Consecutive Days Of Treatment Research Articles

Role of Perivascular Oligodendrocyte Precursor Cells in Angiogenesis After Brain Ischemia.

BackgroundOligodendrocyte precursor cells (OPCs) regulate neuronal, glial, and vascular systems in diverse ways and display phenotypic heterogeneity beyond their established role as a reservoir for mature oligodendrocytes. However, the detailed phenotypic changes of OPCs after cerebral ischemia remain largely unknown. Here, we aimed to investigate the roles of reactive OPCs in the ischemic brain.Methods and ResultsThe behavior of OPCs was evaluated in a mouse model of ischemic stroke produced by transient middle cerebral artery occlusion in vivo. For in vitro experiments, the phenotypic change of OPCs after oxygen glucose derivation was examined using a primary rat OPC culture. Furthermore, the therapeutic potential of hypoxic OPCs was evaluated in a mouse model of middle cerebral artery occlusion in vivo. Perivascular OPCs in the cerebral cortex were increased alongside poststroke angiogenesis in a mouse model of middle cerebral artery occlusion. In vitro RNA‐seq analysis revealed that primary cultured OPCs increased the gene expression of numerous pro‐angiogenic factors after oxygen glucose derivation. Hypoxic OPCs secreted a greater amount of pro‐angiogenic factors, such as vascular endothelial growth factor and angiopoietin‐1, compared with normoxic OPCs. Hypoxic OPC‐derived conditioned media increased the viability and tube formation of endothelial cells. In vivo studies also demonstrated that 5 consecutive daily treatments with hypoxic OPC‐conditioned media, beginning 2 days after middle cerebral artery occlusion, facilitated poststroke angiogenesis, alleviated infarct volume, and improved functional disabilities.ConclusionsFollowing cerebral ischemia, the phenotype of OPCs in the cerebral cortex shifts from the parenchymal subtype to the perivascular subtype, which can promote angiogenesis. The optimal use of hypoxic OPCs secretome would provide a novel therapeutic option for stroke.

Efficacy of electroacupuncture in regulating the imbalance of AMH and FSH to improve follicle development and hyperandrogenism in PCOS rats

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and follicular arrest. These two characteristics may result from an imbalance between anti-Müllerian hormone and follicle stimulating hormone. Electroacupuncture is effective in improving hyperandrogenism and follicular arrest in PCOS; however, the mechanism is not sufficiently clear. This study aimed to elucidate whether electroacupuncture in PCOS is exerted by regulating an imbalance of anti-Müllerian hormone and follicle stimulating hormone. In this study, a rat model of polycystic ovary syndrome was treated with low-frequency electroacupuncture at acupoints (CV-3 and CV-4). To observe the mechanism of electroacupuncture in PCOS, we first observed the estrous cycle. We then observed ovarian morphology by hematoxylin-eosin staining and evaluated levels of testosterone, estradiol, P450arom, follicle stimulating hormone and its receptor, and anti-Müllerian hormone and its receptor by enzyme-linked immunosorbent assay, western blotting, double immunofluorescence assay and real-time PCR. Our results showed that in 80% of rats in the electroacupuncture acupoints group, their estrous cycle recovered, ovarian morphology significantly improved, testosterone level significantly decreased, and levels of estradiol and P450arom significantly increased in peripheral serum after 14 consecutive days of treatment (P < 0.01). The expression of anti-Müllerian hormone and anti-Müllerian hormone type II receptor decreased (P < 0.05), whereas the expression of follicle stimulating hormone receptor increased (P < 0.05). These results indicated that electroacupuncture improved hyperandrogenism and follicular arrest by decreasing the excessive expression of AMH to regulate FSH and AMH imbalance in granulosa cells in PCOS.

Health Care Utilization and Financial Impact of Acute Graft-Versus-Host Disease (aGVHD) Among Children Undergoing Allogeneic Hematopoietic Cell Transplantation (alloHCT)

