Effects Of Concurrent Treatment Research Articles

Insight into inflammation involvement in varicocele: A narrative review.

Varicocele is one of the main causes of male infertility. Although the pathophysiology mechanism of varicocele is very well described and understood, there are some unanswered questions that remains unknown. Some studies have previously described the state of testicular inflammation and sperm in animal models, especially the mouse model, and the seminal plasma of men with varicocele, with or without changes in semen parameters. This review intended to verify the role of inflammatory mechanism in varicocele, using clinical studies as well as animal model studies on the effect of inflammation caused by varicocele on the function of testicular somatic and germ cells. In-vivo studies confirmed whether anti-inflammatory molecules could treat the semen of men with varicocele and rats with varicocele. The use of different anti-inflammatory agents in mouse model studies provided a new perspective for future clinical studies to investigate the effect of concurrent treatment with surgery to improve surgical outcomes. Similar to animal model studies, previously conducted clinical trials have demonstrated the effectiveness of anti-inflammatory therapy in varicocele patients. However, clinical trials using anti-inflammatory are needed to be conducted agents to evaluate different aspects of this therapeutical approach in varicocele patients.

Synergistic Anticancer Effect of a Combination of Berbamine and Arcyriaflavin A against Glioblastoma Stem-like Cells.

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. Relapse is frequent and rapid due to glioblastoma stem-like cells (GSCs) that induce tumor initiation, drug resistance, high cancer invasion, immune evasion, and recurrence. Therefore, suppression of GSCs is a powerful therapeutic approach for GBM treatment. Natural compounds berbamine and arcyriaflavin A (ArcA) are known to possess anticancer activity by targeting calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ) and cyclin-dependent kinase 4 (CDK4), respectively. In this study, we evaluated the effects of concurrent treatment with both compounds on GSCs. Combined treatment with berbamine and ArcA synergistically inhibited cell viability and tumorsphere formation in U87MG- and C6-drived GSCs. Furthermore, simultaneous administration of both compounds potently inhibited tumor growth in a U87MG GSC-grafted chick embryo chorioallantoic membrane (CAM) model. Notably, the synergistic anticancer effect of berbamine and ArcA on GSC growth is associated with the promotion of reactive oxygen species (ROS)- and calcium-dependent apoptosis via strong activation of the p53-mediated caspase cascade. Moreover, co-treatment with both compounds significantly reduced the expression levels of key GSC markers, including CD133, integrin α6, aldehyde dehydrogenase 1A1 (ALDH1A1), Nanog, Sox2, and Oct4. The combined effect of berbamine and ArcA on GSC growth also resulted in downregulation of cell cycle regulatory proteins, such as cyclins and CDKs, by potent inactivation of the CaMKIIγ-mediated STAT3/AKT/ERK1/2 signaling pathway. In addition, a genetic knockdown study using small interfering RNAs (siRNAs) targeting either CaMKIIγ or CDK4 demonstrated that the synergistic anticancer effect of the two compounds on GSCs resulted from dual inhibition of CaMKIIγ and CDK4. Collectively, our findings suggest that a novel combination therapy involving berbamine and ArcA could effectively eradicate GSCs.

Radiotherapy programs neutrophils to an antitumor phenotype by inducing mesenchymal-epithelial transition.

BackgroundNeutrophils can play a pro-tumor or anti-tumor role depending on the tumor microenvironment. The effects of concurrent treatment with granulocyte colony-stimulating factor (G-CSF) and radiotherapy (RT) on neutrophils have not yet to be described.MethodsHypofractionated radiation of 8 Gy ×3 fractions was administered with or without recombinant G-CSF to Lewis lung carcinoma tumor-bearing C57BL/6 model mice. The activation status of cytotoxic T cells in the mice was measured, along with the levels of tumor-associated neutrophils, cytotoxic T cells, and Treg cells. Tumor growth, survival, cytokine expression, and signaling pathways underlying anti-tumor effects of tumor-associated neutrophils after treatment were also studied. To ascertain the effects of concurrent RT and G-CSF on tumor-associated neutrophils, neutrophil depletion was performed.ResultsRT affected early neutrophil infiltration, which is the first-line immune response. Subsequently, enhanced accumulation of lymphocytes, particularly CD8 cytotoxic T cells, was observed. Notably, lymphocytic infiltration was inhibited by neutrophil depletion but enhanced by G-CSF treatment. RT generated persistent DNA damage, as evidenced by an accumulation of phosphorylation of histone H2AX (γH2AX), and subsequently triggered inflammatory chemokine secretion. The chemokines CXCL1, CXCL2, and CCL5 were upregulated in both radiation-treated cells and the corresponding supernatants. Neutrophils that were newly recruited after RT improved radiosensitivity by inhibiting epithelial–mesenchymal transition via the reactive oxygen species-mediated PI3K/Akt/Snail signaling pathway, and G-CSF treatment enhanced this effect.ConclusionsThe results of this study suggest that RT activates neutrophil recruitment and polarizes newly recruited neutrophils toward an antitumor phenotype, which is enhanced by the concurrent administration of G-CSF. Mesenchymal-epithelial transition induced by reactive oxygen species accumulation plays a major role in this process. Thus, the polarization of tumor-associated neutrophils might play a role in future cancer immunotherapies.

