Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy.

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.

Inhibition of Biofilm Formation in Cutibacterium acnes, Staphylococcus aureus, and Candida albicans by the Phytopigment Shikonin.

Skin microbiota, such as acne-related Cutibacterium acnes, Staphylococcus aureus, and fungal Candida albicans, can form polymicrobial biofilms with greater antimicrobial tolerance to traditional antimicrobial agents and host immune systems. In this study, the phytopigment shikonin was investigated against single-species and multispecies biofilms under aerobic and anaerobic conditions. Minimum inhibitory concentrations of shikonin were 10 µg/mL against C. acnes, S. aureus, and C. albicans, and at 1-5 µg/mL, shikonin efficiently inhibited single biofilm formation and multispecies biofilm development by these three microbes. Shikonin increased porphyrin production in C. acnes, inhibited cell aggregation and hyphal formation by C. albicans, decreased lipase production, and increased hydrophilicity in S. aureus. In addition, shikonin at 5 or 10 µg/mL repressed the transcription of various biofilm-related genes and virulence-related genes in C. acnes and downregulated the gene expression levels of the quorum-sensing agrA and RNAIII, α-hemolysin hla, and nuclease nuc1 in S. aureus, supporting biofilm inhibition. In addition, shikonin prevented multispecies biofilm development on porcine skin, and the antimicrobial efficacy of shikonin was recapitulated in a mouse infection model, in which it promoted skin regeneration. The study shows that shikonin inhibits multispecies biofilm development by acne-related skin microbes and might be useful for controlling bacterial infections.

Long-Term Progression of Pericentral Hydroxychloroquine Retinopathy.

PURPOSE: To investigate the long-term progression of pericentral hydroxychloroquine retinopathy. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: Eighty eyes (60 with pericentral pattern) of 41 Korean patients with hydroxychloroquine retinopathy followed up for 2 years or more after drug cessation. METHODS: Patients were screened for hydroxychloroquine retinopathy using spectral-domain or swept-source OCT, fundus autofluorescence (FAF), and Humphrey visual field (VF) tests. Follow-up was divided into short-term (≤2 years) and subsequent periods, and progression was evaluated in each period and severity group. Retinopathy progression on OCT was defined as increased length of the ellipsoid zone defect, decreased distance from the fovea to the photoreceptor defects, or newly developed or enlarged retinal pigment epithelium defects. On FAF, progression was defined as an increase in the area of hyperautofluorescence or hypoautofluorescence. Functional progression was defined as a regression coefficient of less than 0 dB/year for mean deviation and more than 0 dB/year for pattern standard deviation, based on linear regression analysis of 3 or more VF tests. Structural and functional progression rates were calculated using the slopes of retinal thicknesses on the Early Treatment Diabetic Retinopathy Study grid and perimetric parameters over time, respectively. MAIN OUTCOME MEASURES: Structural and functional progression of retinopathy. RESULTS: Approximately one third of eyes with early pericentral retinopathy showed limited progression during the short-term period after drug cessation, but they subsequently showed stable or improved photoreceptors. Most eyes with moderate pericentral retinopathy showed continuous progression, particularly when converted to the severe stage. Severe eyes showed progressive damage throughout the follow-up period. In all severity groups, the rates of retinal thinning decreased over time. In eyes with pericentral retinopathy showing progression, circumferential enlargement of retinal damage was prominent in earlier stages, whereas centripetal enlargement of the ring-shaped lesion was noted in advanced stages. Functional progression, noted in 58.7% of the pericentral eyes, corresponded with structural progression. CONCLUSIONS: Pericentral hydroxychloroquine retinopathy showed severity-dependent progression. Moderate pericentral retinopathy usually progressed, but centripetal progression threatening the fovea was remarkable mostly in severe retinopathy. Our results suggest that early detection of retinopathy may minimize the risk of progression to foveal involvement in pericentral retinopathy.