Introduction Steroids are the only effective treatment for acute GVHD and optimal salvage regimen for steroid refractory (SR) GVHD remains elusive. Impact of steroid sensitive (SS) and SR-AGVHD on healthcare utilization and cost is not well described. Methods In this is a single center study, we analyzed data on of 97/240 (40%) consecutive pediatric patients who developed grade I-IV AGVHD. Among patients with AGVHD, we analyzed cost, healthcare utilization and patient outcomes for the first year post-alloHCT. Costs were estimated from charges recorded in the PHIS database and hospital accounting. SR-AGVHD was defined as failure to respond to steroid treatment. Failure to respond was defined as any Grade II-IV AGVHD that showed progression within 3 days or had no improvement within 7 consecutive days of treatment with 2 mg/kg/day methylprednisolone or equivalent. Results The median age of children with SS-AGVHD vs. SR-AGVHD was 9.44 years (0.26-21.0) vs. 12.2 years (0.42-21.0), p=0.204. The incidence of SR-AGVHD was 27%. Median time to onset of AGVHD was 28 days (6-232). AGVHD was grade III at diagnosis in 71% patients with SR-AGVHD vs. 29% patients with SS-AGVHD, P In multivariable analysis, patients with aGVHD had an average of 45.4 days (p 1-year OS for SR-AGVHD compared to SS-AGVHD was 50% (SE=9.81%) vs. 69.0% (SE=5.49%), p=0.046. Conclusion SR-AGVHD is associated with prolonged hospitalization, higher cost and inferior survival among children. Better AGVHD prevention strategies are desperately needed. Despite significant advances, lack of effective salvage regimens for SR-AGVHD remains a major concern.

In vivo Anticancer Activity on Ehrlich Ascites Carcinoma (EAC) Cells and in vitro Antimicrobial Activity of Psidium guajava Bark Extracts

This study was performed to evaluate the in vivo anticancer activity against ehrlich ascites carcinoma (EAC) cells and in vitro antimicrobial activity of Psidium guajava bark extracts. By soxhlet apparatus, the P. guajava bark extracts were obtained using four solvents (n-hexane, petroleum benzene, chloroform, and methanol) according to their increasing solubility. In case of in vivo anticancer activity of the sample extracts, mice were seeded with approximately 1x105 ehrlich ascites carcinoma (EAC) cells. After seven days of consecutive treatment, the negative and positive control groups (n=8 each group) showed an average EAC cell count of 2.4x108 and 1.8x108 respectively, and the experimental groups showed the cell count of 2.2x 108, 2.1x108, 1.9x108, and 1.41x108 when mice received h-hexane, petroleum benzene, chloroform, and methanol extract respectively. Experimental group that received methanol extract showed percent increase of life span (% ILS) of 33.3 when compared with the negative control. However, treatment in a cyclic manner of the mice showed % ILS of 52.15 for experimental group when compared negative control. In antimicrobial activity experiment, an intermediate zone of sensitivity of the crude methanol extract was found against Escherichia coli, Shigella flexneri, and Staphylococcus aureus when compared with amoxicillin. All these results indicated the anticancer activity and antimicrobial activity of the methanol extract of P. guajava barks on different experimental models.&#x0D; Bangladesh J Microbiol, Volume 35 Number 1 June 2018, pp 79-81

XANTHINE OXIDASE INHIBITORY, ANTIHYPERURICEMIC, ANTI-INFLAMMATORY, ANTINOCICEPTIVE ACTIVITY OF α-LIPOIC ACID IN GOUTY ARTHRITIS MODEL

Objective: The current study was carried out to investigate the xanthine oxidase inhibitory, antihyperuricemic, anti-inflammatory, and antinociception activity of α-lipoic acid (LA) in gouty model of rats.Methods: Enzyme assay was done using bovine milk xanthine oxidase (XO). The XO inhibitory activity in vitro was performed using different doses of α-LA, and the degree of XO inhibition was expressed as IC50. The antihyperuricemic activity of α-LA was tested in the potassium oxonate-induced hyperuricemic rats for 7 consecutive days of oral treatment of 10, 25, and 50 mg/kg doses. The anti-inflammatory activity was achieved through monosodium urate crystal-induced inflammation hind paw model in mice. The antinociception effects of α-LA were explored using both of writhings induced by acetic acid test and hot plate test.Results: The study results revealed that the α-LA has a potent activity of XO inhibition with IC50 = 2.93 μg/mL. Furthermore, these results showed that all doses of α-LA were able to significant reduce of each the following: Serum uric acid levels in the hyperuricemic rats, hind paw thickness of mice at all periods of time assessment, and writhings number in the acetic acid-induced writhing test, while, the same doses significantly increased the reaction latency in mice at hot plate test.Conclusion: The α-LA showed a significant effect on the evaluated models, and therefore it may be a promising agent for the treatment of gout since it possesses XO inhibitory, antihyperuricemic, anti-inflammatory, and antinociception activity.

