DNA Adjuvant Hydrogel-Optimized Enzymatic Cascade Reaction for Tumor Chemodynamic-Immunotherapy.

Chemodynamic therapy (CDT) shows immense potential in cancer treatment as it not only directly kills tumor cells but also induces anti-tumor immune responses. However, the efficacy of CDT is hampered by challenges in targeting CDT catalysts specifically to tumors using nanomaterials, along with the limitations of low H2 O2 levels and short catalyst duration within the tumor microenvironment. In this study, DNA adjuvant hydrogel to arrange a glucose oxidase-ferrocene cascade for continuously generating reactive oxygen species (ROS) from glucose in situ for tumor CDT combined with immunotherapy is employed. By precisely tuning the catalyst spacing with DNA double helix, ROS production efficiency is elevated by up to nine times compared to free catalysts, resulting in stronger immunogenetic cell death. Upon intratumoral injection, the DNA hydrogel system elicited potent anti-tumor immune responses, thereby effectively inhibiting established tumors and rejecting re-challenged tumors. This work offers a novel platform for integrated CDT and immunotherapy in cancer treatment.

Effects of sphingolipid metabolism disorders on endothelial cells.

Many cardiovascular disorders, including atherosclerosis, hypertension, coronary heart disease, diabetes, etc., are characterized by endothelial cell dysfunction. Endothelial cell function is closely related to sphingolipid metabolism, and normal sphingolipid metabolism is critical for maintaining endothelial cell homeostasis. Sphingolipid metabolites or key enzymes in abnormal situation, including sphingosine, ceramide (Cer), sphingosine-1-phosphate (S1P), serine, sphingosine kinase (SPHK), ceramide kinase (Cerk), sphingosine-1-phosphate lyase (S1PL) etc., may have a protective or damaging effect on the function of endothelial cells. This review summarizes the effects of sphingolipid metabolites and key enzymes disordering in sphingolipid metabolism on endothelial cells, offering some insights into further research on the pathogenesis of cardiovascular diseases and corresponding therapeutic targets.

Ferroptosis-related gene ATG5 is a novel prognostic biomarker in nasopharyngeal carcinoma and head and neck squamous cell carcinoma.

Nasopharyngeal carcinoma (NPC), a subtype of head and neck squamous cell carcinoma (HNSCC), is a malignant tumor that originates in the mucosal epithelium of the nasopharynx. Ferroptosis plays a key role in tumor suppression, while its prognostic value and critical factors in NPC have not been further explored. We select the Cancer Genome Atlas (TCGA) HNSCC dataset and the Gene Expression Omnibus (GEO) dataset of NPC samples, and find that ferroptosis-related factor ATG5 shows a high expression level with poor overall survival (OS) in HNSCC and NPC samples and is positively correlated with PD-L1/PD-L2 expression (p < 0.05). Furthermore, ATG5 high expression HNSCC patients show poor efficacy and short survival after receiving immune checkpoint blockade therapy treatment (p < 0.05). Moreover, ATG5 is significantly positively correlated with G2M checkpoint pathway (ρ Spearman = 0.41, p < 0.01), and G2M checkpoint inhibitor drugs have lower IC50 in HNSCC patients with high expression of ATG5 (p < 0.01), indicating the potential value of G2M inhibitors in HNSCC/NPC treatment. In summary, our study shows that ferroptosis-related factors play a key role in immune infiltration in NPC and HNSCC, and ATG5, as a key immune invasion-related ferroptosis-related factor, has the potential to be a novel prognostic biomarker and a potential target in therapy for NPC and HNSCC.

Resolving heterogeneity in schizophrenia through a novel systems approach to brain structure: individualized structural covariance network analysis.

Reliable mapping of system-level individual differences is a critical first step toward precision medicine for complex disorders such as schizophrenia. Disrupted structural covariance indicates a system-level brain maturational disruption in schizophrenia. However, most studies examine structural covariance at the group level. This prevents subject-level inferences. Here, we introduce a Network Template Perturbation approach to construct individual differential structural covariance network (IDSCN) using regional gray-matter volume. IDSCN quantifies how structural covariance between two nodes in a patient deviates from the normative covariance in healthy subjects. We analyzed T1 images from 1287 subjects, including 107 first-episode (drug-naive) patients and 71 controls in the discovery datasets and established robustness in 213 first-episode (drug-naive), 294 chronic, 99 clinical high-risk patients, and 494 controls from the replication datasets. Patients with schizophrenia were highly variable in their altered structural covariance edges; the number of altered edges was related to severity of hallucinations. Despite this variability, a subset of covariance edges, including the left hippocampus-bilateral putamen/globus pallidus edges, clustered patients into two distinct subgroups with opposing changes in covariance compared to controls, and significant differences in their anxiety and depression scores. These subgroup differences were stable across all seven datasets with meaningful genetic associations and functional annotation for the affected edges. We conclude that the underlying physiology of affective symptoms in schizophrenia involves the hippocampus and putamen/pallidum, predates disease onset, and is sufficiently consistent to resolve morphological heterogeneity throughout the illness course. The two schizophrenia subgroups identified thus have implications for the nosology and clinical treatment.

