Efficient Gene Delivery Mediated by a Helical Polypeptide: Controlling the Membrane Activity via Multivalency and Light-Assisted Photochemical Internalization (PCI)

The development of robust and nontoxic membrane-penetrating materials is highly demanded for nonviral gene delivery. Herein, a photosensitizer (PS)-embedded, star-shaped helical polypeptide was developed, which combines the advantages of multivalency-enhanced intracellular DNA uptake and light-strengthened endosomal escape to enable highly efficient gene delivery with low toxicity. 5,10,15,20-Tetrakis-(4-aminophenyl) porphyrin as a selected PS initiated ring-opening polymerization of <i>N</i>-carboxyanhydride and yielded a star-shaped helical polypeptide after side-chain functionalization with guanidine groups. The star polypeptide afforded a notably higher transfection efficiency and lower cytotoxicity than those of its linear analogue. Light irradiation caused almost complete (∼90%) endosomal release of the DNA cargo via the photochemical internalization (PCI) mechanism and further led to a 6–8-fold increment of the transfection efficiency in HeLa, B16F10, and RAW 264.7 cells, outperforming commercial reagent 25k PEI by up to 3 orders of magnitude. Because the PS and DNA cargoes were compartmentalized distantly in the core and polypeptide layers, respectively, the generated reactive oxygen species caused minimal damage to DNA molecules to preserve their transfection potency. Such multivalency- and PCI-potentiated gene delivery efficiency was also demonstrated in vivo in melanoma-bearing mice. This study thus provides a promising strategy to overcome the multiple membrane barriers against nonviral gene delivery

Additional file 1: Table S1. of Recombinant SFRP5 protein significantly alleviated intrahepatic inflammation of nonalcoholic steatohepatitis

The intrahepatic steatosis and inflammation scoring system (DOC 35 kb

Radiologic Predictors for Clinical Stage IA Lung Adenocarcinoma with Ground Glass Components: A Multi-Center Study of Long-Term Outcomes

<div><p>Objective</p><p>This study was to define preoperative predictors from radiologic findings for the pathologic risk groups based on long-term surgical outcomes, in the aim to help guide individualized patient management.</p><p>Methods</p><p>We retrospectively reviewed 321 consecutive patients with clinical stage IA lung adenocarcinoma with ground glass component on computed tomography (CT) scanning. Pathologic diagnosis for resection specimens was based on the 2011 IASLC/ATS/ERS classification of lung adenocarcinoma. Patients were classified into different pathologic risk grading groups based on their lymph node status, local regional recurrence and overall survival. Radiologic characteristics of the pulmonary nodules were re-evaluated by reconstructed three-dimension CT (3D-CT). Univariate and multivariate analysis identifies independent radiologic predictors from tumor diameter, total volume (TV), average CT value (AVG), and solid-to-tumor (S/T) ratio. Receiver operating characteristic curves (ROC) studies were carried out to determine the cutoff value(s) for the predictor(s). Univariate cox regression model was used to determine the clinical significance of the above findings.</p><p>Results</p><p>A total of 321 patients with clinical stage IA lung adenocarcinoma with ground glass components were included in our study. Patients were classified into two pathologic low- and high- risk groups based on their distinguished surgical outcomes. A total of 134 patients fell into the low-risk group. Univariate and multivariate analyses identified AVG (HR: 32.210, 95% CI: 3.020–79.689, P<0.001) and S/T ratio (HR: 12.212, 95% CI: 5.441–27.408, P<0.001) as independent predictors for pathologic risk grading. ROC curves studies suggested the optimal cut-off values for AVG and S/T ratio were-198 (area under the curve [AUC] 0.921), 2.9 (AUC 0.996) and 54% (AUC 0.907), respectively. The tumor diameter and TV were excluded for the low AUCs (0.778 and 0.767). Both the cutoff values of AVG and S/T ratio were correlated with pathologic risk classification (p<0.001). Univariate Cox regression model identified clinical risk classification (RR: 3.011, 95%CI: 0.796–7.882, P = 0.095) as a good predictor for recurrence-free survival (RFS) in patients with clinical stage IA lung adenocarcinoma. Statistical significance of 5-year OS and RFS was noted among clinical low-, moderate- and high-risk groups (log-rank, p = 0.024 and 0.010).</p><p>Conclusions</p><p>The AVG and the S/T ratio by reconstructed 3D-CT are important preoperative radiologic predictors for pathologic risk grading. The two cutoff values of AVG and S/T ratio are recommended in decision-making for patients with clinical stage IA lung adenocarcinoma with ground glass components.</p></div

Relation of clinical and pathologic factors with lymph node metastasis and postoperative recurrence in 321 patients with clinical stage IA lung adenocarcinoma.

