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Nawar, Nagwa, Essam Ell-Sawaah, Nasser M. Hosny i Mohsen M. Mostafa. "Synthesis and Spectral Characterization of Some Complexes Derived From N-Benzoyl-N′-Carboxylmethylthiopropylidine Thiourea (Bcmt)". Phosphorus, Sulfur, and Silicon and the Related Elements 187, nr 8 (7.06.2012): 976–89. http://dx.doi.org/10.1080/10426507.2012.658980.
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Prastowo, T., L. Cholifah, L. O. Ngkoimani i L. O. Safiuddin. "TSUNAMI-MAGNETIC SIGNALS AND MAGNETIC ANOMALY GENERATED BY TSUNAMI WAVE PROPAGATION AT OPEN SEAS". Jurnal Pendidikan Fisika Indonesia 13, nr 1 (3.01.2017): 59–70. http://dx.doi.org/10.15294/jpfi.v13i1.7822.
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This research examines the generation of tsunami-induced magnetic signals, where local magnetic anomaly were measured as variations in the vertical bz and horizontal bH components of the secondary field. The maximum amplitudes of bz and bH were analytically estimated and compared to magnetogram provided by INTERMAGNET and BCMT for the 2010 Chilean, the 2011 Tohoku, the 2010 Mentawai and the 2004 Aceh tsunamis. For the first two cases, frozen-flux theory was used to estimate bz and bH where the phase lag between bz and bH was ?/2, relevant to time interval of T/4 between the two signals. For the Mentawai case, oceanic diffusion was unignored and bz significantly deviated from that calculated using the theory. However, the data from Mentawai where bz ? 2 nT were in good agreement with bz generated by large tsunamis occurring in regions near the equator and with magnetogram from the Aceh event.
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Haider, Mohammad N., Samantha L. Johnson, Rebekah Mannix, Alexander J. Macfarlane, Dylan Constantino, Blair D. Johnson, Barry Willer i John Leddy. "The Buffalo Concussion Bike Test for Concussion Assessment in Adolescents". Sports Health: A Multidisciplinary Approach 11, nr 6 (5.09.2019): 492–97. http://dx.doi.org/10.1177/1941738119870189.
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Background: The Buffalo Concussion Treadmill Test (BCTT) is a graded exertion test for assessing exercise tolerance after concussion, but its utility is limited for certain populations. Hypothesis: We developed the Buffalo Concussion Bike Test (BCBT) and tested its comparability with the BCTT. We hypothesize that heart rate (HR) at symptom exacerbation on the BCBT will be equivalent to the BCTT. Study Design: Case-control study. Level of Evidence: Level 3. Methods: Adolescents with acute concussion (AC) (n = 20; mean age, 15.9 ± 1.1 years; 60% male) presenting to a concussion clinic within 10 days of injury and age- and sex-matched healthy controls (n = 20; mean age, 15.9 ± 1.1 years; 60% male) performed the BCTT at first visit and returned within 3 days to perform the BCBT. Test duration, HR, symptom severity (measured using a visual analog scale), and exertion (measured using the Borg Rating of Perceived Exertion) were collected during each test. Results: Adolescents with AC who were exercise intolerant on the BCTT were also intolerant on the BCBT, with symptom exacerbation occurring at a mean 8.1 ± 2.8 minutes on the BCTT versus 14.6 ± 6.0 minutes on the BCBT ( P < 0.01). Two 1-sided t tests showed that the HR at symptom exacerbation in AC patients (137 ± 28 bpm on BCTT vs 135 ± 25 bpm on BCBT; 95% CI, <0.01-0.03) and at voluntary exhaustion for controls (175 ± 13 bpm on BCTT vs 175 ± 13 bpm on BCBT; 95% CI, 0.03-0.03) on each test were statistically equivalent. Conclusion: The HR at symptom exacerbation on BCBT is equivalent to the BCTT for the assessment of exercise tolerance after concussion in adolescents. Clinical Relevance: The BCBT can be used in patients with limited mobility or for research interventions that require limited participant motion.
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Wong, Y. W., A. F. Williams, S. F. Kingsmore i M. F. Seldin. "Structure, expression, and genetic linkage of the mouse BCM1 (OX45 or Blast-1) antigen. Evidence for genetic duplication giving rise to the BCM1 region on mouse chromosome 1 and the CD2/LFA3 region on mouse chromosome 3." Journal of Experimental Medicine 171, nr 6 (1.06.1990): 2115–30. http://dx.doi.org/10.1084/jem.171.6.2115.
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The mouse BCM1 (OX45, Blast-1) antigen has been cDNA cloned and sequenced to provide data supporting the view that BCM1, LFA3, and CD2 constitute a subgroup within the Ig superfamily. Mouse BCM1 is widely expressed on leukocytes and is likely to be anchored to the cell surface by a glycosyl-phosphatidylinositol anchor, as is the case for rat and human BCM1 antigen. Genetic linkage studies by recombination and pulse field analysis showed the BCM1 locus (Bcm-1) to be on distal mouse chromosome 1 and to be linked within 1,600 kb to the locus for an ATPase alpha chain gene (Atpa-3). A similar relationship was established between the human BCM1 locus (BCM1) and ATP1A2, and other markers on chromosome 1q. Conservation of genomic organization within a segment of human chromosome 1q and mouse chromosome 1 was demonstrated. A similar situation is seen in the region of the CD2 and LFA3 genes between mouse chromosome 3 and human chromosome 1p. Furthermore, the CD2/LFA3 genes are linked within 580 kb to Atpa-1/ATP1A1 genes to provide a parallel situation to the linkage between Bcm-1/BCM1 and Atpa-3/ATP1A2 on chromosomes 1 (mouse) and 1q (human). Taken together, the data suggest duplication of a chromosome region including the precursors of the genes for BCM1, CD2, and LFA3, and the ATPase genes to give rise to the linkage groups now observed. The duplicated regions may have stayed together on chromosome 1 in the human (with the insertion of a centromere), while in the mouse, the genetic regions are proposed to have become dispersed in the formation of chromosomes 1 and 3. CD2 and LFA3 are more dissimilar in sequence than BCM1 and LFA3, and if the precursors of the CD2 and LFA3 loci formed before the proposed chromosome segment duplication, then a gene encoding a recognizer molecule for BCM1 may exist in linkage with Bcm-1/BCM1 on chromosome 1 (mouse) and 1q (human).
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Malachová, Hana, i Alena Oulehlová. "Application of Business Continuity Management System into the Crisis Management Field". TRANSACTIONS of the VŠB – Technical University of Ostrava, Safety Engineering Series 11, nr 2 (1.09.2016): 43–50. http://dx.doi.org/10.1515/tvsbses-2016-0016.
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Abstract Establishing business continuity management (BCM) creates the basis of every organization’s strategy. BCM includes complex procedures that help solving unexpected situations of natural and anthropogenic nature (e.g. fire or flood). Planning of the BCM is a process that helps organizations identify critical processes and implement plans for securing and restoring key processes. The aim of this paper is to demonstrate the application of a systemic approach to BCM known as Business Continuity Management System (BCMS) into the military field. This article describes the life cycle of the BCMS, which is based on PDCA cycle. Subsequently it is applied to the activities carried out by the University of Defence during activation of forces and means in the frame of the Integrated Rescue System (IRS) in case of emergency - an accident in a nuclear power plant in the Czech Republic. Activities in various stages of deployment of allocated forces and means are managed and evaluated using the Military Continuity Management System (MCMS) application.
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Pfister, Sara, Luca Sauser, Ilche Gjuroski, Julien Furrer i Martina Vermathen. "Monitoring the encapsulation of chlorin e6 derivatives into polymer carriers by NMR spectroscopy". Journal of Porphyrins and Phthalocyanines 23, nr 11n12 (grudzień 2019): 1576–86. http://dx.doi.org/10.1142/s1088424619501815.
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The encapsulation of five derivatives of chlorin e6 with different hydrophobicity and aggregation properties into a series of five poloxamer-type triblock copolymer micelles (BCMs) with varying numbers of polyethylene and polypropylene glycol (PEG, PPG) units was monitored using 1H NMR spectroscopy. NMR chemical shift and line shape analysis, as well as dynamic methods including diffusion ordered spectroscopy (DOSY) and T1 and T2 relaxation time measurements of the chlorin and the polymer resonances, proved useful to assess the chlorin–BCM compatibility. The poloxamers had high capability to break up aggregates formed by chlorins up to intermediate hydrophobicity. Physically entrapped chlorins were always localized in the BCM core region. The loading capacity correlated with chlorin polarity for all poloxamers among which those with the lowest number of PPG units were most efficient. DOSY data revealed that relatively weakly aggregating chlorins partition between the aqueous bulk and micellar environment whereas more hydrophobic chlorins are well retained in the BCM core region, rendering these systems more stable. T1 and T2 relaxation time measurements indicated that motional freedom in the BCM core region contributes to encapsulation efficiency. The BCM corona dynamics were rather insensitive towards chlorin entrapment except for the poloxamers with short PEG chains. The presented data demonstrate that 1H NMR spectroscopy is a powerful complementary tool for probing the compatibility of porphyrinic compounds with polymeric carriers such as poloxamer BCMs, which is a prerequisite in the development of stable and highly efficient drug delivery systems suitable for medical applications like photodynamic therapy of tumors.
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Kriegeskorte, Nikolaus, i Jörn Diedrichsen. "Inferring brain-computational mechanisms with models of activity measurements". Philosophical Transactions of the Royal Society B: Biological Sciences 371, nr 1705 (5.10.2016): 20160278. http://dx.doi.org/10.1098/rstb.2016.0278.
