (e.g., retinoic acid receptor, peroxisome proliferator-activated receptor, retinoid X receptor) and influences the barrier and immune cells responsible for pathogen control. Children and adults in developed and developing countries are often vitamin A-deficient or insufficient, characteristics associated with poor health outcomes. To gain a better understanding of the protective mechanisms influenced by vitamin A, we examined immune factors and epithelial barriers in vitamin A deficient (VAD) mice, vitamin D deficient (VDD) mice, double deficient (VAD+VDD) mice, and mice on a vitamin-replete diet (controls). Some mice received insults, including intraperitoneal injections with complete and incomplete Freund’s adjuvant (emulsified with PBS alone or with DNA + Fus-1 peptide) or intranasal inoculations with Sendai virus (SeV). Both before and after insults, the VAD and VAD+VDD mice exhibited abnormal serum immunoglobulin isotypes (e.g., elevated IgG2b levels, particularly in males) and cytokine/chemokine patterns (e.g., elevated eotaxin). Even without insult, when the VAD and VAD+VDD mice reached 3–6 months of age, they frequently exhibited opportunistic ascending bacterial urinary tract infections. There were high frequencies of nephropathy (squamous cell hyperplasia of the renal urothelium, renal scarring, and ascending pyelonephritis) and death in the VAD and VAD+VDD mice. When younger VAD mice were infected with SeV, the predominant lesion was squamous cell metaplasia of respiratory epithelium in lungs and bronchioles. Results highlight a critical role for vitamin A in the maintenance of healthy immune responses, epithelial cell integrity, and pathogen control.

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Chauhan, Dharminder, Ajita V. Singh, Madhavi Bandi, Noopur Raje, Robert L. Schlossman, G. Kenneth Lloyd, Paul Richardson, Michael A. Palladino und Kenneth C. Anderson. „NPI-2358, a Novel Vascular Disrupting Agent Blocks Growth and Angiogenesis in Multiple Myeloma Cells.“ Blood 114, Nr. 22 (20.11.2009): 3842. http://dx.doi.org/10.1182/blood.v114.22.3842.3842.

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Abstract Abstract 3842 Poster Board III-778 Background and Rationale Vascular disrupting agents (VDAs) act via selectively disrupting established tumor vasculature and have shown remarkable clinical success as anti-cancer therapies. NPI-2358 is a novel VDA with a distinct structure and mechanism of action from other available VDAs. NPI-2358 binds to the colchicine-binding site of beta-tubulin preventing polymerization and disrupting the cytoplasmic microtubule network, thereby causing loss of vascular endothelial cytoskeletal function, and inducing cytotoxicity in cancer cells. Here, we examined the anti-angiogenic and anti-tumor activity of NPI-2358 in multiple myeloma (MM) cells using both in vitro and in vivo model systems. Material and Methods We utilized MM.1S, MM.1R, RPMI-8226, U266, and INA-6 human MM cell lines, as well as purified tumor cells from MM patients relapsing after prior anti-MM therapies. Cell viability/apoptosis assays were performed using MTT, trypan blue exclusion, and Annexin V/PI staining. Angiogenesis was measured in vitro using Matrigel capillary-like tube structure formation assays: Since human vascular endothelial cells (HUVECs) plated onto Matrigel differentiate and form capillary-like tube structures similar to in vivo neovascularization, this assay measures anti-angiogenic effects of drugs/agents. Migration assays were performed using transwell insert assays. Immunoblot analysis was performed using antibodies to caspase-8, caspase-9, caspase-3, PARP, Bcl-2, Bax, pJNK and GAPDH. Statistical significance was determined using a Student t test. Results Treatment of MM.1S, RPMI-8226, MM.1R, INA-6, and KMS-12BM with NPI-2358 for 24h induces a dose-dependent significant (P < 0.005) decrease in viability of all cell lines (IC50 range: 5-8 nM; n=3). To determine whether NPI-2358-induced decrease in viability is due to apoptosis, MM cell lines were treated with NPI-2358 for 24h; harvested, and analyzed for apoptosis using Annexin V/PI staining. A significant increase in NPI-2358-induced apoptosis was observed in all MM cell lines (% Annexin V+/PI- apoptotic cells: MM.1S, 48 ± 2.3%; MM.1R, 46.6 ± 3.1%; RPMI-8226, 61.7 ± 4.5%; and INA-6, 59.9 ± 3.2%; P < 0.05; n=3). Importantly, NPI-2358 decreased viability of freshly isolated MM cells from patients (IC50 range: 3-7 nM; P < 0.005), without affecting the viability of normal peripheral blood mononuclear cells, suggesting specific anti-MM activity and a favorable therapeutic index for NPI-2358. Examination of in vitro angiogenesis using capillary-like tube structure formation assay showed that even low doses of NPI-2358 (7 nM treatment for 12h; IC50: 20 nM at 24h) significantly decreased tubule formation in HUVECs (70-80% decrease; P < 0.05). Transwell insert assays showed a marked reduction in serum-dependent migration of NPI-2358-treated MM cells (42 ± 2.1% inhibition in NPI-2358-treated vs. control; P < 0.05). NPI-2358 at the concentrations tested (5 nM for 12h) in the migration assays did not affect survival of MM cells (> 95% viable cells). A similar anti-migration activity of NPI-2358 was noted against HUVEC cells (48 ± 1.7% decrease in migration; P < 0.05). Mechanistic studies showed that NPI-2358-induced apoptosis was associated with activation of caspase-8, caspase-9, caspase-3 and PARP. Importantly, treatment of MM.1S cells with NPI-2358 (5 nM) triggered phosphorylation of c-Jun amino-terminal kinase (JNK), a classical stress response protein, without affecting Bcl-2 family members Bax and Bcl-2. Blockade of JNK using dominant negative strategy markedly abrogated NPI-2358-induced apoptosis. Conclusion Our preclinical data provide evidence for remarkable anti-angiogenic and anti-tumor activity of NPI-2358 against MM cells, without significant toxicity in normal cells. Ongoing studies are examining in vivo anti-MM activity of NPI-2358 in animal models. Importantly, a Phase-1 study of NPI-2358 as a single agent in patients with advanced malignancies (lung, prostrate and colon cancer) has already established a favorable pharmacokinetic, pharmacodynamic and safety profile; and, a Phase-2 study of the combination of NPI-2358 and docetaxel in non-small cell lung cancer showed encouraging safety, pharmacokinetic and activity data. These findings, coupled with our preclinical studies, provide the framework for the development of NPI-2358-based novel therapies to improve patient outcome in MM. Disclosures: Chauhan: Nereus Pharmaceuticals, Inc: Consultancy. Lloyd:Nereus Pharmaceuticals, In: Employment. Palladino:Nereus Pharmaceuticals, Inc: Employment. Anderson:Nereus Pharmaceuticals, Inc: Consultancy.

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Read, W. L., P. Rosen, P. Lee, S. Anthony, R. Korn, N. Raghunand, B. Tseng, J. Whisnant, D. Von Hoff und R. Tibes. „Pharmacokinetic and pharmacodynamic results of a 4-hr IV administration phase I study with EPC2407, a novel vascular disrupting agent“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): 3569. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3569.

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3569 Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor with vascular disrupting and apoptotic activity at nanomolar concentrations. In an earlier phase I study dosing by 1 hr infusions daily x3 on a 21 day cycle, DLT at 21 mg/m2 was pain at tumor sites and vasoconstriction with increases of BP and QTc. MTD was 13 mg/m2 over 1 hr (ASCO 2008, Abst 2531). All drug-related toxicities resolved within an hour of stopping the infusion. Prolonged infusion of EPC2407 to extend exposure of tumor vasculature was designed with administration of EPC2407 over 4 hrs for 3 consecutive days of a 21 day cycle. Eleven patients have received this schedule and their cancers included leiomyosarcoma, colo-rectal, ovary, hepatocellular (2), NSCLC, pancreas, carcinoid, hemangiopericytoma, larynx and small bowel. Results: Doses escalated from 13 to 30 mg/m2 over 4 hours, with MTD determined to be 24 mg/m2. DLTs at 30 mg/m2 were similar to those seen in the 1 hr infusion, with pain at tumor sites in 1 participant and asymptomatic ST depression in a second. Other toxicities were also similar and included transient hypertension. QTc increases were not significant and no new toxicities were encountered. T1/2 with 4 hr infusion was ∼2hr, also seen with 1 hr infusion. AUC and Cmax values were similar to that predicted from the 1 hr data except AUC at 13 mg/m2 was lower than expected. DCE-MRI was done at baseline and after infusion on day 3, cycle 1. Analysis to date of DCE-MRI data of 4 patients showed a median decrease of 40% in both tumor permeability (Ktrans) and tumor perfusion volume (Vp). The two patients with hepatocellular carcinoma had notable stable disease and clear clinical benefit. Both patients received 18 mg/m2 dose, with one receiving 7 cycles over 5 months, and the other still on study (cycle 6) with stable disease for at least 4 cycles. Conclusions: EPC2407 shows clinical promise, with infusion-associated toxicities characteristic of the VDA drug class but without sustained or cumulative toxicity. Studies combining EPC2407 with conventional cytotoxic/cytostatic regimens are being designed. [Table: see text]

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Yoshihiro, Michishita, Makoto Hirokawa, Naohito Fujishima, Yukiko Abe, Masumi Fujishima, Yong-Mei Guo, Kumi Ubukawa et al. „CDR3-Independent Expansion of Vδ1 γδ T Lymphocytes and Depletion of Vδ2 T Cells Are Unique Features in Acquired Chronic Pure Red Cell Aplasia“,. Blood 118, Nr. 21 (18.11.2011): 3429. http://dx.doi.org/10.1182/blood.v118.21.3429.3429.

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Abstract Abstract 3429 Background: Idiopathic PRCA and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are major subtypes of adult-onset chronic PRCA. We have previously shown that these types of PRCA are responsive to immunosuppressive therapy but most patients require long-term maintenance immunosuppressive treatment. These results suggest that acquired chronic PRCA is an autoimmune disorder mediated by T lymphocytes and pathogenic T cell clones may be persistently present during remission. We have previously made an interesting observation that a thymoma-associated PRCA patient had an increase of Vd1 gd T cells in blood. We have also reported that recipients of allogeneic hematopoietic stem cell grafts had an oligoclonal expansion of Vd1 gd T cells and that Vd1 gd T clones had cytotoxicity against autologous EBV-transformed B cell line. Thus, gd T cell repertoires may be altered in PRCA patients in response to certain antigens. Objective: In order to clarify the role for gd T cells in the pathogenesis of chronic acquired PRCA, we have examined the gd T cell receptor repertoire in acquired chronic PRCA patients. Materials and Methods: Nineteen PRCA (8 idiopathic, 6 thymoma, 3 LGL-leukemia and 2 SLE) and 107 healthy volunteer donors were included in the study. This study was approved by the Institutional Review Board at Akita University and conducted in accordance with the Declaration of Helsinki. Blood lymphocyte subsets were analyzed by flow cytometry. Clonality of T cells was determined by complementarity-determining region 3 (CDR3) size distribution analysis and junctional sequence was determined by subcloning of PCR products and DNA sequencing. In some experiments, purified gd T cells from PRCA patients were co-cultured with allogeneic erythroid progenitor cells derived from CD34-positive cells in vitro in order to learn whether patient's gd T cells would exert cytotoxic or growth-inhibitory effect on erythroid progenitor cells. Results: The absolute numbers of ab T cells and gd T cells were normal in patients with PRCA, but there were an increase of Vd1 gd T cells and a decrease of Vd2 T cells (Table 1). More than 50% of Vd1 T cells from PRCA patients expressed HLA-DR, while 20 to 30% of those from healthy individuals expressed HLA-DR (Fig. 1). CDR3 size spectratyping revealed that CDR3 size distribution patterns were skewed in 9 out of 13 PRCA patients examined, although skewed CDR3 size distribution patterns were also observed in 7 out of 10 healthy individuals. In order to determine whether a particular Vd1-Jd rearrangement size was selected in PRCA patients, we performed statistical analysis comparing the CDR3 size distribution of 115 Vd1 TCR clones obtained by subcloning of PCR products in 7 PRCA patients versus 7 controls. No significant difference was found between the two groups (p=0.795 by Mann-Whitney test). Moreover, no apparent consensus amino acid motifs were identified in PRCA patients. Although the T cell clone carrying the -YWGIR- sequence in the CDR3d region was detected in 3 PRCA patients, the T cell clone carrying the -YWGIR- sequence was also detected in one healthy donor. Purified gdT lymphocytes from idiopathic PRCA neither showed an inhibitory effect on proliferation nor cytotoxicity against erythroid progenitor cells in vitro. Adjusted p value was calculated by Kruskal-Wallis ANOVA test. Conclusions: Expansion of Vd1 T cells and depletion of Vd2 T cells are unique features for chronic acquired PRCA. Expansion of Vd1 T cells does not seem to be the consequence of CDR3-dependent selection. Depletion of Vd2 T cells may be the result of chronic stimulation, because our previous study has revealed that the numbers of Vd2 T cells show an age-dependent decrease and Vd2 T cells are susceptible to activation-induced cell death (Int J Hematol, in press). Failure to demonstrate the cytotoxicity of gd T cells from a PRCA patient against erythroid progenitor cells suggests that expanded gd T cells are not effector T cells. Disclosures: No relevant conflicts of interest to declare.

