Single Arms Research Articles

Чешская Республика: Оборонная политика и стратегия безопасности в рамках Европейского союза

The article examines the defense strategy of the Czech Republic. Based on the analysis of government documents («Defense Strategy of the Czech Republic 2017,» «Priorities of the Czech Presidency in V4») reveals the goals and objectives of the Czech Republic in the field of European security and defense at the present stage. The country is an independent element not only of global security, but, due to its geographical location in the middle of Europe, and an important element of European security. The article explores the Czech Republic's position on participation in the Permanent Structured Cooperation on Security and Defense (PESCO), multilateral projects outside the EU, military missions and operations of the EU and NATO, as well as bilateral cooperation and within the Visegrad Group (V4) comprising Poland, Hungary, the Czech Republic, Slovakia. The Czech Republic's position on military expenditures is being considered, as well as the problem of coexistence of European military structures and NATO. The Czech Republic intends to develop a single European arms market. This includes mandatory investments in the defense industry and the formation of the European Defense Fund, which will be used to invest in member countries. The Czech Republic actively supports and develops bilateral and multilateral defense cooperation with neighboring countries, as well as in a regional format. Defense regional cooperation focuses on two main areas: cooperation with Germany and within the Visegrad Group. Also it observes risks to Czech defense construction revealed due to Coronavirus pandemic.

Panobinostat (LBH589) in Combination with the β-Catenin Inhibitor Tegavivint (BC2059) Exerts Significant Anti-Myeloma Activity Both in Vitro and In Vivo

Introduction: Panobinostat (LBH589) is approved for the treatment of relapsed multiple myeloma (MM). The Wnt canonical pathway and its key player, β-catenin are dysregulated in advanced MM supporting the evaluation of β-catenin inhibition as a potential therapy. We evaluated the anti-MM effect of Tegavivint in combination with Panobinostat in vitro and in vivo. Results and Methods : In vitro combination of low doses (BC2059≤100nM; LBH589≤10nM) for 48h was synergistic against OCI-My1 and U266 MM cells, with combination indices from 0.569 to 0.883 (CI<1: synergism). The combination demonstrated synergistic killing of primary MM tumour cells in an autologous co-culture assay with synergism quotients from 1.2 to 2 (SQ>1: synergism). The combination rapidly (<24h) decreased the expression of downstream β-catenin targets myc, cyclin D1 and cyclin D2 as shown by immunoblotting. Furthermore, by 20h, the combination decreased both oxidative phosphorylation and aerobic glycolysis as measured by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively (Seahorse XFe96 analyser). Basal, maximal and ATP coupled OCR were significantly reduced by the combination when compared to vehicle (for OCI-My1 from 203.93 to 56.20, 105.81 to 33.29 and 156.29 to 34.67 pmol/min/50K cells OCR respectively). Similarly, basal glycolysis and glycolytic capacity were both reduced by the combination (from 48.88 to 9.77 and 61.68 to 8.58 mpH/min/50K cells ECAR, respectively). In vivo, the combination was superior to either single drug treatment in a murine xenograft of U266-luciferase cells. Disease burden was reduced in the combination arm compared to single drug and vehicle arms as early as day 14 after inoculation (p=0.02). This difference increased further until the last bioluminescence imaging (day 49, p<0.001) and translated into significantly prolonged OS for the combination (p=0.006). Potential on-target toxicities with BC2059 are a concern as the Wnt canonical pathway is essential for stem cell maintenance in several organs and has a role in bone homeostasis, but the combination did not result in cytopenias nor body weight loss. After euthanasia, µCT demonstrated that neither BC2059 nor the combination negatively affected bone morphometric indices (bone volume fraction, trabecular thickness, connectivity density). Likewise, osteoblastic activity as measured by serum osteocalcin was unaffected, whereas osteoclastic activity (as indicated by serum CTX1) was reduced when compared to healthy mice (p=0.008 and p=0.013, respectively). In conclusion Tegavivint in combination with Panobinostat may be a useful therapeutic modality for MM patients with advanced/refractory disease and warrants further evaluation. Disclosures Khong: Novartis Oncology: Research Funding. Spencer:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Specialised Therapeutics Australia: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria; Secura Bio: Consultancy, Honoraria.