A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation.

BACKGROUND: Lymphatic malformations (LMs) are benign congenital malformations that stem from the abnormal development of the lymphatic vessels during early embryogenesis. Somatic PIK3CA gene mutations are conventional cause leading to LMs. Both macrocystic and microcystic LMs arise due to lymphatic endothelial cell-autonomous defects, depending on the time in development at which PIK3CA gene mutation occurs. Recent study finds a PIK3CA mutation in 79% of LMs. However, discovering new genetic events in this disease is crucial to identify the molecular mechanism of the pathogenesis and further develop new targeted therapies. RESULTS: Here, we initially performed whole-exome sequencing in six children with LMs to find a new causal gene. Somatic mutations in PIK3CA (c.1633G > A [p. E545K] and PIK3CD (c.1997T > C [p.L666P]) were discovered in two different individuals. In vitro functional studies were conducted to demonstrate the pathogenicity of the novel mutation c.1997T > C in PIK3CD. We found that L666P promoted the cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) and induced hyperactivation of the mTOR pathway. These findings indicate that the PIK3CD mutation affects downstream signalling in endothelial cells, which may impair normal lymphangiogenesis. CONCLUSIONS: This study reveals a novel candidate gene associated with the development of LMs, which is consistent with previous researches. These findings in our study may offer a novel gene target for developing therapies, which acts in tight interaction with the previously known PIK3CA.

Toxicity of insecticidal proteins from entomopathogenic bacteria to Galleria mellonella larvae.

Entomopathogenic bacteria have great potential in insect control in the agricultural production because they produce a large variety of protein toxins that can kill their hosts by damaging the insect midgut. However, the mechanisms on how these toxins or specific insecticidal proteins act on insects are very diverse and elusive. Here we select Galleria mellonella larvae as the host to explore the effects of insecticidal proteins on the activities of three protective enzymes (SOD, POD, and CAT) and on the morphology of the midgut tissues. As a result, the activities of the three enzymes consistently increased and then decreased when the host was injected with the insecticidal proteins from the entomopathogenic bacterium Enterobacter cloacae. Moreover, the microscopy analysis showed that tissues, cells, and organelles of the host midgut are all diseased after uptake of the insecticidal proteins. Remarkably, the protein toxins contributed to the deformation of the midgut, blackening of the midgut surface, dissolution of cell membrane, shrinkage of cell nucleus, and chromatin condensation. Our findings will advance the explanation of G. mellonella pathogenesis caused by the insecticidal proteins.

Efficacy of Initial Sirolimus Therapy for 27 Patients with Intractable Lymphatic Malformations.

OBJECTIVE/HYPOTHESIS: To evaluate the efficacy of initial sirolimus therapy in the treatment of intractable head and neck lymphatic malformations (LMs) in children. STUDY DESIGN: Prospective open-label study. METHODS: In this study, Twenty-seven children diagnosed with LMs were given oral sirolimus as primary treatment over a minimum 6-month trial. The major parameter to evaluate therapeutic outcome was percentage of lesion volume change compared with baseline. Average serum sirolimus concentrations, and adverse side effects, were monitored throughout the study period. RESULTS: Fifteen girls and twelve boys, average age 27 months (16 days-171 months), constitute the study group. Treatment was deemed effective for twenty-three participants, judged as fair in seven, good in nine, and excellent in seven. Two patients had minimal improvement, and two had increased volume to some degree. Effectiveness differed among LMs subtypes with responsiveness of macrocystic LMs exceeding that of microcystic LMs (P < .05). Adverse drug reactions totaled 27 events in ten patients, the majority being mild with upper respiratory infections being most common. CONCLUSIONS: Sirolimus as initial therapy is effective in decreasing lesion volume in intractable LMs in head and neck region, especially in macrocystic subtypes. Although most cases cannot be completely cured, side effects are few and tolerable. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1902-1908, 2021.

Bioactive Elastic Scaffolds Loaded with Neural Stem Cells Promote Rapid Spinal Cord Regeneration.

