7 research outputs found
Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
No full textRituximab, a monoclonal antibody which targets CD20 on B-cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 mAb are continually being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAb are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B-cells, despite both operating exclusively via activatory FcR-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B-cells leading to reduced macrophage recruitment and the degradation of CD20:mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors, and most cases of Chronic Lymphatic Leukemia (CLL) and Mantle Cell Lymphoma, showed rapid CD20 internalization which paralleled that seen in the Tg mouse B cells, while most Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic. <br/
Visual influences on Arabic linguistic sciences
No full textAssociated with reliance on vision unaided by hearing, tashīf adversely affected several scholarly fields, especially grammatical study since a large part of its data originates in Qur'anic readings, prophetic tradition and poetry, all influenced by tashīf. Further, because of concern with the analysis of linguistic usage, the grammarians' reliance on the written form of language was prone to errors in analysis due to the inherent deficiencies of any written system in representing spoken language. In Arabic linguistics, sarf (morphology) is the only branch in which analysis was largely made on the written form of words. However, Arabic, like most Semitic scripts, indicates consonants and long vowels as the skeleton of words to which short vowels and other markers may be added externally. Although this 'skeletal' writing of Arabic fairly reflects its spirit as a Semitic language, it greatly misled the grammarians. This article dwells on four types of morphological rules traceable in the tradition to visual influences. These are: hadf (elision), i'lāl (vowel mutation), naql al-haraka (vowel transfer), and ibdāl (alternation).ABDALHAMID MMI, 1959, MUGNI LLABIB KUTUB A; ABDALHAMID MML, 1963, ALUMDA MAHASIN ALSIR; ABDU D, 1973, ABHAT LLUGA LARABIYY; ABUFIRAS, 1959, DIWAN DIWAN ABI FIRA; ABUNUWAS, DIWAN DIWAN ABI NUWA; AHMAD AB, 1980, KITAB ALSABA LQIRAAT; ALBARQUQI A, ALTALHIS ULUM ALBALA; ALBITAR MB, 1957, ASRAR ALARABIYYA; ALHASAN MN, 1982, SARH SAFIYAT ALHAGIB; ALMAWLA MAG, ALMUZHIR ULUM ALLUGA; ALNADIM AYI, 1971, KITAB ALFIHRIST; ALNAGGAR MA, 1952, ALHASAIS; ALRAWABIDA M, 1997, MUTA LILBUHUT WALDIR, V12, P86; ALSAMARRAI SA, 1986, AHBAR ALMUSAHHIFIN; ALSAMMARRAI I, 1970, NUZHAT ALALIBBA TABA; ALSUYUTI AB, HAM ALHAWAMI SARH GA; ALYASIN MH, 1967, ALTANBIH ALA HUDUT A; ALZAYN A, 2000, HAWLIYYAT KULLIYYAT, V10, P110; AMIN A, 1991, SARH DIWAN ALHAMASA; ASTARABADI, 1310, SARH KAFIYAT ALHAGIB; BAALBAKI R, 1999, FIQH ALARABIYYA ALMU; BAALBAKI R, 2005, ALLTAGSLEBEN MAT KUL, P39; BAALBAKI R, 1995, P C AR LING BUCH A 1, P85; Baalbaki R., 1988, MISCELLANY MIDDLE E, P163; BAALBAKI R, 1981, ALKITABA ALARABIYYA; Baalbaki Ramzi, 1983, Z ARABISCHE LINGUIST, V11, P7; BAALBAKI RM, 1992, SARH AQIL ALFIYYAT M; BAGDADI, 1967, HIZANAT ALADAB WULUB; BERGSTRASSER G, 1982, GAYAT ALNIHAYA TABAQ; GUMAHI, 1980, TABAQAT FUHUL ALSUAR; HADITI H, 1981, MAWQIF ALNUHAT ALIHT; HAFAGI, 1932, SIRR ALFASAHA; HARUN AM, 1977, ALKITAB; HINDAWI H, 1985, SIRR SINAAT ALIRAB; IBRAHIM MA, 1979, BUGYAT ALWUAT TABAQA; IBRAHIM MAI, 1973, TABAQAT