Antihyperuricemic and xanthine oxidase inhibitory activities of Silymarin in a rat gout model

Introduction: Gout is a common metabolic defect spread around the world. It characterized by hyperuricemia, which resulting from the prolonged rise of uric acid (UA) levels in the blood, leading to increase the deposition of urate crystals in the joints and kidneys. The present study performed to investigate the efficacy of silymarin as antihyperuricemic agent. Materials and Methods: Enzyme assay was done using bovine milk xanthine oxidase (XO). The XO inhibitory activity in vitro was carried out using different doses of silymarin, and the degree of XO inhibition (XOI) was expressed as IC50. The antihyperuricemic of silymarin was investigated in the potassium oxonate-induced hyperuricemic rat model for 7 consecutive days of oral treatment of 10, 25, and 50 mg/kg doses. Results: The study results revealed that the silymarin has a potent activity of XOI with IC50 = 5.84 μg/mL as compared to standard drug, allopurinol IC50 = 1.85 μg/mL. In addition, these results showed that all doses of silymarin were able to be significant reduced serum UA levels in the hyperuricemic rats. Conclusion: Silymarin showed a significant effect on lowering the level of UA in the evaluated model, and therefore, it may be a promising agent for treating gout because of the possession of an antihyperuricemic effect through the inhibitory activity of xanthine oxide.

Sham-Controlled Study of Optokinetic Stimuli as Treatment for Mal de Debarquement Syndrome.

Introduction: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a perception of self-motion in the absence of a stimulus, with two onset types: Motion-Triggered and Spontaneous. Currently, the pathophysiology is unknown and consequently, the therapeutic options are limited. One proposed treatment protocol, developed by Dai and colleagues is based on optokinetic stimulation, which aims to re-adapt the vestibular ocular reflex. This study aimed to reproduce the treatment protocol developed by Dai and colleagues and to assess if a placebo effect is present in the treatment protocol and lastly, aimed to further investigate the treatment on MdDS patient outcomes.Method: Twenty-five MdDS patients (13 Motion-Triggered and 12 Spontaneous) were exposed to 5 consecutive days of optokinetic treatment (consisting of exposure to optokinetic stimuli with head movements). Eleven of these 25 patients were also exposed to 2 days of a sham treatment prior to the OKN treatment. Posturography measurements and reported symptoms [e.g., using the visual analog scale (VAS)] of patients were assessed throughout the treatment. Posturography data of the patients was compared with the data of 20 healthy controls.Results: No placebo effect was recorded with any changes in postural data and VAS scale. After the optokinetic treatment, a significant improvement in postural control was observed in 48% of patients, of whom 70% were of the Motion-Triggered subtype (p-values: Area under the Curve—Anterior Posterior < 0.001; Area under the Curve—Medio Lateral p < 0.001, Confidence Ellipse Area (CEA) < 0.001, Velocity < 0.001).Conclusion: The protocol was effective in approximately half of the MdDS patients that took part in the study, with no placebo effect recorded. The Motion-Triggered group responded better to treatment than the Spontaneous group. In addition to this, this study indicates that the greatest postural changes occur within the first 3 days of treatment, suggesting that a shorter protocol is possible. Overall, these findings support what was previously observed in Dai's studies, that optokinetic stimulation can reduce and ease self-motion perception in those with MdDS. Thus, validating the reproducibility of this protocol, suggesting that a consistent and uncomplicated implementation across treatment centers is possible.

Salidroside Improves Bone Histomorphology and Prevents Bone Loss in Ovariectomized Diabetic Rats by Upregulating the OPG/RANKL Ratio.

Postmenopausal diabetic women have a high risk of fractures. Salidroside has preventive effects on estrogen deficiency-induced osteoporosis and has hypoglycemic effects on diabetes in rats. However, whether salidroside inhibits bone loss in postmenopausal diabetic patients is still unknown. Here, we established a rat model of osteoporosis to investigate the protective effects of salidroside on bone loss induced by ovariectomy combined with diabetes, also investigating the underlying mechanisms. Two-month-old female Sprague-Dawley rats were divided into three equal groups (10 rats in each group): control group (with sham operation, treated with drug vehicle); OVX/T1DM group (ovariectomized diabetic rats); OVX/T1DM-SAL group, comprising ovariectomized diabetic rats treated with salidroside (20 mg/kg body weight) by gavage. The results showed that after 60 consecutive days of treatment, the bone mineral density (BMD) of OVX/T1DM-SAL increased significantly compared with the OVX/T1DM group (p < 0.01). The level of serum bone turnover markers, including alkaline phosphatase (ALP), cross linked c-telopeptide of type I collagen (CTX-1), osteocalcin, N-terminal propeptide of type I procollagen (PINP), and tartrate-resistant acid phosphatase 5b (TRACP 5b) were all increased in the OVX/T1DM group compared with the control (p < 0.01), and those were decreased by salidroside treatment. Meanwhile, the bone histopathological changes were also attenuated, and the bone marrow adipogenesis was inhibited in salidroside treated rats. Moreover, protein and mRNA ratio of bone osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) was upregulated in ovariectomized diabetic rats by salidroside treatment. The results above indicated that the protective effect of salidroside on bone loss induced by ovariectomy and diabetes was mainly due to its ability to suppress bone turnover, inhibit bone marrow adipogenesis, and up-regulate the OPG/RANKL ratio.