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High-resolution functional imaging is providing increasingly rich measurements of brain activity in animals and humans. A major challenge is to leverage such data to gain insight into the brain's computational mechanisms. The first step is to define candidate brain-computational models (BCMs) that can perform the behavioural task in question. We would then like to infer which of the candidate BCMs best accounts for measured brain-activity data. Here we describe a method that complements each BCM by a measurement model (MM), which simulates the way the brain-activity measurements reflect neuronal activity (e.g. local averaging in functional magnetic resonance imaging (fMRI) voxels or sparse sampling in array recordings). The resulting generative model (BCM-MM) produces simulated measurements. To avoid having to fit the MM to predict each individual measurement channel of the brain-activity data, we compare the measured and predicted data at the level of summary statistics. We describe a novel particular implementation of this approach, called probabilistic representational similarity analysis (pRSA) with MMs, which uses representational dissimilarity matrices (RDMs) as the summary statistics. We validate this method by simulations of fMRI measurements (locally averaging voxels) based on a deep convolutional neural network for visual object recognition. Results indicate that the way the measurements sample the activity patterns strongly affects the apparent representational dissimilarities. However, modelling of the measurement process can account for these effects, and different BCMs remain distinguishable even under substantial noise. The pRSA method enables us to perform Bayesian inference on the set of BCMs and to recognize the data-generating model in each case. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.
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Tian, Yongshang, Yansheng Gong, Dawei Meng, Hao Deng i Boya Kuang. "Low-temperature sintering and electric properties of BCT–BZT and BCZT lead-free ceramics". Journal of Materials Science: Materials in Electronics 26, nr 6 (7.03.2015): 3750–56. http://dx.doi.org/10.1007/s10854-015-2898-2.
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Wu, Jianing, Shaoze Yan i Yongxia Gu. "On stability optimization of the deployable bistable compliant structures mounted in the morphing skin: Method and implementation". Proceedings of the Institution of Mechanical Engineers, Part C: Journal of Mechanical Engineering Science 229, nr 5 (30.06.2014): 943–56. http://dx.doi.org/10.1177/0954406214541634.
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Morphing skin is the surface of the deployable frame which could reconfigure its shape to present optimal performance in all stages of a task for the re-entry aerospace vehicle. After many years of research effort, design concept and manufacturing methodologies of morphing skin have been developed, especially in the adoption of bistable compliant mechanism (BCM). In order to make morphing skins more stable to accommodate to the air flow and change its profile more accurately, one method on the design and optimization of stability characteristics for deployable BCMs of morphing skin is proposed in this paper. The optimization is developed by the aeroelastic formulation of the deployable BCM mounted on the morphing skin. The optimization problem is considered as a multi-objective-constraint issue and the parametric equations to get the optimal parameters are solved by the immune genetic algorithm. Besides, a case study is proposed to provide evidence that the method can come to the optimal stiffness of BCM, with which the effectiveness about the new method of design and optimization can be testified.
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Premkumar, S., S. Radhakrishnan i V. L. Mathe. "Understanding A and B-site engineered lead-free Ba(1−x)CaxZryTi(1−y)O3 piezoceramics: a perspective from DFT". Journal of Materials Chemistry C 9, nr 12 (2021): 4248–59. http://dx.doi.org/10.1039/d0tc05724j.
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DFT has been used to investigate the structural and polarization of Ba(1-x)CaxZryTi(1−y)O3, perovskite solid solutions namely BaTiO3 (BT), Ba(Zr0.125Ti0.875)O3 (BZT), (Ba0.875Ca0.125)TiO3 (BCT) and Ba0.875Ca0.125(Zr0.125Ti0.875)O3 (BCZT).
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Samples, Laura S., Dora M. Banjanin, Booyeon Kim i Solomon A. Graf. "Adherence of oral targeted agents in patients with B-cell malignancies." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): e18301-e18301. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18301.
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e18301 Background: Oral targeted agents (OTAs) are rapidly changing the management of B-cell malignancies (BCM) and introducing challenges in prescribing practices and communication between patients, their clinicians, and pharmacists. Emerging data suggests dose interruptions impair OTA efficacy in BCM. However, infrastructure to ensure best practices may be outstripped by increasing OTA use in some clinics. We evaluated adherence to OTAs for BCMs at the Veterans Affairs Puget Sound Health Care System to identify opportunities for quality improvement in prescribing practices and patient education. Methods: Consecutive patients treated with OTAs for BCMs from 2014 to 2018 were examined by detailed chart review and included if they used an OTA uninterrupted for ≥ 30 days. OTA adherence was assessed by 1) identification of medication gaps ≥ 8 days not attributable to medication toxicity or disease progression and 2) ReComp, a validated electronic pharmacy refill adherence algorithm in which a value of 1 corresponds with perfect adherence and deviations from 1 correlate linearly with either over- or under- supply. Logistic regression modeling assessed for independent predictors of adherence. Results: Fifty patients were evaluated and 39 met inclusion criteria. They were prescribed 42 unique OTAs, including ibrutinib, venetoclax, idelalsib, and acalabrutinib over a total of 33,655 days, with a median duration of 420 days (range 60 to 1687). Twenty-three patients (59%) had at least one medication adherence gap ≥ 8 days. Five patients (13%) had ≥ 3 eight-day gaps. The study population had a mean ReComp value of 1.02 (median 0.99, standard deviation 0.15). Medication over-supply was identified in 46% and a quarter of patients were adherent < 93% of the time. No statistically significant correlations were identified between either measure of adherence and examined factors related to socio-demographics and comorbidities. Conclusions: In our institution, a significant percentage of patients prescribed OTAs for BCMs experienced suboptimal adherence. These data identify opportunities to improve disease-related outcomes and costs. Initiatives to improve education and automated monitoring of OTA refills are under evaluation.
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Hennenlotter, Joerg, Severine Huber, Tilman Todenhöfer, Ursula Kuehs, David Schilling, Stefan Aufderklamm, Georgios Gakis, Christian Schwentner i Arnulf Stenzl. "Point-of-Care Tests for Bladder Cancer: The Influencing Role of Hematuria". Advances in Urology 2011 (2011): 1–5. http://dx.doi.org/10.1155/2011/937561.
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Introduction. Several point-of-care tests (POCT) are available for the diagnosis of bladder cancer (BC). We evaluate the impact of HU (hematuria) on performance of POCTs.Materials and Methods. Urine from 10 donors was diluted with blood from 0.5 to 0.00625%. BladderCheckR, BTAstatR, BCMR, and BTARtests were applied. Tests were additionally conducted in 54 patients with HU. HU was stratified according to the amount of erythrocytes (RBC)/μL using two systems: (1) no HU; mild microscopic HU; severe microscopic HU; gross HU; (2) I <25 RBCs; <250 II; ≥250 III. Results were compared to HU status and histopathology.Results. Gross HU became evident between 2090 RBCs/μL and 1065/μL. Addition of blood led to default tests in all 4: BladderCheckR0.25%; BCM 0.025%, BioNexia 0.00625%, and BTAstat <0.00625%. Rates of false positives for BladderCheck, BTAstat, BCM, and BioNexia were 5.9, 11.8, 0, and 1.8% without HU and 0, 66.7, 44.4, and 66.7% with HU. BTAstat, BCM, and BioNexia were independently influenced by HU (P<0.0002).Conclusions. NMP22-BladderCheck was most resistant to blood. The diagnostic yield of all others was significantly influenced by HU. A well-defined HU grading helps to define limits of HU for a reliable interpretation of BC-POCTs.
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GUZMÁN-GÓMEZ, GERARDO, MIGUEL A. AYALA VALDOVINOS, ELISA CABRERA-DÍAZ, JULIA A. PÉREZ-MONTAÑO, JOSÉ FRANCISCO MUÑOZ-VALLE, M. R. TORRES-VITELA i SANDRA L. RUIZ-QUEZADA. "Frequency of Salmonella and Listeria monocytogenes in Five Commercial Brands of Chicken Eggs Using a Combined Method of Enrichment and Nested-PCR". Journal of Food Protection 76, nr 3 (1.03.2013): 429–34. http://dx.doi.org/10.4315/0362-028x.jfp-12-213.
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Eggs or egg-based foods, either raw or undercooked, have been identified as vehicles of Salmonella outbreaks. The low numbers of Salmonella organisms in eggs makes it difficult to detect them in frequency studies. The nested-PCR (n-PCR) technique shows more sensitivity and specificity than bacteriological culture methods (BCMs). A preenrichment method followed by enrichment and n-PCR is a good alternative for the investigation of Salmonella and Listeria monocytogenes in eggs. A total of 2,650 chicken eggs representing five commercial brands were purchased from 10 grocery stores. Ten eggs of each brand were combined in order to obtain 265 pooled samples (53 per brand). The shells and yolks of 100 pooled samples were analyzed for Salmonella, while the shells of 65 pooled samples were analyzed for L. monocytogenes, using BCM and a combined method of enrichment and n-PCR (CM-n-PCR). Sixteen eggshell pooled samples tested positive for Salmonella by CM-n-PCR, compared with only two by BCM. Three egg yolk pooled samples tested positive for this pathogen by CM-n-PCR; none tested positive by BCM. Three eggshell pooled samples tested positive for L. monocytogenes by CM-n-PCR and none by BCM. In Mexico, as in other countries, official methods for detection of Salmonella and L. monocytogenes in foods are based on standard bacteriological culture techniques. The inclusion of more sensitive methods such as the one used in the present investigation would increase the probability of detecting positive samples, particularly in those foods in which a very low number of cells is expected.
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Vasilopoulos, Yannis, Eliška Skořepová i Miroslav Šoóš. "COMF: Comprehensive Model-Fitting Method for Simulating Isothermal and Single-Step Solid-State Reactions". Crystals 10, nr 2 (24.02.2020): 139. http://dx.doi.org/10.3390/cryst10020139.
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It is well known that the implementation of the conventional model-fitting (CMF) method leads to several indistinguishable ‘best’ candidate models (BCMs) for a single-step isothermal solid-state reaction (ISSR), meaning that subjective selection becomes unavoidable. Here, we developed a more robust comprehensive model-fitting method (COMF) which, while maintaining the mathematical simplicity of CMF, utilizes a ranking criterion that enables automatic and unambiguous determination of the BCM. For each model evaluated, COMF, like CMF, fits the integral reaction rate, but, unlike CMF, it also fits the experimental conversion fraction and reaction speed. From this, three different determination coefficients are calculated and combined to rank the considered models. To validate COMF, we used two sets of experimental kinetic data from the literature regarding the isothermal desolvation of pharmaceutical solvates: (i) tetrahydrofuran solvates of sulfameter, and (ii) methanol solvates of ciclesonide. Our results suggest that from an algorithmic perspective, COMF could become the model-fitting method of choice for ISSRs making the selection of BCM easier and more reliable.