ALNAHWIYYIN; IBRAHIM MAI, 1974, MARATIB ALNAHWIYYIN; KRENKOW F, 1936, AHBAR ALNAHWIYYIN AL; MAKDSISI G, 1981, RISE COLL I LEARNING; MUHAMMAD AB, 1987, MIFTAH ALULUM; MUHYILDIN M, 1956, AWDAH ALMASALIK ALFI; MUKRAM AS, 1979, ALHUGGA LQIRAAT ALSA; MUSTAFA I, 1954, ALMUNSIF SARH KITAB; QABAWA FA, 1983, ALGANA IDANI HURUF A; QABAWA FA, 1979, ALMUMTI LTASRIF; RAMADAN ML, 1984, KITAB ALKASF WUGUH A; SALABI AI, MAANI LHURUF; SAQQAL D, 1998, ALTASRIF ALMULUKI; UDAYMA MA, 1965, ALMUQTADAB; VAJDA G, 1983, TRANSMISSION SAVOIR; YAHYA U, 1979, ALWAFI LARUD WALQAWA; YAQUT, 1993, MUGAM ALUDABA; YUSUF AM, 1975, SARH YAQA FIHI LTASH; ZALSAYN A, 1999, BAYN ALASALA WALHADA; SARH ALMUFASSAL0
Stem cell expansion and bioreactor development
No full textPhDA major challenge to the clinical success of cell-based tissue engineering strategies is the ability to obtain sufficient numbers of cells within an acceptable time frame. The expansion of cells on microcarriers within spinner flask bioreactor has shown promise in meeting that challenge. Spinner flask microcarrier technology is space-saving and media utilisation efficient. However, further optimisation in terms of, for example, seeding efficiency, expansion rates and harvest efficiency is necessary to realise the clinical potential of this technology. The present work is designed to improve cell expansion rates. It involves investigation of microcarrier composition and surface structure and spinner flask shear stress on cell growth.
BMSC growth on PHBV microcarriers was superior to PCL and PLGA microcarriers and comparable to Cytodex 1 microcarriers. Lower density PHBV microcarriers showed promise as a superior alternative to Cytodex 1. Two different impeller designs employed in the w/o/w method of microcarrier synthesis resulted in smoother and rougher PCL microcarriers with Ra = 1.77 ± 0.42 μm to 6.4 ± 1.48 μm respectively. Superior BMSC growth was observed on the rougher PCL microcarriers. Differentiation potential along the osteogenic and adipogenic lineages of BMSCs expanded on the microcarrier types was retained.
Particle Image Velocimetry was used to quantify shear stress within a spinner flask bioreactor. It was found that 80% of the shear stress was localised within the impeller region which occupied 55% of the bioreactor working volume. Shear stress increased as Cytodex 1 microcarrier concentration and impeller rotational speed increased. Superior BMSC growth rates on microcarriers were observed for the lowest shear stress experimental group (3.4 x 10-3 N/m2 ≤ impeller region mean shear stress ≤ 4.6 x 10-3 N/m2) as compared to the three higher shear stress groups (5.5 x 10-3 N/m2 ≤ mean shear stress ≤ 1.3 x 10-2 N/m2). Expanded BMSCs on the cytodex 1 microcarriers retained multipotentiality for the range of shear stresses investigated
The clinical and biological consequences of different FLT3 mutations in patients with AML
No full textCharacterisation of pathogenic markers in acute myeloid leukaemia (AML) may benefit
patients through refinement of risk stratification, application of molecularly targeted
therapy and improved understanding of AML biology. Whilst the presence of an
internal tandem duplication (ITD) within the fms-like tyrosine kinase-3 (FLT3) gene is
known to predict adverse outcome in young adults with AML, the clinical significance
of activating mutations in the tyrosine kinase domain (TKD) of FLT3 is unclear.