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Li, Z., und Z. Jiao. „P61 Population pharmacokinetics of vancomycin in chinese ICU neonates: initial dosage recommendations“. Archives of Disease in Childhood 104, Nr. 6 (17.05.2019): e42.2-e42. http://dx.doi.org/10.1136/archdischild-2019-esdppp.99.

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The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population.1 2 The study population consisted of 80neonates in the neonatal intensive care unit (ICU)from which 165 trough and peak concentrations of vancomycin were obtained.Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin.4 The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errorsandthe bootstrap method.Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin.5 6 The average clearance was 0.309L/h for a neonate with Scr of 23.3mmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15mmol/L,current guideline recommendationswould likely not achieve therapeuticarea under the concentration-time curve over24 h/minimum inhibitoryconcentration (AUC24h/MIC) ≥ 400.3 The exceptions to this areBritish National Formulary (2016–2017), Blue Book (2016) and Neofax (2017). Recommended dose regimensfor neonates with differentScrlevelsandpostmenstrual ageswere estimatedbased on Monte Carlo simulations andthe established model.These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.ReferencesAbdel HO, Al OS, Nazer LH., Mubarak S, Le, J. Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients. Journal of Oncology Pharmacy Practice 2015;22(3):448–453doi: 10.1177/1078155215591386Anderson, B. J., Allegaert, K., Jn, V. D. A., Cossey, V., &Holford, N. H. ( 2007). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. British Journal of Clinical Pharmacolog;63(1):75–84. doi: 10.1111/j.1365-2125.2006.02725.xAllegaert K, Anderson BJ, Jn, VDA, Vanhaesebrouck, S., & De, Z. F. ( 2007). Renal drug clearance in preterm neonates: relation to prenatal growth. Therapeutic Drug Monitoring, 29(3), 284–291. doi: 10.1097/FTD.0b013e31806db3f5Byon, W., Smith, M. K., Chan, P., Tortorici, M. A., Riley, S., & Dai, H., et al. ( 2013). Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CptPharmacometrics & Systems Pharmacology,2(7), e51. doi: 10.1016/j.cmpb.2010.04.018Capparelli, E. V., Lane, F. R., Romanowski, G. L., Pharm, M. F., Murray, W., & Sousa, P., et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. Journal of Clinical Pharmacology, 41(9), 927–934.Centers for Disease Control and Prevention. ( 2009). WHO Child Growth Standards. http://www.who.int/childgrowth/en. [EB/OL] 2017-09-12Disclosure(s)Nothing to disclose

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Valiulis, Skirmundas Jonas. „Lietuvos fotožurnalistikos pradžia Europos kontekste“. Žurnalistikos Tyrimai 1 (01.01.2008): 143–53. http://dx.doi.org/10.15388/zt/jr.2008.1.89.

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Pirmasis fotožurnalistikos raidą Lietuvoje yra iš dalies apžvelgęs V. Juodakis knygoje „Lietuvos fotografijos istorija“ (iki 1940m.)1. Ši knyga skirta visos fotografijos istorijai, tad fotožurnalistika buvo analizuojama tik kaip vienas iš fotografijos plėtotės barų, glaustai ir eskiziškai, bet pasitelkus būtiniausius faktus, svarbiausius leidinius, aptarus fotožurnalistikos žanrus, parodžius kiekybišką augimą įvairiuose leidiniuose. V. Juodakis pirmasis plačiau įvedė XIX a. – XXa. pradžios Lietuvos fotografiją į tarptautinę erdvę Londone leidžiamame žurnale „Fotografijos istorija“2.Per atsikūrusios Lietuvos dešimtmetį pasirodė daug naujų mokslinių tyrimų, fotografijos istorijos knygų: „Vilniaus fotografija. 1858–1915“3, „Dagerotipai, ambrotipai, ferotipai Lietuvos muzie uose“4, „Czechowicz. XIXa. Vilniaus vaizdai“5, „Tyszkiewicz. Fotografijų albumas“6, J. Bulhak „Vilniaus barokas“7, A. Snitkuvienė „Raudondvaris. Grafai Tiškevičiai ir jų palikimas“8, „Lietuvos fotografija iki XXa.“9, Sk. Valiulio ir S. Žvirgždo „Fotografijos slėpiniai“10. Paraleliai suintensyvėjo to pačio laikotarpio, net tų pačių autorių tyrinėjimai Lenkijoje: „Žvilgsniai į Vilnių“ („Spojrzenia na Wilno“. Fotografia wileńska 1839–1939)11, „Vilnius ir Vilnija ant amžių sandūros Stanislovo Flerio fotografijose“ („Wilno i Wileńszczyzna na przełomie wieków w fotografii Stanisława Filiberta Fleury (1858–1915)“ ir kiti.12 Užsienyje padaugėjo mėginimų parašyti pasaulinę fotografijos istoriją:M. Frizot „Naujoji fotografijos istorija“ („The new history of photography“), Vokietija13, M. W. Marien „Fotografija. Ir kultūros istorija“ („Photography. A cultural history“)14. Daugėja atskirų kraštų istorijų iratskiriems autoriams ir periodams skirtų monografijų. Pasak M. Marien, „per kelis pastaruosius dešimtmečius fotografijos istorijos erdvė labai išsiplėtė, atsirado daug šviežios medžiagos, o nauji analizės būdai padėjo atsirasti gyvybingam interdisciplininių studijų laukui […] Menas, fotožurnalistika, socialinė dokumentika ir moksliškas žvilgsnis konverguoja, išblukina tradicinius apribojimus, skatina ir naują fotografijos praktiką“15. Nebepatenkina ir įsigalėjusi XX a. antroje pusėje tendencija į fotografijos istoriją žiūrėti vien menotyriniu žvilgsniu, dar papildant jos istoriją technikos ir technologijos kaitos apžvalga (žr. lietuviškai išleistą J. Jeffrey knygą „Fotografijos istorija“16 ar VDA išleistą „Lietuvos dailės istoriją“17). Toks vertinimų siaurumas knygoje „Fotografija. Istorijos krizė“18 vadinamas pačių fotografijos istorikų krize. Čia iškeliamas ir toliau tebevyraujantis anglo-amerikietiškasis centrizmas, nustumiantis į periferiją ištisus žemynusir regionus. Toks likimas ištiko ir Rytų Europą: jai nelengva prasiskinti kelią į globalinį fotografijos raidos kontekstą. Todėl minėto metodologinių fotografijos istorijos studijų rinkinio autoriai siūlo kitą kelią: pradėti nuo savo šalies ar platesnio regiono fotografijos istorijos tyrimo visais aspektais,bet paraleliai atsižvelgti į tarptautinį kontekstą.Bandydami taip pažvelgti į Lietuvos fotožurnalistikos raidą pamėginkime paanalizuoti porą jos paralelių su Europos fotožurnalistikos raida ir atsakyti į klausimus: 1) Kur yra fotožurnalistikos pradžia? 2) Kaip fotožurnalistika ateina į spaudą ir kokioje spaudoje ji geriausiai plėtoja savogalimybes?Esminiai žodžiai: fotožurnalistika, ištakos, iliustruota spauda, fotoreportažas.

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Astapova, Elena V., Max E. Stachura, Cynthia Chernecky und Marlene M. Rosenkoetter. „Low-End Videoconferencing for Vascular Access Device Site Assessment in Homecare“. Journal of the Association for Vascular Access 13, Nr. 3 (01.09.2008): 135–38. http://dx.doi.org/10.2309/java.13-3-6.

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Abstract Vascular access devices (VAD) represent high technology and are used frequently in infant, pediatric, adult, and geriatric populations for vascular infusion of chemotherapy, immunotherapy, blood products, biologic response modifiers, nutrition support, analgesics, ionotropics, antibiotics, and other medications, as well as for extraction of pleural fluid from patients with chronic effusions and for treatment with dialysis. Increasingly, these devices are migrating to the home setting as they are used in chronic care and as insurance requirements reduce access to prolonged hospital stays. Surveillance of infections in high risk patients such as those with cancer, cardiac conditions, or post-trauma convalescence is essential to avoid adverse events and to offer early treatment. VAD site and blood stream infections are common VAD complications, occurring in up to 50% of home care patients, usually during days 4–25 after hospital discharge. Our literature search for reports of remote home monitoring for support of VAD patients and their caregivers found none. The use of videoconferencing technology to assess VAD sites in the post-discharge environment would significantly enhance patient safety, facilitate continuity of care, and meet the Communicable Disease Center's stated need for the development of surveillance systems to monitor infections in home care settings. Low-cost Internet- or telephone-based videoconferencing technology that could be deployed easily and used during risk periods would be highly beneficial to patients and increase the cost-effective use of homecare nursing personnel. We report criteria-based protocols for remote assessment of VAD status, for monitoring VAD care procedures employed in the home, and for conducting VAD-care teaching of patients and their caregivers. In addition, we report an initial evaluation of the ability to assess VAD status using low-end videoconferencing technologies.

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Ranzoni, Carlo. „THE RIGHT TO EXAMINE WITNESSES UNDER ARTICLE 6 §§ 1 AND 3 (D) OF THE EUROPEAN CONVENTION ON HUMAN RIGHTS“. Visnyk of the Lviv University. Series Law, Nr. 67 (24.12.2018): 85–93. http://dx.doi.org/10.30970/vla.2018.67.085.

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Setiadi, D., P. M. Sarro und P. P. L. Regtien. „A 3 × 1 integrated pyroelectric sensor based on VDF/TrFE copolymer“. Sensors and Actuators A: Physical 52, Nr. 1-3 (März 1996): 103–9. http://dx.doi.org/10.1016/0924-4247(96)80133-6.

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Marwaha, Ramank K., M. K. Garg, Sushil Gupta, Mohd Ashraf Ganie, Nandita Gupta, Archna Narang, Manoj Shukla et al. „Association of insulin-like growth factor-1 and IGF binding protein-3 with 25-hydroxy vitamin D in pre-pubertal and adolescent Indian girls“. Journal of Pediatric Endocrinology and Metabolism 31, Nr. 3 (28.03.2018): 289–95. http://dx.doi.org/10.1515/jpem-2017-0275.