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Kearns, Kathryn N., Ching-Jen Chen, Petr Tvrdik, Min S. Park i M. Yashar S. Kalani. "Outcomes of Surgery for Brainstem Cavernous Malformations". Stroke 50, nr 10 (październik 2019): 2964–66. http://dx.doi.org/10.1161/strokeaha.119.026120.
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Background and Purpose— The goal of this study was to systematically review the outcomes and complications after surgical resection of brain stem cavernous malformations (BCMs). Methods— A systematic literature review was performed using the PubMed database for studies published between 1986 and 2018. All studies comprising ≥2 patients with surgically resected BCMs and available follow-up data were included. Data extracted from studies included patient demographics, BCM location, and surgical outcomes. Results— Eighty-six studies comprising 2493 patients (adult and pediatric) were included for final analysis. Complete resection was achieved in 92.3% (fixed-effects pooled estimate [FE], 92.9% [91.7%–94.0%]; random-effects pooled estimate [RE], 89.4% [86.5%–92.0%]) of patients, and rehemorrhage of residual BCMs occurred in 58.6% (FE, 58.8% [49.7%–67.6%]; RE, 57.2% [43.5%–70.2%]). Postoperative morbidity occurred in 34.8% (FE, 30.9% [29.0%–32.8%]; RE, 31.1% [25.8%–36.6%]) of patients. Postoperative morbidities included motor deficit in 11.0% (FE, 9.9% [8.1%–11.7%]; RE, 11.1% [7.0%–16.0%]), sensory deficit in 6.7% (FE, 6.3% [4.8%–7.9%]; RE, 7.6% [4.5%–11.5%]), tracheostomy/gastrostomy in 6.0% (FE, 5.2% [4.3%–6.1%]; RE, 3.8% [2.6%–5.3%]), and other cranial nerve deficits in 29.4% (FE, 27.6% [25.3%–29.9%]; RE, 33.9% [25.7%–42.6%]) of patients. At final follow-up, 57.9% (FE, 57.6% [55.6%–59.6%]; RE, 57.2% [52.1%–62.3%]) and 25.9% (FE, 24.1% [22.4%–25.9%]; RE, 18.5% [14.6%–22.8%]) of patients had improvement and stability of preoperative symptoms, respectively. Mortality rate was 1.6% (FE, 1.9% [1.4%–2.5%]; RE, 1.8% [1.4%–2.5%]). Conclusions— High cure rates and low rates of postoperative morbidity can be achieved with surgery in patients with BCMs. Most patients had improved preoperative symptoms at final follow-up. To avoid rehemorrhage, complete resection should be the goal of surgery.
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Schwenkel, Johannes, i Björn Maronga. "Towards a Better Representation of Fog Microphysics in Large-Eddy Simulations Based on an Embedded Lagrangian Cloud Model". Atmosphere 11, nr 5 (5.05.2020): 466. http://dx.doi.org/10.3390/atmos11050466.
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The development of radiation fog is influenced by multiple physical processes such as radiative cooling and heating, turbulent mixing, and microphysics, which interact on different spatial and temporal scales with one another. Once a fog layer has formed, the number of fog droplets and their size distribution have a particularly large impact on the development of the fog layer due to their feedback on gravitational settling and radiative cooling at the fog top, which are key processes for fog. However, most models do not represent microphysical processes explicitly, or parameterize them rather crudely. In this study we simulate a deep radiation fog case with a coupled large-eddy simulation (LES)–Lagrangian cloud model (LCM) approach for the first time. By simulating several hundred million fog droplets as Lagrangian particles explicitly (using the so-called superdroplet approach), we include a size-resolved diffusional growth including Köhler theory and gravitational sedimentation representation. The results are compared against simulations using a state of the art bulk microphysics model (BCM). We simulate two different aerosol backgrounds (pristine and polluted) with each microphysics scheme. The simulations show that both schemes generally capture the key features of the deep fog event, but also that there are significant differences: the drop size distribution produced by the LCM is broader during the formation and dissipation phase than in the BCM. The LCM simulations suggest that its spectral shape, which is fixed in BCMs, exhibits distinct changes during the fog life cycle, which cannot be taken into account in BCMs. The picture of the overall fog droplet number concentration is twofold: For both aerosol environments, the LCM shows lower concentrations of larger fog droplets, while we observe a higher number of small droplets and swollen aerosols reducing the visibility earlier than in the BCM. As a result of the different model formulation we observe higher sedimentation rates and lower liquid water paths for the LCM. The present work demonstrates that it is possible to simulate fog with the computational demanding approach of LCMs to assess the advantages of high-resolution cloud models and further to estimate errors of traditional parameterizations.
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Nanri, Satoshi, Taishi Shinobu, Sho Otsuka i Seiji Nakagawa. "Intelligibility of bone-conducted speech detected on the scalp". INTER-NOISE and NOISE-CON Congress and Conference Proceedings 263, nr 2 (1.08.2021): 4394–401. http://dx.doi.org/10.3397/in-2021-2689.
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Bone-conduction microphones (BCMs) can detect speakers' voices with high signal-to-noise ratio even under extremely noisy environments like a machine factory or an engine room of a watercraft. BCMs are ordinarily attached to the front of the neck (larynx), therefore, it is sometimes accompanied by discomfort and esthetic problems. In order to solve such problems, we have been developing a novel BCM system built in a helmet, however, characteristics of bone-conducted speech detected on the scalp need to be clarified. In this study, mono-syllable articulations of bone-conducted speech detected at several locations on the head and neck were measured. Also, the speech transmission index (STI), objective measure of signal transmission quality, was calculated. The results indicated that the forehead and the vertex showed better articulation and STI than the mastoid process of the temporal bone, the mandibular condyle, and the occiput. In terms of the gender difference, the forehead and the vertex showed higher scores for the male voice, whereas the cheek showed the highest for the female voice. Additionally, the larynx showed lower scores than others. These results indicated that the attenuation of high-frequency components are smaller at the forehead and the vertex.
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Strausbaugh, C. A., P. N. Miklas, S. P. Singh, J. R. Myers i R. L. Forster. "Genetic Characterization of Differential Reactions Among Host Group 3 Common Bean Cultivars to NL-3 K Strain of Bean common mosaic necrosis virus". Phytopathology® 93, nr 6 (czerwiec 2003): 683–90. http://dx.doi.org/10.1094/phyto.2003.93.6.683.
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A previously unrecognized recessive resistance gene (or allele) was identified in three host group (HG) 3 common bean (Phaseolus vulgaris) cvs. Olathe, Victor, and UI 37, based on genetic analysis of plants from five populations screened with the NL-3 K strain of Bean common mosaic necrosis virus (BCMNV). The gene (or allele) was associated with resistance to leaf stunting and deformity and reduction in plant height. The gene (or allele) provides similar, but slightly better resistance than the bc-12 gene that is characteristic of HG 3 cultivars. Traditional HG 3 cultivars like Redlands Greenleaf B with bc-12 are susceptible to NL-3 K, whereas this newly identified gene (or allele) conditions resistance to NL-3 K. Other slight variations in disease reaction pattern to a wide array of bean common mosaic (BCM)-inducing strains were noted among HG 3 differentials, indicating that additional resistance to BCM exists in common bean that remains to be exploited. To gauge the full breeding value of this newly identified gene (or allele), allelism tests with existing genes, namely bc-12, and further characterization of responses to all Bean common mosaic virus (BCMV) and BCMNV strains need to be conducted. Meanwhile, breeders should consider introgressing this more effective gene (or allele) into susceptible cultivars while plant pathologists continue to decipher the genetic variability present among HG 3 differential cultivars.
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Hu, Yongxian, Zhang Yanlei, Guoqing Wei, Chang alex Hong i He Huang. "Potent Anti-Tumor Activity of Bcma CAR-T Therapy Against Heavily Treated Multiple Myeloma and Dynamics of Immune Cell Subsets Using Single-Cell Mass Cytometry". Blood 134, Supplement_1 (13.11.2019): 1859. http://dx.doi.org/10.1182/blood-2019-130341.
