A copper chelate selectively triggers apoptosis in myeloid-derived suppressor cells in a drug-resistant tumor model and enhances antitumor immune response

Myeloid-derived suppressor cells (MDSCs), one of the major orchestrators of immunosuppressive network are present in the tumor microenvironment suppress antitumor immunity by subverting Th1 response in tumor site and considered as a great obstacle for advancement of different cancer immunotherapeutic protocols. Till date, various pharmacological approaches have been explored to modulate the suppressive functions of MDSCs in vivo. The present study describes our endeavor to explore a possibility of eradicating MDSCs by the application of a copper chelate, namely copper N-(2-hydroxy acetophenone) glycinate (CuNG), previously found to be a potential immunomodulator that can elicit antitumorogenic Th1 response in doxorubicin-resistant EAC (EAC/Dox) bearing mice. Herein, we demonstrated that CuNG treatment could reduce Gr-1+CD11b+ MDSC accumulation in ascitic fluid and spleen of EAC/Dox tumor model. Furthermore, we found that CuNG mediated reduction in MDSCs is associated with induction of Th1 response and reduction in Treg cells. Moreover, we observed that CuNG could deplete MDSCs by inducing Fas-FasL mediated apoptotic cell death where death receptor Fas expression is enhanced in MDSCs and FasL is provided by activated T cells. However, MDSC expansion from bone marrow cells and their differentiation was not affected by CuNG. Altogether, these findings suggest that the immunomodulatory property of CuNG is attributed to, at least in part, by its selective cytotoxic action on MDSCs. So, this preclinical study unveils a new mechanism of regulating MDSC levels in drug-resistant cancer model and holds promise of translating the findings into clinical settings.     

Influence of Zeolite Coating on the Corrosion Resistance of AZ91D Magnesium Alloy

The protective performance of zeolite coating on AZ91D magnesium alloy was evaluated using potentiodynamic polarisation and electrochemical impedance spectroscopy (EIS) in 0.1 M sodium chloride solution (NaCl). Electrical equivalent circuit (EEC) was developed based upon hypothetical corrosion mechanisms and simulated to correspond to the experimental data. The morphology and the chemical nature of the coating were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis. Post corrosion morphologies of the zeolite coated and the uncoated AZ91D alloy were investigated using SEM. The corrosion resistance of the zeolite coated specimen was at least one order of magnitude higher than the uncoated specimen.     

Association of pulse pressure,pulse pressure index,and ambulatory arterial stiffness index with kidney function in a cross‐sectional pediatric chronic kidney disease cohort from the CKiD study

The morbidity and mortality of adult and pediatric chronic kidney disease (CKD) and end‐stage renal disease (ESRD) populations are mainly driven by cardiovascular disease (CVD). Improving CVD outcomes focuses on risk assessment of factors including diastolic blood pressure (DBP), systolic blood pressure (SBP), left ventricular mass index (LVMI), pulse pressure (PP), and pulse pressure index (PPi), which is calculated as PP/SBP. These markers are also proven predictors of CKD progression; however, their role in children has not been established. This study aims to evaluate the relationship between PP, PPi, ambulatory arterial stiffness index (AASI), and proteinuria with kidney function in pediatric CKD patients; it is a retrospective analysis of 620 patients (1‐16 years) from the NIDDK Chronic Kidney Disease in Children (CKiD) registry. The authors analyzed data for three separate cohorts: an overall CKD as well as immunological versus non‐immunological cause for CKD groups. An inverse relationship was found between SBP, DBP, and PP with iGFR and LVMI in the overall CKD group. Our immunological CKD subgroup showed significantly higher serum creatinine, SBP, DBP, and PP values with significantly lower serum albumin levels compared to the non‐immunological group. There were no significant differences with iohexol‐based glomerular filtration rate (iGFR), LVMI, PPi, or high‐sensitivity C‐reactive protein (hs‐CRP) between the two groups. A subgroup analysis demonstrated that SBP, DBP, and PP all correlated significantly with LVMI in the immunological CKD patients but not the non‐immunological subgroup. Additionally, AASI data in the overall CKD population were significantly correlated with PP, PPi, and DBP. This study is one of the first to correlate noninvasive measurements of vascular compliance including PP, PPi, and AASI with iGFR and LVMI in a pediatric CKD cohort. Improving our understanding of surrogate markers for early CVD is integral to improving the care of pediatric CKD population as these patients have yet to develop the hard end points of ESRD, heart failure, myocardial infarction, or stroke.     