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AbstractBackground:There is a high prevalence of vitamin D deficiency (VDD) in India. Molecular mechanisms suggest a strong relationship between vitamin D and growth factors. However, there is a paucity of literature with regard to a relationship between insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) and vitamin D particularly in subjects with VDD. The objective of the study was to assess the relationship between growth factors and serum vitamin D-parathormone (PTH) status in school girls and study the impact of vitamin D supplementation on growth factors in pre-pubertal girls with VDD.Methods:Our study subjects were apparently healthy school girls aged 6–18 years. The baseline height, weight, body mass index (BMI), pubertal status, serum 25-hydroxy vitamin D (25OHD), PTH, IGF-1 and IGFBP-3 were assessed in 847 girls aged 6–18 years and in 190 pre-pubertal girls with VDD following supplementation.Results:The mean age, BMI and serum 25OHD of girls were 11.5±3.2 years, 18.7±4.8 kg/m2and 9.9±5.6 ng/mL, respectively. VDD was observed in 94.6% of girls. Unadjusted serum IGF-1 levels and IGF-1/IGFBP-3 molar ratio were significantly higher in girls with severe VDD as compared to girls with mild-to-moderate VDD. However, these differences disappeared when adjusted for age, height or sexual maturation. The serum IGF-1 and IGFBP-3 levels increased significantly post supplementation with vitamin D.Conclusions:There were no differences in serum IGF-1 levels and the IGF-1/IGFBP-3 molar ratio among VDD categories when adjusted for age, height and sexual maturation in girls. Vitamin D supplementation resulted in a significant increase in serum IGF-1 levels in VDD pre-pubertal girls.

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Grand, Beatriz, Jorge Solimano, Adriana Ventura, Ernesto Quiroga Micheo und Dardo Riveros. „Carotid and Vertebral Artery Dissection Syndromes.“ Blood 106, Nr. 11 (16.11.2005): 4145. http://dx.doi.org/10.1182/blood.v106.11.4145.4145.

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Abstract Objetives: To describe the clinical presentation, diagnosis and treatment of patients with carotid and vertebral artery dissection (CAD, VAD). Design: Retrospective, observational Patients and methods: Clinical recording were evaluated from 1996 to 2005; 6 patients (3 women, 3 men, mean age 37 years) with CAD (3) and VAD (3) were referred to our hematology unit. Clinical presentation: progressing stroke 4/6 and transient ischemic attack (TIA) 2/6; warning sings and symptoms preceding the onset of stroke in 80%. Vascular risk factors included smoking and hypertension; associated features were headache, visual symptoms and Horner’s syndrome; Predisposing factors as physical exercise and trauma were found in 4/6. One patient was at 20 weeks of pregnancy. Diagnosis: Diagnostic tests included: Doppler ultrasound, magnetic resonance imaging (MRI) and angiography (MRA). On admission angiographic studies showed occlusion or stenoses of dissected arteries. Treatment: Anticoagulation with heparin or low molecular weight heparin followed by oral anticoagulants. Outcome: No hemorrhagic complication, no recurrence, complete recovery in 5 patients and mild dysarthria in one. Conclusion: TIA and progressing stroke in young patients are presenting features of CAD and VAD. The diagnosis is based on clinical signs and confirming angiographic investigation. Our experience shows that anticoagulation is the treatment of choice, although controlled studies to show their effectiveness are lacking.

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Shibahara, Tomoya, Masahiro Yasaka, Yoshiyuki Wakugawa, Koichiro Maeda, Takeshi Uwatoko, Takahiro Kuwashiro, Gregory Y. H. Lip und Yasushi Okada. „Improvement and Aggravation of Spontaneous Unruptured Vertebral Artery Dissection“. Cerebrovascular Diseases Extra 7, Nr. 3 (17.10.2017): 153–64. http://dx.doi.org/10.1159/000481442.

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Background: Intracranial vertebral artery dissection (VAD) is a well-recognized cause of stroke in young and middle-aged individuals, especially in Asian populations. However, a long-term natural course remains unclear. We investigated the long-term time course of VAD using imaging findings to examine the rate and predisposing factors for improvement. Methods: We registered 56 consecutive patients (40 males; mean age, 51.8 ± 10.7 years) with acute spontaneous VAD and retrospectively investigated neuroimaging and clinical course within 1 month and at 3 months ± 2 weeks, 6 months ± 2 weeks, and 12 months ± 2 weeks after onset to ascertain predisposing factors and time course for improvement. Results: The most common presenting symptoms were headache and/or posterior neck pain, seen in 41 patients (73%). Magnetic resonance imaging showed brainstem and/or cerebellum infarction in only 32 patients (57%). Of the 56 VADs, 16 (28%) presented with pearl and string sign, 5 (9%) with pearl sign, 15 (27%) with string sign, and 20 (36%) with occlusion sign. VAD occurred on the dominant side in 20 patients and on the nondominant side in the other 36 patients. The pearl and string sign was more frequently noted on the dominant side than on the nondominant side (50 vs. 17%, p = 0.008). On the other hand, occlusion occurred more often on the nondominant side than on the dominant side (47 vs. 15%, p = 0.016). Furthermore, the pearl and string sign was more frequently seen in the improvement group (41 vs. 15%, p = 0.028), whereas the occlusion sign was evident more frequently in the nonimprovement group (21 vs. 52%, p = 0.015). Follow-up neuroimaging evaluation was performed at 1 and 3 months in 91% each, and at 6 and 12 months in 82% each. VAD aggravation was identified within 1 month after onset in 14%, while VAD improvement was seen in 14, 38, 50, and 52% at each period, mainly within 6 months after onset. Older patients and current smoking were negatively associated with VAD improvement. Conclusions: VAD improvement primarily occurs within 6 months after onset, and VAD aggravation within 1 month. It seems that older patients and current smoking are negative predictors of VAD improvement as risk factors, and as image findings, the pearl and string sign is a positive predictor and occlusion a negative predictor.

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Alaofè, Halimatou, Jennifer Burney, Rosamond Naylor und Douglas Taren. „Prevalence of anaemia, deficiencies of iron and vitamin A and their determinants in rural women and young children: a cross-sectional study in Kalalé district of northern Benin“. Public Health Nutrition 20, Nr. 7 (25.01.2017): 1203–13. http://dx.doi.org/10.1017/s1368980016003608.

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AbstractObjectiveTo identify the magnitude of anaemia and deficiencies of Fe (ID) and vitamin A (VAD) and their associated factors among rural women and children.DesignCross-sectional, comprising a household, health and nutrition survey and determination of Hb, biochemical (serum concentrations of ferritin, retinol, C-reactive protein and α1-acid glycoprotein) and anthropometric parameters. Multivariate logistic regression examined associations of various factors with anaemia and micronutrient deficiencies.SettingKalalé district, northern Benin.SubjectsMother–child pairs (n 767): non-pregnant women of reproductive age (15–49 years) and children 6–59 months old.ResultsIn women, the overall prevalence of anaemia, ID, Fe-deficiency anaemia (IDA) and VAD was 47·7, 18·3, 11·3 and 17·7 %, respectively. A similar pattern for anaemia (82·4 %), ID (23·6 %) and IDA (21·2 %) was observed among children, while VAD was greater at 33·6 %. Greater risk of anaemia, ID and VAD was found for low maternal education, maternal farming activity, maternal health status, low food diversity, lack of fruits and vegetables consumption, low protein foods consumption, high infection, anthropometric deficits, large family size, poor sanitary conditions and low socio-economic status. Strong differences were also observed by ethnicity, women’s group participation and source of information. Finally, age had a significant effect in children, with those aged 6–23 months having the highest risk for anaemia and those aged 12–23 months at risk for ID and IDA.ConclusionsAnaemia, ID and VAD were high among rural women and their children in northern Benin, although ID accounted for a small proportion of anaemia. Multicentre studies in various parts of the country are needed to substantiate the present results, so that appropriate and beneficial strategies for micronutrient supplementation and interventions to improve food diversity and quality can be planned.

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Chuk, M. K., F. M. Balis, C. Mackall, D. Hawkins, N. Avila, B. C. Widemann, L. J. Helman und E. Fox. „Radiographic tumor response in pediatric patients with newly diagnosed localized (LOC) or metastatic (MET) Ewing’s sarcoma (EWS) following neoadjuvant chemotherapy“. Journal of Clinical Oncology 25, Nr. 18_suppl (20.06.2007): 20008. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.20008.

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20008 Background: Standard treatment for EWS includes vincristine, doxorubicin, cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE). Using this therapy, overall survival is 70% in patients with LOC EWS and 30% in patients with MET EWS. We compared the radiographic response to VDC and IE in patients with LOC or MET EWS. Methods: We conducted a randomized trial comparing pegfilgrastim to filgrastim in patients treated with VDC (cycles 1, 2, 5, 9, 11, 13) and IE (cycles 3, 4, 6–8, 10, 12, 14). Local control with radiation or surgery was initiated after cycle 5. We assessed radiographic response after VDC (C1,2) and IE (C3,4) using 1-dimensional (RECIST) and 2-dimensional (WHO) criteria. Measurements were performed using MEDx. Results: Twenty-one patients with EWS, median age 20y (6–25y), were enrolled; 16 were evaluable for this analysis. Primary tumors were in extremity (n=5) or central axis (n=11). Eight patients had MET disease (pulmonary only, n=4). Median (range) decrease in tumor size by WHO after C4 was 61% (40–92%) for LOC and 83% (47–94%) for MET. Decrease by treatment is presented in the table . Overall responses after 4 cycles for LOC patients were 5 PR, 3 SD using RECIST, and 6 PR, 2 SD using WHO. For MET patients, overall responses were the same using RECIST and WHO, 7 PR, and 1SD. Conclusion: Patients with MET EWS responded as well as those with LOC EWS after 4 cycles of neoadjuvant chemotherapy. Similar overall response was demonstrated using RECIST or WHO. Tumor response after VDC was greater than after IE, possibly due to sequence of administration, but patients had continued tumor response with IE. [Table: see text] No significant financial relationships to disclose.

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Meng, Deng-Hong, Ying Zhang, Shuang-Shuang Ma, Hong-Lin Hu, Jing-Jing Li, Wan-Jun Yin, Rui-Xue Tao und Peng Zhu. „The role of parathyroid hormone during pregnancy on the relationship between maternal vitamin D deficiency and fetal growth restriction: a prospective birth cohort study“. British Journal of Nutrition 124, Nr. 4 (26.03.2020): 432–39. http://dx.doi.org/10.1017/s0007114520001105.

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AbstractPrevious studies have shown conflicting findings regarding the relationship between maternal vitamin D deficiency (VDD) and fetal growth restriction (FGR). We hypothesised that parathyroid hormone (PTH) may be an underlying factor relevant to this potential association. In a prospective birth cohort study, descriptive statistics were evaluated for the demographic characteristics of 3407 pregnancies in the second trimester from three antenatal clinics in Hefei, China. The association of the combined status of vitamin D and PTH with birth weight and the risk of small for gestational age (SGA) was assessed by a multivariate linear and binary logistic regression. We found that declined status of 25-hydroxyvitamin D is associated with lower birth weight (for moderate VDD: adjusted β = −49·4 g, 95 % CI −91·1, −7·8, P < 0·05; for severe VDD: adjusted β = −79·8 g, 95 % CI −127·2, −32·5, P < 0·01), as well as ascended levels of PTH (for elevated PTH: adjusted β = −44·5 g, 95 % CI −82·6, −6·4, P < 0·05). Compared with the non-VDD group with non-elevated PTH, pregnancies with severe VDD and elevated PTH had the lowest neonatal birth weight (adjusted β = −124·7 g, 95 % CI −194·6, −54·8, P < 0·001) and the highest risk of SGA (adjusted risk ratio (RR) = 3·36, 95 % CI 1·41, 8·03, P < 0·01). Notably, the highest risk of less Ca supplementation was founded in severe VDD group with elevated PTH (adjusted RR = 4·67, 95 % CI 2·78, 7·85, P < 0·001). In conclusion, elevated PTH induced by less Ca supplementation would further aggravate the risk of FGR in pregnancies with severe VDD through impaired maternal Ca metabolism homoeostasis.