Conditioned place preference following concurrent treatment with 3, 4-methylenedioxypyrovalerone (MDPV) and methamphetamine in male and female Sprague-Dawley rats

Synthetic cathinones gained initial popularity on the illicit drug market as a result of attempts to evade legal restrictions on other commonly abused psychostimulants. A body of published research has determined that the psychopharmacology of the synthetic cathinone 3, 4-methylenedioxypyrovalerone (MDPV) is comparable to cocaine and methamphetamine (METH). Few preclinical studies have systematically investigated concurrent use of synthetic cathinones with other psychostimulant drugs. The present study utilized conditioned place preference (CPP), a rodent model of conditioned drug reward, to evaluate the effects of concurrent treatment with MDPV and METH. Male (N = 72) and female (N = 105) Sprague-Dawley rats underwent a two-compartment biased CPP procedure, with one trial per day for eight consecutive days. Subjects were randomly assigned to the following treatment groups: saline, METH (1 mg/kg), MDPV (1, 3.2, 5.6 mg/kg) or a mixture consisting of METH (1 mg/kg) and MDPV (1, 3.2, 5.6 mg/kg). All treatments increased locomotor activity during drug conditioning trials, and most treatments produced higher activity increases in females compared to males. Although the level of CPP established by MDPV and MDPV + METH mixtures varied between males and females, sex differences were not statistically significant. Although none of the MDPV+METH mixtures produced stronger CPP than either substance alone, some mixtures of MDPV and METH produced higher increases in locomotor activity compared to either drug alone. Further studies with higher doses may be warranted to determine if concurrent use of MDPV and METH pose an enhanced risk for abuse.

The effects of concurrent treatment of silymarin and lactulose on memory changes in cirrhotic male rats.

Introduction: Chronic liver disease frequently accompanied by hepatic encephalopathy (HE). Changes in the permeability of the blood-brain barrier in HE, make an easier entrance of ammonia among other substances to the brain, which leads to neurotransmitter disturbances. Lactulose (LAC), causes better defecation and makes ammonia outreach of blood. Silymarin (SM) is a known standard drug for liver illnesses. The purpose of this research was to determine the results of LAC and SM combined treatment, on the changes in memory of cirrhotic male rats. Methods: The cirrhotic model established by treatment with thioacetamide (TAA) for 18 weeks. Cirrhotic rats randomized to four groups (n = 7): TAA group (received drinking water), LAC group (2 g/kg/d LAC in drinking water), SM group (50 mg/kg/d SM by food), SM+ LAC group (similar combined doses of both compounds) for 8 weeks. The control group received drinking water. The behavior examined by wire hanging (WH), passive avoidance (PA), and open field (OF) tests. Results: Our findings showed that treatment with SM+LAC effectively increased PA latency, compared with the control group. The results showed that the administration of LAC and SM+LAC affected the number of lines crossed, the total distance moved and velocity in the OF tests. Conclusion: SM and LAC have anti-inflammatory effects that are memory changing. It may be due to their useful effects. These results indicated that SM+LAC restored memory disturbance and irritated mood in the cirrhotic rats. Comparable neuroprotection was never previously informed. Such outcomes are extremely promising and indicate the further study of SM+LAC.

PP2A Activators Enhance Efficacy of FLT3 Inhibitors in FLT3-ITD Acute Myeloid Leukemia Cells through AKT Inactivation-Dependent Pim-1 and c-Myc Proteasomal Degradation

