Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.     

Social Support and Social Strain Among Husbands and Wives: A Multilevel Analysis.

In response to recent calls in the literature for within-person examinations of social support processes over time, this study explores the relationships of spousal support, spousal strain, and well-being among husbands and wives, both within the same day and across days. Eighty-three couples were interviewed and completed a structured diary twice daily for 1 week. The results of multilevel hierarchical modeling suggest that both spousal support and spousal strain made significant, independent contributions to concurrent negative affect, although only spousal support was a significant predictor of next-day negative affect. Spousal strain interacted with spousal support to predict next-day negative affect. Direct and moderating effects of perceived marital adjustment on negative affect were discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of perspective in the accessibility of goals during reading.

An implicit assumption of several causal reasoning models is that readers adopt the goals of a narrative's protagonist during text comprehension. In apparent violation of this assumption, readers participating in Experiment 1 of the present study drew inferences relevant to a protagonist's goal even when that goal was already satisfied from the perspective of the protagonist. In Experiments 2 and 3, participants were explicitly asked to view the text situation from the point of view of the protagonist. In this case, the goals of the reader and the protagonist should be the same. In these experiments, participants focused on the goals of the protagonist only when those goals had not been satisfied from the perspective of the protagonist. These results are discussed in terms of reader- and character-based perspectives and in terms of text characteristics that cue perspective taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

InAs quantum dot photonic crystal lasers and their temperature dependence

We report on the demonstration of optically pumped photonic crystal lasers with InAs quantum dot active regions operating at room temperature near 1310 nm. Absorbed threshold pump powers as low as 25 /spl mu/W are observed. We also extract a characteristic temperature of 17 K, which is attributed to limitations caused by surface recombination.     

把DAC的输出从单端模式转换到差分模式的电路

高速DAC,比如模拟器件(AnalogDevices)公司的AD9776/78/79TxDAC系列,能提供差分输出,但对于低端交流电应用或高精度电平设置应用,配备差分转换电路的单端电流输出DAC提供了一种新颖的方法来生成差分波形控制功能。图1中的基本电路组合了电流输出DAC(即IC1,如8位AD5424D A C)和一个单端至差分运算放大级IC2、IC3A、IC3B——来产生要求的输出。对于双电源应用,可选择DAC的单极工作模式来达到DAC的最优性能。DAC利用单一运算放大器提供了双象限倍增或单极输出电压摆动。DAC的输出需要缓冲器,这是因为对施加到DAC输入端的代…     

Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.     

Maintaining global coherence during reading.

Previous research demonstrated a contradiction effect: Although text currently being processed was locally coherent, readers were aware of inconsistencies between a protagonist's actions and characteristics of the protagonists that were described earlier in the text and subsequently backgrounded. In the present experiments, not only the critical characteristics but also the protagonist were backgrounded. When the protagonist was reintroduced into the narrative in the context of carrying out an inconsistent action, the contradiction effect again occurred. In Exps 1–3, we examined the effects of several variables on the onset of the effect. In Exp 4, we presented probes at various points in the passage with results that supported the conclusion that the critical characteristics had been backgrounded before the sentence that contradicted them. Results are discussed in terms of several recent models in which currently active representational elements serve as retrieval cues for other inactive, but highly related, elements. (PsycINFO Database Record (c) 2010 APA, all rights reserved)