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Background BCMA CAR-T cells have demonstrated substantial clinical activity against relapsed/refractory multiple myeloma (RRMM). In different clinical trials, the overall response rate (ORR) varied from 50% to 100%. Complete remission (CR) rate varied from 20% to 80%. Here we developed a BCMA CAR-T cell product manufactured via lentiviral vector-mediated transduction of activated T cells to express a second-generation CAR with 4-1BB costimulatory domain and evaluated the efficacy and safety, moreover, dynamics of immune cell subsets using single-cell mass cytometry during treatment were analyzed. Methods Our trial (ChiCTR1800017404) is a phase 1, single-arm, open-label single center study to evaluate the safety and efficacy of autologous BCMA CAR-T treatment for RRMM. Patients were subjected to a lymphodepleting regimen with Flu and Cy prior to CAR-T infusion. BCMA CAR-T cells were administered as a single infusion at a median dose of 3.5 (1 to 6) ×106/kg. MM response assessment was conducted according to the International Uniform Response Criteria. Cytokine-release syndrome (CRS) was graded as Lee DW et al described (Blood.2014;124(2):188-195). Phenotypic analysis of peripheral blood mononuclear cells (PBMCs), frozen BCMA CAR-T aliquots, phenotype and in vivo kinetics of immune cell subsets after CAR-T infusion were performed by single-cell mass cytometry. Results As of the data cut-off date (August 1st, 2019), 33 patients, median age 62.5 (49 to 75) years old were infused with BCMA CAR-T cells. The median observation period is 8.0 (0.7 to 18) months. ORR was 100% (The patient who died of infection at 20 days after CAR-T infusion were excluded). All the 32 patients achieved MRD negative in bone marrow by flow cytometry in 2 weeks after CAR-T infusion. Partial response (4 PR, 12.1%), VGPR (7 VGPR, 21.2%), and complete response (21 CR, 63.6%) within 12 weeks post CAR-T infusion were achieved. Durable responses from 4 weeks towards the data cut-off date were found in 28/33 patients (84.8%) (Figure 1a). All patients had detectable CAR-T expansion by flow cytometry from Day 3 post CAR-T cell infusion. The peak CAR-T cell expansion in CD3+ lymphocytes of peripheral blood (PB) varied from 35% to 95% with a median percentage of 82.9%. CRS was reported in all the 33 patients, including 4 with Grade 1, 13 with Grade 2 and 16 with Grade 3. During follow-up, 1-year progression-free survival (PFS) was 70.7% (Figure 1b) and overall survival (OS) was 71.7% (Figure 1c). Multivariate analysis of patients with PR and patients with CR+VGPR revealed that factors including extramedullary infiltration, age>60 years old, high-risk cytogenetics, late stage and CAR-T cell dose were not associated with clinical response (P>0.05). Single-cell mass cytometry revealed that the frequency of total T cells, CD8+ T cells, NK cells and CD3+CD56+ NKT cells in PB was not associated with BCM CAR-T expansion or clinical response. CD8+ Granzyme B+ Ki-67+ CAR-T cells expanded prominently in CRS period. As serum cytokines increased during CRS, non-CAR-T immune cell subsets including PD1+ NK cells, CD8+ Ki-67+ ICOS+ T cells expanded dominantly implying that non-CAR-T cells were also activated after CAR-T treatment. After CRS, stem cell like memory CAR-T cells (CD45RO+ CCR7- CD28- CD95+) remain the main subtype of CAR-T cells (Figure 1d). Conclusions Our data showed BCMA CAR-T treatment is safe with prominent efficacy which can overcome the traditional high-risk factors. We also observed high expansion level and long-term persistence of BCMA CAR-T cells contribute to potent anti-myeloma activity. Stem cell like memory CAR-T cells might be associated with long-term persistence of BCMA CAR-T cells. These initial data provide strong evidence to support the further development of this anti-myeloma cellular immunotherapy. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Savage, Beth A., Ann E. Titus, Jennifer G. Manns i Rachel A. Lee. "BCMA Scanning Stars". CIN: Computers, Informatics, Nursing 32, nr 9 (wrzesień 2014): 413–19. http://dx.doi.org/10.1097/cin.0000000000000097.
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Mullard, Asher. "The BCMA bonanza". Nature Reviews Drug Discovery 18, nr 7 (13.06.2019): 481–84. http://dx.doi.org/10.1038/d41573-019-00105-9.
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Smigel, K. "BCPT: Participant Update". JNCI Journal of the National Cancer Institute 86, nr 13 (6.07.1994): 962. http://dx.doi.org/10.1093/jnci/86.13.962.
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Springer, Günter. "Zielgerichtet gegen BCMA". InFo Hämatologie + Onkologie 23, nr 12 (grudzień 2020): 62. http://dx.doi.org/10.1007/s15004-020-8328-5.
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Lv, Yanyan, Xiaopeng Deng, Lingtong Quan, Yan Xia i Zhenguo Shen. "Metallothioneins BcMT1 and BcMT2 from Brassica campestris enhance tolerance to cadmium and copper and decrease production of reactive oxygen species in Arabidopsis thaliana". Plant and Soil 367, nr 1-2 (12.10.2012): 507–19. http://dx.doi.org/10.1007/s11104-012-1486-y.
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Carpenter, Robert O., Moses O. Evbuomwan, Stefania Pittaluga, Jeremy J. Rose, Mark Raffeld, Shicheng Yang, Ronald E. Gress, Frances T. Hakim i James N. Kochenderfer. "B-Cell Maturation Antigen Is a Promising Target for Genetically-Modified T-Cell Therapy of Multiple Myeloma". Blood 120, nr 21 (16.11.2012): 937. http://dx.doi.org/10.1182/blood.v120.21.937.937.
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Abstract Abstract 937 Multiple myeloma (MM) is a usually incurable malignancy of plasma cells. New therapies are urgently needed for MM. Development of immunotherapies targeting antigens expressed by MM cells could improve the outcomes of patients with multiple myeloma (MM). Chimeric antigen receptors (CARs) are fusion proteins containing antigen-recognition moieties and T-cell activation domains. T cells genetically modified to express CARs can specifically recognize tumor antigens, and CAR-expressing T cells have potent in vivo activity against some types of lymphoma and leukemia. Unfortunately, development of CAR-expressing T-cell therapies for MM has been hindered because most proteins expressed on MM cells are also expressed on essential normal cells. We report here our work developing CARs that target B-cell maturation antigen (BCMA). BCMA is a protein that has been reported to be selectively expressed by B-lineage cells including MM cells. We hypothesized that BCMA would be a suitable target for CAR-expressing T cells. We evaluated BCMA expression in all major human organs, and we designed and tested the first anti-BCMA CARs. We assessed BCMA RNA expression in all major human organs by quantitative PCR. Although BCMA RNA expression was mainly limited to hematologic tissues, low levels of BCMA RNA were detected in gastrointestinal organs, trachea, and testes. Next, we assessed BCMA protein expression in samples of 33 normal human organs by immunohistochemistry (IHC). BCMA-expressing plasma cells were detected in the lamina propria of several gastrointestinal organs by IHC, but BCMA protein was not detected in other gastrointestinal tissues. BCMA-expressing gastrointestinal plasma cells were probably the source of the low levels of BCMA RNA detected in normal gastrointestinal organs. Except for plasma cells, BCMA expression was not detected in any normal human tissues by IHC. Furthermore, BCMA was not detected on primary human CD34+hematopoietic cells by flow cytometry. In contrast, we detected uniform BCMA cell-surface expression by either flow cytometry or IHC on primary MM cells from 5 of 5 patients. Because BCMA is expressed by MM cells but not by normal essential tissues, we reasoned that BCMA would be an appropriate target for CAR-expressing T cells. We designed anti-BCMA CARs that contained antigen receptor domains derived from anti-BCMA monoclonal antibodies. The CARs also contained the signaling moiety of the CD28 molecule and the signaling domains of the CD3-zeta molecule. DNA encoding these CARs was ligated into a self-inactivating lentiviral vector, and human T cells were transduced with the anti-BCMA CARs. After transduction, anti-BCMA CAR expression was routinely detected on more that 60% of the transduced T cells by flow cytometry. Notably, we were able to successfully culture and transduce T cells from heavily treated patients with advanced MM. T cells expressing anti-BCMA CARs produced IFN-gamma, IL-2, and tumor necrosis factor in a BCMA-specific manner. T cell degranulation, which is required for perforin-mediated cytotoxicity, is associated with upregulation of CD107a. Anti-BCMA-CAR-transduced T cells upregulated CD107a when stimulated with BCMA-expressing target cells but not when stimulated with BCMA-negative target cells. Anti-BCMA-CAR-transduced T cells proliferated in a BCMA-specific manner. Anti-BCMA-CAR-transduced T cells killed BCMA-expressing multiple myeloma cells lines but not BCMA-negative cell lines. Importantly, anti-BCMA-CAR-transduced T cells produced interferon-gamma when cultured with BCMA-expressing primary MM cells but not when cultured with BCMA-negative peripheral blood mononuclear cells. Anti-BCMA-CAR-transduced T cells killed 66% of autologous primary MM cells in a BCMA-specific manner at a T cell to MM cell ratio of 7:1 in a 4-hour cytotoxicity assay. In summary, BCMA is expressed on MM cells of many patients, and BCMA is not expressed by normal essential tissues; therefore, BCMA is a suitable target for CAR-expressing T cells. We constructed and tested the first reported anti-BCMA CARs, and we showed that these T cells exhibited BCMA-specific functions including killing of primary MM cells. Adoptive transfer of anti-BCMA-CAR-transduced T cells is a promising new strategy for treating MM. These findings are the first steps toward clinical trials of anti-BCMA CAR-expressing T cells. Disclosures: Kochenderfer: National Cancer Institute: Inventor on patent application by National Cancer Institute., Inventor on patent application by National Cancer Institute. Patents & Royalties.
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Li, Luoman, Yaxin Jiang, LiLi Su, Deming Feng, Jing Wei i Jian Sun. "Study on the Mechanism of Selective Interaction of BR3 and BCMA with BAFF and APRIL". Protein & Peptide Letters 27, nr 11 (16.11.2020): 1114–23. http://dx.doi.org/10.2174/0929866527666200413101757.
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Background: B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) can activate signaling pathways by binding to specific receptors. BR3 (BAFF receptor) shows a unique selectivity for BAFF ligand, while B-cell maturation antigen (BCMA) exhibits a stronger interaction between APRIL-BCMA rather than BAFF-BCMA interaction. Objective: The combined domains were fused with IgG1 Fc to better understand which domain affects the selective interaction of the receptor with BAFF and APRIL. Methods: Since BR3 and BCMA both contain cysteine-rich repeat domains (CRD) with DxL motif, the binding domains of BR3 and BCMA were segmented into two parts in this study. BR3-1 (CFDLLVRHGVAC) and BCMA-1 (YFDSLLHACIPC) contained the conservative DxL motif, while BR3-2 (GLLRTPRPKPA) and BCMA-2 (QLRCSSNTPPLT) were adjacent to the CRDs yet still joined with BR3-1 and BCMA-1. Affinity between all possible combinations was then tested. Results: The affinity of BR3-1-BCMA-2-Fc and BR3-1-BR3-2-Fc for BAFF was higher than BCMA-1-BR3-2-Fc and BCMA-1-BCMA-2-Fc. Moreover, BR3-1-BCMA-2-Fc and BCMA-1-BCMA- 2-Fc had affinity for APRIL, while BR3-1-BR3-2-Fc and BCMA-1-BR3-2-Fc hardly interacted with APRIL. Conclusion: BR3-1 region played a key role for interaction with BAFF, while BCMA-1 region exhibited weaker binding with BAFF. BCMA-2 region having an α-helix might contribute towards selectivity of APRIL-BCMA binding and BR3-2 rigid region had deleterious effects on the APRIL-BR3 interaction. These results provide comprehensive insights of the mechanism of selective interactions, and may promote specific antagonist design in the future.
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Stojkovic, Milan, i Slobodan P. Simonovic. "System Dynamics Approach for Assessing the Behaviour of the Lim Reservoir System (Serbia) under Changing Climate Conditions". Water 11, nr 8 (6.08.2019): 1620. http://dx.doi.org/10.3390/w11081620.
