Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy

Immune checkpoint blockade (ICB) therapy targeting PD-L1 via monoclonal antibody (mAb) has shown extensive clinical benefits in the diverse types of advanced malignancies. However, most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism. Herein, we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes (immune checkpoint blockade liposomes; ICB-LPs) to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells. The ICB-LPs are prepared by formulation of DC8,9PC with photo-polymerized diacetylenic moiety, 1,2-dipalmitoylphosphatidylcholine (DPPC) and anti-PD-L1 peptide (D-form NYSKPTDRQYHF)-conjugated DSPE-PEG2k (anti-PD-L1-DSPE-PEG2k) in a molar ratio of 45:45:10, followed by cross-linking of liposomal bilayer upon UV irradiation. The 10 mol% anti-PD-L1-DSPE-PEG2k incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7 ± 1.04 nm, showing a high stability in serum condition. Importantly, the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane, which are endocytosed with aim to deliver PD-L1 to the lysosomes, wherein the durable PD-L1 degradation is observed for 72 h, in contrast to anti PD-L1 mAbs showing the rapid PD-L1 recycling within 9 h. The in vitro co-culture experiments with CD8+ T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis. When ICB-LPs are intravenously injected into colon tumor-bearing mice, they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting, inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation. Collectively, this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosomes

Neuroanatomical abnormalities in fragile X syndrome during the adolescent and young adult years.

Abnormal brain development and cognitive dysfunction have been reported both in children and in adults with fragile X syndrome (FXS). However, few studies have examined neuroanatomical abnormalities in FXS during adolescence. In this study we focus on adolescent subjects with FXS (N = 54) as compared to age- and sex-matched subjects with idiopathic intellectual disability (Comparison Group) (N = 32), to examine neuroanatomical differences during this developmental period. Brain structure was assessed with voxel-based morphometry and independent groups t-test in SPM8 software. Results showed that the FXS group, relative to the comparison group, had significantly larger gray matter volume (GMV) in only one region: the bilateral caudate nucleus, but have smaller GMV in several regions including bilateral medial frontal, pregenual cingulate, gyrus rectus, insula, and superior temporal gyrus. Group differences also were noted in white matter regions. Within the FXS group, lower FMRP levels were associated with less GMV in several regions including cerebellum and gyrus rectus, and less white matter volume (WMV) in pregenual cingulate, middle frontal gyrus, and other regions. Lower full scale IQ within the FXS group was associated with larger right caudate nucleus GMV. In conclusion, adolescents and young adults with FXS demonstrate neuroanatomical abnormalities consistent with those previously reported in children and adults with FXS. These brain variations likely result from reduced FMRP during early neurodevelopment and mediate downstream deleterious effects on cognitive function

Clinical impact of pre-existing acute exacerbation in patients with interstitial lung disease who underwent lung transplantation

Abstract Background Acute exacerbation of interstitial lung disease (AE-ILD) significantly impacts prognosis, leading to high mortality rates. Although lung transplantation is a life-saving treatment for selected patients with ILD, its outcomes in those presenting with AE-ILD have yielded conflicting results compared with those with stable ILD. This study aims to investigate the impact of pre-existing AE on the prognosis of ILD patients who underwent lung transplantation. Method We conducted a single-center retrospective study by reviewing the medical records of 108 patients who underwent lung transplantation for predisposing ILD at Asan Medical Center, Seoul, South Korea, between 2008 and 2022. The primary objective was to compare the survival of patients with AE-ILD at the time of transplantation with those without AE-ILD. Results Among the 108 patients, 52 (48.1%) experienced AE-ILD at the time of lung transplantation, and 81 (75.0%) required pre-transplant mechanical ventilation. Although the type of ILD (IPF vs. non-IPF ILD) did not affect clinical outcomes after transplantation, AE-ILD was associated with worse survival outcomes. The survival probabilities at 90 days, 1 year, and 3 years post-transplant for patients with AE-ILD were 86.5%, 73.1%, and 60.1%, respectively, while those for patients without AE-ILD were higher, at 92.9%, 83.9%, and 79.6% (p = 0.032). In the multivariable analysis, pre-existing AE was an independent prognostic factor for mortality in ILD patients who underwent lung transplantation. Conclusions Although lung transplantation remains an effective treatment option for ILD patients with pre-existing AE, careful consideration is needed, especially in patients requiring pre-transplant mechanical respiratory support

Cost-effective synthesis of copper sulfide nanoparticles and flexible films for photocatalytic and antibiotic applications

Herein, we investigate the effects of temperature and thiourea addition rate on the synthesis of copper sulfide nanoparticles (CuS NPs) via a chemical co-precipitation method, exploring their impact on the size and morphology of CuS NPs. Our systematic approach resulted in the successful synthesis of CuS NPs with significantly smaller nanoflower sizes than previously reported in the literature, providing insights into the nucleation and growth mechanisms under various synthesis conditions. Furthermore, the photocatalytic activity of the synthesized CuS NPs with three types of distinctive morphologies, namely, nanoflowers with 50 nm diameter (F-50), nanoflowers with 200 nm diameter, and nanogravels with 50 nm diameter, is comparatively analyzed. Notably, the F-50 exhibits a superior photocatalytic performance compared to the other samples, demonstrating the considerable influence of the NP size and morphology on their functional properties. Furthermore, the antibacterial property of the small CuS nanoflowers is examined using an antibacterial film fabricated by coating the NPs on a polyethylene terephthalate substrate, which is widely used as a protective or packaging film in various industries because of its transparency and flexibility. The antibacterial film can be used to kill both gram-positive and -negative bacteria effectively. This research contributes significantly to the understanding and optimization of CuS NP synthesis and application, emphasizing the potential of small-sized nanoflower CuS NPs in photocatalysis and antibacterial applications

Incidence, risk factors, and clinical characteristics of airway complications after lung transplantation

Abstract Airway complications may occur after lung transplantation and are associated with considerable morbidity and mortality. We investigated the incidence, risk factors, and clinical characteristics of these complications. We retrospectively reviewed the medical records of 137 patients who underwent lung transplantation between 2008 and 2021. The median follow-up period was 20 months. Of the 137 patients, 30 (21.9%) had postoperative airway complications, of which 2 had two different types of airway complications. The most common airway complication was bronchial stenosis, affecting 23 patients (16.8%). Multivariable Cox analysis revealed that a recipient’s body mass index ≥ 25 kg/m2 (hazard ratio [HR], 2.663; p = 0.013) was a significant independent risk factor for airway complications, as was postoperative treatment with extracorporeal membrane oxygenation (ECMO; HR, 3.340; p = 0.034). Of the 30 patients who had airway complications, 21 (70.0%) were treated with bronchoscopic intervention. Survival rates did not differ significantly between patients with and without airway complications. Thus, our study revealed that one fifth of patients who underwent lung transplantation experienced airway complications during the follow-up period. Obesity and receiving postoperative ECMO are risk factors for airway complications, and close monitoring is warranted in such cases