Therefore, a highly sensitive and specific denaturing-HPLC technique was developed to
screen for FLT3/TKDs in 1339 young adult patients with AML. Mutations were
detected in 161 (12%) cases, with a high incidence in patients with inv(16) (24%;
P=.009), a group in which FLT3/ITDs are uncommon. Unlike FLT3/ITDs, FLT3/TKDs
were associated with a favourable long-term outcome with a 10-year overall survival
(OS) of 36% for FLT3 WT, 51% for FLT3/ITD-TKD+ and 24% for FLT3/ITD+TKDpatients
(P<.001). The relative FLT3/TKD mutant level was highly variable with the
favourable prognosis residing in those patients with greater than 25% mutant alleles
(10-year OS of 59%), possibly reflecting the stage at which the mutation is acquired.
The mechanism of FLT3 activation also influenced sensitivity to FLT3-inhibitor
induced cytotoxicity, with FLT3/ITD+ blast cells more sensitive than FLT3/TKD+ cells.
Following lentiviral transduction, FLT3/ITD-transduced 32Dcl3 and Ba/F3 cells
demonstrated more rapid proliferation than FLT3/TKD-transduced cells. In an NB4 cell
line model of ATRA-induced myeloid differentiation, the presence of a FLT3/ITD
inhibited differentiation unlike a FLT3/TKD mutation which increased differentiation.
Furthermore, FLT3/ITD-transduced CD34 positive haematopoietic stem cells showed
greater cytokine-free survival of colony forming cells than FLT3/TKD-transduced cells.
Signalling studies also revealed that a FLT3/ITD induced stronger STAT5 activation
than a FLT3/TKD mutation. This unexpected genotype-phenotype relationship is of
direct relevance to current clinical decision making in AML, and may also provide
insights into mechanisms of chemoresistance
工业企业数字化转型战略：引入智能制造技术的影响
No full textThe socio-economic effects from the introduction of smart manufacturing technologies are of significant interest in terms of their generalisation and systematisation at the current stage of the digital transformation on industrial enterprises, as well as the objectives in the context of industrial modernization and new business model development. The proposed systematisation is based on the allocation of three groups of socio-economic effects according to the main direction of their action. The first group of effects primarily leads to reduction in the costs of industrial enterprises. The second group of effects leads mainly to an increase in revenues: some effects to a greater extent in the short and medium term, others in the long term, including through the creation of long-term distinctive capabilities, unique competencies, and sustainable competitive advantages for industrial companies. The third group of effects includes social and economic effects that are broader in focus and have a multiplicative effect, as well as the character of positive externalities (external effects).As a result of systematisation, the author identified in three groups, respectively, 12, 8 and 13 effects from the implementation of the complex of smart manufacturing technologies. The author stresses the particular importance of studying the socio-economic effects from the implementation of smart manufacturing technologies, since many improvements at the intersection of production and social transformation are currently insufficiently studied. It contrasts to the core production effects, many of which have been studied in sufficient detail by the scientific and expert communities. Systematisation, classification, differentiation and quantitative assessment of various socio-economic effects of the complex of smart manufacturing technologies can and even in a certain sense should (in the context of the tasks to modernise the economy and industries of the Russian Federation) become a separate subject area at the intersection of performance management and smart production.