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Mologni, Luca, Isabella Ponzanelli, Filippo Bresciani, Gabriele Sardiello, Daniele Bergamaschi, Maurizio Giannı́, Uwe Reichert, Alessandro Rambaldi, Mineko Terao und Enrico Garattini. „The Novel Synthetic Retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437) Causes Apoptosis in Acute Promyelocytic Leukemia Cells Through Rapid Activation of Caspases“. Blood 93, Nr. 3 (01.02.1999): 1045–61. http://dx.doi.org/10.1182/blood.v93.3.1045.

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Abstract The synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which was originally developed as an retinoic acid receptor (RAR)-γ agonist, induces rapid apoptosis in all-trans retinoic acid (ATRA)-sensitive and ATRA-resistant clones of the NB4 cell line, a widely used experimental model of acute promyelocytic leukemia (APL). In addition, the compound is apoptogenic in primary cultures of freshly isolated APL blasts obtained from a newly diagnosed case and an ATRA-resistant relapsed patient. NB4 cells in the S-phase of the cycle are most sensitive to CD437-triggered apoptosis. CD437-dependent apoptosis does not require de novo protein synthesis and activation of RAR-γ or any of the other nuclear retinoic acid receptors. The process is preceded by rapid activation of a caspase-like enzymatic activity capable of cleaving the fluorogenic DEVD but not the fluorogenic YVAD tetrapeptide. Increased caspase activity correlates with caspase-3 and caspase-7 activation. Inhibition of caspases by z-VAD suppresses the nuclear DNA degradation observed in NB4 cells treated with CD437, as well as the degradation of pro–caspase-3 and pro–caspase-7. CD437-dependent activation of caspases is preceded by release of cytochrome c from the mitochondria into the cytosol of treated cells. Leakage of cytochrome c lays upstream of caspase activation, because the phenomenon is left unaffected by pretreatment of NB4 cells with z-VAD. Treatment of APL cells with CD437 is associated with a caspase-dependent degradation of promyelocytic leukemia-RAR-, which can be completely inhibited by z-VAD.

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Mologni, Luca, Isabella Ponzanelli, Filippo Bresciani, Gabriele Sardiello, Daniele Bergamaschi, Maurizio Giannı́, Uwe Reichert, Alessandro Rambaldi, Mineko Terao und Enrico Garattini. „The Novel Synthetic Retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437) Causes Apoptosis in Acute Promyelocytic Leukemia Cells Through Rapid Activation of Caspases“. Blood 93, Nr. 3 (01.02.1999): 1045–61. http://dx.doi.org/10.1182/blood.v93.3.1045.403k22_1045_1061.

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The synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which was originally developed as an retinoic acid receptor (RAR)-γ agonist, induces rapid apoptosis in all-trans retinoic acid (ATRA)-sensitive and ATRA-resistant clones of the NB4 cell line, a widely used experimental model of acute promyelocytic leukemia (APL). In addition, the compound is apoptogenic in primary cultures of freshly isolated APL blasts obtained from a newly diagnosed case and an ATRA-resistant relapsed patient. NB4 cells in the S-phase of the cycle are most sensitive to CD437-triggered apoptosis. CD437-dependent apoptosis does not require de novo protein synthesis and activation of RAR-γ or any of the other nuclear retinoic acid receptors. The process is preceded by rapid activation of a caspase-like enzymatic activity capable of cleaving the fluorogenic DEVD but not the fluorogenic YVAD tetrapeptide. Increased caspase activity correlates with caspase-3 and caspase-7 activation. Inhibition of caspases by z-VAD suppresses the nuclear DNA degradation observed in NB4 cells treated with CD437, as well as the degradation of pro–caspase-3 and pro–caspase-7. CD437-dependent activation of caspases is preceded by release of cytochrome c from the mitochondria into the cytosol of treated cells. Leakage of cytochrome c lays upstream of caspase activation, because the phenomenon is left unaffected by pretreatment of NB4 cells with z-VAD. Treatment of APL cells with CD437 is associated with a caspase-dependent degradation of promyelocytic leukemia-RAR-, which can be completely inhibited by z-VAD.

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Jakubowiak, Andrzej, Tara Kendall, Ammar Al-Zoubi, Yasser Khaled, Shin Mineishi, Christine Brozo, Erica Campagnaro, Moshe Talpaz und Mark S. Kaminski. „Initial Treatment with Bortezomib (Velcade®), Doxil®, and Dexamethasone (VDD) Is Superior to Thalidomide and Dexamethasone (TD) as Initial Therapy Prior to Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma (MM)“. Blood 112, Nr. 11 (16.11.2008): 3713. http://dx.doi.org/10.1182/blood.v112.11.3713.3713.

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Abstract A number of novel combinations used in initial therapy of myeloma show improved overall response (OS) and complete and near complete response (CR/nCR) rates. However, it is not clear if improved responses impact the results after the subsequent ASCT and the overall outcome of MM therapy. To address this issue, we performed a retrospective analysis of patients with symptomatic myeloma who were initially treated with TD (N= 31) or VDD (N =30) followed by ASCT, as part of 2 consecutive clinical studies conducted at the University of Michigan Cancer Center. From July 2003 to May 2005, 31 pts were enrolled in a phase II study of treatment of newly diagnosed myeloma with initial therapy using three 5-week cycles of TD. Thalidomide was given daily starting at 50 mg/d up to 400 mg/d and dexamethasone at 40 mg on days 1–4, 9–12, and 17–20. The outcomes were compared with 30 pts who were enrolled from July 2005 to January 2007 in a phase II trial of initial therapy with six 3-week cycles of VDD regimen. VDD included Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg on days 1–4 in the first 10 pts and 40 mg (cycle 1) then 20 mg (cycle 2–6) Dexamethasone on days of Velcade and the day after in the remaining patients. There were no significant differences in eligibility criteria between both studies. The characteristics of pts in the TD vs. VDD trial were as follows: median age 57 (26–65) vs. 58 (38–71), stage III in 23 vs. 27 pts, ch13 del in 12 vs. 13 pts, and median beta2-microglobulin 3.1 vs. 4.6. Best response to initial therapy (≥PR by modified EBMT criteria) was observed in 80% of pts treated with TD vs. 93% with VDD, CR/nCR in 10% treated with TD vs. 40% with VDD, ≥ very good partial response (VGPR) in 29% treated with TD vs. 63% with VDD (P < 0.01). Grade 3–4 toxicities related to TD included DVT/PE in 5 pts, constipation in 2, CHF in 2, and diabetes in 2. Three pts were removed from the TD study due to toxicities, and 1 died of unexplained cause. Grade 3–4 toxicities during VDD therapy included 4 pts with fatigue, 2 with DVT/PE, 2 with hand-foot syndrome, 1 with pneumonia. There was no death on VDD therapy. In the TD group, 27/27 patients collected median 8.8 × 106 CD34+ cell/kg and 27 completed at least a single ASCT (21 tandem, 6 single). In VDD group, 30/30 collected median 7.5 × 106 CD34+ cell/kg and 28 completed at least a single ASCT (17 tandem, 12 single, 1 single then reduced intensity allo). For pts initially treated with TD, 74 % achieved ≥PR, 48% ≥VGPR and 29% CR/nCR at 3 months after the completion of ASCT. For patients initially treated with VDD, response rates at 3 months post transplant were significantly better with ≥PR in 87%, ≥VGPR in 77%, and CR/nCR in 57% of pts (P ≤ 0.01). After a median follow-up of 49.75 (TD) and 23.8 (VDD) months, progression-free survival (PFS) is 27 months in TD group and not reached in VDD group, with 2 year PFS 53% in TD group and 83% in VDD group (P < 0.01). OS is not reached in both groups with 2 year OS slightly better (NS) in VDD (92%) compared to TD (85%). Based on these observations, it appears that high CR/nCR and VGPR rates in response to initial treatment with VDD persist post transplant, resulting in an improved probability of longer progression-free survival and possibly overall survival. Updated survival curves will be presented at the meeting.

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Kim, Chul Soo, Moon Hee Lee, Inho Kim, Yeonsook Moon, Chung Hyun Nahm, Hun Chung Kim, Woo Cheol Kim und John J. K. Loh. „Combination Chemotherapy Using Cyclophosphamide and High Dose Dexamethasone with or without Radiotherapy for the Treatment of Multiple Myeloma.“ Blood 106, Nr. 11 (16.11.2005): 5168. http://dx.doi.org/10.1182/blood.v106.11.5168.5168.

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Abstract Forty two people (men 22, women 20) diagnosed as Durie-Salmon stage IIIA or B multiple myeloma were treated with a combination chemotherapy consisting of cyclophosphamide at 400mg and dexamethasone at 40mg (CHD) regardless of body surface for 4 or 5 consecutive days every 3 or 4 weeks from August 1996 through July 2005. The treatment was repeated as long as the patient could tolerate or until disease progressed. The chemotherapy was given to 36 chemo-naïve patients as primary therapy and to 6 patients exposed to VAD (vincristine, doxorubicin, dexamethasone) as salvage therapy. Palliative loco-regional radiotherapy was also given to 20 of 44 patients. A total of 433 cycles (mean 10.3, range 2~28 per individual) of chemotherapy were given and the response evaluation was made in accordance to the criteria of Dr. Blade. SD (stable disease) was defined as reduction or increase of myeloma protein within 25%. Six of 36 chemo-naïve patients who did not respond to CHD received salvage therapy consisting of VAD or MP (melphalan plus prednisone). Eleven patients (26%) attained CR (complete remission) at a median of 7 cycles (range 4~10), 15 (36%) achieved PR (partial remission) at a median of 3 cycles (range 2~16), 12 (28%) stayed at SD, and 4 patients (10%) showed PD (progressive disease). The measurement of survival duration was started at the beginning of the CHD chemotherapy. The measurement was censored in 6 patients at the time of stem cell transplant, 5 autologous (one was disease free at 108 months after transplant), and 1 allogeneic. On a mean follow-up period of 15.1 months (range 3~59), 15 people remained alive at 3, 3, 3, 4, 6, 6, 8, 10, 14, 15, 16, 16, 16, 26, and 37 months. The mean response duration and OS (overall survival) of the patients who entered CR were 7 (range 2~18) and 31.3 (range 6+~59) months respectively. The correspondent durations of the patients in PR were 7.9 (range 2+~28) and 15 (range 3+~37+). The corresponding durations of the patients in SD were 8.3 (range 2~26) and 13.5 (3+~48). The mean OS duration of the patients in PD was 5.3 (range 3~8). The difference in OS durations between patients in PR and those in SD was not statistically meaningful. Five of 6 patients exposed to VAD responded to CHD, whereas one of 5 patients exposed to CHD did to VAD. Two of 4 patient exposed to CHD responded to MP. Adverse effect was minimal with non-fatal events including 5 febrile episodes of unknown origin, 3 cases of pneumonia, 2 cases of urinary tract infection, 1 case of peritonitis, 1 case of herpes zoster, and 1 case of intractable nausea during the 433 chemotherapy courses. There were 2 cases of fatal septicemia and 1 case of fatal pneumonia during the period. CHD combination chemotherapy seems an active and less toxic regimen in the treatment of multiple myeloma.

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Meerbach, A., A. Holý, P. Wutzler, E. De Clercq und J. Neyts. „Inhibitory Effects of Novel Nucleoside and Nucleotide Analogues on Epstein—Barr Virus Replication“. Antiviral Chemistry and Chemotherapy 9, Nr. 3 (Juni 1998): 275–82. http://dx.doi.org/10.1177/095632029800900309.