Left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation reduces the development of long-term muscle pain.

The left dorsolateral prefrontal cortex (DLPFC) is involved in the experience and modulation of pain, and may be an important node linking pain and cognition. Repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC can reduce chronic and experimental pain. However, whether left DLPFC rTMS can influence the development of chronic pain is unknown. Using repeated intramuscular injection of nerve growth factor to induce the development of sustained muscle pain (lasting weeks), 30 healthy individuals were randomized to receive 5 consecutive daily treatments of active or sham left DLPFC rTMS, starting before the first nerve growth factor injection on day 0. Muscle soreness and pain severity were collected daily for 14 days and disability on every alternate day. Before the first and 1 day after the last rTMS session, anxiety, depression, affect, pain catastrophizing, and cognitive performance on the attention network test were assessed. Left DLPFC rTMS treatment compared with sham was associated with reduced muscle soreness, pain intensity, and painful area (P < 0.05), and a similar trend was observed for disability. These effects were most evident during the days rTMS was applied lasting up to 3 days after intervention. Depression, anxiety, pain catastrophizing, and affect were unchanged. There was a trend toward improved cognitive function with rTMS compared with sham (P = 0.057). These data indicate that repeated left DLPFC rTMS reduces the pain severity in a model of prolonged muscle pain. The findings may have implications for the development of sustained pain in clinical populations.

Effect of fibroblast growth factor 21 on hepatic fibrosis in mice and its mechanism

Objective To investigate the effect of fibroblast growth factor 21 (FGF21) on hepatic fibrosis in mice and the mechanism of its action. Methods Male ICR mice were randomly divided three groups: control group, model group (treated with CCl4) , and treatment group (treated with CCl4+ 1. 0 mg/kg FGF21) . All mice were sacrificed to collect serum and liver tissues after 36 consecutive days of treatment. Serum levels of alanine transaminase (ALT) , aspartate aminotransferase (AST) , alkaline phosphatase (ALP) , total bilirubin (TBil) , interleukin-6 (IL-6) , interleukin-1β (IL-1β) , and tumor necrosis factor-α (TNF-α) were measured. Liver pathological changes were analyzed by Masson staining. The hepatic 4-hydroxyproline (4-Hyp) level was measured using a hydroxyproline detection kit. The mRNA levels of hepatic collagen I, α-smooth muscle actin (α-SMA) , transforming growth factor-β (TGF-β) , IL-6, IL-1β, and TNF-α were determined by quantitative real-time PCR. Comparison between multiple groups was made by one-way analysis of variance, and comparison between any two groups weas made using the LSD-t test. Results The Masson staining showed that the model group had a significantly higher degree of hepatic fibrosis than the control group, and the treatment group had a significantly lower degree of hepatic fibrosis than the model group. The model group had significantly higher serum levels of ALT, AST, ALP, and TBil (all P < 0. 05) , and the treatment group showed significant reductions in the above parameters compared with the model group (all P < 0. 05) . Enzyme-linked immunosorbent assay indicated that the model group had significantly higher serum levels of IL-1β, IL-6, and TNF-α than the control group (all P < 0. 05) , and the treatment group showed significant reductions in the above parameters compared with the model group (all P < 0. 05) . The hepatic 4-Hyp level and mRNA levels of collagen I and α-SMA were significantly higher in the model group than in the control group (P = 0. 04, < 0. 001, and < 0. 001) , and they were significantly lower in the treatment group than in the model group (P = 0. 005, < 0. 001, and < 0. 001) . The hepatic mRNA levels of TGF-β, IL-6, IL-1β, and TNF-α were significantly higher in the model group than in the control group (all P < 0. 001) , and they were significantly lower in the treatment group than in the control group (all P < 0. 001) . Conclusion FGF21 attenuates hepatic fibrogenesis in mice, possibly by inhibiting the expression of TGF-β, IL-6, IL-1β, and TNF-α in the liver.