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Investigating the impact of climate change on the management of a complex multipurpose water system is a critical issue. The presented study focuses on different steps of the climate change impact analysis process: (i) Use of three regional climate models (RCMs), (ii) use of four bias correction methods (BCMs), (iii) use of three concentration scenarios (CSs), (iv) use of two model averaging procedures, (v) use of the hydrological model and (vi) use of the system dynamics simulation model (SDSM). The analyses are performed for a future period, from 2006 to 2055 and the reference period, from 1971 to 2000. As a case study area, the Lim water system in Serbia (southeast Europe) is used. The Lim river system consists of four hydraulically connected reservoirs (Uvac, Kokin Brod, Radojnja, Potpec) with a primary purpose of hydropower generation. The results of the climate change impact analyses indicate change in the future hydropower generation at the annual level from −3.5% to +17.9%. The change has a seasonal variation with an increase for the winter season up to +20.3% and decrease for the summer season up to −33.6%. Furthermore, the study analyzes the uncertainty in the SDSM outputs introduced by different steps of the modelling process. The most dominant source of uncertainty in power production is the choice of BCMs (54%), followed by the selection of RCMs (41%). The least significant source of uncertainty is the choice of CSs (6%). The uncertainty in the inflows and outflows is equally dominated by the choice of BCM (49%) and RCM (45%).
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Lesley, Gerry, Paul Nguyen, Nicholas J. Taylor, Todd B. Marder, Andrew J. Scott, William Clegg i Nicholas C. Norman. "Synthesis and Characterization of Platinum(II)−Bis(boryl) Catalyst Precursors for Diboration of Alkynes and Diynes: Molecular Structures ofcis-[(PPh3)2Pt(B-4-Butcat)2],cis-[(PPh3)2Pt(Bcat)2],cis-[(dppe)Pt(Bcat)2],cis-[(dppb)Pt(Bcat)2], (E)-(4-MeOC6H4)C(Bcat)CH(Bcat), (Z)-(C6H5)C(Bcat)C(C6H5)(Bcat), and (Z,Z)-(4-MeOC6H4)C(Bcat)C(Bcat)C(Bcat)C(4-MeOC6H4)(Bcat) (cat = 1,2-O2C6H4; dppe = Ph2PCH2CH2PPh2; dppb = Ph2P(CH2)4PPh2)". Organometallics 15, nr 24 (styczeń 1996): 5137–54. http://dx.doi.org/10.1021/om950918c.
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Cheung, Chong Soo, Dong Keun Yoon i Tae hwan Kim. "Comparative Analysis of Certification in between Performance of Disaster Safety Technology and Business Continuity Management System (BCMS)". Journal of Korean Society of Hazard Mitigation 15, nr 5 (31.10.2015): 67–77. http://dx.doi.org/10.9798/kosham.2015.15.5.67.
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Berahovich, Robert, Hua Zhou, Shirley Xu, Yuehua Wei, Jasper Guan, Jian Guan, Hizkia Harto i in. "CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth". Cancers 10, nr 9 (11.09.2018): 323. http://dx.doi.org/10.3390/cancers10090323.
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The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-γ in vitro. BCMA-dependent cytotoxicity and IFN-γ secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development.
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Feng, Xue, Gardenia E. Orellana, James C. Green, Michael J. Melzer, John S. Hu i Alexander V. Karasev. "A New Strain of Bean Common Mosaic Virus From Lima Bean (Phaseolus lunatus): Biological and Molecular Characterization". Plant Disease 103, nr 6 (czerwiec 2019): 1220–27. http://dx.doi.org/10.1094/pdis-08-18-1307-re.
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Lima bean (Phaseolus lunatus) is a popular cultivated legume vegetable grown in the United States for dry bean or canned bean production. In 2017, two symptomatic P. lunatus plants exhibiting mosaic, vein banding, and growth retardation were collected in a public garden in Honolulu, HI. Both samples contained bean common mosaic virus (BCMV), and the two BCMV isolates were subjected to biological characterization on a panel of 11 differential cultivars of common bean (P. vulgaris), and to molecular characterization through whole genome sequencing. Both samples contained nearly identical BCMV sequences, named BCMV-A1, which, in turn, were 93% identical to the peanut stripe virus strain of BCMV. BCMV-A1 induced an unusually severe systemic necrosis in cultivar ‘Dubbele Witte’, and pronounced necrotic or chlorotic reaction in inoculated leaves of five other bean differentials. BCMV-A1 was able to partially overcome resistance alleles bc-1 and bc-2 expressed singly in common bean, inducing no systemic symptoms. Phylogenetic analysis of the BCMV-A1 sequence, and distinct biological reactions in common bean differentials suggested that BCMV-A1 represented a new lima bean strain of BCMV. In 2017, two BCMV isolates were collected in Idaho from common bean, and based on partial genome sequences were found 99% identical to the BCMV-A1 sequence. The data suggest that the lima bean strain of BCMV may have a wider circulation, including common bean as a host. This new strain of BCMV may thus pose a significant threat to common bean production.
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Bae, Jooeun, Parayath Neha, Mansoor Amiji, Nikhil Munshi i Kenneth Anderson. "Bcma Heteroclitic Peptide Encapsulated Nanoparticle Enhances Antigen Stimulatory Capacity and Tumor-Specific CD8+ cytotoxic T Lymphocytes Against Multiple Myeloma". Blood 132, Supplement 1 (29.11.2018): 3195. http://dx.doi.org/10.1182/blood-2018-99-117292.
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Abstract Background: B-cell Maturation Antigen (BCMA), a member of the tumor necrosis factor (TNF) receptor superfamily and the receptor for binding of B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), is a promising therapeutic target for MM. Due to its restricted expression pattern on MM cells and plasma cells along with its role in promoting MM cells growth, survival, and drug resistance, BCMA is being targeted by several immunotherapeutic strategies including antibodies, immunotoxins, bispecific T-cell engagers, and CAR-T cells. Recently, we have identified nanomedicine-based therapeutics targeting BCMA as a promising area of translational research to effectively evoke and augment anti-tumor responses in MM patients. Several nanomedicines are available and more advanced nanoparticle constructs are under development for antigen encapsulation. To this end, we have designed a heteroclitic BCMA peptide encapsulated nanoparticle-based cancer vaccine to overcome the limitations of free peptide vaccines including poor peptide stability, susceptibility to enzyme degradation, and low antigen uptake and delivery. Furthermore, the nanotechnology-based cancer vaccine was developed to induce more robust BCMA-specific CD8+ cytotoxic T lymphocytes (CTL) activities in MM patients, with more sustained antigen release and increased bioavailability and presentation of the immunogenic peptide. Here, we examine the potential of a novel nanomedicine-based therapeutic delivery system specific to BCMA antigen to treat the patients with MM. Objective: The purpose of this study was to design the optimal nanoparticle encapsulated BCMA antigen constructs to efficiently evoke and develop the BCMA-specific CD8+ CTL with functional anti-myeloma activities. Findings: Nanoparticles [liposome or poly(D,L-lactide-co-glycolide) (PLGA)] with different antigen-release kinetics demonstrated their capacity to effectively deliver heteroclitic BCMA peptideto antigen-presenting cells and evoke BCMA antigen-specific CTL with anti-MM activities. The heteroclitic BCMA peptide encapsulated nanoparticles demonstrated a higher uptake by human dendritic cells than free peptide, with the highest uptake mediated with liposome-based nanoparticles. In contrast, BCMA-specific CTL induced with PLGA-based nanoparticle demonstrated the highest functional activities and specific immune responses against MM cells. The PLGA/BCMA peptide nanoparticle induced BCMA-specific CTL displayed the highest increases in CD107a degranulation, the antigen-specific CD8+ T cells proliferation and Th-1 type cytokines (IFN-g, IL-2, TNF-a) production to MM patients' tumor cells and MM cell lines compared to BCMA-CTL generated with free BCMA peptide or liposome/BCMA peptide nanoparticle. These observations were aligned with the highest level of CD28 costimulatory molecules upregulation, Tetramer+ CTL generation and peptide-specific responses within the BCMA-CTL generated by PLGA/BCMA nanoparticles. Furthermore, the PLGA/BCMA nanoparticles triggered a more robust induction of antigen-specific memory CD8+ T cells, which demonstrated significantly higher anti-tumor activities, evidenced by CD107a degranulation and IFN-g production, compared to non-memory CD8+ T cells within the BCMA-CTL. Especially, the increased central memory CTL development and their anti-tumor activities evoked by PLGA/BCMA peptide were associated with the optimal peptide release kinetics and enhanced immunogenicity of the antigen via this nanotechnology. Thus, these results demonstrate that the heteroclitic BCMA peptide encapsulated nanoparticle strategy supports the peptide delivery into dendritic cells and then subsequently to T cells, resulting in effective induction of BCMA-specific central memory CTL with poly-functional activities against MM. Significance: These results demonstrate the utility of nanotechnology using encapsulated heteroclitic BCMA peptide to enhance the immunogenicity of BCMA peptide-specific therapeutics against MM. Importantly, our observations provide the framework for therapeutic application of PLGA-based heteroclitic BCMA peptide delivery to enhance the BCMA-specific memory T cell immune responses, overcome the limitations of current peptide-based cancer vaccine, and improve the patient outcome in MM. Disclosures Munshi: OncoPep: Other: Board of director. Anderson:Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Millennium Takeda: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees.
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Cohen, Adam D., Alfred L. Garfall, Ahmet Dogan, Simon F. Lacey, Chris Martin, Nikoletta Lendvai, Dan T. Vogl, Matthew Spear i Alexander M. Lesokhin. "Serial treatment of relapsed/refractory multiple myeloma with different BCMA-targeting therapies". Blood Advances 3, nr 16 (26.08.2019): 2487–90. http://dx.doi.org/10.1182/bloodadvances.2019000466.
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Key Points Myeloma patients progressing on BCMA-targeted therapy can maintain BCMA expression and still respond to different BCMA-targeted therapy. These observations suggest this patient population could be included in ongoing BCMA-targeted therapy trials.