Despite decades of research, spinal cord injury (SCI) still causes irreparable damage to the human body. Key challenges that hinder the regeneration and extension of neurons following SCI must be overcome, including the overexpressed glial scar formation and strong inflammatory responses in lesion tissue. Transplantation of neural stem cells (NSCs) represents a promising therapeutic method due to its beneficial roles like growth factor secretion and anti-inflammation. However, NSCs usually differentiate into astrocytes, which is considered as one potential limitation of current NSC therapy. Herein, we fabricate an elastic poly(sebacoyl diglyceride) (PSeD) scaffold to mimic the mechanical properties of the natural spinal cord. The PSeD scaffold is coated with poly(sebacoyl diglyceride)-isoleucine-lysine-valine-alanine-valine-serine (PSeD-IKVAVS) to create a bioactive interface. The core point of this topic is divided into two parts. First, PSeD is a bioelastomer and its mechanical properties are similar to those of the natural spinal cord. This feature reduces the direct stimulation to the spinal cord tissue by the elastomer and then reduces the immune response or resistance caused by the host spinal cord tissue. Second, the IKVAVS peptide modifies PSeD to create a bioactive interface to support NSC growth and differentiation. In the in vivo study, the number of CD68-positive macrophages decreased in the PSeD-IKVAVS/NSC group compared to that in the SCI group (20% vs 60%). The low inflammation induced by the scaffold was beneficial to NSCs, resulting in increased locomotor recovery, as indicated by the increased Basso-Beattie-Bresnahan score (5, the average score in the PSeD-IKVAVS/NSC group, vs 2, the average score in the SCI group). Based on the above two characteristics, a PSeD-IKVAVS bioelastomer is fabricated, which provides a beneficial and bioactive microenvironment for NSCs after transplantation.

Clinical analysis of surgical treatment for head and neck lymphatic malformations in children: a series of 128 cases.

Background: Lymphatic malformations (LMs) are caused due to abnormal lymphatic development, and mainly occur in neonates or young children. At present, the role of surgery in the treatment of head and neck LMs is still controversial, focusing mainly on surgical efficacy and indications. Objective: This study aimed to explore the effect and influential factors of surgical treatment in children with head and neck LMs, hoping to provide a basis for rational selection of surgical indications. Methods: This retrospective study enrolled 128 children with head and neck LMs and underwent surgical treatment in Beijing Children's Hospital from May 2007 to June 2016. They were classified into three morphological groups: macrocystic, microcystic, and mixed. Based on de Serres staging, they were divided into five groups: stage I to V. The local lesion control rate, complication rate, and recurrence rate were summarized and analyzed. Results: The rate of completely controlled and almost completely controlled in cases with head and neck LMs was 71.1%. The postoperative complication rate was 13.3%, and the postoperative recurrence rate was 11.9%. Statistically significant difference was found for local lesion control and postoperative recurrence rates between different morphological and clinical staging groups. Furthermore, the complication rate showed a significant difference between different morphological groups, but not between clinical staging groups. Conclusions: Surgical resection in children with macrocystic, low-stage, or neck-limited LMs demonstrated better therapeutic effect, with fewer complications. However, the effect remained poor and had more complications for microcystic, diffused and high-stage patients. High stage and incomplete resection are considered as the main factors for postoperative recurrence. Current staging system for LMs has important predictive value in the prognosis of head and neck LMs. For LMs in posterior pharyngeal space, plasma ablation has certain advantages.

Gelatin Methacrylate (GelMA)-Based Hydrogels for Cell Transplantation: an Effective Strategy for Tissue Engineering.

Gelatin methacrylate (GelMA)-based hydrogels are gaining a great deal of attention as potentially implantable materials in tissue engineering applications because of their biofunctionality and mechanical tenability. Since different natural tissues respond differently to mechanical stresses, an ideal implanted material would closely match the mechanical properties of the target tissue. In this regard, applications employing GelMA hydrogels are currently limited by the low mechanical strength and biocompatibility of GelMA. Therefore, this review focuses on modifications made to GelMA hydrogels to make them more suitable for tissue engineering applications. A large number of reports detail rational synthetic processes for GelMA or describe the incorporation of various biomaterials into GelMA hydrogels to tune their various properties, e.g., physical strength, chemical properties, conductivity, and porosity, and to promote cell loading and accelerate tissue repair. A novel strategy for repairing tissue injuries, based on the transplantation of cell-loaded GelMA scaffolds, is examined and its advantages and challenges are summarized. GelMA-cell combinations play a critical and pioneering role in this process and could potentially accelerate the development of clinically relevant applications.

Systematic investigation of childhood sleep-disordered breathing (SDB) in Beijing: validation of survey methodology.