Photobiomodulation mechanisms in the kinetics of the wound healing process in rats

ObjectivesThe healing process of cutaneous lesions is considered a complex event divided into distinct and overlapping phases, which responds satisfactorily to photobiomodulation (PBM). PBM is indicated as a therapeutic resource capable of assisting tissue repair. The present study aimed to analyze the kinetics of cutaneous wounds healing process after application of the GaAlAs laser for treating wounds on the dorsum of rats. Materials and MethodsThis study was approved by the Animal Ethics Committee of UFSCar. The animals were divided into 2 groups (n = 10); control group (CG) used 0.9% saline solution and the laser group (LG) used GaAlAs, 670 nm continuous pulse, 30 mW power, 14.28 J/cm2 energy density, irradiating 1 point per wound for 30s, totaling 15 consecutive days of treatment. Samples were collected on the 4th, 11th and 16th days for histological analysis of HE, Picrosirius-Red, immunohistochemistry (Collagen1, TNF-α, VEGF). Statistical analyzes used the one-way ANOVA test for intra and inter group evaluations, and the Tukey post-test. Level of significance was set at p < 0.05. ResultsThe histopathological analysis (HE) showed a statistically significant difference for lower values of inflammatory infiltrate in LG versus CG on the 16th day; and for the increase of collagen in the 11th and 16th days of treatment. There was a statistically significant difference in the increase of VEGF on the 11th day for LG; decrease of TNF-α on the 4th and 11th day for LG, and increase of collagen type 1 on the 4th and 16th days for LG. The birefringence analysis of the percentage of collagen fibers presented on the 11th day of treatment revealed a greater quantity and significant statistical difference. Collagen fibers showed improved organization and arrangement on the 11th day for LG. ConclusionOur results show that PBM is effective in helping the kinetics of the cutaneous wound healing process in rats and promotes the necessary stimuli for the satisfactory evolution of healing process, ultimately leading to structurally desirable tissue.

The rabbit vagina as an in vivo model for vaginal fenticonazole permeability and toxicity

IntroductionVaginal route is often used in topical antifungal formulations. Vaginal permeability assays are generally performed as in vitro tests. MethodAn in vivo vaginal permeability assay was developed using female rabbits. Fenticonazole permeability was evaluated by assessing fenticonazole bioavailability in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Toxicity was monitored histopathologically after 8 consecutive days of antifungal treatment (20 mg/animal). ResultsThe method of quantification was linear with a lower limit of quantification (LLOQ) of (0.1 ng/mL). The area-under-the-curves (AUC) of fenticonazole on day 1 and 8 of treatment were 280.3 ± 86.1 ng/mL ∗ h and 805.7 ± 252.4 ng/mL ∗ h, respectively. The calculated systemic bioavailability was 12.73% ± 0.14%. No signs of toxicity were observed both macroscopically and histologically after 8 days fenticonazole treatment. DiscussionThe plasma levels of fenticonazole observed in rabbits are similar to that observed in human. Rabbit vagina may be a suitable model to evaluate vaginal antifungal formulations.

The Effects of a Selective Serotonin 2C (5HT2C) Receptor Agonist WAY 163909 on Cocaine Self‐Administration in Male and Female Rhesus Macaques Exposed to Early Life Stress

Cocaine use disorder represents a prominent health concern in the United States, and there are currently no accepted pharmacotherapies for the treatment of ongoing cocaine use. Additionally, the occurrence of stressors early in life, such as physical abuse and neglect, is a major predictor in the emergence of cocaine abuse later in life. Rhesus monkeys demonstrate a similar prevalence rate of infant abuse and rejection as humans, and serve as ideal candidates to examine the relationship between early life stress (ELS) and cocaine use. Finally, previous data suggest serotonin 2C (5HT2C) agonists may be viable candidates in the treatment of ongoing drug use. Accordingly, the effectiveness of the 5HT‐2C agonist WAY 163909 (WAY) to decrease cocaine self‐administration was examined in male and female rhesus macaques.Subjects were 8 adolescent male and female rhesus macaques who experienced infant maltreatment (MALT) or competent maternal care (MALT males n=4; MALT females, n=2; Control males, n=0; Control females, n=2). During adolescence, animals were trained to respond under a fixed‐ratio 20 response (FR 20) schedule of reinforcement to receive an infusion of cocaine (0.01–0.1 mg/kg/infusion). After meeting criteria for stable self‐administration (SA), animals progressed through a full dose‐effect curve to establish the dose that engendered the highest response rate (EDMax), and were then examined under maintenance conditions. During each testing week, WAY pretreatments (3 consecutive daily treatments administered 45 minutes prior to sessions) were preceded by normal maintenance sessions without any pretreatments, which provided a baseline of responding. Each WAY dose (0.1–1 mg/kg IM) was tested weekly interspersed by weeks of vehicle treatment.WAY dose‐dependently decreased cocaine self‐administration in males and females, with males demonstrating significantly lower response rates in comparison to females at 0.3 mg/kg WAY. MALT animals also demonstrated an overall lower response rate across doses of WAY in comparison to control subjects.These preliminary data suggest that females may be more resistant to serotonergic interventions of ongoing cocaine SA, given that females from MALT and Control groups were less sensitive to the effects of WAY in comparison to males. Furthermore, MALT animals overall showed a lower response rate in comparison to control animals across doses of WAY, suggesting that MALT subjects may be uniquely sensitive to serotonergic interventions aimed at decreasing ongoing drug use. The addition of male controls will be critical in determining whether robust sex differences persist, and if male controls demonstrate a similar response pattern as female controls.Support or Funding InformationThis research was supported by USPHS grants DA 038588 (MMS/LLH), DA 010344 (LLH), DA 031246 (LLH), and P51OD11132 (YNPRC).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