<p>^aFisher exact test or X² test.</p><p>Pathologic low-risk group consisted of atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive, lepidic predominant, papillary predominant and invasive mucinous. Pathologic high-risk group included micropapillary predominant, solid predominant and acinar predominant.</p><p>Relation of clinical and pathologic factors with lymph node metastasis and postoperative recurrence in 321 patients with clinical stage IA lung adenocarcinoma.</p

Area under the curve (AUC) of the receiver-operating characteristics (ROC) for differentiation of pathologic high- and low-risk group.

<p>(A) solid-to-tumor (S/T) ratio: AUC, 0.921 (95%CI: 0.857–0.958). (B) average CT value (AVG): AUC, 0.921 (95%CI: 0.857–0.958). (C) Total volume (TV): AUC, 0.767 (95% CI: 0.678–0.856). (D) Tumor diameter: AUC, 0.778 (95% CI:0.691–0.865).</p

Overall survival (OS) and recurrence-free survival (RFS) curves for the patients with clinical stage IA lung adenocarcinoma with ground-glass components who underwent surgical resection in group1, group2 and group 3.

<p>Group 1 = clinical high-risk group, group 2 = clinical moderate-risk group, group 3 = clinical low-risk group.</p

Comparisons of the clinical classification with lymph node metastasis and a Univariate Cox regression model of clinical risk classification.

<p>Comparisons of the clinical classification with lymph node metastasis and a Univariate Cox regression model of clinical risk classification.</p

Independent predictors for pathologic risk grading.

<p>CI = confidence interval; HR = hazard ratio.</p><p>^a pathologic low-risk group</p><p>^b pathologic high-risk group.</p><p>Independent predictors for pathologic risk grading.</p

Three-dimensional computed tomography (3D-CT) of clinical stage IA lung adenocarcinoma with ground glass component.

<p>(A) AVG = -134, S/T ratio = 59%, postoperative pathologic subtype: solid predominant adenocarcinoma (SPA); (B) AVG = -187, S/T ratio = 24%, postoperative pathologic subtype: acinar predominant adenocarcinoma (APA); (C) AVG = -149, S/T ratio = 63%, postoperative pathologic subtype: micropapillary predominant adenocarcinoma (MPA). All parameters of the 3D-CT were computed automatically after the operator placed a marker on the nodule. All postoperative specimens were reexamined by two pathologists.</p

Table_1_Prevalence of depressive symptoms and correlates among individuals who self-reported SARS-CoV-2 infection after optimizing the COVID-19 response in China.DOCX

BackgroundThe burden of depression symptoms has increased among individuals infected with SARS-CoV-2 during COVID-19 pandemic. However, the prevalence and associated factors of depressive symptoms among individuals infected with SARS-CoV-2 remain uncertain after optimizing the COVID-19 response in China.MethodsAn online cross-sectional survey was conducted among the public from January 6 to 30, 2023, using a convenience sampling method. Sociodemographic and COVID-19 pandemic-related factors were collected. The depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). Logistic regression analysis was performed to explore the associated factors with depressive symptoms.ResultsA total of 2,726 participants completed the survey. The prevalence of depression symptoms was 35.3%. About 58% of the participants reported experiencing insufficient drug supply. More than 40% of participants reported that they had missed healthcare appointments or delayed treatment. One-third of participants responded experiencing a shortage of healthcare staff and a long waiting time during medical treatment. Logistic regression analysis revealed several factors that were associated with depression symptoms, including sleep difficulties (OR, 2.84; 95% CI, 2.34–3.44), chronic diseases (OR, 2.15; 95% CI, 1.64–2.82), inpatient treatment for COVID-19 (OR, 3.24; 95% CI, 2.19–4.77), with COVID-19 symptoms more than 13 days (OR, 1.30, 95% CI 1.04–1.63), re-infection with SARS-CoV-2 (OR, 1.52; 95% CI, 1.07–2.15), and the increased in demand for healthcare services (OR, 1.32; 95% CI, 1.08–1.61).ConclusionThis study reveals a moderate prevalence of depression symptoms among individuals infected with SARS-CoV-2. The findings underscore the importance of continued focus on depressive symptoms among vulnerable individuals, including those with sleeping difficulties, chronic diseases, and inpatient treatment for COVID-19. It is necessary to provide mental health services and psychological interventions for these vulnerable groups during the COVID-19 epidemic.</p