Introduction fms-like tyrosine like kinase 3 internal tandem duplication (FLT3-ITD), present in acute myeloid leukemia (AML) cells of 30% of patients, results in constitutive and aberrant FLT3 signaling and, clinically, short disease-free survival. Efficacy of FLT3 inhibitors is limited and transient, but may be enhanced by dual targeting of FLT3-ITD signaling pathways. The tumor suppressor protein phosphatase 2A (PP2A) is inhibited in cells with FLT3-ITD. The oncogenic serine/threonine kinase Pim-1 is transcriptionally upregulated and also stabilized by PP2A inhibition in cells with FLT3-ITD. Pim-1 contributes directly to FLT3-ITD proliferative and anti-apoptotic effects, and also phosphorylates and stabilizes FLT3-ITD in a positive feedback loop. Moreover FLT3-ITD, PP2A and Pim-1 all regulate the transcription factor c-Myc. PP2A-activating drugs enhance efficacy of FLT3 inhibitors. We sought to identify mechanisms underlying the efficacy of this combination. Methods Ba/F3-ITD and MV4-11 cells, with FLT3-ITD, and blasts from patients with AML with FLT3-ITD were cultured with the FLT3 inhibitors gilteritinib (15 nM) or quizartinib (1 nM) and/or the PP2A-activating drugs FTY720 (2-4 µM) or DT-061 (10 µM), or with DMSO control. Pim-1, c-Myc, p-AKT (S473 and T308) and AKT protein expression was measured by immunoblotting, along with p-STAT5 (Y694), STAT5, p-PP2A (Y307) and PP2A expression. To study post-translational regulation, cells were cultured with cycloheximide (100 µg/mL) with and without the proteasome inhibitor MG-132 (20 µM). Ubiquitinated c-Myc was measured by co-immunoprecipitation and immunoblotting with c-Myc and ubiquitin antibodies. Ba/F3-ITD cells were stably transfected with estrogen receptor (ER)-c-Myc, kinase-dead Pim-1 or myristoylated AKT plasmids or corresponding empty vectors. Apoptosis was detected by Annexin V and propidium iodine staining, measured by flow cytometry. Cells were also cultured with the pan-Pim kinase inhibitor AZD1208 (1 µM), the Myc inhibitor 10058-F4 (100 µM) or the pan-AKT inhibitor MK-2206 (5 µM). Results Concurrent treatment of Ba/F3-ITD and MV4-11 cells and primary AML cells with FLT3-ITD with a FLT3 inhibitor (gilteritinib or quizartinib) and a PP2A-activating drug (FTY720 or DT-061) decreased growth and increased apoptosis induction, relative to treatment with single drugs. Concurrent FLT3 inhibitor and PP2A-activating drug treatment decreased expression of both Pim-1 and c-Myc protein. Concurrent treatment decreased Pim-1 half-life from 15 to 5 minutes, and c-Myc half-life from 30 to 5 minutes, while half-lives were restored by concurrent treatment with the proteasome inhibitor MG-132. Concurrent treatment was also shown to increase c-Myc ubiquitination. Effects of concurrent treatment on Pim-1 and c-Myc were independent, as transfection with kinase-dead Pim-1 or treatment with Pim inhibitor AZD1208 did not alter c-Myc downregulation, and c-Myc overexpression or treatment with Myc inhibitor 10058-F4 did not alter Pim-1 downregulation. Concurrent treatment with FLT3 inhibitor and PP2A-activating drug did not alter expression of c-Myc deubiquitinases, but rapidly decreased AKT S473 and T308 phosphorylation. FLT3 inhibitor and PP2A activator co-treatment did not induce downregulation or increased turnover of Pim-1 and c-Myc protein or apoptosis in cells with constitutive AKT activation caused by transfection of myristoylated AKT. Moreover, AKT inhibition downregulated Pim-1 and c-Myc protein expression, decreased Pim-1 and c-Myc protein half-lives from 15 to 5 minutes and 30 to 10 minutes, respectively, and induced apoptosis of cells with FLT3-ITD, replicating the effects of FLT3 inhibitor and PP2A activator co-treatment. Conclusion PP2A activators enhance the efficacy of FLT3 inhibitors in AML cells with FLT3-ITD through AKT inactivation-dependent increased Pim-1 and c-Myc proteasomal degradation, which is a novel mechanism. The data support further preclinical and clinical testing of this dual targeting approach to treatment of AML with FLT3-ITD. Disclosures Baer: Takeda: Research Funding; Incyte: Research Funding; Kite: Research Funding; Forma: Research Funding; AI Therapeutics: Research Funding; Abbvie: Research Funding; Astellas: Research Funding.