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The anti-Epstein–Barr virus (EBV) activity of different classes of compounds was assessed by means of an EBV DNA hybridization assay using a digoxigenin-labelled probe specific for the BamHI W fragment of the EBV genome, as well as by measuring viral capsid antigen (VCA) expression after a 7 day incubation period of P3HR-1 producer cells with the test substances. Acyclovir, ganciclovir, cidofovir and zidovudine were included as reference compounds. Several compounds proved to be potent and selective inhibitors of EBV DNA synthesis and VCA expression. Of the new compounds that were evaluated for their anti-EBV activity, the highest efficacy (lowest EC50) and highest selectivity index (SI) were shown by the purine nucleoside analogue 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine (S2242) (EC50 0.6 ng/ml; SI 600), the acyclic nucleoside phosphonate analogues 9-(2-phosphonomethoxyethyl)-6-dimethylaminopurine (EC50 1.1 μg/ml; SI 91), 9-(2-phosphonomethoxyethyl)-2-amino-6-benzhydrylaminopurine (EC501.3 μg/ml; SI 29), 7-(2-phosphonomethoxyethyl)-6-dimethylaminopurine (EC50 0.8 μg/ml; SI 56), 9-( R)-(2-phosphonomethoxypropyl)-6-(2-dimethylaminoethyl)-aminopurine (EC50 0.5 μg/ml; SI 42), the 2′,3′-dideoxythymidine derivative 3′-oximino-2′,3′-dideoxythymidine (EC501.5 μg/ml; SI 65), and 1-(2,3-dideoxy-3- N-hydroxyamino-β-d-threo-pentafuran yl)pentafuranosyl)thymine (EC50 4.1 μg/ml; SI >24).

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Laxmaiah, Avula, Madhavan K. Nair, Nimmathota Arlappa, Pullakhandam Raghu, Nagalla Balakrishna, Kodavanti Mallikharjuna Rao, Chitty Galreddy et al. „Prevalence of ocular signs and subclinical vitamin A deficiency and its determinants among rural pre-school children in India“. Public Health Nutrition 15, Nr. 4 (02.09.2011): 568–77. http://dx.doi.org/10.1017/s136898001100214x.

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AbstractObjectiveTo assess the magnitude and determinants of vitamin A deficiency (VAD) and coverage of vitamin A supplementation (VAS) among pre-school children.DesignA community-based cross-sectional study was carried out by adopting a multistage, stratified, random sampling procedure.SettingRural areas of eight states in India.SubjectsPre-school children and their mothers were covered.ResultsA total of 71 591 pre-school children were clinically examined for ocular signs of VAD. Serum retinol concentrations in dried blood spots were assessed in a sub-sample of 3954 children using HPLC. The prevalence of Bitot spots was 0·8 %. The total ocular signs were significantly higher (P < 0·001) among boys (2·6 %) compared with girls (1·9 %) and in older children (3–4 years) compared (P < 0·001) with younger (1–2 years), and were also high in children of labourers, scheduled castes and illiterate mothers. The odds of having Bitot spots was highest in children of scheduled caste (OR = 3·8; 95 % CI 2·9, 5·0), labourers (OR = 2·9; 95 % CI 2·1, 3·9), illiterate mothers (OR = 2·7; 95 % CI 2·2, 2·3) and households without a sanitary latrine (OR = 5·9; 95 % CI 4·0, 8·7). Subclinical VAD (serum retinol level <20 μg/dl) was observed in 62 % of children. This was also relatively high among scheduled caste and scheduled tribe children. The rate of coverage of VAS was 58 %.ConclusionsThe study revealed that VAD is a major nutritional problem and coverage of VAS was poor. The important determinants of VAD were illiteracy, low socio-economic status, occupation and poor sanitation. Strengthening the existing VAS programme and focused attention on dietary diversification are essential for prevention of VAD.

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Oliveira, Cristieli SM, Patrícia Sampaio, Pascoal T. Muniz und Marly A. Cardoso. „Multiple micronutrients in powder delivered through primary health care reduce iron and vitamin A deficiencies in young Amazonian children“. Public Health Nutrition 19, Nr. 16 (30.05.2016): 3039–47. http://dx.doi.org/10.1017/s1368980016001294.

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AbstractObjectiveWe evaluated the effect of home fortification with multiple micronutrient powder (MNP) on anaemia and micronutrient status of young Amazonian children.DesignA pragmatic controlled trial was performed. A control group (CG) of children aged 11–14 months was recruited in the routine of primary health-care centres for assessing anaemia and micronutrient status. At the same time, an intervention group (IG) of infants aged 6–8 months was recruited in the same health centres to receive MNP daily in complementary feeding for 2 months. The IG children were assessed 4–6 months after enrolment (n112) when they had reached the age of the CG participants (n128) for comparisons.SettingPrimary health centres in Rio Branco city, Brazilian Amazon.SubjectsA total of 240 children aged<2 years.ResultsIn the CG, the prevalence of anaemia (Hb<110 g/l), iron deficiency (ID; plasma ferritin <12 μg/l or soluble transferrin receptor >8·3 mg/l) and vitamin A deficiency (VAD; serum retinol <0·70 μmol/l) was 20·3 %, 72·4 % and 18·6 %, respectively. Among the IG participants (aged 11–14 months), the prevalence of anaemia, ID and VAD was 15·2 %, 25·2 % and 4·7 %, respectively. The IG had a lower likelihood of ID (prevalence ratio (95 % CI): 0·34 (0·24, 0·49)) and VAD (0·25 (0·09, 0·64)).ConclusionsHome fortification of complementary feeding delivered through primary health care was effective in reducing iron and vitamin A deficiencies among young Amazonian children.

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Kanitakis, Jean, Palmina Petruzzo, Aram Gazarian, Sylvie Testelin, Bernard Devauchelle, Lionel Badet, Jean-Michel Dubernard und Emmanuel Morelon. „Premalignant and Malignant Skin Lesions in Two Recipients of Vascularized Composite Tissue Allografts (Face, Hands)“. Case Reports in Transplantation 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/356459.

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Recipients of solid organ transplants (RSOT) have a highly increased risk for developing cutaneous premalignant and malignant lesions, favored by the lifelong immunosuppression. Vascularized composite tissue allografts (VCA) have been introduced recently, and relevant data are sparse. Two patients with skin cancers (one with basal cell carcinoma and one with squamous cell carcinomas) have been so far reported in this patient group. Since 2000 we have been following 9 recipients of VCA (3 face, 6 bilateral hands) for the development of rejection and complications of the immunosuppressive treatment. Among the 9 patients, one face-grafted recipient was diagnosed with nodular-pigmented basal cell carcinoma of her own facial skin 6 years after graft, and one patient with double hand allografts developed disseminated superficial actinic porokeratosis, a potentially premalignant dermatosis, on her skin of the arm and legs. Similar to RSOT, recipients of VCA are prone to develop cutaneous premalignant and malignant lesions. Prevention should be applied through sun-protective measures, regular skin examination, and early treatment of premalignant lesions.

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Sandra, Ferry, Karina Febriani Hudono, Amelia Astriani Putri und Chantika Amardhia Paramita Putri. „Caspase Inhibitor Diminishes Caffeic Acid-induced Apoptosis in Osteosarcoma Cells“. Indonesian Biomedical Journal 9, Nr. 3 (01.12.2017): 160. http://dx.doi.org/10.18585/inabj.v9i3.334.

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BACKGROUND: Caffeic acid has been shown to induce apoptosis in MG63 osteosarcoma cells. Along with the apoptotic induction, caffeic acid was shown to activate caspase-8, -9 and -3. However, the role of caspase in mediating caffeic acid-induced apoptosis in MG63 cells are not clear yet. In this study, caspase role was further investigated by inhibiting caspase activity in the caffeic acid-induced apoptosis system in the MG63 cells.METHODS: MG63 cells were cultured, starved, pretreated with/without Z-VAD FMK and treated with/without 10 µg/mL caffeic acid. To quantify the number of apoptotic MG63 cells, Sub-G1 method was performed. The caffeic acid-induced apoptotic morphology was confirmed with 4',6-diamidino-2-phenylindole (DAPI) staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Meanwhile, to detect apoptotic underlying mechanism, immunoblotting was performed to detect caspase-8, -9 and -3.RESULTS: MG63 cells were significantly induced into apoptosis with the treatment of 10 µg/mL caffeic acid for 48 hours. However, pretreatment of 100 µM Z-VAD-FMK, a pan caspase inhibitor, for 2 hours, the percentage of apoptotic MG63 cells was significantly diminished. The apoptotic phenomenon induced by caffeic acid as well as the inhibition of Z-VAD-FMK were confirmed by DAPI staining and TUNEL assay. Cleaved caspase-8, -9 and -3 were formed markedly upon the treatment of caffeic acid. Pretreatment of 100 µM Z-VAD-FMK could inhibit the cleaved caspase-8, -9 and -3.CONCLUSION: Taken together, caffeic acid has the potential to induce apoptosis in MG63 cells, specifically through the caspase signaling pathway.KEYWORDS: caffeic acid, apoptosis, MG63, caspase, Z-VAD FMK

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Kumar, Shaji, Ian W. Flinn, Paul G. Richardson, Parameswaran Hari, Natalie Scott Callander, Stephen J. Noga, A. Keith Stewart et al. „Novel Three- and Four-Drug Combination Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously Untreated Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study“. Blood 116, Nr. 21 (19.11.2010): 621. http://dx.doi.org/10.1182/blood.v116.21.621.621.

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Abstract Abstract 621 Background: Two- and three-drug regimens incorporating bortezomib (Velcade®, V), lenalidomide (Revlimid®, R), dexamethasone (D), or cyclophosphamide (C) have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining all four drugs in a single regimen (VDCR) may further enhance efficacy. Published results from the phase 1 dose-escalation portion of the non-comparative, multi-center EVOLUTION study showed that the VDCR regimen was highly active and generally well tolerated (Kumar et al Leukemia 2010). Here we present updated results from the phase 2 portion of the trial, focusing on efficacy and safety of the VDCR, VDR, and VDC regimens. Methods: Previously untreated patients with measurable disease were randomized to one of four treatment groups receiving up to eight 21-d cycles of VDCR (V 1.3 mg/m2 d 1, 4, 8, 11; D 40 mg d 1, 8, 15; R 15 mg d 1–14; C 500 mg/m2 d 1, 8), VDR (VD as in VDCR but with R 25 mg d 1–14), VDC (VDC as in VDCR), or VDC-mod (as for VDC but with an additional dose of C on d 15) as induction therapy, followed by four 42-d maintenance cycles of V 1.3 mg/m2 (d 1, 8, 15, 22) (all treatment arms). Patients eligible for autologous stem cell transplant (SCT) could undergo stem cell mobilization any time after cycle 2 and SCT any time after cycle 4. The primary endpoint was the combined complete response (CR) + very good partial response (VGPR) rate; secondary endpoints included safety/tolerability, time to response, duration of response, progression-free survival, and rate of minimal residual disease (MRD) negativity. Responses were assessed according to International Myeloma Working Group (IMWG) uniform criteria using an automated computer algorithm. Adverse events (AEs) were graded using the CTCAE v3.0. Results: Patient characteristics were similar among the groups with respect to age, performance status, ISS stage, and proportion of patients with high-risk cytogenetic features. Patients received a median of 5, 6, 6, and 6 treatment cycles in the VDCR, VDR, VDC, and VDC-mod arms, respectively; 65%, 60%, 52%, and 47% of patients had dose reductions of any drug. In the VDCR, VDR, VDC, and VDC-mod arms, respectively, 52%, 62%, 58%, and 65% of patients completed treatment; 31%, 43%, 24%, and 41%, respectively, underwent SCT. In the phase 2 response-evaluable patients (n=132), all treatment regimens showed substantial efficacy, with CR+VGPR rates of 59% (VDCR), 50% (VDR), 41% (VDC), and 59% (VDC-mod) (Table) (includes pre-transplant responses only in SCT patients). Of MRD-assessed patients, 46% (21/46) of those who achieved CR (including sCR) or nCR were MRD-negative; 48% (10/21), 75% (9/12), 0% (0/7) and 33% (2/6) in the VDCR, VDR, VDC and VDC-mod arms, respectively. Median time to first response was similar across arms (range 1.6–1.8 months); median time to best response of CR+VGPR was 4.0 months (VDCR), 3.4 months (VDR), 5.1 months (VDC), and 3.1 months (VDC-mod). Median duration of response has not been reached in any arm to date. All treatment regimens were generally well tolerated. In the VDCR, VDR, VDC, and VDC-mod arms, at least one grade ≥3 AE was observed in 81%, 76%, 79%, and 88% of enrolled patients, respectively; serious AEs were experienced by 42%, 40%, 21%, and 41% of patients, and AEs resulting in study discontinuation were reported for 19%, 17%, 12%, and 6% of patients. The five most common all-grade AEs across all treatment groups were fatigue (range 47–67%), nausea (36–67%), constipation (40–62%), diarrhea NOS (42–65%), and neutropenia (19–52%). The incidence of grade ≥3 (grade ≥2) peripheral neuropathy (PN) was 13% (40%) in the VDCR arm, 14% (45%) VDR, 9% (48%) VDC, and 18% (41%) VDC-mod; there was no grade 4 PN. Rates of grade ≥3 neutropenia/thrombocytopenia were 42%/10% for VDCR, 7%/7% VDR, 36%/12% VDC, and 65%/18% VDC-mod. Conclusions: All regimens appear highly active and generally well tolerated in previously untreated MM patients. The four-drug combination did not result in a substantial increase in response rate and was associated with a modest increase in the incidence of hematologic toxicities. Continuous weekly C in the VDC regimen was associated with high response rates and rapid responses, comparable to the VDR and VDCR arms. Outcome data will be presented following longer follow-up. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Richardson:Celgene, Millennium, Novartis, Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Research Funding. Callander:Millennium Pharmaceuticals, Inc.: Research Funding. Noga:Amgen: Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ortho-Centicor: Honoraria, Speakers Bureau; Cephalon: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Stewart:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding; Celgene: Honoraria. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Wolf:Millennium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Genentech and Multiple Myeloma Research: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; OrthoBiotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Estevam:Millennium Pharmaceuticals: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals: Employment. Webb:Millennium Pharmaceuticals: Employment.

