Preparat BG-12 w stwardnieniu rozsianym

Fumaran dimetylu (DMF, dimethyl fumarate) jest doustnym lekiem stosowanym od ponad 40 lat w leczeniu łuszczycy. W przeprowadzonych ostatnio badaniach wykazano immunomodulacyjne i neuroprotekcyjne działanie DMF in vivo oraz na zwierzęcym modelu zapalenia ośrodkowego układu nerwowego i neurodegeneracji o podłożu autoimmunologicznym. Fumaran dimetylu działa poprzez chemiczną modyfikację białka represorowego Keap1, która umożliwia stabilizację i przemieszczenie do jądra komórkowego czynnika transkrypcyjnego Nrf2, co w konsekwencji prowadzi do aktywacji kaskady kilku szlaków o działaniu cytoprotekcyjnymi antyoksydacyjnym. Ponadto hamowanie przekazywania sygnałów prozapalnych, zależnych od czynnika transkrypcyjnego NF-kappaB, powoduje supresję odpowiedzi prozapalnej oraz indukcję cytokin przeciwzapalnych. Preparat BG-12 jest preparatem DMF w postaci podawanej doustnie mikrotabletki dojelitowej. W dwóch badaniach III fazy u chorych z rzutowo-remisyjną postacią stwardnienia rozsianego (SM, sclerosis multiplex) stosowanie BG-12 wiązało się ze zmniejszeniem o 44–53% rocznej częstości rzutów i zmniejszeniem o 71–85% częstości występowania nowych zmian w sekwencjach T w badaniu metodą rezonansu magnetycznego. Do najczęstszych działań niepożądanych BG-12 należą zaczerwienienie skóry i objawy żołądkowo-jelitowe, a ich częstość jest największa w pierwszym miesiącu po rozpoczęciu leczenia. W badaniach II i III fazy nie zaobserwowano żadnych poważnych sygnałów dotyczących bezpieczeństwa stosowania leku; nie stwierdzono zwiększenia ryzyka zakażeń oportunistycznych ani nowotworów. Podsumowując, nowy mechanizm działania BG-12 wydaje się zapewniać korzystną równowag ęmiędzy skutecznością, bezpieczeństwem i tolerancją preparatu w leczeniu chorych na SM

Gain dynamics and ultrafast spectral hole burning in In(Ga)As self-organized quantum dots

Using a femtosecond three-pulse pump-probe technique, we investigated spectral hole-burning and gain recovery dynamics in self-organized In(Ga)As quantum dots. The spectral hole dynamics are qualitatively different from those observed in quantum wells, and allow us to distinguish unambiguously the gain recovery due to intradot relaxation and that due to carrier capture. The gain recovery due to carrier–carrier scattering-dominated intradot relaxation is very fast ( ∼ 130 fs),(∼130fs), indicating that this is not the factor limiting the bandwidth of directly modulated quantum dot lasers. © 2002 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70041/2/APPLAB-81-4-670-1.pd

Support for smoke-free multi-unit housing policies among racially and ethnically diverse, low-income seniors in south florida

Open access: http://link.springer.com/article/10.1007/s10823-014-9247-4/fulltext.html Previous studies have gauged support for implementing smoke-free MUH policies in the United States, but none have specifically examined attitudes among racially and ethnically diverse seniors living in low-income MUH. As part of an evaluation of a Community Transformation Grant funded program, we surveyed senior residents 62 years of age and older (n = 807) in 24 low-income housing properties in Broward County, Florida, to assess residents’ smoking behaviors, exposure to SHS, and support for smoke-free MUH policies. The study sample was ethnically and racially diverse with Hispanics comprising more than 61% of the population, and 22% of the population identified as Black or other races. Although close to 22% of the sample were former smokers, only 9% of residents reported being current smokers. The majority of residents surveyed supported no-smoking policies: 75% support no-smoking policies for individual units; 77% supported no-smoking policies in common areas; and, 68% supported no-smoking policies in outdoor areas. Over 29% of residents surveyed reported being exposed to secondhand smoke entering their units from elsewhere in their building. In sub-group analysis, Hispanic residents were significantly more likely to support both indoor (84.3 vs. 76.5, p\u3c.05) and outdoor (80.0 vs. 67.4, p\u3c.01) policies compared to non-Hispanic residents. Support for smoke-free policies did not vary significantly by race. This study demonstrates that senior residents living in low-income MUH properties overwhelmingly supported the implementation of smoke-free policies

Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model.

Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341luc were tested for effects of BRAFV600E and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAFV600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341luc tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341luc engraftment model application have clinical implications for the management of BRAFV600E glioma

Clinical Outcomes of Intraoperative Radiation Therapy for Extremity Sarcomas

Purpose. Radiation of extremity lesions, a key component of limb-sparing therapy, presents particular challenges, with significant risks of toxicities. We sought to explore the efficacy of intraoperative radiation therapy (IORT) in the treatment of soft tissue sarcomas of the extremities. Patients. Between 1995 and 2001, 17 patients received IORT for soft tissue sarcomas of the extremities. Indications for IORT included recurrent tumors in a previously radiated field or tumors adjacent to critical structures. Results. Gross total resections were achieved in all 17 patients. Two patients experienced locoregional relapses, six patients recurred at metastatic sites, and one patient died without recurrence. Thirty-six month estimates for locoregional control, disease free survival, and overall survival were 86%, 50%, and 78%, respectively. IORT was extremely well tolerated, with no toxicities referable to IORT. Conclusions. For patients with soft tissue sarcomas of the extremities, IORT used as a boost to EBRT provides excellent local control, with limited acute toxicities

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study.

OBJECTIVE: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. METHODS: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). RESULTS: DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. CONCLUSIONS: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment

Band alignment of Sb2O3 and Sb2Se3

Antimony selenide (Sb2Se3) possesses great potential in the field of photovoltaics (PV) due to its suitable properties for use as a solar absorber and good prospects for scalability. Previous studies have reported the growth of a native antimony oxide (Sb2O3) layer at the surface of Sb2Se3 thin films during deposition and exposure to air, which can affect the contact between Sb2Se3 and subsequent layers. In this study, photoemission techniques were utilized on both Sb2Se3 bulk crystals and thin films to investigate the band alignment between Sb2Se3 and the Sb2O3 layer. By subtracting the valence band spectrum of an in situ cleaved Sb2Se3 bulk crystal from that of the atmospherically contaminated bulk crystal, a valence band offset (VBO) of −1.72 eV is measured between Sb2Se3 and Sb2O3. This result is supported by a −1.90 eV VBO measured between Sb2O3 and Sb2Se3 thin films via the Kraut method. Both results indicate a straddling alignment that would oppose carrier extraction through the back contact of superstrate PV devices. This work yields greater insight into the band alignment of Sb2O3 at the surface of Sb2Se3 films, which is crucial for improving the performance of these PV devices

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

BACKGROUND: BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate). METHODS: In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate. RESULTS: At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12. CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).clinical trial, phase iiicomparative studyjournal articlemulticenter studyrandomized controlled trialresearch support, non-u.s. gov't2012 Sep 20importedErratum in : N Engl J Med. 2012 Oct 25;367(17):1673