Effects of concurrent treatment with amitriptyline hydrochloride tablets and fluoxetine hydrochloride on therapeutic indicator levels in patients with depression

Purpose: To investigate the effects of combined treatment of amitriptyline hydrochloride tablets and fluoxetine hydrochloride on therapeutic indicator levels in depressive patients. Methods: Patients with depression ( n = 104) were divided into control group and study group (52 cases each) using random number table method. Control group was treated with oral fluoxetine hydrochloride (FH) tablets only, while the study group received amitriptyline hydrochloride tablets, in addition to fluoxetine hydrochloride tablets. Both treatments lasted 3 months. Clinical effects and thyroid function indices were determined and compared for the two groups. Results: Treatment effectiveness in the study group (92.3 %) was markedly higher than that in control group (75.0 %, p < 0.05). In both groups, Pittsburgh Sleep Quality Index, Hamilton Depression Scale and Hamilton Anxiety Table scores significantly decreased post-treatment ( p < 0.05). In contrast, there was significant increase in γ-aminobutyric acid (GABA) and serotonin (5-HT) levels in the two groups. In both groups, T3 and T4 significantly decreased while thyroid stimulating hormone (TSH) increased significantly ( p < 0.05). Thyroid function in the study group was markedly higher than in the control group ( p < 0.05). Conclusion: Combination treatment with amitriptyline hydrochloride tablets and FH is more effective than FH alone in the treatment of patients with depression. The combined treatment has a high degree of safety and is recommended for clinical application. Keywords: Amitriptyline hydrochloride, Fluoxetine hydrochloride, Depression, PSQI score, HAMD-17 score, HAMA score, GABA, 5-HT

Concurrent treatment with ursolic acid and low-intensity treadmill exercise improves muscle atrophy and related outcomes in rats.

The objective of this study was to analyze the concurrent treatment effects of ursolic acid (UA) and low-intensity treadmill exercise and to confirm the effectiveness of UA as an exercise mimetic to safely improve muscle atrophy-related diseases using Sprague-Dawley (SD) rats with skeletal muscle atrophy. Significant muscle atrophy was induced in male SD rats through hind limb immobilization using casting for 10 days. The muscle atrophy-induced SD rats were group into four: SED, sedentary; UA, daily intraperitoneal UA injection, 5 mg/kg; EX, low-intensity (10–12 m/min, 0° grade) treadmill exercise; and UEX, daily intraperitoneal UA injection, 5 mg/kg, and low-intensity (10–12 m/min, 0° grade) treadmill exercise. After 8 weeks of treatment, endurance capacity was analyzed using a treadmill, and tissues were extracted for analysis of visceral fat mass, body weight, muscle mass, expression of muscle atrophy- and hypertrophy-related genes, and endurance capacity. Although the effects of body weight gain control, muscle mass increase, and endurance capacity improvement were inadequate in the UA group, significant results were confirmed in the UEX group. The UEX group had significantly reduced body weight and visceral fat, significantly improved mass of tibialis anterior and gastrocnemius muscles, and significantly decreased atrophy-related gene expression of MuRF1 and atrogin-1, but did not have significant change in hypertrophy-related gene expression of Akt and mTOR. The endurance capacity was significantly improved in the EX and UEX groups. These data suggest that concurrent treatment with low-intensity exercise and UA is effective for atrophy-related physical dysfunctions.

Effects of Parent Training on Callous-Unemotional Traits, Effortful Control, and Conduct Problems: Mediation by Parenting.

Callous-unemotional (CU) traits and effortful control (EC) are personality and temperament traits implicated in early-onset antisocial trajectories. This secondary analysis of Hitkashrut's randomized controlled trial first tested parent training's effects on EC and CU traits while controlling for more general treatment effects on conduct problems (CP), and subsequently tested mediation by parenting. Prekindergarten teachers in three Israeli cities identified 209 3-5year-old (163 boys; 46 girls) preschoolers with subclinical-clinical range conduct problems. All participants were Jewish ranging from ultra-orthodox to secular. They were assigned to 14-session co-parent training groups (n=140 couples), or to minimal intervention control groups with referral to local services as necessary (n=69 couples). We employed averaged indices of pre- and post-intervention questionnaires completed by both parents. The testing of all hypothesized models controlled for treatment effects on CP in order to strengthen the robustness of the analyses. We found significant concurrent treatment effects on CP and on either CU traits or EC. All effects were mediated by ineffective parenting (IP): a latent variable that was indicated by negative/inconsistent practices and perceived parenting inefficacy. This is the first demonstration of parenting mediated treatment effects on both EC and CU traits in a randomized controlled study conducted in everyday practice contexts. This finding supports a disruption model of change: the reduction of IP facilitates a caregiving environment that affects children's behavior and developing personality. The changing of personality and temperament characteristics implicated in early-onset pathways suggests an innovative prevention strategy for disruptive behavior disorders.

Assessment of mitochondrial membrane potential in HEI-OC1 and LLC-PK1 cells treated with gentamicin and mitoquinone.