The effects of Engelhardtia chrysolepis Hance on long-term memory and potential dopamine involvement in mice.

Engelhardtia chrysolepis Hance (ECH) is a perennial plant used in traditional medicine. A major active ingredient of ECH is astilbin (ASB), which has recently been shown to have neuroprotective effects as well as to affect catecholamine neurotransmissions in brain areas such as the prefrontal cortex. In this study, we investigated the effects of ECH and ASB on long-term memory in mice using a battery of behavioral tests. Acute ECH treatments dose-dependently facilitated nonspatial, but not spatial, memory. ECH treatments also upregulated expression of tyrosine hydroxylase, the enzyme mediating catecholamine synthesis, in neuroblastoma cell culture. Acute ASB treatments similarly improved nonspatial memory, whereas chronic ASB treatments improved both nonspatial and spatial memory. In accordance with such behavioral effects, the increased ratio of tissue concentrations of dopamine metabolites over dopamine in striatal regions was observed in mice with chronic ASB treatments. These results suggest that ECH and its active ingredient ASB may facilitate long-term memory by modulating catecholamine transmission.

Histamine H3 receptor antagonists ameliorate attention deficit/hyperactivity disorder-like behavioral changes caused by neonatal habenula lesion.

A partial agonist and a full antagonist of the histamine H3 receptor have been suggested to have therapeutic effects on cognitive deficits in psychiatric disorders. We have previously shown that neonatal habenula lesion (NHL) induces behavioral deficits that resemble the symptoms of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the effects of three H3 antagonists on ADHD-like behavioral changes caused by NHL in rats. Behavioral tests and administration of the H3 receptor antagonists were performed in juvenile rats with NHL. H3 antagonist administration to juvenile rats dose dependently improved NHL-induced hyperlocomotion, impulsive behavior, and attention deficit. These results suggest that histamine H3 antagonists may be used as alternative therapeutic drugs for the treatment of ADHD.

Combination Cancer Therapy Using Chimeric Antigen Receptor-Engineered Natural Killer Cells as Drug Carriers.

The therapeutic limitations of conventional chemotherapeutic drugs include chemo-resistance, tumor recurrence, and metastasis. Numerous nanoparticle-based active targeting approaches have emerged to enhance the intracellular concentration of drugs in tumor cells; however, efficient delivery of these systems to the tumor site while sparing healthy tissue remains elusive. Recently, much attention has been given to human immune-cell-directed nanoparticle drug delivery, because immune cells can traffic to the tumor and inflammatory sites. Natural killer cells are a subset of cytotoxic lymphocytes that play critical roles in cancer immunosurveillance. Engineering of the human natural killer cell line, NK92, to express chimeric antigen receptors to redirect their antitumor specificity has shown significant promise. We demonstrate that the efficacy of chemotherapy can be enhanced in vitro and in vivo while reducing off-target toxicity by using chimeric antigen receptor-engineered NK92 cells as carriers to direct drug-loaded nanoparticles to the target site.

Clinical features and outcome of corneal opacity associated with congenital glaucoma.

BACKGROUND: To investigate the clinical features of corneal opacity and the surgical outcome of penetrating keratoplasty (PK) in eyes with congenital glaucoma. METHODS: A retrospective review was made of the records from 320 eyes of 193 patients who were diagnosed with congenital glaucoma between January 1981 and January 2016. Anterior segment photographs at disease presentation were examined for the presence and severity of corneal opacity. Data on patient demographics, intraocular pressure (IOP), ocular and systemic comorbidities, ocular surgery and its outcome were collected. RESULTS: Overall, corneal opacification was observed in 248 of 320 eyes (77.5%). Out of 248 eyes with corneal opacification, 53 eyes had Haab striae alone, and 195 eyes presented with either nebulomacular corneal opacity (128 eyes, iris details visible through opacity) or leukomatous corneal opacity (67 eyes, iris details invisible through opacity). In 12 eyes with severe leukomatous corneal opacity, PK was performed at the mean age of 18.6 months (range 4-57 months). The grafts failed in 6 eyes (50%) due to endothelial rejection (4 eyes) or graft infection (2 eyes) during the mean 80.6 months of follow-up (range 15-228 months). The median survival time was 36 months. The graft failure was significantly associated with smaller corneal diameter at the time of surgery, but not with the age, IOP, combined aniridia, simultaneous glaucoma or lens surgery. CONCLUSION: Congenital glaucoma was combined with corneal opacity in 77.5%. The corneal transplant survival was 50% in eyes with congenital glaucoma and total corneal opacity.