57P - NOX66 plus low dose carboplatin: A phase 1 safety and signalling study

Background: NOX66 is under development to enhance standard chemotherapy and radiotherapy. The target of idronoxil (the active constituent of NOX66), ENOX2, is an optimal candidate anti-cancer drug due to its tumour-cell specific expression. Inhibition of ENOX2 leads to a disruption of the TMEP, causing a cascade of intracellular actions leading to direct cytotoxicity and inhibition of DNA repair pathways. Three Phase 1 studies are underway to observe safety and efficacy signals - investigating multiple dose levels of NOX66 as monotherapy and in combination with carboplatin, palliative dose EBRT, and 177Lu-PSMA (a theranostic for treatment of prostate cancer). Data has previously been presented showing NOX66 400mg to be well tolerated as monotherapy and in combination with carboplatin. Here we present data for patients receiving 800mg NOX66. Methods: Nineteen patients with end stage metastatic cancer (breast, lung, prostate and ovarian) were enrolled between March and September 2017 across four centres in Georgia. Patients were allocated to one of three treatment cohorts: Cohort 1 (n = 8) receives 400mg NOX66 daily, Cohort 2 (n = 8) and 3 (n = 3) receive 800mg daily. Each patient receives NOX66 for up to seven months in the following regimen: - Part A: Monotherapy - 14 consecutive days of NOX66 treatment followed by 7 Days rest (Cohorts 1 and 2 only); - Part B: Carboplatin AUC4 - 3 x 28 Day cycles; NOX66 Days 1-7, Carboplatin Day 2; - Part C: Carboplatin AUC6 - 3 x 28 Day cycles; NOX66 Days 1-7, Carboplatin Day 2. Efficacy is measured by change in from baseline in radiological scans (using RECIST v 1.0 criteria) at End of Cycle 3 and Cycle 6. Adverse Events are monitored from enrolment until 30 days post Cycle 6. Results: Data presented is for Cohort 2, Part A and B (Cohort 1 presented at ESMO2017). Of the 8 patients treated with 800mg NOX66, 7 completed monotherapy (one withdrawal prior to dosing). No AEs related to NOX66 were reported. Following three cycles of combination with carboplatin AUC4, 1 patient reported partial response, 4 stable disease and 1 disease progression. No AEs related to NOX66 have been reported. Conclusions: NOX66 at 800mg is well tolerated as monotherapy and in combination with low dose carboplatin. Efficacy signals support further investigation of NOX66 in combination with standard chemotherapy. Clinical trial identification: Protocol NOX66-001A; NCT02941523 Legal entity responsible for the study: Noxopharm Funding: Noxopharm Disclosure: G. Kelly: Employee, board member and significant shareholder of the sponsor company, Noxopharm Limited. I. Minns: Employee of the sponsor company, Noxopharm Limited.

Abstract OT1-05-03: TRIO030: A presurgical tissue-acquisition study to evaluate molecular alterations in human breast cancer tissue following short-term exposure to the androgen receptor antagonist darolutamide