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Matsuo, Yutaka. "BCFT and sliver state". Physics Letters B 513, nr 1-2 (lipiec 2001): 195–99. http://dx.doi.org/10.1016/s0370-2693(01)00739-0.
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Brøsen, Kim. "BCPT Focused Nordic Conference". Basic & Clinical Pharmacology & Toxicology 108, nr 5 (13.04.2011): 293–94. http://dx.doi.org/10.1111/j.1742-7843.2011.00704.x.
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Smigel, Kara. "BCPT Drops Enrollment Target". JNCI: Journal of the National Cancer Institute 88, nr 19 (2.10.1996): 1340. http://dx.doi.org/10.1093/jnci/88.19.1340.
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Beutler, Ernest. "BCMD: The First Year". Blood Cells, Molecules, and Diseases 22, nr 1 (kwiecień 1996): 1. http://dx.doi.org/10.1006/bcmd.1996.0001.
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Stirling, David. "Report of BCME-5". MSOR Connections 1, nr 4 (listopad 2001): 55. http://dx.doi.org/10.11120/msor.2001.01040055.
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Lippman, Marc. "BCRT: a brief valedictory". Breast Cancer Research and Treatment 178, nr 3 (16.10.2019): 483. http://dx.doi.org/10.1007/s10549-019-05475-7.
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Evans, D. Gareth. "BCRT response to Moller". Breast Cancer Research and Treatment 148, nr 3 (15.11.2014): 693. http://dx.doi.org/10.1007/s10549-014-3200-7.
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Kumar, Gaurav, Zahra Maria, Uday Kohli, Agnieshka Agasing, James L. Quinn, Rose M. Ko, Scott S. Zamvil i Robert C. Axtell. "CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS". Neurology - Neuroimmunology Neuroinflammation 8, nr 3 (1.03.2021): e973. http://dx.doi.org/10.1212/nxi.0000000000000973.
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ObjectiveB cells have emerged as a therapeutic target for MS. Anti-CD20 antibodies, which deplete B cells, are effective therapies for MS. However, atacicept (TACI-Fc), which blocks BAFF and APRIL and reduces B cells, unexpectedly exacerbates MS. We tested the hypothesis that B cell maturation antigen (BCMA), a receptor for BAFF and APRIL, plays a role in the paradoxical effects of anti-CD20 antibody and TACI-Fc using experimental autoimmune encephalomyelitis (EAE).MethodsEAE was induced in wild-type (BCMA+/+) and BCMA-deficient (BCMA−/−) mice with an immunization of rodent myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. Treatment with anti-CD20 antibody, TACI-Fc, and isotype controls was administered by intraperitoneal injections. CNS infiltration was evaluated by histology; immune cell phenotypes were evaluated by flow cytometry; MOG-specific antibodies were determined by ELISA. Mixed bone marrow chimeras and cell culture assays were used to identify the specific subsets of immune cells affected by BCMA deficiency.ResultsFirst, we found that BCMA−/− mice had more severe EAE compared with BCMA+/+ mice and the increased disease was associated with elevated anti-MOG B-cell responses. Second, we found that anti-CD20 therapy attenuated EAE in BCMA−/− mice but not in BCMA+/+ mice. Third, TACI-Fc attenuated EAE in BCMA+/+ mice but not in BCMA−/− mice. Mixed bone marrow chimeric and cell culture experiments demonstrated that BCMA deficiency elevates inflammatory B-cell responses but inhibits inflammatory responses in macrophages.ConclusionsBCMA has multifaceted roles during inflammation that affects therapeutic efficacies of anti-CD20 and TACI-Fc in EAE. Our results from BCMA-deficient mice provide insights into the failure of atacicept in MS.
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BERGMAN, P., i G. HAUSER. "BIOSOCIAL AND NUTRITIONAL EFFECTS ON BODY COMPOSITION IN YOUNG ADULTS FROM WROCŁAW, POLAND". Journal of Biosocial Science 38, nr 6 (23.11.2005): 721–34. http://dx.doi.org/10.1017/s0021932005001124.
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This work concerns the questions if and to what extent social variables past and present, and actual sports activity and nutritional and smoking habits, have an influence on body compartment indices, and how this differs between female and male medical students from Wrocław, Poland. Backward stepwise regression was applied to four dependent variables, i.e. Body Mass Index (BMI), %Fat Mass (%FM), Extracellular Water/Intracellular Water Index (100×ECW/ICW) and Body Cell Mass Index (BCMI=BCM/height2), and for eighteen independent variables including nutrition, parents’ social status, smoking and sports activity. Females ate meat less frequently and fruit and vegetables more often, and drank beer less frequently but milk more often than did male students. It seems that there exists some effect on fat accumulation resulting from difference in nutrition between females and males. The results may be interpreted in terms of a parental gender effect on body composition of children associated with different conditions of life and nutrition in childhood and youth for female and male students in Wrocław.
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Pont, Margot J., Tyler Hill, Gabriel O. Cole, Joe J. Abbott, Jessica Kelliher, Alexander I. Salter, Michael Hudecek i in. "γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma". Blood 134, nr 19 (25.09.2019): 1585–97. http://dx.doi.org/10.1182/blood.2019000050.
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Despite notably high response rates to B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells in multiple myeloma, few patients have a sustained, very good partial or complete response. This article presents a novel strategy to increase the efficacy of BCMA-directed CAR T-cell therapy and shows that γ-secretase inhibitors improve the efficacy of BCMA CAR T cells by increasing BCMA expression and reducing soluble BCMA.
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Green, Damian J., Margot Pont, Andrew J. Cowan, Gabriel O. Cole, Blythe Duke Sather, Anne M. Nagengast, Xaoling Song i in. "Response to Bcma CAR-T Cells Correlates with Pretreatment Target Antigen Density and Is Improved By Small Molecule Inhibition of Gamma Secretase". Blood 134, Supplement_1 (13.11.2019): 1856. http://dx.doi.org/10.1182/blood-2019-129582.
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Introduction: The adoptive transfer of B-Cell Maturation Antigen (BCMA) chimeric antigen receptor (CAR) T cells is demonstrating early promise in multiple myeloma [MM], however durable responses remain elusive and most studies report >50% of patients relapsing within 18 months of receiving CAR-T cell therapy. The mechanism of relapse is likely the consequence of multiple factors including the variable distribution of BCMA on tumor cells, allowing cells with low antigen density to escape. Initial target density, receptor downregulation and the emergence of antigen loss variants have all been implicated in relapse following CAR-T cells directed against CD22 and CD19. Reduced or absent BCMA expression may similarly be linked to relapse in MM. We have previously demonstrated that BCMA cleavage by the γ-secretase complex reduces ligand density for CAR-T cell recognition, and that a small molecule γ-secretase inhibitor (GSI) markedly increases surface BCMA levels in a dose-dependent fashion while improving CAR-T cell recognition in preclinical models. Methods and Results: In a phase I first-in-human study (NCT03338972) employing a CAR-T cell construct encoding a fully human BCMA scFv and 4-1BB/CD3z, rapid and deep objective responses at CAR-T cell doses starting at 5 x 107 have been observed. All patients had bone marrow (BM) involvement at baseline (mean 42.5 % CD138+ by IHC) and 14/15 had no detectable disease in the BM 28 days after therapy. One patient with comparatively very low BCMA expression (BCMA antibody binding capacity [ABC; QuantiBRITE] = 269; 16.9% of the malignant plasma cells (PCs) BCMA+ by flow cytometry) was the only subject with persistent tumor cells in the BM 28 days after therapy. Despite complete BM responses in all remaining patients, late relapses have occurred. Differences in the BCMA expression level on tumor cells prior to CAR-T cells between long term responders and those with relapse are evident. Among the 12 subjects with at least 3 months of follow up, those remaining in remission (median 12 months, range 3-16; data cut off 7/15/19) demonstrated a median pre-treatment BCMA ABC of 1761 (range 781-2922, n=5), in contrast patients with relapse (mean of 7.3 months, range 2-12) had a median pre-treatment BCMA ABC of 920 (range 260-1540, n=7). Six patients with a pretreatment mean ABC of 919 (range 260-1540) had BM evaluable for BCMA expression at relapse and the mean ABC decreased to 304 (range 121-519). The percent PCs expressing BCMA decreased from 77.5% (range 13 - 99.8) to 30% (range 10.4-60.4). The impact of gamma secretase inhibition on BCMA expression was assessed on BM cells obtained from a patient relapsing after BCMA CAR-T cells. At relapse a 9.5-fold decrease in ABC from baseline was observed. The cells were cultured for 5 hours in the presence of GSI (JSMD194) at a concentration of 1mM, which is readily achievable by oral administration. A significant increase in BCMA antigen expression was observed (ABC=917). The impact of modulating BCMA expression on tumor cells by concurrently administering an oral GSI with CAR-T cells is being explored in a phase one clinical trial (NCT03502577). In this setting, the GSI has increased BCMA expression when low level residual BCMA was observed following relapse after prior BCMA therapy failure. Two patients have been evaluated for response to an JSMD194 after failing other BCMA targeted agents. One received a prior BCMA CAR-T cell product and after relapse demonstrated a BCMA ABC of 769. Target expression increased in this patient almost nine-fold to 6828 (ABC) after three oral doses of JSMD194. A second patient had a BCMA ABC of 666 after failing a BCMA bispecific T cell engager. BCMA density increased over 14-fold to 9583 after GSI. Comprehensive data from the combination GSI and BCMA CAR-T cell trial are being reported separately. Conclusion: Pretreatment BCMA target density quantified with a uniform flow cytometry method of measurement and performed on all patients enrolled on a single center BCMA CAR-T cell clinical trial is associated with the durability of response. Further, BCMA expression can be significantly increased following GSI exposure in patients evidencing low BCMA ABC at baseline or when downregulation is the consequence of prior BCMA targeting therapy. The capacity for GSIs to increase BCMA target density and decrease soluble BCMA levels is a promising approach to be exploited in clinical trials. Disclosures Green: Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy; GSK: Consultancy; Seattle Genetics: Research Funding; Cellectar: Research Funding. Pont:Fred Hutchinson Cancer Research Center: Other: Inventor on a patent. Cowan:Sanofi: Consultancy; Juno: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellectar: Consultancy. Sather:Lyell Immunopharma: Employment, Equity Ownership. Blake:Celgene: Employment, Equity Ownership. Works:Celgene: Employment, Equity Ownership. Maloney:Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options ; BioLine RX, Gilead,Genentech,Novartis: Honoraria; Celgene,Kite Pharma: Honoraria, Research Funding. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; Lyell Immunopharma: Equity Ownership, Patents & Royalties, Research Funding. OffLabel Disclosure: Oral Gamma Secretase Inhibitor. Purpose is to increase expression of B Cell Maturation Antigen
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Tai, Yu-Tzu, Chirag Acharya, Mike Y. Zhong, Michele Cea, Antonia Cagnetta, Paul G. Richardson, Nikhil C. Munshi i Kenneth C. Anderson. "Constitutive B-Cell Maturation Antigen (BCMA) Activation In Human Multiple Myeloma Cells Promotes Myeloma Cell Growth and Survival In The Bone Marrow Microenvironment Via Upregulated MCL-1 and NFκB Signaling". Blood 122, nr 21 (15.11.2013): 681. http://dx.doi.org/10.1182/blood.v122.21.681.681.