The relationship between anemia and pulse pressure and hypertension: The Korea National Health and Nutrition Examination Survey 2010-2012.

The present study was conducted to assess the relationship between anemia and pulse pressure (PP) and hypertension (HTN). Data from 16,060 adults (aged ≥20 years) in the fifth Korean National Health and Nutrition Examination Survey (2010-2012) were analyzed. Several key findings were identified. First, after adjusting for related variables, the odds ratio (OR) of anemia (hemoglobin <13 and <12 g/dL, in men and women, respectively), using the normal PP group (PP ≤61 mmHg) as a reference, was significant for the high PP cohort (PP >61 mmHg; OR, 1.517; 95% confidence interval [CI], 1.270-1.812). Second, after adjusting for related variables (except body mass index [BMI] and waist measurement [WM]), the OR of anemia, with a normal blood pressure group as a reference, was significant for the HTN group (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or use of HTN medications; OR, 0.835; 95% CI, 0.709-0.983). However, when further adjusted for BMI and WM, anemia was not associated with HTN (OR, 0.884; 95% CI, 0.750-1.042). In conclusion, anemia was positively associated with high PP, but was not associated with HTN.

The Relationship Between Pulse Pressure, the Estimated Glomerular Filtration Rate, and Urine Microalbumin/Creatinine Ratio in Korean Adults.

BACKGROUND/AIMS: Pulse pressure (PP) is a predictor of adverse outcomes in patients on haemodialysis. Thus, the present study was conducted to assess the relationship between PP, estimated glomerular filtration rate (eGFR), and urine microalbumin/creatinine ratio (uACR) in Korean adults. METHODS: Data of 9,409 adults (4,206 men and 5,203 women) aged ≥ 20 years from the Sixth Korean National Health and Nutrition Examination Survey (2013-2014) were analyzed. RESULTS: A multivariate analysis revealed that systolic blood pressure (SBP) (ß = -0.170, 95% confidence interval [CI], -0.216 to -0.159), diastolic blood pressure (DBP) (ß = 0.088, 95% CI 0.108-0.200; p < 0.001), and PP (ß = -0.134, 95% CI -0.215 to -0.157) were significant factors determining eGFR. In contrast, SBP (ß = 0.152, 95% CI, 0.985-1.456; p < 0.001), DBP (ß = -0.062, 95% CI -1.141 to -0.442; p < 0.001), and PP (ß = 0.118, 95% CI 0.965-1.436; p < 0.001) were the significant factors determining uACR. The odds ratios (ORs) of a high PP (PP ≥ 60 mmHg) with a normal group [eGFR ≥ 60 ml/min/1.73 m2 and uACR < 30 mg/g] as a reference were significant for decreased eGFR [eGFR < 60 ml/min/1.73 m2, 1.484 (95% CI, 1.003-2.196)], elevated uACR [uACR ≥ 30 mg/g, 2.592 (95% CI, 2.085-3.223)], and decreased eGFR plus elevated uACR [eGFR < 60 ml/min/1.73 m2 and uACR ≥ 30 mg/g, 3.889 (95% CI, 2.519-6.004)]. CONCLUSION: Enhanced PP was associated with a decreased eGFR and an increase in uACR in Korean adults. In addition, the PP increased greatly when a decrease in eGFR and an increase in uACR appeared simultaneously.