To determine the effects of concurrent treatment with gentamicin and the mitochondria-targeted antioxidant mitoquinone (MitoQ; which may prevent gentamicin ototoxicity) on change in the mitochondrial membrane potential (Δψ(m)), a precursor of apoptosis. Prospective and controlled. Academic research laboratory. LLC-PK1 (Lilly Laboratories Culture-Pig Kidney Type 1) and HEI-OC1 (House Ear Institute Organ of Corti 1) cells-renal and auditory cell lines, respectively-were used in this study. Δψ(m) was assessed by flow cytometry through the MitoProbe JC-1 Kit for Flow Cytometry in untreated LLC-PK1 and HEI-OC1 cells and cells exposed to low- (100µM) or high- (2000µM) dose gentamicin for 24 hours, with and without 0.5µM each of MitoQ or idebenone (IDB; an untargeted ubiquinone). Δψ(m) was not different in untreated LLC-PK1 cells and cells coincubated with low-dose gentamicin and MitoQ or IDB (P > .05). In HEI-OC1 cells, coincubation with low-dose gentamicin and MitoQ decreased Δψ(m) (P = .002). Coincubation of LLC-PK1 cells with high-dose gentamicin and DMSO, MitoQ, or IDB depolarized Δψ(m) (P < .0001), with MitoQ depolarizing the Δψ(m) to a greater extent than that of IDB (P = .03). In contrast, HEI-OC1 cells demonstrated a hyperpolarized Δψ(m) when coincubated with high-dose gentamicin and DMSO, MitoQ, or IDB (P < .001). The combination of gentamicin and MitoQ holds the potential to disrupt Δψ(m). This suggests a heightened need to monitor for toxicity in patients receiving both agents.

Abstract 3353: Docosahexaenoic acid enhances 2-deoxyglucose treatment in breast and lung cancer cells in vitro

Abstract Increased aerobic glycolysis is a common phenotype of cancer cells and is known as the Warburg effect. Recent studies have focused on targeting cellular metabolism to impede cancer cell growth. Previous findings in our laboratory have demonstrated that docosahexaenoic acid (DHA; C22:6 n-3), a long-chain omega-3 polyunsaturated fatty acid (PUFA), can inhibit cancer cell metabolism and reduce intracellular ATP levels. This study investigated the effects of concurrent treatment with DHA with 2-deoxyglucose (2DG), an inhibitor of glucose metabolism, in multiple cancer cell models in vitro, BT-474 human breast ductal carcinoma, MDA-MB-231 human breast adenocarcinoma, and A549 human lung adenocarcinoma. Dose-dependent decreases in intracellular ATP levels were observed with DHA and 2DG, both alone and in combination. In addition to the significant decreases in ATP levels, large decreases in extracellular lactate concentrations were observed in all three cell lines as well, suggesting that the combination of 2DG and DHA can augment treatment, mimic glucose deprivation and play a role in reducing the Warburg effect. Moreover, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were significantly reduced with the combination of DHA and 2DG, which suggests that the combination of DHA with other metabolic inhibitors, like 2DG, may sensitize cells to current treatment. Our findings show that combining DHA with 2DG enhances the efficacy of 2DG treatment alone, which may help to reduce the cytotoxic effects by 2DG on normal cells. Other metabolic inhibitors are being employed in combination with DHA to determine the mechanisms behind the DHA-induced sensitizing effects, which will provide additional treatment strategies for oncologists and cancer patients. Citation Format: Michael Mouradian, Irvin V. Ma, Erika D. Vicente, Amy M. Chattin, Ronald S. Pardini. Docosahexaenoic acid enhances 2-deoxyglucose treatment in breast and lung cancer cells in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3353. doi:10.1158/1538-7445.AM2014-3353

Assessment of Mitochondrial Function and Membrane Potential in PK1 Cells Treated with Gentamicin and MitoQ