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Abstract B cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), is selectively induced during plasma cell (PC) differentiation and is commonly expressed at high levels in malignant PCs. Using real time RT-PCR, we here first showed that BCMA mRNA was upregulated in CD138+ PCs from MM patients compared to normal healthy donors (p<0.04), consistent with high and restrictive BCMA expression in PCs but not normal tissues by gene expression profiling and immunohistochemistry (IHC) in a recent report (Clin Cancer Res 2013;19:2048-60). As a specific MM antigen, BCMA is universally expressed on the MM cell surface, confirmed by CD38+BCMA+ dual immunofluorescence staining. We next found that plasmacytoid dendritic cells (pDC), which support MM cell growth, survival, and drug resistance in the bone marrow (BM) microenvironment, have detectable BCMA mRNA at significantly (9-50-fold) lower levels than CD138+ plasma PCs (p<0.005 for each paired sample) from either MM patients or normal donors. Interestingly, as seen in CD138+ PCs, BCMA transcript is considerably elevated in pDC from MM patients vs. normal donors (p<0.03). In contrast, BCMA is hardly detectable in CD138-negative cells from BM aspirates of MM patients. We further define molecular mechanisms of BCMA activation in MM cells. Overexpression of BCMA in multiple MM cell lines (RPMI8226. MM1S, MM1R) by BCMA-expression vector significantly upregulates MCL-1 expression and MIP-1a, as well as NFkB p65 DNA binding activity. Conversely, BCMA siRNA blocked NFkB signaling and expression of anti-apoptotic proteins, leading to decreased MM cell viability. Importantly, stimulation of MM cells by APRIL, which is a cognate ligand for BCMA and mainly secreted by osteoclasts in the BM milieu, activated the canonical NFκB and PI3K/AKT pathways. APRIL also induces pro-survival/anti-apoptotic targets (BCL2A1, NFκB1, NFκB2) and chemotactic/osteoclast activating factors (MIP-1α and MIP1β) in a dose-dependent manner. Angiogenesis and adhesion/chemoattractant factors (IL-8, CXCL10, RANTES, MDC/ccl22) were also significantly induced upon APRIL stimulation. Conversely, BCMA-Fc protein inhibited APRIL to bind BCMA and inhibit secretion of APRIL-induced chemokines, indicating specific response of engagement of BCMA by APRIL in BCMA-expressing MM cells. Finally, APRIL induced adhesion and migration of MM cells whereas BCMA-Fc blocked APRIL-induced responses. Together, our results established active APRIL/BCMA signaling in MM in the BM microenvironment, thus providing a niche for MM disease progression. Moreover, these results strongly support rapid bench to bedside translation of the novel antagonistic anti-BCMA antibody drug conjugate (abstract #56099) to treat MM patients with a likely favorable therapeutic window. Disclosures: Tai: Onyx: Consultancy. Richardson:Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.
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Ramkumar, Poornima, Jaime Leong, Meghan Seyler, Stratton J. Georgoulis, Axel Hyrenius Wittsten, Priya Choudhry, Kole Roybal, Arun P. Wiita i Martin Kampmann. "Identifying Factors in Multiple Myeloma Controlling Response to B-Cell Maturation Antigen (BCMA)-Targeted Immunotherapy Using CRISPR-Based Functional Genomics". Blood 132, Supplement 1 (29.11.2018): 1926. http://dx.doi.org/10.1182/blood-2018-99-115368.
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Abstract Introduction: Multiple myeloma (MM) is the second most common blood cancer in the United States. Recent breakthroughs in immunotherapy have the potential to transform MM treatment. An immunotherapy target that shows considerable promise in myeloma is the B-cell maturation antigen (BCMA). BCMA is specifically expressed in myeloma cells and plasma cells, making it an ideal target in myeloma. Results from two early-phase clinical trials using anti-BCMA therapy, showed remarkable response in most patients. Although immunotherapy has been promising, recent findings suggest that patients can develop resistance to such therapies by lowering the levels of the target. Here we employ our innovative CRISPR-interference/activation (CRISPRi/a)-based functional genomics platform to identify mechanisms that regulate BCMA expression, which would enable us to design strategies to improve the efficacy of available BCMA immunotherapy agents. Methods: The CRISPRi/a platform utilizes a catalytically dead Cas9 (dCas9) fused to a transcriptional repressor domain to silence genes (CRISPRi) or to activator domains to activate transcription (CRISPRa). The CRISPR machinery is targeted to specific genes using single guide-RNAs (sgRNA). We have engineered a panel of myeloma cell lines to express components of the CRISPRi system. Here we transduced CRISPRi-AMO1 cell line with sgRNAs targeting the human genome. The sgRNA expressing cells were stained with a fluorescent-tagged BCMA antibody and FACS sorted into cells expressing high and low levels of BCMA. The cells were processed for next generation sequencing to determine the frequency of sgRNA in each of these populations. To develop BCMA chimeric antigen receptor-T (CAR-T) cells, CD8+ T cells were transduced with BCMA CAR construct specifically recognizing BCMA. To examine the anti-myeloma activity of the BCMA CAR-T cells, CAR-T cells were co-cultured with MM cell lines at a ratio of 1:2 (Effector:Target) for 24hrs. The cells were analyzed by flow cytometry for expression of CD69, an activation marker on T cells and for apoptosis of cancer cells using propidium iodide. Results: Our FACS-based genome-wide CRISPRi screen identified several genes and pathways regulating BCMA cell surface expression. In addition to previously reported gamma-secretase complex and transcription factor POU2AF1 we identified genes involved in peroxisome biogenesis, subunits of the proteasome, transcription factors and a few druggable targets regulating cell surface expression of BCMA. We are currently validating the novel genes identified from our primary genome-wide screen in a panel of MM cell lines and developing MM cell lines expressing CRISPRa machinery to perform gain-of-function screens that will complement our CRISPRi screen. Furthermore, we have developed active CAR-T cells targeting BCMA and demonstrated its efficacy in MM cell lines expressing different levels of BCMA. We are currently testing the novel genes identified from our CRISPRi screen in combination with BCMA CAR-T cells to identify genes that alter sensitivity to BCMA immunotherapy. Conclusions: Our studies have identified several novel genes and pathways regulating BCMA expression including some druggable targets. Through these studies, we expect to uncover mechanisms regulating expression of BCMA and its impact on sensitivity to BCMA immunotherapy, and pinpoint potential combination therapy targets that pre-empt resistance to BCMA immunotherapy. Disclosures Wiita: Sutro Biopharma: Research Funding; TeneoBio: Research Funding.
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Acharya, Chirag, Gang An, Mike Y. Zhong, Michele Cea, Antonia Cagnetta, Hua Jiang, Yu-Tzu Tai i Kenneth C. Anderson. "NFκB Signaling and Mcl-1 Are Critical in B Cell Maturation Antigen-Promoted Multiple Myeloma Cell Growth and Survival". Blood 124, nr 21 (6.12.2014): 3384. http://dx.doi.org/10.1182/blood.v124.21.3384.3384.
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Abstract B cell maturation antigen (BCMA), selectively elevated in malignant plasma cells, is an ideal target antigen for immunotherapies for multiple myeloma (MM). Most recently, we reported novel antagonistic anti-BCMA antibody drug conjugates (ADCs) showing potent and specific anti-MM activities via effector cell-dependent and -independent mechanisms in vitro and in vivo (Blood 2014; 123:3128) We here further characterize molecular mechanisms of BCMA activation in MM cells in the bone marrow microenvironment by directly manipulating BCMA receptor levels in MM cells and ligation of a proliferation-inducing ligand (APRIL) to MM cells. Three MM cell lines H929, MM1S, and RPMI8226 with highest, medium, and low BCMA, respectively, were either transfected with lentiviruses of BCMA shRNA or cDNA. First, downregulation of BCMA significantly blocked viability of all 3 MM cells and induced caspase3/7 activities, which led to potent reduction of colony formation in a 3-week methylcellulose culture. Next, MM1R and H929 transfectants with the Doxycyclin (dox)-inducible lentiviral expression vector pTRIPZ shBCMA were generated. Time-dependent BCMA reduction only occurred in dox (1 ug/ml)-containing media. Dox-dependent BCMA inhibition was followed by decreased anti-apoptotic genes (Mcl1, Bcl-2, XIAP, NAIP, NFκB1, NFκB2) and proliferative genes (CCND2, CDK4/6, c-MYC). Conversely, overexpression of BCMA in RPMI8226 by either pCMV6/BCMA vector or pLocBCMA lentiviruses significantly increased NFκB (p65, p50, p52) DNA binding activity. Anti-apoptotic gene and cell proliferation genes were also up-regulated in BCMA-overexpressing MM cells. In addition, osteoclast activation factors MIP-1α/β, SDF-1, angiogenesis factors (VEGF, PECAM-1), adhesion proteins (CD44, ICAM1), as well as immunosuppressive factor TGFβ were augmented in BCMA-overexpressing MM cells. Importantly, opposite effects on these downstream genes were seen in BCMA-knockdown MM cells. Moreover, stimulation of 3 MM cells by APRIL robustly induces NFκB DNA binding activity (p65, p50, and p52, to a lesser extend) and activates PI3K/AKT and ERK1/2 signaling. APRIL also induces pro-survival/anti-apoptotic targets (BCL2A1, NFκB1, NFκB2) and chemotactic/osteoclast activating factors (MIP1α and MIP1β) in a dose-dependent manner. Angiogenesis and adhesion/chemoattractant factors (VEGF, IL-8, CXCL10, and RANTES) were also significantly induced upon APRIL stimulation. In contrast, BCMA-Fc protein that blocks APRIL binding to BCMA, inhibits secretion of these cytokines/chemokines, indicating specific response of engagement of BCMA by APRIL in BCMA-expressing MM cells. APRIL induced adhesion and migration of MM cells whereas BCMA-Fc blocked APRIL-induced responses. Finally, RPMI8226/pLocBCMA cells induce earlier tumor onset and more tumor growth in mouse xenograft model when compared with control RPMI8226 cells. In contrast, pTRIPZ shBCMA H929 cells induce significantly less tumor formation and further prolong survival of mice fed with dox(2 ug/ml)-containing water than those without dox. Together, these results define molecular regulators of active APRIL/BCMA signaling cascade in the MM BM milieu, further supporting targeting APRIL/BCMA in MM. Disclosures Anderson: Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.
