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Nanoparticles consisting of a condensed nucleic acid core surrounded by protective layers which aid to overcome extracellular and intracellular hurdles to gene delivery (i. e., core-shell nanoparticles, CSNPs) synthetically mimic viruses. The outer shells shield the core and are particularly designed to enable facilitated release of the gene payload into the cytoplasm, the major limiting step in intracellular gene delivery. The hypothetical proton sponge effect and degradability in response to a stimulus (i. e., mildly acidic pH in the endosome) are two prevailing, although contested, principles in designing effective carriers for intracellular gene delivery via endosomal escape. Utilizing the highly flexible chemical-tuning of the polymeric shell via surface-initiated photo-polymerization of the various monomers at different molecular ratios, the effects of proton buffering capacity, acid-degradability, and endosomal membrane-lysis property on intracellular delivery of plasmid DNA by CSNPs were investigated. This study demonstrated the equivalently critical roles of proton buffering and acid-degradability in achieving efficient intracellular gene delivery, independent of cellular uptake. Extended proton buffering resulted in further improved transfection as long as the core structure was not compromised. The results of the study present a promising synthetic strategy to the development of an efficient, chemically-tunable gene delivery carrier.

Objective The objective of this study was to assess the effectiveness of tofacitinib vs TNF inhibitors (TNFis) in Korean patients with RA. Methods The study used data from a single academic referral hospital's registries of biologic DMARDs (bDMARDs) and tofacitinib and examined remission rates based on the DAS28-ESR after 12 months. Multivariable logistic regression analysis was used to estimate the odds ratio (OR) for achieving remission with tofacitinib compared with TNFi, adjusting for potential confounders. Results This analysis included 665 patients (200 on tofacitinib and 455 on TNFis) who were followed up for at least 12 months. Of these, 96 patients in the tofacitinib group (48.0%) and 409 patients in the TNFi group (89.9%) were treatment-naïve to bDMARDs. Intention-to-treat analysis revealed no significant difference in the remission rates between the two groups (18.0% vs 19.6%, P  = 0.640). Multivariable analysis demonstrated comparable remission rates with tofacitinib and TNFi (OR 1.204, 95% CI 0.720–2.013). In the subpopulation naïve to Janus kinase inhibitors (JAKis) and bDMARDs, tofacitinib showed better remission rates than TNFis (OR 1.867, 95% CI 1.033–3.377). Tofacitinib had more adverse events but similar rates of serious adverse events to TNFis. Conclusion In real-world settings, there was no significant difference in remission rates at 12 months between the tofacitinib and TNFi groups. In terms of safety, tofacitinib exhibited a higher incidence of adverse events compared with TNFis, while the occurrence of serious adverse events was comparable between the groups. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov , NCT02602704. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the trends in immunomodulator use and pregnancy outcomes among pregnant women with systemic lupus erythematosus (SLE), a condition requiring medication to maintain disease activity. Methods: This descriptive study used data from the National Health Information Database in Korea from 2002 to 2018. We included 5,044 pregnancies initiated between 2005 and 2017 in 3,120 SLE patients. Annual trends in SLE therapy, drug utilisation patterns during the preconception and pregnancy periods, and pregnancy outcomes were analysed. Results: Pregnancy compatible immunosuppressant (PC-IS) and hydroxychloroquine use during the first trimester were 10.7% and 41.4%, respectively. Most SLE medications exhibited a decline in usage from the preconception period to the first trimester. A prescription rate of 0.9% for pregnancy incompatible immunosuppressants (PIC-IS) was observed during the first trimester, and the incidence of live births, stillbirths, and abortions remained consistent from 2005 to 2017. Conclusions: Insufficient usage of hydroxychloroquine and PC-IS, along with a reduction in PIC-IS usage primarily during early pregnancy rather than before conception, highlights the unmet need for preconceptional family planning with appropriate medication management strategies in SLE pregnancies. [ABSTRACT FROM AUTHOR]