Objectives: Determine the effects of concurrent treatment with the aminoglycoside antibiotic gentamicin and mitoquinone (MitoQ), a mitochondria-targeted derivative of the antioxidant ubiquinone that may protect against aminoglycoside ototoxicity, on mitochondrial function and membrane potential. Methods: This study was prospective and controlled. Mitochondrial membrane potential (MMP) was assessed by flow cytometry using MitoProbeTM JC-1 Kit in untreated PK1 cells and cells exposed to low (100 µM) or high (2000 µM) dose gentamicin for 24 hours, with and without 0.5 µM each of MitoQ or idebenone (an untargeted ubiquinone). Mitochondrial function was determined using the Seahorse XF-24TM flux analyzer. Results: MMP was not different in untreated cells and cells co-incubated with low-dose gentamicin and MitoQ or idebenone ( P &gt; .05). Co-incubation with high-dose gentamicin and MitoQ or idebenone decreased MMP ( P &lt; .0001), with MitoQ co-incubation decreasing MMP to a greater extent compared with idebenone ( P = .0001). Basal oxygen consumption rate (OCR) was not different between treatments ( P = .15). Maximal OCR was not different between untreated cells and cells treated with MitoQ alone, low dose gentamicin alone, or the combination of MitoQ and low dose gentamicin ( P &gt; .05). In contrast, cells treated with high dose gentamicin and in combination with MitoQ have reduced maximal OCR ( P = .037 and .026). Conclusions: The combination of gentamicin and MitoQ holds the potential to disrupt mitochondrial function and membrane potential. This suggests a heightened need to monitor for toxicity in patients receiving both agents.

Relating relapse and T2 lesion changes to disability progression in multiple sclerosis: a systematic literature review and regression analysis

BackgroundIn the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS. The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS).MethodsA systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS).ResultsRegression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p < 0.01. Lower treatment effects were associated with higher relative rates of disease progression. Significant associations between T2 lesion measures and EDSS measures also were found (p < 0.05), with some suggestion that the strength of the association may differ for older versus newer DMTs.ConclusionsTreatment differences in relapse reduction and T2 lesions are positively related to differences in disease progression over the first two years of treatment.

MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials

A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on MRI lesions and clinical relapses. We aimed to validate that relation using data from a large and independent set of clinical trials in multiple sclerosis. We searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1, 2008, to Oct 31, 2012. We extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R(2) value was estimated to quantify the strength of the correlation, and we used an interaction test to test for a difference in slope from the previously estimated equation. We also ran several sensitivity analyses. We identified 31 eligible trials, which provided data for 18 901 patients with relapsing-remitting multiple sclerosis. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0·52; R(2)=0·71), much the same as was previously estimated (pinteraction=0·45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6-9 months) can also predict the effects on relapses over longer follow-up periods (12-24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials. Our findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for multiple sclerosis can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults. None.

Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models.

3061 Background: Interaction of immune checkpoint molecules PD-1 and CTLA-4 and their respective ligands attenuates antitumor T cell responses. In clinical studies, PD-1 blocking antibody (Ab) nivolumab (BMS-936558) or the CTLA-4 blocking Ab ipilimumab result in durable responses in multiple human malignancies. We describe the evaluation of concurrent treatment with anti-PD-1 and anti-CTLA-4 mAbs in preclinical models. Methods: Antitumor activity of treatment with murine homologs of anti-PD-1 (4H2-mIgG1) and anti-CTLA-4 (9D9-mIgG2b) was evaluated in MC38, a murine colon adenocarcinoma model. The effects of concurrent treatment on T cell infiltration of tumors, tumoral expression of PD-L1 and cytokine levels were explored. The preclinical safety profile of concurrent nivolumab + ipilimumab was assessed in a cynomolgus macaque model. Results: Concurrent treatment of MC38 tumors with 4H2-mIgG1 + 9D9-mIgG2b (10 mg/kg Q3d x 3) results in synergistic antitumor activity whereas efficacy with sequential dosing was similar to either agent alone. With concurrent treatment, dose reductions of one Ab relative to a fixed dose of the other resulted in retention of some antitumor activity. Anti-PD-1 enhanced CD8+ T cell infiltration of MC38 tumors and increased tumor PD-L1 expression. Anti-CTLA-4 treatment increased intratumoral CD8+ T cells and reduced intratumoral T regulatory cells. While concurrent treatment did not result in further increases in T cell infiltration, it increased expression of intratumoral cytokines. Anti-PD-1 resulted in down regulation of cell surface and intracellular levels of PD-1 in CD8+ T cells. In cynomolgus macaques, concurrent nivolumab + ipilimumab resulted in dose-dependent gastrointestinal toxicities (diarrhea; body weight loss) not observed in earlier cynomolgus studies with nivolumab and rarely with ipilimumab. These preclinical observations provided the rationale for a dose escalation trial (NCT01024231) of combined nivolumab + ipilimumab in advanced melanoma. Conclusions: Concurrent treatment with anti-PD-1/anti-CTLA-4 resulted in synergistic antitumor activity in preclinical models and supports the evaluation of the combination in clinical studies.

Beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral ischemia–reperfusion injury in rats

Theanine and caffeine, 2 naturally occurring components in tea, have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. In this study, we assessed the beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral damage in rats. Theanine and caffeine had no effect on physiological variables, including pH, partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2), mean arterial blood pressure, plasma glucose, or regional cerebral blood flow. Treatment with theanine (1 mg/kg body mass, intraperitoneal injection) alone significantly reduced cerebral infarction induced by cerebral ischemia-reperfusion, but caffeine (10 mg/kg, intravenous administration) alone only had a marginal effect. However, the combination of theanine plus caffeine resulted in a significant reduction of cerebral infarction and brain edema compared with theanine monotherapy. Meanwhile, increased malondialdehyde levels as well as decreased superoxide dismutase activity, glutathione peroxidase activity, and glutathione levels observed in the cerebral cortex after cerebral ischemia-reperfusion were significantly ameliorated by the combination therapy. Furthermore, the elevated inflammatory response levels observed in the cortex after cerebral ischemia-reperfusion were markedly attenuated by the combined treatment. Thus, it is suggested that the neuroprotective potential of a combination therapy with theanine and caffeine against cerebral ischemia-reperfusion is partly ascribed to their antioxidant and anti-inflammatory properties.

Short flap rhytidectomy and fractional CO2 laser rejuvenation of the aging face

There is currently a high demand for a concurrent system of skin rejuvenation accompanying rhtidectomy. CO2 laser treatment prior to surgical ablative reduction has produced promising results, but the adjunct service of laser treatment at the time of surgery has never been reviewed. Determine the effects of concurrent treatment of rhytides and evidence of aging in the skin with surgical correction followed by fractional CO2 laser application. During study time from September 2008 to February 2009 treat patients who have underwent short flap rhytidectomy to the Lutronic eCO2™ fractional laser using the patented "Controlled Chaos Technology." Complications included 2.3% herpes simplex outbreak, 4% persistent erythema past 2 weeks, four cases of prolonged edema to 5 days, one case of impetigo, and no evidence of dyspigmentation. Patient satisfaction data demonstrated no refunds at 12 months. Combination fractional laser resurfacing with short flap, high-Superficial muscular aponeurotic system rhytidectomy is a safe procedure with excellent patient satisfaction and clinical outcomes.

Effect of Concurrent Prescription Antiarthralgia Pharmacotherapy on Persistence to Aromatase Inhibitors in Treatment-Naïve Postmenopausal Females

Aromatase inhibitors function by suppressing estrogen biosynthesis in peripheral tissues. The resulting estrogen deprivation is considered the underlying cause for aromatase inhibitor-induced arthralgia, which affects patients' quality of life and may affect their persistence to aromatase inhibitor therapy. The effect of concurrent treatment with aromatase inhibitors and prescription antiarthralgia pharmacotherapy on improving persistence to aromatase inhibitor therapy is unknown. To evaluate the effect of concurrent prescription antiarthralgia pharmacotherapy on persistence to aromatase inhibitor therapy in treatment-naïve postmenopausal women. This retrospective cohort pharmacy claims study examined the drug utilization pattern between July 2008 and October 2009 of postmenopausal females, naïve to aromatase inhibitor therapy, with 18 months of continuous prescription benefit eligibility. Patients were divided into 2 groups: group A (control) included patients who did not have a claim for a prescription antiarthralgia medication in a 1-year follow-up period, while group B (active) included patients with prescription antiarthralgia medications started within the 1-year follow-up period after starting treatment with an aromatase inhibitor. Persistence to aromatase inhibitor therapy was compared between the 2 groups. The study population comprised 29,967 patients: 24,804 (82.8%) in group A, and 5163 (17.2%) in group B. Aromatase inhibitor discontinuation rates within the first year of therapy were not statistically significantly different between groups: 40.9% in group A (10,145/24,804) and 34.5% in group B (1781/5163) (HR 1.127; 95% CI 0.900-1.411; p = 0.297). Persistence for the 2 groups did not differ statistically significantly for any of the 3 aromatase inhibitors measured separately. Postmenopausal females treatment-naïve to aromatase inhibitor therapy who also received treatment with a prescription antiarthralgia medication did not have significantly higher persistence with aromatase inhibitor therapy. Further research should focus on other possible causes of poor persistence in patients using aromatase inhibitor therapy.

