Co-axial fibrous scaffolds integrating with carbon fiber promote cardiac tissue regeneration post myocardial infarction.

Myocardium is an excitable tissue with electrical conductivity and mechanical strength. In this work, carbon fibers (CFs) and co-axial fibrous mesh were integrated which combined the high modulus and excellent electrical conductivity of CFs and the fibrous and porous structures of the electrospun fibers. The scaffold was fabricated by simply integrating coaxial electrospun fibers and carbon fibers through a freeze-drying procedure. It was shown that the integration of carbon fibers have the conductivity and Young's modulus of the fibrous mesh increased significantly, meanwhile, upregulated the expression of CX43, α-actinin, RhoA of the neonatal rat primary cardiomyocytes and primary human umbilical vein endothelial cells (HUVECs), and promoted the secretion of VEGF of HUVECs. Moreover, the cardiomyocytes grown on the scaffolds increased the ability of HUVECs migration. When implanted to the injury area post myocardial infraction, the scaffolds were able to effectively enhance the tissue regeneration and new vessel formation, which rescued the heart dysfunction induced by the myocardial infraction, evidenced by the results of echocardiography and histochemical analysis. In conclusion, the composite scaffolds could promote the myocardium regeneration and function's recovery by enhancing cardiomyocytes maturation and angiogenesis and establishing the crosstalk between the cardiomyocytes and the vascular endothelial cells.

A panel of DNA methylation biomarkers for detection and improving diagnostic efficiency of lung cancer.

Lung cancer remains the leading cause of cancer deaths worldwide. Although low-dose spiral computed tomography (LDCT) screening is used for the detection of lung cancer in a high-risk population, false-positive results of LDCT remain a clinical problem. Here, we developed a blood test of a novel panel of three established lung cancer methylation biomarkers for lung cancer detection. Short stature homeobox 2 gene (SHOX2), ras association domain family 1A gene (RASSF1A), and prostaglandin E receptor 4 gene (PTGER4) methylation was analyzed in a training cohort of 351 individuals (197 controls, 154 cases) and validated from an independent cohort of 149 subjects (89 controls, 60 cases). The novel panel biomarkers distinguished between malignant and benign lung disease at high sensitivity and specificity: 87.0% sensitivity [95% CI 80.2-91.5%], 98.0% specificity [95% CI 94.9-99.4%]. Sensitivity in adenocarcinoma, squamous cell carcinoma, small cell lung cancer, and other lung cancer was 89.0%, 87.5%, 85.7%, and 77.8%, respectively. Notably, cancer patients in stage I and II showed high diagnostic sensitivity at 82.5% and 90.5%, respectively. Moreover, the diagnostic efficiency did not show bias toward age, gender, smoking, and the presence of other (nonlung) cancers. The performance of the panel in the validation cohort confirmed the diagnostic value. These findings clearly showed that this panel of DNA methylation biomarkers was effective in detecting lung cancer noninvasively and may provide clinical utility in stand-alone or in combination with current imaging techniques to improve the diagnosis of lung cancer.

Association between syphilis seroprevalence and age among blood donors in Southern China: an observational study from 2014 to 2017.

OBJECTIVE: This study investigated the association between syphilis seroprevalence and age among blood donors, and described the distribution of serological titres among syphilis-infected donors, aiming to confirm the syphilis epidemic characteristics and to promote effective interventions for older adults. METHODS: Data were obtained from the Shenzhen Programme for Syphilis Prevention and Control in 2014-2017. Blood samples were screened using the ELISAs, and confirmed using the Treponema pallidum particle agglutination assay (TPPA) and toluidine red unheated serum test (TRUST). RESULTS: Among 394 792 blood donors, 733 tested TPPA and TRUST positive (active infection), and 728 tested only TPPA positive (historical infection). The overall prevalence of syphilis seropositivity was 370.1 per 100 000 (95% CI 351.1 to 389.0 per 100 000); the prevalence of active infection was 185.7 per 100 000 (95% CI 172.2 to 199.1 per 100 000). People aged ≥45 years displayed a prevalence of 621.8 per 100 000 in syphilis seropositivity and 280.5 per 100 000 in active infection, which were 3.8 times and 2.4 times higher than that for people aged <25 years, respectively. The prevalence of syphilis seropositivity (χ2trend=311.9, p trend<0.001) and active infection (χ2trend=72.1, p trend<0.001) increased significantly with age. After stratification by gender and year of donation, the increasing trend of prevalence with age remained (p trend<0.05), except for the prevalence of active infection in males and females in 2014. About 16.3% of donors with active infection and aged ≥45 years had a TRUST titre of ≥1∶8, lower than that of patients aged <25 years (51.3%) and 25-34 years (34.1%). CONCLUSIONS: The findings confirm the high prevalence of syphilis among older adults, and suggest the need to increase awareness among healthcare providers and deliver more targeted prevention interventions for older adults to promote early testing.