Социально-экономические эффекты внедрения технологий умного производства представляют существенный интерес с точки зрения их обобщения и систематизации на текущем этапе цифровой трансформации промышленных предприятий, а также тех задач, которые стоят в контексте модернизации промышленности и построения новых моделей бизнеса. Предложенная в статье систематизация базируется на выделении трех групп социально-экономических эффектов по основной направленности их действия. Первая группа эффектов по основному вектору действия приводит к снижению затрат промышленных предприятий. Вторая группа эффектов ведет преимущественно к повышению выручки: одни эффекты в большей степени в краткосрочном и среднесрочном периоде, другие – в долгосрочной перспективе, в том числе благодаря созданию долгосрочных отличительных способностей, уникальных компетенций, устойчивых конкурентных преимуществ у промышленных компаний. Третья группа эффектов – это более широкие по фокусу воздействия социально-экономические эффекты, имеющие мультипликативное воздействие, а также характер действия положительных экстерналий (внешних эффектов).В результате систематизации автором выявлено по трем группам соответственно 12, 8 и 13 эффектов внедрения комплекса технологий умного производства. Автор отмечает особую важность исследования социально-экономических эффектов внедрения технологий умного производства, поскольку многие улучшения на стыке производства и социальной трансформации являются в настоящее время недостаточно изученными, в отличие от собственно производственных эффектов, некоторые из которых научное и экспертное сообщества исследовали достаточно подробно. Систематизация, классификация, разграничение и количественная оценка различных социально-экономических эффектов комплекса технологий умного производства могут и даже в некотором смысле должны (в контексте задач модернизации экономики и промышленности Российской Федерации) стать отдельной предметной областью на стыке управления эффективностью (Performance Management) и умного производства (Smart Manufacturing). 在工业企业数字化转型的现阶段引入智能制造技术的社会经济效应就其概括和系统化方面而言具有重要意义，它们对于工业现代化和建立新商业模式的任务也很重要。文章中提出的系统化是基于根据其作用方向分配三组社会经济影响。主要作用方向上的第一组影响导致工业企业成本降低。第二组影响主要导致收入增加：一些影响在短期和中期更为明显，其他影响长期有效，包括通过为工业公司创造长期独特的能力、可持续的竞争优势。第三组影响是关注范围更广，具有乘法效应以及积极外部性质的社会经济影响。作为数据系统化的结果，作者在三组中确定了引入智能制造技术的 12、8 和 13 影响。由于目前对生产和社会转型交叉点的许多改进研究不足，作者指出研究引入智能生产技术的社会经济影响特别重要至于直接的生产效应，其中一些已经被科学界和专家界进行了足够详细的研究。在俄罗斯联邦经济和工业现代化任务的背景下，对复杂的智能制造技术的各种社会经济影响的系统化、分类、差异化和定量评估可以甚至在某种意义上应该成为绩效管理（Performance Management）和智能制造（Smart Manufacturing）交界处的单独学科领域
Multiphasic effects of blood pressure on survival in hemodialysis patients
No full textDialysis patients exhibit an inverse, L- or U-shaped association between blood pressure and mortality risk, in contrast to the linear association in the general population. We prospectively studied 9333 hemodialysis patients in France, aiming to analyze associations between predialysis systolic, diastolic, and pulse pressure with all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular endpoints for a median follow-up of 548 days. Blood pressure components were tested against outcomes in time-varying covariate linear and fractional polynomial Cox models. Changes throughout follow-up were analyzed with a joint model including both the time-varying covariate of sequential blood pressure and its slope over time. A U-shaped association of systolic blood pressure was found with all-cause mortality and of both systolic and diastolic blood pressure with cardiovascular mortality. There was an L-shaped association of diastolic blood pressure with all-cause mortality. The lowest hazard ratio of all-cause mortality was observed for a systolic blood pressure of 165 mm Hg, and of cardiovascular mortality for systolic/diastolic pressures of 157/90 mm Hg, substantially higher than currently recommended values for the general population. The 95% lower confidence interval was approximately 135/70 mm Hg. We found no significant correlation for either systolic, diastolic, or pulse pressure with myocardial infarction or nontraumatic amputations, but there were significant positive associations between systolic and pulse pressure with stroke (per 10-mm Hg increase: hazard ratios 1.15, 95% confidence interval 1.07 and 1.23; and 1.20, 1.11 and 1.31, respectively). Thus, whereas high pre-dialysis blood pressure is associated with stroke risk, low pre-dialysis blood pressure may be both harmful and a proxy for comorbid conditions leading to premature death