Significant Improvement in Overall Survival Among Patients Diagnosed with Low-Risk Myelodysplastic Syndrome (MDS) Treated with Selective-Serotonin-Reuptake-Inhibitors (SSRIs)

AbstractAbstract 3818 Background:Clinical outcomes in patients diagnosed with low risk MDS are heterogeneous and molecular characterization can distinguish subgroups with a more aggressive disease progression. Those patients determined to have a higher risk for transformation would seek therapy. Given a median age of 65, many of these elderly patients are not suitable for intensive interventions and options such as SSRI’s are reasonable. Gene expression profiling in low-risk MDS patients suggests deregulation of apoptosis and cytokine signaling pathways. SSRI treatment promotes normalization of deranged proinflammatory cytokines in patients diagnosed with depression such as TNF α and IL12. (Sutcigil et al. Clin and Dev Immunol 2007) In animal model of arthritis, sertraline abrogated manifestation of autoimmune arthritis by reducing TNF α (Baharav et al. Neuroimmunomodulation.2012) In addition, SSRI’s have been shown to induce anti-proliferative effect on colon and prostate cell lines.(Huang et al. Basic Clin Phar Tox.2011; Gil et al. Int J Onc. 2008) Here, we report our single institution retrospective epidemiological analysis of low grade MDS patients treated with SSRIs agents. Methods:After Institutional Review Boards approval, all patients over 18-years-old with an initial morphological diagnosis of low grade MDS per bone marrow examination from January 1, 2000 to December 31, 2010 were identified from the Michael E. DeBakey VA Medical Center cancer registry. 118 patients were included for analysis. Patients were considered to be in the selective serotonin reuptake inhibitor (SSRI positive) group if they had received at least 6 months of an SSRI (including fluoxetine, sertraline, paroxetine, or citalopram) during the 12 month period prior and after the diagnosis of MDS. Patients who did not meet the above criteria were assigned to the SSRI negative- group. We analyzed Overall Survival (OS) for patients receiving or not receiving SSRIs agents. Results:The median OS for patients with lower-risk disease was 1750 and 728 days in the SSRI+ and SSRI- group, respectively (P=0.0104, HR=0.493, 95% CI=0.287–0.847) (Fig. 1). To avoid any possible confounding effect of concurrent treatment, the same analysis was repeated after excluding patients who had received any disease-modifying agents (including azanucleosides, lenalidomide, thalidomide, anti-thymocyte globulin, or induction chemotherapy). Among patients with best supportive care (BSC) only (9 SSRI+ vs. 53 SSRI-), the improvement seen in the median OS remained significant at 1919 and 506 days for the SSRI+ and SSRI- group, respectively (P=0.0359, HR=0.477, 95% CI=0.239–0.952)(Fig. 2). Of interest, within the 9 SSRI+ patients, they were all males with a median age of 72 (range 55–82), and a predominance of RCMD category 6/9 (67%) and good karyotype 8/9 (89%). In order to further examine the impact of SSRI agents on clinical outcomes, we examined the OS per individual agent. There was a non-significant trend of improved OS for patients receiving sertraline (P=0.0519) (Fig.3). Conclusions:In this retrospective cohort analysis, we detected a significant improvement in OS for lower-risk MDS patients treated with SSRIs (such as sertraline), regardless concurrent administration of other MDS directed therapy. This data suggests a biological benefit from SSRIs in this entity and supports the possible combination of these agents with MDS targeted therapy. Our findings suggest a selective survival benefit from treatment with sertraline. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

NMDA receptor antagonism: escalation of aggressive behavior in alcohol-drinking mice

Memantine is a potential treatment for alcoholic patients, yet few studies investigate the effect of concurrent treatment with memantine and ethanol on aggression. We evaluated aggressive behavior following ethanol consumption and treatment with glutamatergic drugs to characterize interactions between these compounds. This study aimed to use rodent models of aggression to examine interactions between glutamatergic compounds and ethanol. Once male CFW mice reliably self-administered 1 g/kg ethanol or water, they were assessed for aggression in resident-intruder confrontations. Alternatively, aggression was evaluated following a social-instigation procedure. Animals were then injected with memantine, ketamine, neramexane, MTEP, or LY379268 before aggressive confrontations. Effects of the pharmacological manipulations on salient aggressive and non-aggressive behaviors were analyzed. Moderate doses of memantine, neramexane, and MTEP interacted with ethanol to increase the frequency of attack bites while ketamine did not. The highest dose of LY379268, an mGluR(2/3) agonist, reduced both aggressive and non-aggressive behaviors after water and ethanol self-administration. Attack bites increased with social instigation and decreased with administration of high doses of MTEP and LY379268. Memantine and MTEP both reduced attack bite frequency in the instigation condition without reducing locomotor behavior. Memantine and neramexane interacted with ethanol to heighten aggression. The binding characteristics of these compounds allow for 'partial trapping' by which some NMDARs are unblocked between depolarizations. We propose that this feature may contribute to the differential aggression-heightening interactions between these compounds and ethanol. MTEP also interacted with ethanol to escalate aggression, possibly through inhibition of mGluR(5) modulation of NMDARs.