A humanized monoclonal antibody against interleukin-2 that can inactivate the cytokine/receptor complex

Inhibition of the interleukin-2 (IL-2) pathway has potent immunosuppressive activity in humans as is evident from the broad therapeutic utility of cyclosporine, rapamycin, tacrolimus, and monoclonal antibodies blocking the high-affinity subunit of the IL-2 receptor (CD25). Here we describe a humanized antibody, MT204, interfering with IL-2 signaling by a novel mechanism. Although MT204 did not prevent IL-2 from binding to CD25, it potently antagonized downstream signaling events of IL-2 at sub-nanomolar concentrations, such as STAT3 tyrosine phosphorylation, expression of CD124, production of gamma-interferon and cell proliferation. While MT204 and the anti-CD25 mAb daclizumab were equally effective in inhibiting autocrine growth of human CD4(+) T cells, MT204 was far superior in preventing proliferation of NKL lymphoma cells, production of gamma-interferon by natural killer (NK) cells and proliferation of primary NK cells. MT204 has potential as a novel immunosuppressive and anti-proliferative therapy with an apparently broader spectrum of activities than anti-CD25 antibodies.     

Renal function in the freshwater rainbow trout (Oncorhynchus mykiss) following acute and prolonged exposure to waterborne nickel

Renal function was investigated in adult rainbow trout following acute and prolonged exposure to waterborne Ni in moderately hard Lake Ontario water (approximately 140 mgL(-1) as CaCO3). Fish were exposed for 36 days to a sublethal concentration of 442 microg Ni L(-1), followed by 96 h of exposure to 12,850 microg Ni L(-1) (approximately 33% of the 96 h LC50). Prolonged exposure markedly affected only the renal handling of Ni, with no substantial effect on the plasma concentration, urinary excretion rate (UER) or clearance ratio (CR) of Na+, Cl-, K+, Ca2+, Mg2+, inorganic phosphate (P(i)), glucose, lactate, total ammonia (T(amm)), protein and free amino acids (FAA). Glomerular filtration rate (GFR) was reduced by 75% over 96 h of acute Ni challenge in both fish previously exposed to Ni and naive fish, with no significant change in urine flow rate (UFR), suggesting a substantial reduction in water reabsorption to maintain urine flow and water balance. Renal Mg2+ handling was specifically impaired by acute Ni challenge, leading to a significantly increased UER(Mg2+) and significantly decreased plasma [Mg2+] only in naive fish. Previously-exposed fish were well-protected against Ni-induced Mg2+ antagonism, indicating true acclimation to Ni. Only in naive, acutely challenged fish was there an increased UER of titratable acidity (TA-HCO3), net acidic equivalents, P(i), T(amm) and K+. Again, all of these parameters were well-conserved in previously-exposed fish during acute Ni exposure, strongly suggesting that prolonged, sublethal exposure protected against acute Ni-induced respiratory toxicity.     

The effects of nepafenac and amfenac on retinal angiogenesis

PurposeNepafenac is a potent NSAID that rapidly penetrates the eye following topical ocular administration. In the eye, nepafenac is converted to amfenac, which has unique time-dependent inhibitory properties for COX-1 and COX-2. The purpose of the present study was to investigate the capacity of amfenac to inhibit discrete aspects of the angiogenic cascade in vitro, and to test the efficacy of amfenac and nepafenac in vivo, using the rat OIR model.MethodsMüller cells were treated with amfenac, celecoxib (COX-2), or SC-560 (COX-1), and hypoxia-induced VEGF and PGE₂ assessed. Endothelial cells were treated with amfenac, celecoxib, or SC-560, and VEGF-induced proliferation and tube formation assessed. Rat pups were subjected to OIR, received intravitreal injections of amfenac, celecoxib, or SC-560, and neovascularization (NV), prostanoid production, and VEGF assessed. Other OIR-exposed pups were treated with topical nepafenac, ketorolac, or diclofenac, and inhibition of NV assessed.ResultsAmfenac treatment failed to inhibit hypoxia-induced VEGF production. Amfenac treatment significantly inhibited VEGF-induced tube formation and proliferation by EC. Amfenac treatment significantly reduced retinal prostanoid production and NV in OIR. Nepafenac treatment significantly reduced retinal NV in OIR; ketorolac and diclofenac had no effect.ConclusionsNepafenac and amfenac inhibit OIR more effectively than the commercially available topical and injectable NSAIDs used in this study. Our data suggests there are COX-dependent and COX-independent mechanisms by which amfenac inhibits OIR. Because it is bioavailable to the posterior segment following topical delivery, nepafenac appears to be a promising advancement in the development of therapies for neovascular eye diseases.     

Psychosocial Predictors of Weight Loss after Bariatric Surgery

Background: The authors investigated the predictive value of various parameters such as age, preoperative weight, eating behavior, psychiatric disorders, adverse childhood experiences and self-efficacy with regard to weight loss after gastric restrictive surgery. Methods: After a minimum follow-up of 30 months (median follow-up 50 months; range 30-84 months), a questionnaire concerning extent of, satisfaction with, and consequences of weight loss was mailed to 220 morbidly obese female patients following laparoscopic Swedish adjustable gastric banding (SAGB). Results: Questionnaires were completed and returned by 140 patients (63%). Average BMI loss was 14.6 kg/m². Most patients (85%) were happy with the extent of weight loss. Satisfaction with weight loss showed a significant correlation with extent of weight loss. BMI loss was greatest in the obese with an atypical eating disorder (20.0 kg/m²), and BMI loss was least in the obese with no eating-disordered behavior before surgery (13.4 kg/m²). Obese patients with two or more psychiatric disorders showed significantly less weight loss than did obese patients with one or no psychiatric disorder (BMI units 10.8 vs 14.0 vs 16.1; P=.047). Conclusions: The findings indicate a less successful outcome for obese patients with psychiatric disorders (particularly adjustment disorders, depression and/or personality disorders), compared to patients not mentally ill. An eating disorder preceding surgery, however, was not a negative predictor of success following bariatric surgery. To improve outcome of bariatric surgery in obese patients with psychiatric disorders, more individual psychosocial intervention strategies are necessary.     