OBJECTIVE: To systematically investigate and validate the survey methodology for the epidemiological study of childhood sleep-disordered breathing (SDB) in mainland China using the Mandarin version of the Pediatric Sleep Questionnaire-Sleep-Related Breathing Disorder (PSQ-SRBD). DESIGN: A cross-sectional study using randomised, stratified, multistage, cluster sampling method. SETTING: A total of 11 kindergartens, 7 primary schools and 8 middle schools from 7 districts of Beijing, China. PARTICIPANTS: A total of 9198 children with valid questionnaires (4736 boys and 4462 girls; age range 3.0-14.4 years) were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Data on sociodemographic characteristics and PSQ-SRBD were collected. The score on PSQ-SRBD and the included factors were calculated with the effective data after data cleaning. Logistic regression and factor analysis with the principal components method were used to evaluate the validity of the questionnaire; reliability was assessed by retesting 5% of the respondents after 2±4 weeks of the initial test, and the intraclass correlation coefficient was calculated. RESULTS: The effective response rate of80.54% matched the sociodemographic characteristics of the respondents with respect to age group ratio and sex ratio in Beijing. With regard to construct validity of the PSQ-SRBD, the item score, except that of 'delayed growth', was highly correlated to the SRBD score as assessed by the logistic regression model. The exploratory factor analysis displayed a credible construct validity, with majority of the items grouped as the original dimensions. The test-retest reliability coefficient of each dimension's score ranged from 0.758 to 0.901, with an SRBD score of 0.730 indicating significant retest reliability. CONCLUSIONS: This study conducted and validated a successful survey methodology for investigation of childhood SDB in Beijing, China. The questionnaire demonstrated credible construct validity and retest reliability, thereby supporting the applicability and generalisability of the PSQ-SRBD in a large epidemiological survey of childhood SDB in China.

Sleep Duration and Factors Related to Sleep Loss in 3-14-Year-Old Children in Beijing: A Cross-Sectional Survey.

BACKGROUND: It is known that short sleep duration adversely affects children's behavior and physical development. This study aimed to investigate the status of sleep duration in 3-14-year-old children in Beijing and explore the related factors of sleep loss with them. METHODS: In this study, a cross-sectional study of random stratified cluster sampling was conducted on 3-14-year-old children and adolescents in Beijing. According to the proportion of children in each district and school, the final cohort included a total of 11 kindergartens, 7 primary schools, and 8 junior high schools from 7 districts of Beijing. Children of sampled classes were included, and their parents were invited to fill a series of questionnaires including the simplified Chinese version of Pediatric Sleep Questionnaire, Sleep Questionnaire Scale, and Hong Kong-Children Sleep Questionnaire about the performance of the last 6 months. RESULTS: Out of the total 11,420 questionnaires, 9198 questionnaires were valid and effective with the response rate of 80.54%. The age of the investigated children was 8.8 ± 3.8 years, including 4736 males and 4462 females. The daily sleep duration of children in Beijing was 9.7 ± 0.7 h. The prevalence of sleep loss (<9 h/day) of children in Beijing was 11.8%. The daily sleep duration of children aged <6, 6 ≤ age <11, and ≥11 years was 9.7 ± 0.6 h, 9.6 ± 0.6 h, and 9.5 ± 0.8 h, respectively. The sleep duration reduced significantly in children aged ≥11 years as compared to younger children in Beijing which was mainly contributed by the variation tendency of sleep duration on weekdays. The multivariate logistic regression analysis identified factors associated with sleep loss (P < 0.05): male (odds ratio [OR] = 1.32, 95% confidence interval [CI]: 1.15-1.51), age ≥11 years (OR = 2.37, 95% CI: 1.92-2.93), overweight (OR = 1.34, 95% CI: 1.17-1.54), family history of snoring (OR = 1.35, 95% CI: 1.13-1.61) and activities before bedtime with watching TV (OR = 1.24, 95% CI: 1.08-1.43), sports (OR = 1.22, 95% CI: 1.01-1.48), playing cellphone (OR = 1.91, 95% CI: 1.31-2.73) and surfing the Internet (OR = 1.27, 95% CI: 1.06-1.52) and among them age ≥11 years and playing cellphone before bedtime had greater impact on children's short sleep duration than that of other factors. CONCLUSIONS: Sleep loss was common among 3-14-year-old children in Beijing. Sleep duration decreased with age, especially among children over 11 years old. Factors associated with sleep loss covered sociodemographic characteristics, family sleep habits and routine activities before bedtime, and among those variables, age ≥11 years and playing with cellphones before bedtime had a greater impact on sleep duration, indicating that existing sleep loss in 3-14-year-old children could be, at least partly, improved by paying more attention to children aged of 11 years or entering Grade 5 and Grade 6 and to children with a family history of snoring; by reducing the use of electronic products before bedtime, especially cellphones; by managing weight and keeping fit; and by improving the bedtime routine.