Epirubicin loading in poly(butyl cyanoacrylate) nanoparticles manifests via altered intracellular localization and cellular response in cervical carcinoma (HeLa) cells

Objective: Drug loading into nanocarriers is used to facilitate drug delivery to target cells and organs. We have previously reported a change in cellular localization of epirubicin after loading to poly(butyl cyanoacrylate) (PBCA) nanoparticles. We aimed to further investigate the altered cellular localization and cellular responses to the described drug formulation.

Materials and methods: HeLa cells were treated with epirubicin-loaded PBCA nanoparticles prepared by the pre-polymerization method. A systematic study was performed to evaluate the formulation cytotoxicity. Cellular localization and uptake of the formulation as well as cellular response to the treatment were evaluated.

Results: Our studies revealed decreased cytotoxicity of the nanoparticle-formulated epirubicin compared to the free drug as well as a noticeable change in the drug’s intracellular localization. Epirubicin-loaded nanoparticles were internalized via endocytosis, accumulated inside endosomal vesicles and induced a two-fold stronger pro-apoptotic signal when compared to the free drug. The level of the tumor suppressor protein p53 in HeLa cells increased significantly upon treatment with free epirubicin, but remained relatively unchanged when cells were treated with equivalent dose of nanoparticle-loaded drug, suggesting a possible shift from p53-dependent DNA/RNA intercalation-based induction of cytotoxicity by free epirubicin to a caspase 3-induced cell death by the epirubicin-loaded PBCA formulation.     

Systemic overexpression of matricellular protein CCN1 exacerbates obliterative bronchiolitis in mouse tracheal allografts

Obliterative bronchiolitis (OB) involves airway epithelial detachment, fibroproliferation, and inflammation, resulting in chronic rejection and transplant failure. Cysteine‐rich 61 (CCN1) is an integrin receptor antagonist with a context‐dependent role in inflammatory and fibroproliferative processes. We used a mouse tracheal OB model to investigate the role of CCN1 in the development of lung allograft OB. C57Bl/6 mice received a systemic injection of CCN1‐expressing adenoviral vectors 2 days prior to subcutaneous implantation of tracheal allografts from major MHC‐mismatched BALB/c mice. We treated another group of tracheal allograft recipients with cyclic arginine–glycine–aspartic acid peptide to dissect the role of αvβ3‐integrin signaling in mediating CCN1 effects in tracheal allografts. Allografts were removed 4 weeks after transplantation and analyzed for luminal occlusion, inflammation, and vasculogenesis. CCN1 overexpression induced luminal occlusion (P < 0.05), fibroproliferation, and smooth muscle cell proliferation (P < 0.05). Selective activation of αvβ3‐integrin receptor failed to mimic the actions of CCN1, and blocking failed to inhibit the effects of CCN1 in tracheal allografts. In conclusion, CCN1 exacerbates tracheal OB by enhancing fibroproliferation via an α_vβ₃‐integrin‐independent pathway. Further experiments are required to uncover its potentially harmful role in the development of OB after lung transplantation.     

Effects of gestational age at birth on perinatal structural brain development in healthy term‐born babies

Infants born in early term (37–38 weeks gestation) experience slower neurodevelopment than those born at full term (40–41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain. Here we characterise brain volume and white matter correlates of gestational age at birth in healthy term‐born neonates and their relationship to later neurodevelopmental outcome using T2 and diffusion weighted MRI acquired in the neonatal period from a cohort (n = 454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor‐based morphometry and tract‐based spatial statistics. Neurodevelopment was assessed at age 18 months using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley‐III). Infants born earlier had higher relative ventricular volume and lower relative brain volume in the deep grey matter, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial, and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley‐III subscales at age 18 months. Regression models predicting outcome from gestational age at birth were significantly improved after adding neuroimaging features associated with gestational age at birth. This work adds to the body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term‐born babies.     

Intralesional bleomycin as alternative therapy in the treatment of multiple basal cell carcinomas

An 82-year-old female with with multiple basal cell carcinomas is presented. Her history includes treatment for similar lesions for 15 years with surgical and X-ray methods. We injected intralesional bleomycin to eight new histologically proven basal cell cancers. A followup at 2 years demonstrates the effectiveness of this therapy.     

Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes

Long-standing diabetes causes cardiovascular complications including direct cardiac muscle weakening known as diabetic cardiomyopathy. This is characterized by disturbances in both cardiac contraction and relaxation, which are maintained by calcium homeostasis in cardiac cells. Our recent in vitro and in vivo studies have shown that advanced glycation endproducts (AGE) account for diabetic vasculopathy through their engagement of the receptor for AGE (RAGE). Here we show that AGE and RAGE may directly affect the myocardial Ca(2+) homeostasis. We created transgenic mice that overexpressed human RAGE in the heart and analyzed the Ca(2+) transients in cultivated cardiac myocytes (CM) from the RAGE-transgenic and non-transgenic control fetuses. RAGE overexpression was found to reduce the systolic and diastolic intracellular calcium concentration ([Ca(2+)](i)). Exposure to AGE caused a significant prolongation of the decay time of [Ca(2+)](i) in CM from control mice, and this response was augmented in CM from the RAGE transgenic mice. The results suggest that the AGE and RAGE could play an active role in the development of diabetes-induced cardiac dysfunction.     

Enhancing Racial/Ethnic Equity in College Student Mental Health Through Innovative Screening and Treatment

Although college campuses are diversifying rapidly, students of color remain an underserved and understudied group. Online screening and subsequent allocation to treatment represents a pathway to enhancing equity in college student mental health. The purpose of the current study was to evaluate racial/ethnic differences in mental health problems and treatment enrollment within the context of a largescale screening and treatment research initiative on a diverse college campus. The sample was comprised of n?=?2090 college students who completed an online mental health screening survey and were offered either free online or face-to-face treatment based on symptom severity as a part of a research study. A series of ordinal, binomial and multinomial logistic regression models were specified to examine racial/ethnic differences in mental health problems, prior treatment receipt, and enrollment in online and face-to-face treatment through the campus-wide research initiative. Racial/ethnic differences in depression, anxiety and suicidality endorsed in the screening survey were identified. Students of color were less likely to have received prior mental health treatment compared to non-Hispanic white students, but were equally likely to enroll in and initiate online and face-to-face treatment offered through the current research initiative. Rates of enrollment in online therapy were comparable to prior studies. Online screening and treatment may be an effective avenue to reaching underserved students of color with mental health needs on college campuses. Digital mental health tools hold significant promise for bridging gaps in care, but efforts to improve uptake and engagement are needed.