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Jakubowiak, Andrzej J., Lindsey Brackett, Tara Kendall, Judah Friedman und Mark S. Kaminski. „Combination Therapy with Velcade, Doxil, and Dexamethasone (VDD) for Patients with Relapsed/Refractory Multiple Myeloma (MM).“ Blood 106, Nr. 11 (16.11.2005): 5179. http://dx.doi.org/10.1182/blood.v106.11.5179.5179.

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Abstract Background: Combination regimens with Velcade demonstrate high activity in both relapsed/refractory and newly diagnosed MM, including higher than previously observed rates of complete responses (CR) and near complete responses (nCR). In this study, we evaluated the activity of a combination of Velcade, Doxil, and Dexamethasone (VDD) in relapsed/refractory MM. The rationale for combining these 3 agents was provided in pre-clinical studies which showed that Velcade can synergize with DNA-damaging agents via caspase-8 pathway and with Dexamethasone via caspase-9 pathway. In addition, prior clinical studies showed that combinations of Velcade with either Doxil or dexamethasone are well tolerated and more active than Velcade alone. The primary objective of the study was to assess the overall response to VDD and to estimate whether this combination can improve the rate of CR and nCR. Methods: The trial opened in November 2004 with target accrual of 30 patients. EBMT criteria were used for evaluation of response and nCR was defined as M-protein reduced to a level detectable by only immunofixation. The regimen in both relapsed/refractory and frontline trials was given as follows: Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg orally on days 1–4. VDD was repeated every 3 weeks for a total of 6 cycles. After the completion of 6 cycles, patients in the relapsed/refractory trial were maintained on Velcade weekly and Dexamethasone on days 1–4 in 5-week cycles. Results: To date, 20 pts have been enrolled, 18 of whom are presently evaluable for response after receiving a mean of 3.6 cycles (range 1–6). The characteristics of the evaluable patients included the following: median age 62 (range 39–78), 1–5 prior lines of therapy, single autologous stem cell transplant in 14 patients, tandem transplant in 1 patient, allogeneic transplant in 1 patient, chromosome 13 deletion in 5 patients. Complete or near complete responses (CR + nCR) have been observed in 6 patients (33%), very good partial response and partial response (VGPR + PR) in 4 patients (22%) and minor response in 5 patients (28%) for an overall response (CR, nCR, VGPR, PR, MR) of 83%. One patient achieved stable disease and two progressed (11%). Of the 14 patients who achieved response, 8 continue treatment, 3 are in remission off therapy (2 in nCR and 1 in PR), 2 relapsed, and 1 died of pneumonitis during therapy. Grade 3 and 4 toxicities were mostly related to cytopenias (thrombocytopenia in 7 patients, neutropenia in 7 patients, pneumonitis in 5 patients) and occurred among patients who had baseline cytopenia at study entry. The most common grade 1 and 2 toxicities included fatigue, neuropathy, diarrhea, neutropenia, and thrombocytopenia. Conclusion: VDD combination shows promising overall activity and rate of CR and nCR and appears well tolerated. Based on these preliminary results, we have activated frontline VDD trial with 6 patients enrolled to date.

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Gramberg, U. „Dünnschichttechnologien. Verfahren, Trends. Chancen. Hrsg.:VDI-Technologiezentrum Physikalische Technologien. 82 S.; 43 Abb., 6 Tab., DIN A5. VDI-Verlag, Düsseldorf 1991. Br. DM 20,-. ISBN 3-18-401172-0“. Materials and Corrosion 43, Nr. 7 (Juli 1992): 380. http://dx.doi.org/10.1002/maco.19920430715.

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Yoon, Sung-Soo, Hye Jin Kim, Dong Soon Lee, Hyeon Seok Eom, Jun Ho Jang, Ju Seup Chung, Hye Jin Kang et al. „Sequential VAD (Vincristine, Adriamycin, Dexamethasone) and VTD (VELCADE®, Thalidomide, Dexamethasone) Induction Followed by High-Dose Therapy with Autologous Stem Cell Transplantation and Maintenance Treatment with VELCADE for Newly Diagnosed Multiple Myeloma: Interim Results of Phase II Trial.“ Blood 110, Nr. 11 (16.11.2007): 952. http://dx.doi.org/10.1182/blood.v110.11.952.952.

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Abstract Introduction Effective reduction of myeloma before autologous stem cell transplantation (ASCT) prolongs survival in multiple myeloma patients. Recently, incorporation of novel agents resulted in improved response rate and reduced side effect in newly diagnosed multiple myeloma. Method: Patients are planned to receive 2 cycles of VAD (vincristine 0.4mg D1-4, adriamycin 9mg/m2 D1-4, dexamethasone 40mg D1-4, 9–12 every 3 weeks), and VTD (bortezomib 1.3mg/m2 D1, 4, 8, 11, thalidomide 100mg daily, dexamethasone 40mg D1-4, 9–12 every 3 weeks). High dose melphalan (200mg/m2) is used as a conditioning regimen for ASCT. Bortezomib (1.3mg/m2) as a maintenance treatment is administered weekly x 4 times every 6 weeks for 4 cycles after ASCT. Response was assessed by EBMT criteria, with additional category of nCR. Adverse events were graded by the NCI-CTCAE, Version 3.0. Result: At this interim analysis, 60 patients have been entered into the ongoing trial, and efficacy could be assessed in 53 patients. After 2 cycles of VAD, response rate was 70%. After VTD, two patients showed further improvement with additional CR, and an overall response was 97% with 14% CR. Especially, patients with poor prognostic cytogenetics (n=6) all responded after VTD. So far, autologous stem cells were successfully collected in all 28 patients with a median CD34+ count of 7.8 x 106/kg (range, 2.17–44.7 x 106/kg). In 24 patients who underwent autologous stem cell transplantation, five patients gained additional CR. There was no progression in patients completed bortezomib maintenance (n=9, CR 77%). The median follow-up duration was 6 months, median time to response was 1.4 months, and median overall survival was not reached. Grade 3,4 hematologic toxicity was more frequently observed after VAD than VTD (anemia 15.8%, 4.6%, neutropenia 7.9%, 3.5%), and incidence of grade 2,3 peripheral neuropathy was low (VAD 3.5%, VTD 7%). Conclusion: Sequential VAD and VTD induction therapy in newly diagnosed multiple myeloma was highly effective, even in patients with poor prognostic cytogenetics, and did not prejudice stem cell collection. VTD could have contributed to increased RR and minimized side effects. An updated results will be presented at the ASH meeting. *Protocol Number: KMM51-NCT00378755.

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Urlić, Iris, Željko Verzak und Dubravka Negovetić Vranić. „Measuring the Influence of Galilean Loupe System on Near Visual Acuity of Dentists under Simulated Clinical Conditions“. Acta Stomatologica Croatica 50, Nr. 3 (15.09.2016): 235–41. http://dx.doi.org/10.15644/asc50/3/6.

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Ivanov, P. A., A. M. Fain und M. V. Sychevsky. „LIFE JOURNEY: MEDICAL AND SCIENTIFIC WORK OF PROFESSOR V.A. SOKOLOV“. Sklifosovsky Journal "Emergency Medical Care" 6, Nr. 3 (01.01.2017): 280–86. http://dx.doi.org/10.23934/2223-9022-2017-6-3-280-286.

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Warschburger, Petra. „Prävention kindlicher Adipositas: Was beeinflusst die Inanspruchnahme von Präventionsangeboten?“ Public Health Forum 18, Nr. 4 (01.12.2010): 14–15. http://dx.doi.org/10.1016/j.phf.2010.09.006.

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EinleitungPräventionsangebote werden selten, besonders Risikogruppen, angenommen. Mütter 3- bis 6 jähriger Kinder wurden u.a. zu hinderlichen und förderlichen Faktoren für die Teilnahmebereitschaft befragt. Viele Mütter betrachten demnach Übergewicht nicht als relevantes Problem und unterschätzen die damit verbundenen körperlichen und psychischen Belastungen. Die Teilnahmebereitschaft war gering ausgeprägt; Hinderungsgründe wurden v.a. bezogen auf organisatorische Aspekte benannt.

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Roberts, Scott C., Jonathan D. Rich, Duc T. Pham, Rebecca Harap und Valentina Stosor. „1177. A Spectrum of Infectious Complications in Continuous-Flow Ventricular Assist Devices: A Single-Center Longitudinal Cohort“. Open Forum Infectious Diseases 6, Supplement_2 (Oktober 2019): S421—S422. http://dx.doi.org/10.1093/ofid/ofz360.1040.