Abstract Background: Endocrine treatment remains a mainstay in the treatment of patients with estrogen-receptor (ER) positive breast cancer (BC). Although ER and progesterone receptor (PgR) are well established targets with predictive and prognostic value, the clinical significance and role of the androgen receptor (AR) is poorly understood. Darolutamide is a new AR antagonist developed for the treatment of castration-resistant prostate cancer. Darolutamide potently inhibits testosterone binding to AR and retains antagonistic properties in cells expressing increased AR levels. Understanding the biological impact of AR-blockade when darolutamide targets the AR in BC should provide foundational rationale for its development in BC. Trial Design: TRIO030 is a multi-center, open-label, tissue-acquisition study involving 60 women with early-stage invasive BC. To be able to assess the molecular alterations after darolutamide exposure in different BC subtypes, BC patients with triple-negative, or ER+/HER2 negative, or HER2 positive disease will be enrolled in the study, with 20 subjects in each group. Each participant will receive darolutamide at a dose of 600 mg b.i.d. (daily dose of 1200 mg) for a minimum duration of 14 days until the day prior to BC surgery (recommended duration of 21 days, maximum 35 days). Tumor tissue collection will include 3 pre-treatment cores (2 snap-frozen and 1 paraffin embedded) and 2 cores at surgery (1 snap-frozen and 1 paraffin embedded). Key Eligibility Criteria: Eligible female subjects will have 1) histologically proven invasive breast carcinoma for which surgery is indicated as the primary treatment modality, 2) known ER, PgR and HER2 statuses, 3) tumor confined to either the breast or to the breast and ipsilateral axilla with T1 ≥1.5cm, T2 or T3 and either clinically positive (N1 only) or clinically negative axillary nodes (N0), and 4) no prior systemic nor local treatment for BC. Study Objectives: The primary objective of this study is to identify the molecular changes that occur in BC tissue following short-term exposure to darolutamide in women with early BC. Secondary objectives include the safety and tolerability of short-term darolutamide in women with early BC. Statistical Methods: Evaluability of subjects will require minimum duration of 10 consecutive days of treatment with darolutamide, tumor tissue collection at screening and at surgery and adequacy of tumor tissue samples for molecular assessment as determined by the central laboratory. Molecular analyses will be conducted on the evaluable population. Descriptive statistics will be used to compare pre and post treatment molecular findings. Correlations will be sought among molecular alterations from tumor samples collected at baseline, following administration of darolutamide, and clinicopathologic variables. Accrual: The study will be activated in June 2017. Up to 60 evaluable subjects will be enrolled within 12 months (NCT03004534). Citation Format: Mackey JR, Eiermann W, Fresco R, Fung H, Carrez S, Lopez C, Slamon DJ. TRIO030: A presurgical tissue-acquisition study to evaluate molecular alterations in human breast cancer tissue following short-term exposure to the androgen receptor antagonist darolutamide [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-05-03.

Effects and Mechanisms of Total Flavonoids from Blumea balsamifera (L.) DC. on Skin Wound in Rats.

Chinese herbal medicine (CHM) evolved through thousands of years of practice and was popular not only among the Chinese population, but also most countries in the world. Blumea balsamifera (L.) DC. as a traditional treatment for wound healing in Li Nationality Medicine has a long history of nearly 2000 years. This study was to evaluate the effects of total flavonoids from Blumea balsamifera (L.) DC. on skin excisional wound on the back of Sprague-Dawley rats, reveal its chemical constitution, and postulate its action mechanism. The rats were divided into five groups and the model groups were treated with 30% glycerol, the positive control groups with Jing Wan Hong (JWH) ointment, and three treatment groups with high dose (2.52 g·kg−1), medium dose (1.26 g·kg−1), and low dose (0.63 g·kg−1) of total flavonoids from B. balsamifera. During 10 consecutive days of treatment, the therapeutic effects of rates were evaluated. On day 1, day 3, day 5, day 7, and day 10 after treatment, skin samples were taken from all the rats for further study. Significant increases of granulation tissue, fibroblast, and capillary vessel proliferation were observed at day 7 in the high dose and positive control groups, compared with the model group, with the method of 4% paraformaldehyde for histopathological examination and immunofluorescence staining. To reveal the action mechanisms of total flavonoids on wound healing, the levels of CD68, vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and hydroxyproline were measured at different days. Results showed that total flavonoids had significant effects on rat skin excisional wound healing compared with controls, especially high dose ones (p < 0.05). Furthermore, the total flavonoid extract was investigated phytochemically, and twenty-seven compounds were identified from the total flavonoid sample by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry/diode array detector (UPLC-Q-TOF-MS/DAD), including 16 flavonoid aglucons, five flavonoid glycosides (main peaks in chromatogram), five chlorogenic acid analogs, and 1 coumarin. Reports show that flavonoid glycoside possesses therapeutic effects of curing wounds by inducing neovascularization, and chlorogenic acid also has anti-inflammatory and wound healing activities; we postulated that all the ingredients in total flavonoids sample maybe exert a synergetic effect on wound curing. Accompanied with detection of four growth factors, the upregulation of these key growth factors may be the mechanism of therapeutic activities of total flavonoids. The present study confirmed undoubtedly that flavonoids were the main active constituents that contribute to excisional wound healing, and suggested its action mechanism of improving expression levels of growth factors at different healing phases.

In Vivo Therapeutic Effect of Vaccinium Meridionale Swartz in Ischemia-Reperfusion Induced Male Albino Rats.