To evaluate the incidence and risk of cardiovascular disease (CVD) among Korean patients with systemic lupus erythematosus (SLE) comparing them to diabetes patients and the general population. This nationwide cohort study focused on incident SLE patients aged over 40 years, matched with diabetes patients and the general population (1:4:4 ratio). CVD was defined as ischaemic heart disease, ischaemic stroke, and cardiac arrest. Incidence rate and incidence rate ratio (IRR) of CVD were calculated using generalised estimating equation models. The Fine-Gray model assessed risk factors for CVD in both SLE and diabetes patients. The study included 4272 incident SLE patients, 17,003 diabetes patients, and 17,088 from the general population. SLE patients had higher CVD risk compared to the general population, with adjusted IRRs of 1.99 for overall CVD. Diabetes patients showed increased CVD risk, but to a lesser extent, with an IRR of 1.39. SLE patients aged 40–59 years displayed a significantly elevated CVD risk. Advanced age, male gender, and current use of glucocorticoids, immunosuppressive, and anti-platelet agents were associated with increased CVD risk in SLE patients. SLE patients have a higher risk of CVD compared to the general population, more so than diabetes patients. [ABSTRACT FROM AUTHOR]

Objectives To estimate the direct healthcare cost progression from before to after systemic lupus erythematosus (SLE) diagnosis and to compare healthcare costs by disease severity. Methods Patients with incident SLE diagnosed between 2008 and 2018 were identified from the Korean National Health Insurance database. Annual direct healthcare costs for 5 years before and after SLE were estimated and compared with those of age-, sex- and calendar month-matched (1:4) controls, without SLE. Direct healthcare costs were compared by disease severity of SLE using regression analysis. Results Among 11 173 patients with SLE and 45 500 subjects without SLE, annual direct healthcare costs per person increased in the year before SLE diagnosis and peaked in the first year after diagnosis. They were 7.7-fold greater in the SLE patients than in the subjects without SLE ($5871 vs $759). Severe SLE was associated with 3.284-fold (95% CI: 3.075, 3.507) higher annual costs than mild SLE during the year after diagnosis. Older age (age 60–79 years), lupus nephritis, interstitial lung diseases, and comorbidities such as avascular necrosis and chronic kidney disease were associated with higher annual direct healthcare costs (times [95% CI]) in the first year after diagnosis: age 60–69: 1.119 (1.034, 1.211); age 70–79: 1.470 (1.342, 1.611); lupus nephritis: 1.794 (1.711, 1.881); interstitial lung diseases: 1.435 (1.258, 1.638); avascular necrosis: 6.208 (4.541, 8.487); and chronic kidney disease: 1.858 (1.673, 2.064). Conclusion Patients with SLE incurred significantly higher direct healthcare costs than subjects without SLE during the first year after diagnosis. Disease severity, older age, major organ involvements and comorbidities were associated with increased healthcare costs. [ABSTRACT FROM AUTHOR]

Single modal cancer therapy that targets one pathological pathway often turns out to be inefficient. For example, relapse of chronic myelogenous leukemia (CML) after inhibiting BCR-ABL fusion protein using tyrosine kinase inhibitors (TKI) (e.g., Imatinib) is of significant clinical concern. This study developed a dual modal gene therapy that simultaneously tackles two key BCR-ABL-linked pathways using viral/nonviral chimeric nanoparticles (ChNPs). Consisting of an adeno-associated virus (AAV) core and an acid-degradable polymeric shell, the ChNPs were designed to simultaneously induce pro-apoptotic BIM expression by the AAV core and silence pro-survival MCL-1 by the small interfering RNA (siRNA) encapsulated in the shell. The resulting BIM/MCL-1 ChNPs were able to efficiently suppress the proliferation of BCR-ABL+ K562 and FL5.12/p190 cells in vitro and in vivo via simultaneously expressing BIM and silencing MCL-1. Interestingly, the synergistic antileukemic effects generated by BIM/MCL-1 ChNPs were specific to BCR-ABL+ cells and independent of a proliferative cytokine, IL-3. The AAV core of ChNPs was efficiently shielded from inactivation by anti-AAV serum and avoided the generation of anti-AAV serum, without acute toxicity. This study demonstrates the development of a synergistically efficient, specific, and safe therapy for leukemia using gene carriers that simultaneously manipulate multiple and interlinked pathological pathways.