A novel technique of detecting MRI‐negative lesion in focal symptomatic epilepsy: Intraoperative ShearWave Elastography

Focal symptomatic epilepsy is the most common form of epilepsy that can often be cured with surgery. A small proportion of patients with focal symptomatic epilepsy do not have identifiable lesions on magnetic resonance imaging (MRI). The most common pathology in this group is type II focal cortical dysplasia (FCD), which is a subtype of malformative brain lesion associated with medication‐resistant epilepsy. We present a patient with MRI‐negative focal symptomatic epilepsy who underwent invasive electrode recordings. At the time of surgery, a novel ultrasound‐based technique called ShearWave Elastography (SWE) was performed. A 0.5 cc lesion was demonstrated on SWE but was absent on B‐mode ultrasound and 3‐T MRI. Electroencephalography (EEG), positron emission tomography (PET), and magnetoencephalography (MEG) scans demonstrated an abnormality in the right frontal region. On the basis of this finding, a depth electrode was implanted into the lesion. Surgical resection and histology confirmed the lesion to be type IIb FCD. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Reduced hippocampal brain-derived neurotrophic factor (BDNF) in neonatal rats after prenatal exposure to propylthiouracil (PTU)

Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy.     

Cytodiagnosis of cutaneous histoplasmosis in HIV positive patient initially presenting with multiple umbilicated disseminated skin nodules

Histoplasmosis is usually an opportunistic fungal infection in patients with defective cell mediated immunity, and has been considered as one of the acquired immunodeficiency syndrome (AIDS) defining illness. However, cutaneous involvement in human immunodeficiency virus (HIV) positive patients is less common, and very rarely can be the initial presenting symptom for the diagnosis of AIDS. We present here an unusual case of multiple diffuse cutaneous nodular lesions predominantly in face, trunk, and upper extremities diagnosed initially on aspiration cytology as histoplasmosis. Subsequent serological test revealed positivity for HIV 1 and 2, along with a low CD4 count and low CD4:CD3 ratio. The cytomorphological features were further corroborated by histology and histochemical stains. Hence, cutaneous histoplasmosis can cause multiple wide spread nodular or umbilicated lesions in AIDS patients as the initial presentation. Fine needle aspiration cytology (FNAC) is a rapid, cost effective tool for diagnosis of the fungi from such lesions and initiating work up for immunocompromised states including AIDS. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Ambient Light Regulates Retinal Dopamine Signaling and Myopia Susceptibility

PurposeExposure to high-intensity or outdoor lighting has been shown to decrease the severity of myopia in both human epidemiological studies and animal models. Currently, it is not fully understood how light interacts with visual signaling to impact myopia. Previous work performed in the mouse retina has demonstrated that functional rod photoreceptors are needed to develop experimentally-induced myopia, alluding to an essential role for rod signaling in refractive development.MethodsTo determine whether dim rod-dominated illuminance levels influence myopia susceptibility, we housed male C57BL/6J mice under 12:12 light/dark cycles with scotopic (1.6 × 10⁻³ candela/m²), mesopic (1.6 × 10¹ cd/m²), or photopic (4.7 × 10³ cd/m²) lighting from post-natal day 23 (P23) to P38. Half the mice received monocular exposure to −10 diopter (D) lens defocus from P28–38. Molecular assays to measure expression and content of DA-related genes and protein were conducted to determine how illuminance and lens defocus alter dopamine (DA) synthesis, storage, uptake, and degradation and affect myopia susceptibility in mice.ResultsWe found that mice exposed to either scotopic or photopic lighting developed significantly less severe myopic refractive shifts (lens treated eye minus contralateral eye; –1.62 ± 0.37D and −1.74 ± 0.44D, respectively) than mice exposed to mesopic lighting (–3.61 ± 0.50D; P < 0.005). The 3,4-dihydroxyphenylacetic acid /DA ratio, indicating DA activity, was highest under photopic light regardless of lens defocus treatment (controls: 0.09 ± 0.011 pg/mg, lens defocus: 0.08 ± 0.008 pg/mg).ConclusionsLens defocus interacted with ambient conditions to differentially alter myopia susceptibility and DA-related genes and proteins. Collectively, these results show that scotopic and photopic lighting protect against lens-induced myopia, potentially indicating that a broad range of light levels are important in refractive development.