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Mol, Mayke, Claire van Genugten, Els Dozeman, Digna J. F. van Schaik, Stasja Draisma, Heleen Riper i Jan H. Smit. "Why Uptake of Blended Internet-Based Interventions for Depression Is Challenging: A Qualitative Study on Therapists’ Perspectives". Journal of Clinical Medicine 9, nr 1 (30.12.2019): 91. http://dx.doi.org/10.3390/jcm9010091.
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(1) Background: Blended cognitive behavioral therapy (bCBT; online and face-to-face sessions) seems a promising alternative alongside regular face-to-face CBT depression treatment in specialized mental health care organizations. Therapists are key in the uptake of bCBT. This study focuses on therapists’ perspectives on usability, satisfaction, and factors that promote or hinder the use of bCBT in routine practice; (2) Methods: Three focus groups (n = 8, n = 7, n = 6) and semi-structured in-depth interviews (n = 15) were held throughout the Netherlands. Beforehand, the participating therapists (n = 36) completed online questionnaires on usability and satisfaction. Interviews were analyzed by thematic analysis; (3) Results: Therapists found the usability sufficient and were generally satisfied with providing bCBT. The thematic analysis showed three main themes on promoting and hindering factors: (1) therapists’ needs regarding bCBT uptake, (2) therapists’ role in motivating patients for bCBT, and (3) therapists’ experiences with bCBT; (4) Conclusions: Overall, therapists were positive; bCBT can be offered by all CBT-trained therapists and future higher uptake is expected. Especially the pre-set structure of bCBT was found beneficial for both therapists and patients. Nevertheless, therapists did not experience promised time-savings—rather, the opposite. Besides, there are still teething problems and therapeutic shortcomings that need improvement in order to motivate therapists to use bCBT.
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Leiba, Merav, Jiangchun Xu, Weihua Song, Xian-Feng Li, Peter Burger, Jennifer Kordich, Linda Cassiano i in. "Activation of B-Cell Maturation Antigen (BCMA) on Human Multiple Myeloma Cells by a Proliferation-Inducing Ligand (APRIL) Promotes Myeloma Cell Function in the Bone Marrow Microenvironment." Blood 110, nr 11 (16.11.2007): 1503. http://dx.doi.org/10.1182/blood.v110.11.1503.1503.
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Abstract A proliferation-inducing ligand (APRIL), a close member of B-cell-activating factor (BAFF) belonging to the TNF superfamily that stimulates growth and survival of multiple myeloma (MM) cells, is mainly produced by MM patient bone marrow stromal cells (BMSCs) and osteoclasts in the BM microenvironment. Like BAFF, APRIL binds two receptors, B-cell maturation antigen (BCMA) and transmembrane activator and calcium modulator (TACI). Since BCMA has significantly higher affinity for APRIL than for BAFF (nM vs. mM range), APRIL/BCMA signaling may be more important than BAFF/BCMA in MM. Specifically, BCMA but not TACI is unequivocally expressed at mRNA level in the majority of CD138-expressing MM cell lines and patient MM cells. To date, it is unclear how APRIL signaling through BCMA contributes to BM microenvironment in support of MM cells. We here studied the functional sequelae of APRIL/BCMA pathway in MM cells, and further identified molecular mechanisms regulating these processes. Using flow cytometric analysis, cell surface BCMA expression was confirmed in the majority of MM cell lines. Microarray gene expression analysis showed significant expression of BCMA mRNA in CD138+ patient MM cells (n=105). Higher BCMA mRNA levels were observed in patient MM cells than in normal plasma cells (n=27) (p< 0.03). Importantly, CD138+ patient MM cells express BCMA protein on the cell surface (n=15), as confirmed by CD38+BCMA+ dual immunofluorescence staining followed by flow cytometric analysis and immunohistochemical (IHC) study. Next, H929 MM cell line that expresses only BCMA, but not TACI, and Daudi B cells transduced with huBCMA (huBCMA-Daudi) were stimulated with APRIL. These cells were subjected to mRNA extraction at different time points followed by microarray analysis to identify downstream transcriptional targets. Stimulation of these two cell lines by APRIL activated the NF-kB signaling in a dose-dependent manner. More than 6-fold increase in NF-kB activity was induced by APRIL (100 ng/ml) using a p65 enzyme-linked DNA/protein interaction assay. IL-6 and PI3K/AKT signaling cascades were concurrently induced. Additionally, APRIL upregulated chemotactic/osteoclast activating factors, i.e., MIP-1a and MIP1b, in a dose-dependent manner, which was further validated by specific ELISA. Multi-Analyte Profiles also confirmed that angiogenesis and adhesion/chemoattractant factors, i.e., IL-8, CXCL10, RANTES, MDC (ccl22), were significantly induced upon APRIL stimulation. Conversely, a soluble BCMA-Fc protein inhibited APRIL binding to BCMA and blocked secretion of APRIL-induced chemokines, indicating specific functional interaction of BCMA with APRIL. Importantly, APRIL similarly induced these signaling cascades in CD138+ patient MM cells. Taken together, our studies are the first to demonstrate cell surface BCMA on the majority of CD138+ patient MM cells. Furthermore, APRIL induced osteoclasts-, migration-, and angiogenesis-associated factors in MM cells. These studies therefore establish a role of BCMA activation in the BM microenvironment that provides a niche for MM disease progression, supporting novel therapeutics specifically targeting APRIL/BCMA pathway in MM.
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Hau, Andrew, Tong Zhu, Rengang Wang, Megan Lau, Lingna Li, Xiaoqing Li, Yingqing Sun i in. "Preclinical Development of a Bcma Targeting Antibody-Drug Conjugate with Novel Payload for Multiple Myeloma Therapy". Blood 134, Supplement_1 (13.11.2019): 5623. http://dx.doi.org/10.1182/blood-2019-132080.
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BCMA (B-cell maturation antigen) is an integral membrane protein that belongs to the TNF receptor family with expression restricted to B cell lineage cells. The RNA is near universally detected in multiple myeloma (MM) cells and the protein is expressed on the surface of malignant plasma cells from patients with MM. In contrast, BCMA expression in normal tissues is very limited, making BCMA a promising target for antibody-drug conjugate (ADC) therapy. We have developed a BCMA-targeting ADC, employing a fully human anti-BCMA monoclonal antibody (mAb) identified from Sorrento's G-MAB antibody library, which was conjugated using proprietary Concortis linker-Duo 5.2 toxin technology resulting in BCMA-077 ADC. The mAb has a unique binding profile for BCMA and demonstrated strong preferential binding for BCMA-overexpressing cells but showed much less binding to lower BCMA-expressing cells. This property allows for more selective binding of the ADC on high BCMA-expressing cells, which are usually tumor cells while sparing low BCMA-expressing normal cells. In addition, we modified the Duo 5.2 payload decreasing the potency of the unconjugated toxin while retaining activity when conjugated to the mAb. The resulting ADC, BCMA-024, was compared to BCMA-077 using in vitro assays, including binding, internalization and cytotoxicity against tumor cell lines. The two ADCs exhibited strong activity and no difference in cytotoxic potency evident. The toxicity of the payload derivative was evaluated in a rodent model and it was found to be well tolerated not showing toxicity at a dose 10 times higher than the lethal dose of the parental toxin. Both ADCs carrying either the parental Duo 5.2 toxin or the derivative toxin payload were evaluated in vivo for anti-tumor activity in three different multiple myeloma xenograft models using different dose regimens. The data showed that both ADCs demonstrated potent BCMA-dependent in vivo anti-tumor activity in all xenograft BCMA-positive tumor models. The PK of the parental anti-BCMA mAb was investigated in non-human primates (NHP) and the parameters indicated a T1/2 of about 10 days. The GLP toxicity studies are ongoing. Our BCMA-ADCs have shown favorable anti-tumor activities combined with good safety profiles resulting in an expanded therapeutic window. The data make BCMA-077 and BCMA-024 promising candidates for continued preclinical development. Based on the totality of our preclinical data, we anticipate selecting a BCMA ADC clinical candidate for the treatment of multiple myeloma. Disclosures Hau: Concortis Biotherapeutics: Employment, Equity Ownership. Zhu:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties. Wang:Concortis Biotherapeutics: Employment, Equity Ownership. Lau:Levena Biopharma: Employment, Equity Ownership. Li:Concortis Biotherapeutics: Employment, Equity Ownership. Li:Levena Biopharma: Employment, Equity Ownership. Sun:Levena Biopharma: Employment, Equity Ownership. Kovacs:Levena Biopharma: Employment, Equity Ownership. Khasanov:Levena Biopharma: Employment, Equity Ownership. Deng:Levena Biopharma: Employment, Equity Ownership. Yan:Levena Biopharma: Employment, Equity Ownership. Knight:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Li:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties; Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Concortis Biotherapeutics: Employment, Equity Ownership, Patents & Royalties.