This study was aimed to investigate the cardioprotective and antioxidant effect of Vaccinium meridionale Swartz in ischemia-induced male albino Wistar strain rats. Rats were grouped into 5 of 6 numbers each. Group I served as a sham, group II served as control and group III, IV, and V served for 1, 10, and 25 mg/kg/d of an extract of Vaccinium meridionale Swartz for 15 consecutive days of treatment. Serum marker enzymes, lipid peroxidation, and myeloperoxidase were increased, whereas antioxidant enzymes were reduced in control due to injury. Increased phenol and anthocyanin contents and increased free radical scavenging activity was noted following treatment. Serum marker enzymes, necrosis, and lipid peroxidation, were reduced, whereas antioxidant enzymes and reduced glutathione were increased. Nitric oxide synthase and Akt expression were also increased following treatment. Taking all these data together, it is suggested that Vaccinium meridionale Swartz may be a potential therapeutic agent for the treatment of ischemic injury.

Plasma renin activity in patients with heart failure and reduced ejection fraction on optimal medical therapy.

Background:Renin-angiotensin-aldosterone system (RAAS) activation in heart failure with reduced ejection fraction (HFREF) is detrimental through promotion of ventricular remodeling and salt and water retention.Aims:The aims of this article are to describe RAAS activity in distinct HFREF populations and to assess its prognostic impact.Methods:Venous blood samples were prospectively obtained in 76 healthy volunteers, 72 patients hospitalized for acute decompensated HFREF, and 78 ambulatory chronic HFREF patients without clinical signs of congestion. Sequential measurements were performed in patients with acute decompensated HFREF.Results:Plasma renin activity (PRA) was significantly higher in ambulatory chronic HFREF (7.6 ng/ml/h (2.2; 18.1)) compared to patients with acute decompensated HFREF (1.5 ng/ml/h (0.8; 5.7)) or healthy volunteers (1.4 ng/ml/h (0.6; 2.3)) (all p < 0.05). PRA was significantly associated with arterial blood pressure and renin-angiotensin system blocker dose. A progressive rise in PRA (+4 ng/ml/h (0.4; 10.9); p < 0.001) was observed in acute decompensated HFREF patients after three consecutive days of decongestive treatment. Only in acute HFREF were PRA levels associated with increased cardiovascular mortality or HF readmissions (p = 0.035).Conclusion:PRA is significantly elevated in ambulatory chronic HFREF patients but is not associated with worse outcome. In contrast, in acute HFREF patients, PRA is associated with cardiovascular mortality or HF readmissions.

Dose-exposure-response relationship between AZD6738 and peripheral monocytes.

e14063 Background: AZD6738 is a potent, selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) serine/threonine-specific protein kinase with good selectivity against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members. To support dose/schedule guidance through mathematical modelling of clinical pharmacokinetic/pharmacodynamic relationships, we sought to determine quantitative pharmacodynamic effects of AZD6738 in peripheral blood with respect to drug exposure. Methods: We assessed peripheral blood cell subpopulations in clinical studies of AZD6738 used either as a monotherapy, a combination with the PARP-1 inhibitor olaparib and in combination with the PD-L1 inhibitor durvalumab through both blood analyser and flow cytometry characterization. Peripheral pharmacokinetics of AZD6738 were also assessed. Results: Levels of peripheral monocytes were suppressed in a dose-dependent manner for the duration of AZD6738 dosing resulting in a decrease of up to 80% within the first 7 consecutive days of AZD6738 treatment; these results were consistent across studies. Upon cessation of an AZD6738 dosing interval monocyte levels return to baseline values within 14 days; in combination with durvalumab there is a trend for the rebound in monocyte counts to surpass baseline levels by up to 20%. Monocyte suppression is specific to AZD6738 and not found with either single agent olaparib or single agent durvalumab, possibly attributable to defective base excision repair in monocytes and lack of PARP-1. Monocytes were found to be the most sensitive cell type to AZD6738 treatment compared with neutrophils, platelets, haemoglobin or lymphocytes. Conclusions: This drug effect of AZD6738 is consistent with natural clearance of peripheral monocytes under suppression of monocyte precursor proliferation in the bone marrow, suggestive of a change in the equilibrium between production and elimination of peripheral monocytes. Used as a surrogate marker of target inhibition, a mathematical model of the AZD6738/monocyte dose-exposure-response relationship is described and has been used to inform AZD6738 Phase 2 dose and schedule.

The effect of 1 week of repeated ischaemic leg preconditioning on simulated Keirin cycling performance: a randomised trial

BackgroundCoaches continually seek new ways of doing things and also refine existing techniques to improve sporting performance. Coaches are currently experimenting using ischaemic preconditioning (IPC) over consecutive days in the...