High Modulus Conductive Hydrogels Enhance In Vitro Maturation and Contractile Function of Primary Cardiomyocytes for Uses in Drug Screening.

Effective and quick screening and cardiotoxicity assessment are very crucial for drug development. Here, a novel composite hydrogel composed of carbon fibers (CFs) with high conductivity and modulus with polyvinyl alcohol (PVA) is reported. The conductivity of the composite hydrogel PVA/CFs is similar to that of natural heart tissue, and the elastic modulus is close to that of natural heart tissue during systole, due to the incorporation of CFs. PVA/CFs remarkably enhance the maturation of neonatal rat cardiomyocytes (NRCM) in vitro by upregulating the expression of α-actinin, troponin T, and connexin-43, activating the signaling pathway of α5 and ß1 integrin-dependent ILK/p-AKT, and increasing the level of RhoA and hypoxia-inducible factor-1α. As a result, the engineered cell sheet-like constructs NRCM@PVA/CFs display much more synchronous, stable, and robust beating behavior than NRCM@PVA. When exposed to doxorubicin or isoprenaline, NRCM@PVA/CFs can retain effective beating for much longer time or change the contractile rate much faster than NRCM@PVA, respectively, therefore representing a promising heart-like platform for in vitro drug screening and cardiotoxicity assessment.

Macrophage phenotypic mechanomodulation of enhancing bone regeneration by superparamagnetic scaffold upon magnetization.

Macrophages are involved in all phases of scaffold induced tissue regeneration, orchestrating the transition from an inflammatory to regenerative phenotype to guide all other cell types to complete the wound healing process when a tissue defect advances beyond the critical size. Therefore, harnessing macrophages by scaffolds is important for facilitating tissue regeneration in situ. In this work we utilized the superparamagnetic scaffold upon magnetization as a mechanostimulation platform to apply forces directly to macrophages grown in the scaffold, aiming to figure out whether the functions of macrophages related to bone tissue regeneration can be mechanomodulated and to elucidate the underlying mechanisms. We showed the first evidence that upon magnetization the interaction of superparamagnetic scaffolds to macrophages drove them to polarize towards an M2-like phenotype by inhibiting TLR2/4 activation and enhancing VEGFR2 activation, thereby inhibiting secretion of the pro-inflammatory cytokines IL-1ß, TNF-α and MCP-1, as well as the osteoclast differentiation cytokines MMP-9 and TRAP, and up-regulating VEGF and PDGF. The conditioned media enhanced the osteogenesis of osteoblasts and the angiogenesis of endothelial cells.

Visible light-switched cytosol release of siRNA by amphiphilic fullerene derivative to enhance RNAi efficacy in vitro and in vivo.

Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes. To address this challenge, we designed an amphiphilic fullerene derivative (C60-Dex-NH2) for efficient and controllable siRNA delivery. To synthesize C60-Dex-NH2, terminally aminated dextran was conjugated to C60. The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C60-Dex-NH2 was examined with elemental analyses, gel permeation chromatography, solid-state nuclear magnetic resonance (13C, HPDEC), agarose gel electrophoresis, and dynamic light scattering. The cytotoxicity, cellular uptake, intracellular distribution, and in vitro RNA interference (RNAi) of siRNA/C60-Dex-NH2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C60-Dex-NH2in vivo was evaluated in subcutaneous tumor-bearing mice. The results showed that C60-Dex-NH2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C60-Dex-NH2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo. The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice. STATEMENT OF SIGNIFICANCE: We designed a novel photosensitive amphiphilic carrier (C60-Dex-NH2) for efficient and controllable siRNA delivery, which can be used in gene therapy. We showed that C60-Dex-NH2 could destroy lysosome membrane via controllable generation of ROS when exposed to light, which can help siRNA to escape from lysosome before degradation. This can enhance the gene silencing efficiency significantly and provides a useful way to regulate RNAi efficiency by light. One advantage for C60-Dex-NH2 system is C60 has broad absorbance spectrum and can be activated by weak visible light; Furthermore, C60-Dex-NH2 has a specific amphiphilic structure, which may prevent siRNA from degrading and allows C60-Dex-NH2 to embed into the lipid membrane of lysosome to improve the ROS induced lysosomal disturbance after internalization.