CYP2D6 gene polymorphism as a probable risk factor for Alzheimer's disease and Parkinson's disease with dementia

BACKGROUND AND PURPOSE: The theory of multifactorial inheritance is considered in the pathogenesis of sporadic Alzheimer's disease (AD) and Parkinson's disease (PD); therefore, it makes the genes regulating bioactivation or detoxification of exogenous substances candidates of sensitivity to Alzheimer's and Parkinson's diseases. The aims of the study were: 1) to determine the genotypes of CYP2D6 cytochrome (CYP2D6) in patients with AD and sporadic PD with dementia; 2) to evaluate the relationship between the CYP2D6 genotype and the age of onset of the disease, the extent of dementia in AD and PD, the dose and side effects of L-dopa in PD; 3) to evaluate the usefulness of CYP2D6 genotyping in predicting predispositions to PD and AD. MATERIAL AND METHODS: 53 patients with AD aged 58-84 (mean age 72.6) and 52 patients with PD with dementia aged 51-82 (mean age 70.4) were recruited. Each AD patient satisfied criteria for probable AD. Diagnostic and Statistical Manual of Mental Disorders 4th edition, Mini-Mental State Examination, Clinical Dementia Rating Scale and Global Deterioration Scale were used for dementia evaluation in PD patients. Clinical scales for PD evaluation were used. Methods of molecular biology were used for genetic studies. RESULTS: There were no differences in CYP2D6 genotype and allele distribution in AD and PD patients. There was no relationship between CYP2D6 alleles and the age of onset and advancement of dementia in AD and PD. No relationship between CYP2D6 alleles and the dose and side effects of L-dopa in patients with sporadic PD with dementia was observed. CONCLUSION: As there were no differences in CYP2D6 polymorphism in AD and PD, CYP2D6 does not seem to be a factor predisposing to these diseases.     

Genetic association signal near NTN4 in Tourette syndrome

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10⁻³) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry‐matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10⁻⁴) remained significant after Bonferroni correction. Meta‐analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10⁻⁷). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case–control status (p = 0.042), suggesting that many of these variants are true TS risk alleles. Ann Neurol 2014;76:310–315     

MicroRNA-30c as a novel diagnostic biomarker for primary and secondary B-cell lymphoma of the CNS

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. A variety of targeted agents are being tested in the clinic including cancer vaccines, immunotoxins, antibodies and T cell immunotherapy for GBM. We have previously reported that IL-13 receptor subunits α1 and α2 of IL-13R complex are overexpressed in GBM. We are investigating the significance of IL-13Rα1 and α2 expression in GBM tumors. In order to elucidate a possible relationship between IL-13Rα1 and α2 expression with severity and prognoses of subjects with GBM, we analyzed gene expression (by microarray) and clinical data available at the public The Cancer Genome Atlas (TCGA) database (Currently known as Global Data Commons). More than 40% of GBM samples were highly positive for IL-13Rα2 mRNA (Log2?≥?2) while only less than 16% samples were highly positive for IL-13Rα1 mRNA. Subjects with high IL-13Rα1 and α2 mRNA expressing tumors were associated with a significantly lower survival rate irrespective of their treatment compared to subjects with IL-13Rα1 and α2 mRNA negative tumors. We further observed that IL-13Rα2 gene expression is associated with GBM resistance to temozolomide (TMZ) chemotherapy. The expression of IL-13Rα2 gene did not seem to correlate with the expression of genes for other chains involved in the formation of IL-13R complex (IL-13Rα1 or IL-4Rα) in GBM. However, a positive correlation was observed between IL-4Rα and IL-13Rα1 gene expression. The microarray data of IL-13Rα2 gene expression was verified by RNA-Seq data. In depth analysis of TCGA data revealed that immunosuppressive genes (such as FMOD, CCL2, OSM, etc.) were highly expressed in IL-13Rα2 positive tumors, but not in IL-13Rα2 negative tumors. These results indicate a direct correlation between high level of IL-13R mRNA expression and poor patient prognosis and that immunosuppressive genes associated with IL-13Rα2 may play a role in tumor progression. These findings have important implications in understanding the role of IL-13R in the pathogenesis of GBM and potentially other cancers.     

Association analysis of serotonin 2A receptor gene T102c polymorphism and schizophrenia.

The serotonin neurotransmitter has been associated with the pathogenesis of mood disorders and schizophrenia. Serotonin receptors genes may therefore be candidate genes for the study of the genetics of these disorders. In this study, patients with schizophrenia (n=235) and controls (n=344) were analysed to determine the correlation between the 5HT(2A) receptor gene T102C polymorphism and schizophrenia. No association was found between the studied polymorphism and schizophrenia (p=0.854 for alleles and p=0.945 for genotypes). Results were also not significant when analysed by gender (for male p=0.861-allele frequency and p=0.467-genotype frequency, for female p=0.857-allele frequency and p=0.833-genotype frequency). Subgroups with regard to schizophrenia subtypes, age of onset and clinical course of schizophrenia were analysed with negative results.