脂质纳米粒-mRNA递送系统及其在嵌合抗原受体T细胞治疗中的应用

尽管嵌合抗原受体（CAR）T细胞治疗在血液系统恶性肿瘤患者中取得了显著的临床疗效，但需要进一步优化。脂质纳米粒（LNP）-信使核糖核酸（mRNA）递送系统作为一种非病毒性基因载体运用于CAR-T细胞治疗研究中，一方面通过LNP将密封蛋白-6 mRNA靶向递送至抗原提呈细胞，从而实现抗原提呈细胞辅助性增强密封蛋白-6靶向的CAR-T细胞的功能，以进一步诱导对实体瘤的清除；另一方面，通过LNP将成纤维细胞激活蛋白（FAP）CARmRNA靶向递送至T细胞，实现体内FAP靶向的CAR-T细胞的制备，以通过阻断心脏纤维化过程达到治疗急性心肌损伤的目的。在CAR-T细胞研究和治疗中，LNP-mRNA递送系统具有不与细胞基因组整合、价格便宜、毒副作用小及可修饰等优点，亦存在蛋白瞬时表达导致调控细胞功能的持久性不足及制备等方面的技术局限性。本文综述了LNP-mRNA递送系统及其在CAR-T细胞治疗中的应用研究。     

The infant health effects of starting universal child benefits in pregnancy: Evidence from England and Wales

Child benefits are typically paid from birth. This paper asks whether starting universal child benefits in pregnancy leads to improvements in infant health. Leveraging administrative birth registry and hospital microdata from England and Wales, I study the effects of the Health in Pregnancy Grant, a universal conditional cash transfer equivalent to three months of child benefit (190 GBP) as a lump sum to pregnant mothers from 2009 to 2011. I exploit quasi-experimental variation in eligibility with a regression discontinuity design in the date of birth of the baby. I find that the policy increased birth weight by 8–12 grams on average, reduced low birth weight ($<$2500 g) by 3-6 percent and decreased prematurity by 9–11 percent. Younger mothers, particularly those living in deprived areas, benefit the most. I present evidence that the mechanisms are unlikely to be antenatal care, nutrition or smoking, with reductions in stress remaining a possible explanation.     

Custom made cutting guides and osteosynthesis plates versus CAD/CAM occlusal splints in positioning and fixation of the maxilla in orthognathic surgery: A prospective randomized study

The aim of this study is to compare the accuracy of maxilla positioning in orthognathic surgery with the use of custom-made devices (cutting guides and patient-fitted osteosynthesis plates) comparing to CAD/CAM splints.A prospective randomized study was performed. Patients with dentofacial deformities undergoing orthognathic surgery were compared, using customized guides (experimental group) vs. CAD/CAM surgical splints (control group) for the repositioning of the upper maxilla. Preoperative and postoperative CT scans were used to compare positioning and fixation of the maxilla in the three planes of space.A total of 30 patients were included in the study (15 patients in each study group). The mean error obtained with customized guides was 0.8 mm (range 0.1–1.9) in the anterior-posterior axis, 0.4 mm (range 0–1.4) in the vertical axis and 0.2 mm (range 0–1.1) in the horizontal axis. There were statistically significant differences in the anterior-posterior and vertical axes in favour of the customized implants, whereas there were no differences in the horizontal plane. Furthermore, there was a mean reduction of the operative time of 36.5 min in the experimental group.Within the limitations of the study it seems that patient specific surgical guides should be preferred when accuracy of repositioning of the maxilla and saving operative time are the priority.     

DIEP flap breast reconstruction combined with vascularized lymph node transfer for patients with breast cancer-related lymphedema

IntroductionLymphedema is a condition which heavily impacts patients QoL. For patients who desire autologous breast reconstruction, lymph nodes can be included in the Deep Inferior Epigastric Artery (DIEP) flap combining vascularized lymph node transfer and autologous breast reconstruction.Material and methodsPatients who received autologous breast reconstruction with a DIEP flap in combination with vascularized lymph nodes were included in this study. Volume measurements pre and post-surgery were analyzed and surveys including two versions of the ULL-27 questionnaire to measure QoL before and after surgery were send.ResultsIn total, 45 out of 64 patients returned the questionnaires. The average follow up was 51 months. The total ULL-27 score increased with 12.6 points on average (p = 0.00). The subdomain scores (physical, psychological and social) also significantly increased (p = 0.00). In addition 69% of patients were able to decrease physiotherapy, 63% of patients were able to decrease compression garment usage and the incidence of skin infections decreased in 6 patients out of 7 patients who had recurrent skin infections prior to surgery. The volume difference between the affected and the healthy arm did not significantly change (407 ml–406 ml, p = 0.988).ConclusionsVascularized lymph node transfer in combination with DIEP flap breast reconstruction can cause a significant improvement on lymphedema related QoL, even when a volume difference decrease is absent. It can also decrease compression garment usage and reduce the need for physiotherapy. Future prospective studies should evaluate these findings and identify patients that benefit most from such procedures.     

Temperature-controlled power modulation compensates for heterogeneous nanoparticle distributions: a computational optimization analysis for magnetic hyperthermia

Purpose: To study, with computational models, the utility of power modulation to reduce tissue temperature heterogeneity for variable nanoparticle distributions in magnetic nanoparticle hyperthermia.

Methods: Tumour and surrounding tissue were modeled by elliptical two- and three-dimensional computational phantoms having six different nanoparticle distributions. Nanoparticles were modeled as point heat sources having amplitude-dependent loss power. The total number of nanoparticles was fixed, and their spatial distribution and heat output were varied. Heat transfer was computed by solving the Pennes’ bioheat equation using finite element methods (FEM) with temperature-dependent blood perfusion. Local temperature was regulated using a proportional-integral-derivative (PID) controller. Tissue temperature, thermal dose and tissue damage were calculated. The required minimum thermal dose delivered to the tumor was kept constant, and heating power was adjusted for comparison of both the heating methods.

Results: Modulated power heating produced lower and more homogeneous temperature distributions than did constant power heating for all studied nanoparticle distributions. For a concentrated nanoparticle distribution, located off-center within the tumor, the maximum temperatures inside the tumor were 16% lower for modulated power heating when compared to constant power heating. This resulted in less damage to surrounding normal tissue. Modulated power heating reached target thermal doses up to nine-fold more rapidly when compared to constant power heating.

Conclusions: Controlling the temperature at the tumor-healthy tissue boundary by modulating the heating power of magnetic nanoparticles demonstrably compensates for a variable nanoparticle distribution to deliver effective treatment.