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Abstract Background Infections remain a frequent complication of patients (patients) with ventricular assist devices (VAD). We evaluated the epidemiology and outcomes of VAD infections at our center over a 10-year period. Methods We performed a retrospective cohort study of continuous-flow VAD recipients from July 2008-September 2018. VAD-specific and -related infections were characterized according to 2013 ISHLT definitions. Summary and comparative statistics were performed using IBM® SPSS Statistics version 25.0. Results 433 VADs were implanted into 375 patients. A total of 86 VAD infections occurred in 79 patients, with a mean incidence of 0.19 episodes/VAD and 0.20 episodes/pt. Patients with infections were predominantly male (73.3%) and Caucasian (54.6%), and had mean age of 52.7 years, nonischemic cardiomyopathy (58.1%), and VAD as bridge to transplant (53.5%, n = 46). Types of VAD included 43.0% axial (n = 37) and 57.0% centrifugal flow (n = 49). 78% of patients with infections were colonized with at least one multidrug-resistant organism (MDRO) such as MRSA (29%), VRE (73%), and ESBL (24%). Notably, 15% of infections (n = 13) occurred within 60 d of VAD implantation, with mean time to onset 36 d (5–60 d) post-VAD. Early infections (<60d) involved driveline exit site (DLES) (n = 4), pocket (n = 3), and pump (n = 7) with 7 VAD-related blood stream infections (BSI), 6 infective endocarditis (IE), and 2 mediastinitis. Early infections involved Gram-positive (GP) bacteria (84.6%, n = 11), Gram-negatives (GN) (45.5%, n = 5), anaerobes (23.1%, n = 3), fungi (30.8%, n = 4), MDRO (61.5%, n = 8) and 32 pathogens (69.2%, n = 9). 85% of infections occurred late (n = 73) with mean time to onset 338 d (69–1215 d). In late infections (>60d), impacted sites included DLES (n = 38), pocket (n = 7), and pump (n = 40), with 42 BSI, 36 IE, and 2 mediastinitis. Pathogens were 68.5% GP (n = 50), 37.0% GN (n = 27), 2.7% anaerobes (n = 2), 2.7% fungi (n = 2), 17.8% MDRO (n = 13), and 26.0% polymicrobial (n = 19). Conclusion In this longitudinal retrospective cohort of patients supported with VADs, a majority of infections occurred >9 months post-implantation. GP pathogens predominated at all time-points. GN bacteria, including MDROs, anaerobes, and fungi are increasingly encountered. The vast majority of patients were colonized with ³1 MDRO during the course of VAD implantation. Disclosures All authors: No reported disclosures.

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Suh, Sang Hyun, Byung Moon Kim, Sung Il Park, Dong Ik Kim, Yong Sam Shin, Eui Jong Kim, Eun Chul Chung et al. „Stent-assisted coil embolization followed by a stent-within-a-stent technique for ruptured dissecting aneurysms of the intracranial vertebrobasilar artery“. Journal of Neurosurgery 111, Nr. 1 (Juli 2009): 48–52. http://dx.doi.org/10.3171/2009.2.jns081418.

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Object A ruptured dissecting aneurysm of the vertebrobasilar artery (VBA-DA) is a well-known cause of acute subarachnoid hemorrhage (SAH) with a high rate of early rebleeding. Internal trapping of the parent artery, including the dissected segment, is one of the most reliable techniques to prevent rebleeding. However, for a ruptured VBA-DA not suitable for internal trapping, the optimal treatment method has not been well established. The authors describe their experience in treating ruptured VBA-DAs not amenable to internal trapping of the parent artery with stent-assisted coil embolization (SAC) followed by a stent-within-a-stent (SWS) technique. Methods Eleven patients—6 men and 5 women with a mean age of 48 years and each with a ruptured VBA-DA not amenable to internal trapping of the parent artery—underwent an SAC-SWS between November 2005 and October 2007. The feasibility and clinical and angiographic outcomes of this combined procedure were retrospectively evaluated. Results The SAC-SWS was successful without any treatment-related complications in all 11 patients. Immediate posttreatment angiograms revealed complete obliteration of the DA sac in 3 patients, near-complete obliteration in 7, and partial obliteration in 1. One patient died as a direct consequence of the initial SAH. All 10 surviving patients had excellent clinical outcomes (Glasgow Outcome Scale Score 5) without posttreatment rebleeding during a follow-up period of 8–24 months (mean follow-up 15 months). Angiographic follow-up at 6–12 months after treatment was possible at least once in all surviving patients. Nine VBA-DAs showed complete obliteration; the other aneurysm, which had appeared partially obliterated immediately after treatment, demonstrated progressive obliteration on 2 consecutive follow-up angiography studies. There was no in-stent stenosis or occlusion of the branch or perforating vessels. Conclusions The SAC-SWS technique seems to be a feasible and effective reconstructive treatment option for a ruptured VBA-DA. The technique may be considered as an alternative therapeutic option in selected patients with ruptured VBA-DAs unsuitable for internal trapping of the parent artery.

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Kumar, Shaji, Ian W. Flinn, Parameswaran N. Hari, Natalie Callander, Stephen J. Noga, A. Keith Stewart, Jonathan Glass et al. „Novel Three– and Four–Drug Combinations of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Newly Diagnosed Multiple Myeloma: Encouraging Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study.“ Blood 114, Nr. 22 (20.11.2009): 127. http://dx.doi.org/10.1182/blood.v114.22.127.127.

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Abstract Abstract 127 Two- and three-drug regimens incorporating bortezomib (Velcade®, Vc), lenalidomide (Revlimid®, Rev), dexamethasone (Dex), and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining Vc and Dex with Rev and Cy in a novel four-drug regimen (VDCR) may result in even greater activity with improved quality and duration of response. Results from the phase 1 dose-escalation portion of the multi-center EVOLUTION study showed that the VDCR regimen is a highly active and generally well-tolerated induction therapy in previously untreated MM patients (pts). Here we report the efficacy and safety of VDR, VDC, and VDCR from the non-comparative phase 2 portion of the study. Methods: Pts were randomized to receive up to eight 21-d cycles of VDR (Vc 1.3 mg/m2 d 1, 4, 8, 11; Dex 40 mg d 1, 8, 15; Rev 25 mg d 1–14) or VDC (VD as in VDR, plus Cy 500 mg/m2 d 1, 8) or VDCR (VDC plus Rev 15 mg d 1–14) as induction therapy, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles in all treatment arms. Pts received prophylactic antibiotics, acyclovir, transfusion support, and anticoagulants as required. Eligible pts wishing to undergo autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and undergo ASCT any time after cycle 4. Response categories were based on the IMWG Criteria with the addition of near complete response (nCR). Adverse events (AEs) were graded using the CTCAE v3.0. Results: In the VDR, VDC, and VDCR arms 42, 32, and 43 pts (including 6 pts treated at the maximum planned dose of Cy (500 mg/m2) from phase 1) have been treated, and 42, 31, and 33 are evaluable for response, respectively, as of data cut-off (31 July 2009). Median ages in the VDR, VDC, and VDCR arms were 60, 62, and 62 years, respectively; 62%, 63%, and 66% had International Staging System stage lI/III disease, and 38%, 25%, and 33% had Karnofsky Performance Status ≤80%, respectively. The median number of VDR, VDC, and VDCR cycles received is 4.5, 6, and 4, respectively (range 1–12). Best unconfirmed response rates are shown in the Table; patients categorized as very good partial response (VGPR) include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status. The overall rates of treatment-emergent AEs were 95%, 97%, and 88% for the VDR, VDC, and VDCR arms, respectively, with ≥grade 3 reported in 67%, 59%, and 65%. Peripheral neuropathy (PN) was reported as grade 2/3 in 12%/12% in the VDR, 31%/3% in the VDC, and 12%/9% in the VDCR arms; there was no grade 4 PN reported. Grade 3/4 neutropenia was reported in 5%/5%, 28%/13%, and 23%/9% of pts in the VDR, VDC, and VDCR arms, and grade 3/4 thrombocytopenia in 5%/2%, 9%/0%, and 5%/0% of pts, respectively. One case of grade 3 deep-vein thrombosis was reported in the VDCR arm. Overall rates of serious AEs were 24%, 13%, and 37% in the VDR, VDC, and VDCR arms, respectively. Two pts have died in the VDCR arm, both due to renal failure, considered possibly treatment-related. To date, 6 pts have undergone ASCT in the VDR arm, 5 in the VDC arm, and 3 in the VDCR arm. Median CD34+ yield was 4.7, 6.3, and 6.8 × 106/kg in the VDR, VDC, and VDCR arms, respectively. Conclusions: VDR, VDC, and VDCR are highly active and generally well-tolerated regimens in previously untreated MM. Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms at this early time point, although there also appeared to be higher rates of serious AEs, including possible treatment-related mortality in the VDCR arm. Following an interim analysis, dosing in the VDC arm was modified to include Cy on day 15 to examine if this will improve CR rates. Ten pts have been enrolled to date. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Milennium Pharmaceuticals Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:Millenium: Research Funding. Noga:Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Shi:Millennium Pharmaceutical Inc.: Employment. Webb:Millennium: Employment, Equity Ownership. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Harousseau, Jean-Luc, Gerald Marit, Denis Caillot, Philippe Casassus, Thierry Facon, Mohamad Mohty, Frederic Maloisel et al. „VELCADE/Dexamethasone (Vel/Dex) Versus VAD as Induction Treatment Prior to Autologous Stem Cell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM): An Interim Analysis of the IFM 2005-01 Randomized Multicenter Phase III Trial.“ Blood 108, Nr. 11 (16.11.2006): 56. http://dx.doi.org/10.1182/blood.v108.11.56.56.

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Abstract ASCT is considered the standard of care for patients up to 65 years of age with MM. The optimal induction treatment prior to ASCT is still unknown. VAD is a commonly used regimen but is associated with a number of toxicities, administrative inconvenience, and a complete remission (CR) rate of typically less than 10%. Recently the combination thalidomide/Dex was reported to induce a higher overall response rate than Dex alone in newly diagnosed patients, but with significantly more toxicities, especially deep vein thrombosis, and a 4% CR rate (Rajkumar et al, J Clin Oncol 2006;24:431–6). In a phase II trial we have evaluated the combination of Vel 1.3mg/m2 D1, 4, 8, 11 with Dex 40mg/D D1-4, D9-12, for 4 consecutive 21-D cycles (Dex only on D1-4 during cycles 3–4). This combination was well tolerated and yielded a 21% CR/nCR rate with successful stem cell harvest and engraftment (Harousseau et al, Haematologica 2006). In 2005, the IFM initiated a multicenter randomized phase III trial comparing Vel/Dex with VAD as induction treatment of patients with newly diagnosed MM up to the age of 65. The primary objective of the study is the CR (negative immunofixation) plus nCR (CR but positive immunofixation) rate after 4 cycles. A secondary objective is to evaluate the role of consolidation with 2 courses of DCEP (Dex, cyclophosphamide, etoposide, cisplatin). Patients were randomized at diagnosis among 4 arms (A1: 4 cycles of VAD; A2: 4 cycles of VAD + 2 cycles of DCEP; B1: 4 cycles of Vel/Dex; B2: 4 cycles of Vel/Dex + 2 cycles of DCEP); stratification was by cytogenetics and β2 microglobulin. Stem cell collection was performed between cycle 3 and cycle 4 after priming with G-CSF (10μg/kg/D × 6 D). At the end of induction (± DCEP consolidation) treatment, patients received melphalan 200mg/m2 plus ASCT. Enrollment of 480 patients is planned, to detect a 10% higher CR/nCR rate with Vel/Dex (20% vs 10%) with 80% power (two-sided test, significance level 0.05). An interim analysis is planned when 222 patients have been evaluated for response at the end of induction. As of July 2006, 304 patients have been enrolled. Randomization of the 222 patients to be considered for interim analysis was completed on May 19th. Baseline characteristics include: median age 55y; 140M, 82F; β2 microglobulin >3mg/L in 54%; del13 by FISH in 45%. The occurrence of serious adverse events (SAEs) was similar between the VAD and Vel/Dex arms (31% with VAD, 33% with Vel/Dex). The most frequent SAEs were pneumopathy (5.3% VAD, 4.0% Vel/Dex), thrombosis (2.7% VAD, 3.3% Vel/Dex), and peripheral neuropathy (1.3% VAD, 3.3% Vel/Dex). We intend to present results from the interim analysis.

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Krupa, Tadeusz. „V.A. Gorbatov Theory of Characterization - Principles and Examples“. Foundations of Management 5, Nr. 3 (21.08.2014): 89–102. http://dx.doi.org/10.2478/fman-2014-0022.