The overall objective of the research was to investigate the utility of photochemical internalization (PCI) for the enhanced nonviral transfection of genes into glioma cells. The PCI-mediated introduction of the tumor suppressor gene phosphatase and tensin homolog (PTEN) or the cytosine deaminase (CD) pro-drug activating gene into U87 or U251 glioma cell monolayers and multicell tumor spheroids were evaluated. In the study reported here, polyamine-DNA gene polyplexes were encapsulated in a nanoparticle (NP) with an acid degradable polyketal outer shell. These NP synthetically mimic the roles of viral capsid and envelope, which transport and release the gene, respectively. The effects of PCI-mediated suppressor and suicide genes transfection efficiency employing either “naked” polyplex cores alone or as NP-shelled cores were compared. PCI was performed with the photosensitizer AlPcS 2a and λ=670-nm laser irradiance. The results clearly demonstrated that the PCI can enhance the delivery of both the PTEN or CD genes in human glioma cell monolayers and multicell tumor spheroids. The transfection efficiency, as measured by cell survival and inhibition of spheroid growth, was found to be significantly greater at suboptimal light and DNA levels for shelled NPs compared with polyamine-DNA polyplexes alone.

Drug resistance acquired by cancer cells is a significant challenge in the clinic and requires impairing the responsible pathological pathway. Administering chemotherapeutics along with silencing resistance-basis activity using RNA interference (RNAi) is expected to restore the activity of the chemotherapeutic and generate synergistic cancer eradication. This study attempted to reverse tamoxifen (TAM)-resistance in breast cancer by silencing a mitochondrial enzyme, manganese superoxide dismutase (MnSOD), which dismutates TAM-induced reactive oxygen species (ROS) (i.e., superoxide) to less harmful hydrogen peroxide and hampers therapeutic effects. Breast cancer cells were co-treated with TAM and MnSOD siRNA-delivering nanoparticles (NPs) made of a siRNA/poly(amidoamine) (PAMAM) dendriplex core and an acid-degradable polyketal (PK) shell. The (siRNA/PAMAM)-PK NPs were designed for the PK shell to shield siRNA from nucleases, minimize detrimental aggregation in serum, and facilitate cytosolic release of siRNA from endosomal compartments. This method of forming the PK shell around the siRNA/PAMAM core via surface-initiated photo-polymerization enables ease of tuning NPs' size for readily controlled siRNA release kinetics. The resulting NPs were notably homogenous in size, resistant to aggregation in serum, and invulnerable to heparan sulfate-mediated disassembly, compared to siRNA/PAMAM dendriplexes. Gel electrophoresis and confocal microscopy confirmed efficient siRNA release from the (siRNA/PAMAM)-PK NPs upon stimuli-responsive hydrolysis of the PK shell. Sensitization of TAM-resistant MCF7-BK-TR breast cancer cells with (MnSOD siRNA/PAMAM)-PK NPs restored TAM-induced cellular apoptosis in vitro and significantly suppressed tumor growth in vivo, as confirmed by biochemical assays and histological observations. This study implies that combined gene silencing and chemotherapy is a promising strategy to overcoming a significant challenge in cancer therapy.

Objective Anti-TNF biologics have been widely used to ameliorate disease activity in patients with RA. However, a large fraction of patients show a poor response to these agents. Moreover, no clinically applicable predictive biomarkers have been established. This study aimed to identify response-associated biomarkers using longitudinal transcriptomic data in two independent RA cohorts. Methods RNA sequencing data from peripheral blood cell samples of Korean and Caucasian RA cohorts before and after initial treatment with anti-TNF biologics were analysed to assess treatment-induced expression changes that differed between highly reliable excellent responders and null responders. Weighted correlation network, immune cell composition, and key driver analyses were performed to understand response-associated transcriptomic networks and cell types and their correlation with disease activity indices. Results In total, 305 response-associated genes showed significantly different treatment-induced expression changes between excellent and null responders. Co-expression network construction and subsequent key driver analysis revealed that 41 response-associated genes played a crucial role as key drivers of transcriptomic alteration in four response-associated networks involved in various immune pathways: type I IFN signalling, myeloid leucocyte activation, B cell activation, and NK cell/lymphocyte–mediated cytotoxicity. Transcriptomic response scores that we developed to estimate the individual-level degree of expression changes in the response-associated key driver genes were significantly correlated with the changes in clinical indices in independent patients with moderate or ambiguous response outcomes. Conclusion This study provides response-specific treatment-induced transcriptomic signatures by comparing the transcriptomic landscape between patients with excellent and null responses to anti-TNF drugs at both gene and network levels. [ABSTRACT FROM AUTHOR]