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Chimeric antigen receptor (CAR) T-cell therapies using defined product compositions require high-purity T-cell isolation systems that, unlike immunomagnetic positive enrichment, are inexpensive and leave no trace on the final cell product. Here, we show that DNA aptamers, generated with a modified cell-SELEX (systematic evolution of ligands by exponential enrichment) procedure to display low nanomolar affinity for the T-cell marker CD8, enable the traceless isolation of pure CD8+ T cells at low cost and high yield. Captured CD8+ T cells are released label-free by complementary oligonucleotides that undergo toehold-mediated strand displacement with the aptamer. We also show that CAR-T cells manufactured from these cells are comparable to antibody-isolated CAR-T cells in proliferation, phenotype, effector function and antitumor activity in a mouse model of B-cell lymphoma. By employing multiple aptamers and the corresponding complementary oligonucleotides, aptamer-mediated cell selection could enable the fully synthetic, sequential and traceless isolation of desired lymphocyte subsets from a single system.

BackgroundReal-world prescription pathways leading to triple therapy (TT) (inhaled corticosteroid [ICS] plus long-acting β2-agonist bronchodilator [LABA] plus long-acting muscarinic antagonist) differ from Global initiative for chronic Obstructive Lung Disease [GOLD] and National Institute for Health and Care Excellence treatment recommendations. This study sets out to identify COPD patients without asthma receiving TT, and determine the pathways taken from diagnosis to the first prescription of TT.MethodsThis was a historical analysis of COPD patients without asthma from the Optimum Patient Care Research Database (387 primary-care practices across the UK) from 2002 to 2010. Patient disease severity was classified using GOLD 2013 criteria. Data were analyzed to determine prescribing of TT before, at, and after COPD diagnosis; the average time taken to receive TT; and the impact of lung function grade, modified Medical Research Council dyspnea score, and exacerbation history on the pathway to TT.ResultsDuring the study period, 32% of patients received TT. Of these, 19%, 28%, 37%, and 46% of patients classified as GOLD A, B, C, and D, respectively, progressed to TT after diagnosis (P<0.001). Of all patients prescribed TT, 25% were prescribed TT within 1 year of diagnosis, irrespective of GOLD classification (P=0.065). The most common prescription pathway to TT was LABA plus ICS. It was observed that exacerbation history did influence the pathway of LABA plus ICS to TT.ConclusionReal life UK prescription data demonstrates the inappropriate prescribing of TT and confirms that starting patients on ICS plus LABA results in the inevitable drift to overuse of TT. This study highlights the need for dissemination and implementation of COPD guidelines to physicians, ensuring that patients receive the recommended therapy.

This study examined the effects of attempting social influence on cardiovascular reactivity. Subjects were randomly assigned to a noncontingent reward condition or one of three conditions in which receipt of a monetary reward was contingent on their ability to influence another individual through a persuasive communication. In the contingent conditions, the task was presented as either easy, difficult, or very difficult. Measures of systolic blood pressure, diastolic blood pressure, and heart rate were recorded while subjects prepared and delivered the persuasive communication (contingent conditions) or reviewed and read aloud the same statement without an incentive to influence. The contingent conditions produced significantly higher levels of systolic and diastolic blood pressure and heart rate reactivity during preparation and speaking. Further, reactivity was higher in the difficult condition than in the easy and very difficult conditions. The findings are discussed in terms of an interpersonal equivalent of traditional active coping tasks.

All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making.

BackgroundClinicians are faced with an increasingly difficult choice regarding the optimal bronchodilator for patients with chronic obstructive pulmonary disease (COPD) given the number of new treatments. The objective of this study is to evaluate the comparative efficacy of indacaterol 75/150/300 μg once daily (OD), glycopyrronium bromide 50 μg OD, tiotropium bromide 18 μg/5 μg OD, salmeterol 50 μg twice daily (BID), formoterol 12 μg BID, and placebo for moderate to severe COPD.MethodsForty randomized controlled trials were combined in a Bayesian network meta-analysis. Outcomes of interest were trough and post-dose forced expiratory volume in 1 second (FEV1), St. George’s Respiratory Questionnaire (SGRQ) score and responders (≥4 points), and Transition Dyspnea Index (TDI) score and responders (≥1 point) at 6 months.ResultsIndacaterol was associated with a higher trough FEV1 than other active treatments (difference for indacaterol 150 μg and 300 μg versus placebo: 152 mL (95% credible interval (CrI): 126, 179); 160 mL (95% CrI: 133, 187)) and the greatest improvement in SGRQ score (difference for indacaterol 150 μg and 300 μg versus placebo: -3.9 (95% CrI -5.2, -2.6); -3.6 (95% CrI -4.8, -2.3)). Glycopyrronium and tiotropium 18 μg resulted in the next best estimates for both outcomes with minor differences (difference for glycopyrronium versus tiotropium for trough FEV1 and SGRQ: 18 mL (95% CrI: -16, 51); -0.55 (95% CrI: -2.04, 0.92).ConclusionIn terms of trough FEV1 and SGRQ score indacaterol, glycopyrronium, and tiotropium are expected to be the most effective bronchodilators.

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D-negative patients may be divided into responders and nonresponders when immunized with D-positive red cells (RBC). Forty-nine D-negative oncology patients who received D-positive RBCs via platelet and white cell transfusions were studied to determine if nonresponders to D were likely to form lymphocytotoxic antibody (LCA). Nine patients developed anti-D in 16 to 390 days (mean = 112) after 2.6 to 481 ml (mean = 106) of D-positive RBCs. Forty patients had no evidence of anti-D after 0.8 to 535 ml (mean = 98) of D-positive RBCs and were followed for 14 to 1275 days (mean = 192). The anti-D group had no prior D-positive RBC transfusions, and two of five women making anti-D had previous pregnancies but no record of anti-D. LCA was found in four of nine (44%) patients with anti-D and in 12 of 40 (30%) patients without anti-D (p less than 0.50). Since both D and antigens HLA are considered highly immunogenic, it is of interest that the ability to form anti-D or LCA does not correlate. In fact, more patients (16/49; 32%) made LCA than anti-D (9/49; 18%). Of the 21 alloimmunized patients, 4 made both antibodies, while 17 had selective alloimmunization. It would thus appear that alloimmunization to D and HLA are not strongly linked and may indeed be unrelated.