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AbstractCharacterization theory was developed in the 1970s by a member of the Russian Academy of Sciences, a prominent cybernetics V.A. Gorbatov, and became the nucleus of an international school. Many of today’s academy graduates make a new generation of scholars, more than 150 doctors and assistant professors, developing a new descriptive theory of cybernetic complex systems, based on the canon of the so-called characterization principle, binding the sets of y¥a functioning models and x¥bstructure models using the paradigm of monotone mappings of the considered system. This article presents an overview of the following problems: (1) the issues of functional-structural connection systems from the point of view of their design correctness; (2) the basic postulates of the characterization principle; (3) the nature of interaction between system objects; (4 and 5) mechanisms and functions for initiation of the operation; (6) the mechanisms of control and reaction functions; (7 and 8) the analytical form of initiation function and a network initialization function and (9) the axiom of extensionality (J), feasibility (R) and compatibility (Z).

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Niraula, S., Y. S. Zong, L. Z. Zhai, C. C. Guo und T. Y. Lin. „Investigation on the serum antibodies levels against Epstein-Barr virus in pulmonary lymphoepithelioma-like carcinoma“. Journal of Clinical Oncology 25, Nr. 18_suppl (20.06.2007): 18186. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.18186.

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18186 Background: Pulmonary lymphoepithelioma-like carcinoma (PLELC) belongs to large cell sub-type of non-small cell lung cancer (NSCLC) with just about 160 cases reported previously. Its epidemiology, prognosis and therapeutic approach is evidently different from other NSCLCs. EBV infection is seen in 100% of Asian PLELC patients whenever tested. The aim of this study was to analyze serum antibodies level against EBV in PLELC patients. Methods: Sera of all seven patients with re-confirmed PLELC from a single institute in Canton, China in the past 4 years were collected. Serum levels of 8 different antibodies against EBV (Epstein-Barr virus): EBNA1 (EBV nuclear antigen 1- IgA and IgG), Zta (Bam Z transactivator antigen-IgA and IgG), VCA-p18 (Viral capsid antigen-p18-IgA and IgG), VCA-antigen complex (VCA-IgA) and Early antigen complex (EA-IgA ) were measured in each of these patients using enzyme-linked immunosorbent assay and Immunoenzymatic assay respectively. Results: Out of 7 cases, 6 showed high EBNA-1 level, 4 showed high zta, 3 showed high VCA-p18, 3 showed high titer of VCA complex and 2 showed high EA complex titer ( Table 1 ) Conclusions: Though small sample size, this is the first study in this depth ever to conclude that sera of all Asian patients with pulmonary LELC have high antibody titers against EBV. The infection mainly is latency II type as seen in Nasopharyngeal carcinoma and Hodgkin’s disease as well. A small portion of PLELC express lytic products such as Zta, EA and VCA. The authors assume that pre-therapeutic measurement of serum levels of anti-EBV antibodies (at least 2 kinds) is highly warranted in suspected Asian NSCLC patients. Positive result strongly puts PLELC into differential diagnosis. [Table: see text] No significant financial relationships to disclose.

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Ludwig, Heinz, Werner Linkesch, Hedwig Kasparu, Otto Krieger, Ivan Spicka, Gunther Gastl, Richard Greil et al. „Prospective, Randomized Comparison between Double Transplantation (T) with Melphalan (200 mg/m2) and Triple T with Intermediate Dose Melphalan (100 mg/m2) in Patients with Multiple Myeloma (An Interim Analysis).“ Blood 108, Nr. 11 (16.11.2006): 3083. http://dx.doi.org/10.1182/blood.v108.11.3083.3083.

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Abstract In this study we compare the efficacy and toxicity of double T with M 200 with triple T using M 100 in newly diagnosed pts with MM. 175 pts have as yet been enrolled and 135 have been randomized after VAD induction treatment and stem cell collection to either tandem or triple transplantation. Reasons for non-randomization were too early for T (n=22), PD after induction (n=5), early death (n=3), toxicity (n=3), pt. refusal (n=3), and others (n=4). Median age of the 135 pts randomized was 59 years (range: 27–70 years). Stage I: 8%, stage II: 17%, stage III: 75%, Paraprotein Isotypes: IgG: 55%, IgA: 25%, IgD: 2%, IgM: 1%, Light chain: 17%. Induction treatment: 3 cycles of VAD; stem cell priming: IEV (ifosfamide (2g/m2)-etoposide (150mg/m2), d1–3; epirubicin (50mg/m2), d1) and G-CSF (5mg/kg) from d4. Conditioning regimen: M 200 mg/m2 or M 100 mg/m2 plus G-CSF; day 5 until WBC >2000/ml. Pts with ≥ SD after T were subsequently randomized to interferon 3MU, TIW (Schering Plough) plus prednisone (25mg, po., TIW), or interferon alone. QoL was assessed with the EORTC QLQ C30 instrument. Chi2 test for trend was used for comparison of response and survival endpoints were estimated by the Kaplan-Meier product limit method. Response rates after VAD were CR: 11%, PR: 65%, SD: 22% and PD: 2%. Median time from start of VAD to start of T was 137 in the double and 139 days in the triple T arm. Response rates did not differ between pts treated with double or triple T (CR: 47% vs. 43%, PR: 47% vs. 47%, SD 2% vs. 6%, PD: 4% vs. 4%, p=0.60, respectively). Median PFS for both groups combined was 36 mos, but showed a tendency for shorter PFS in pts on triple T (23 mos. vs. 37.5 mos; HR 1.26, 95% CI: 0.72–2.23, p=0.21). Median of OS has not been reached yet, but did not differ between both groups. Hematological toxicity was similar in both groups. There was a tendency for more grade 2–4 mucositis and for grade 3–4 vomiting, nausea, and fatigue in the double T group. Global QoL (questions 29 and 30) was comparable between both groups, before (5 (2.5–6.5) vs. 5 (4.5–6)) and after double (5.8 (3–8.5) or triple T (6 (2.5–7)). In conclusion, triple T with intermediate dose M resulted in similar response rates, slightly shorter PFS but similar OS and was associated with less mucositis and slightly less vomiting, nausea and fatigue. Progression-free survival by randomization group Progression-free survival by randomization group

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Turner, M. R., und T. L. Pallone. „Vasopressin constricts outer medullary descending vasa recta isolated from rat kidneys“. American Journal of Physiology-Renal Physiology 272, Nr. 1 (01.01.1997): F147—F151. http://dx.doi.org/10.1152/ajprenal.1997.272.1.f147.

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Arginine vasopressin (AVP) can selectively decrease blood flow in the renal medulla, but the sites of vasoconstriction are uncertain. We have examined the effects of vasopressin-receptor agonists and antagonists on the diameters of outer medullary descending vasa recta (OMDVR), isolated and perfused in vitro. AVP can constrict OMDVR, apparently via V1a-receptors. Ablumenal AVP (10(-10)-10(-6)M) or the selective V1a-receptor agonist [Phe2, Ile3, Orn8]-vasopressin (PO-VT, 10(-8) M) constricted OMDVR focally and (at higher AVP concentrations) transiently. The V1b agonist ideamino-Cys1,D-3-(pyridyl)Ala2,Arg8)vasopressin (DP-VP; 10(-8) M) and the V2 agonist [deamino-Cys1, D-Arg8]vasopressin (DDAVP; 10(-8) M) did not constrict OMDVR. The V1a antagonist [d(CH2)5(1), O-Me-Tyr2,Arg8]vasopressin (CTM-VP, 10(-10) 10(-8) M) inhibited vasoconstriction by AVP 10(-9 M), whereas the V2 antagonist [d(CH2)5(1), D-Ile2,Ile4 Arg8]vasopressin (II-VP) at low concentration (10(-10) M) did not. V2 stimulation seems to inhibit V1a constriction of OMDVR. DDAVP prevented constriction by PO-VT (10(-8) M) applied at the same time and dilated OMDVR preconstricted with PO-VT.

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Roussel, Murielle, Anne Huynh, Philippe Moreau, Jean Luc Harousseau, Cyrille Hulin, Denis Caillot, Christophe Fruchart, Gerald Marit, Brigitte Pegourie und Michel Attal. „Bortezomib (BOR) and High Dose Melphalan (HDM) as Conditioning Regimen Before Autologous Stem Cell Transplantation (ASCT) for De Novo Multiple Myeloma (MM): Final Results of the IFM Phase II Study VEL/MEL“. Blood 112, Nr. 11 (16.11.2008): 160. http://dx.doi.org/10.1182/blood.v112.11.160.160.

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Abstract Introduction: ASCT is recommended for young patients (pts) with newly diagnosed MM. The achievement of Complete Response (CR) or at least Very Good Partial Response (VGPR) is the main prognostic factor for survival after ASCT. However, only 40–50% of patients achieve CR and VGPR with current HDM regimen. BOR has demonstrated significant activity in relapsed/refractory pts, a synergistic effect with Melphalan (MEL) and a lack of prolonged hematological toxicity. The combination of BOR and HDM is therefore a logical approach to attempt to improve CR+VGPR rates after ASCT. Methods: In July 2007, the IFM initiated an open-label, multicenter, phase II study. Fifty-seven pts with symptomatic de novo MM were enrolled to receive BOR and HDM as conditioning regimen before ASCT. The choice of induction therapy was not specified in the protocol, and was made on an individual-patient basis by the treating clinician. BOR (1 mg/m2) was delivered on days −6, −3, +1, +4 and MEL (200 mg/m2) on day −2. Peripheral blood stem cells (median 4 × 106 CD34/kg, range 2–12) were infused on day 0. The primary endpoint was the CR+VGPR rates at 3 months post ASCT. The secondary endpoint was the safety profile of this regimen. Baseline characteristics of the pts were: median age = 58; ISS= 1 in 30, 2 in 15 and 3 in 12 cases; chromosome 13q deletion in 27 of 52 assessable; chromosome 17p del in 3 and t(4;14) translocation in 6. Twenty-nine pts received VAD induction therapy while 18 received a BOR-Dexamethasone (DEX) based regimen. Seven pts needed more than 2 lines of therapy to achieve response before ASCT and 3 pts had already received a first course of HDM. Overall response rates before ASCT were: CR=2, VGPR=6, partial response (PR)= 33 and stable disease (SD)=16. Results: All pts but one were assessed for response at 3 months after ASCT. Twenty pts (36%) achieved a CR and 17 (30%) a VGPR. One patient was non-responder. Among the 3 pts receiving a tandem ASCT, no CR or VGPR was observed after BOR+HDM. In the VAD induction group, 12 pts (43%) achieved CR and 7 (25%) VGPR. In the BOR-DEX based induction group, 7 pts (39%) achieved CR and 6 (33%) VGPR. All results are summarized in table 1. From the standpoint of safety, BOR did not increase hematological toxicity. Median duration of neutropenia (< 0.5 × 109/l) and thrombocytopenia (< 50 × 109/l) was 7 (range 1–15) and 8 (range 3–31) days respectively. Grade 3/4 extra-hematological toxicities were limited: mucositis in 22 cases (39%), peripheral neuropathy in 1 case. Other toxicities included: erythroderma in 30%, headache in 20%, hallucinations in 9% and grade 2 peripheral neuropathy in 3 cases (preexisting ASCT). Five serious adverse events were reported: 1 pulmonary embolism, 1 seizure, 1 acute cholecystis and 2 pneumonias. No toxic death was observed. Conclusions: These results suggest that BOR (1 mg/m2) and HDM is a safe and highly effective conditioning regimen in frontline MM pts with almost 70% achieving CR and VGPR. This compares favorably to the updated results of the IFM 2005/01 trial (comparing BOR-DEX versus VAD as induction prior to ASCT in de novo MM pts) reported in last ASH meeting (Harousseau et al.). A matched case-control study will be conducted between our cohort and the pts of the IFM 2005/01 trial. Table 1: IFM VEL/MEL IFM 2005/01 VAD n=28 BOR-DEX n=18 ≥ 2 lines n=7 VAD n=110 BOR-DEX n=112 CR 43% 39% 14% 20% 34% ≥ VGPR 68% 72% 71% 50% 64% ≥ PR 93% 100% 86% SD 7% 0 0 PD 0 0 14%

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