6128Losartan vs Nebivolol vs the association of both on the progression of aortic root dilation in genotyped Marfan Syndrome: 48 months open label randomized controlled phase III trial

Abstract Background Marfan Syndrome (MFS) is a rare multisystemic genetic disease caused by mutations in the Fibrillin 1 (FBN1) gene. Aortic root aneurysm, potentially evolving to dissection and rupture, is the most important clinical complication. Beta blockers (BB) and Angiotensin II receptor blockers (ARB), these latter exerting an anti-TGFbeta1 effect, are current cornerstones of medical therapy in patients diagnosed with MFS and presenting aortic root aneurysm. The study aimed at comparing the effect of single drug (nebivolol and losartan) vs. the combination of both (losartan + nebivolol) in limiting the progression of the growth of the aortic root diameter (ARD) in FBN1 genotyped patients with aortic root aneurysm (z-score>2), who had not undergone prior aortic surgery. Methods We designed a controlled, open-label, single-blinded, 1:1:1 randomized, phase III single-centre study [NCT00683124]. Calculated sample size was 291 (power 90%, type I error 5%, 20% attrition, expected dropout 20%). ARD data collection was performed with annual 2D-transthoracic echocardiograms for four years. ARDs were measured with 2D-transthoracic echocardiogram as absolute values, aortic root ratio (ARR), and z-score. The primary endpoint was the modification of ARD z-score at 48 months. The analysis of the primary endpoint aimed at showing differences of ARD z-score comparing: – The combined treatment arm (group A). – The group aggregating both single treatment arms (group B). – The nebivolol arm (group C). – The losartan arm (group D). Results We enrolled 262 patients (126 adults, aged 17–55, and 136 children, aged 1–16); 236/262 (22 dropout; 4 lost at follow-up) completed the planned follow-up: 81 in the group A, 79 in the BB in the group C and 76 in the group D. No patient developed acute aortic dissection. Both drugs administered either individually or in combination were well tolerated without evidence of side effects. At 48 months, the ARD Z-score decreased from baseline to end-follow-up in all treatment arms. The decrease was significantly higher in the combined treatment arm (A) than in the single treatment aggregated arm (group B) with a difference in ARD z-score change of 0.17 (p=0.009) in the combined arm (A). Similarly, the decrease of z-score was inferior in the nebivolol arm and in the losartan arm than in the combined arm (by 0.16, p=0.032, and by 0.18, p=0.019, respectively). After Bonferroni correction for these post-hoc comparisons only the decrease of z-score in the losartan arm remained significantly inferior (p<0.025). Conclusions This study shows that the current cornerstones of medical therapy in MFS (ARB and BB) are effective in limiting the progression of the growth of the aortic root diameter: their combination exploits a synergistic effect. The combined administration of BB and ARB in patients with aortic root aneurysm is a sustainable, well tolerated treatment that effectively limits the rate of progression of aortic root dilation. Acknowledgement/Funding The financial support of Telethon, Italy (Grant no. GGP08238) is gratefully acknowledged.The drugs are a gift of Menarini and MSD

Assessment of the platelet-derived growth factor receptor alpha antibody olaratumab in a panel of patient-derived soft tissue sarcoma xenografts

BackgroundSoft tissue sarcoma (STS) comprises a family of rare, heterogeneous tumors of mesenchymal origin. Single-agent doxorubicin remains the first-line standard-of-care treatment for advanced and inoperable STS, but response rates are only around 15%. In 2016, phase Ib/II clinical trial results reported an overall survival benefit of 11.8 months when combining doxorubicin and the platelet-derived growth factor receptor alpha (PDGFRA)-directed antibody olaratumab compared to doxorubicin alone, without providing a scientific rationale for such unprecedented therapeutic effect. We decided to evaluate the efficacy of olaratumab in a panel of STS patient-derived xenografts (PDX).MethodsNMRI nu/nu mice were bilaterally transplanted with tumor tissue of patient-derived xenograft models expressing PDGFRA, including models of leiomyosarcoma (UZLX-STS22), malignant peripheral nerve sheath tumor (UZLX-STS39), myxofibrosarcoma (UZLX-STS59) and undifferentiated pleomorphic sarcoma (UZLX-STS84). Mice were randomly divided into four different treatment groups: (1) control, (2) doxorubicin (3 mg/kg once weekly), (3) anti-PDGFRA [olaratumab (60 mg/kg twice weekly) + mouse anti-PDGFRA antibody 1E10 (20 mg/kg twice weekly)] and (4) the combination of doxorubicin and anti-PDGFRA (same dose/schedule as in the single treatment arms). Tumor volume, histopathology and Western blotting were used to assess treatment efficacy.ResultsAnti-PDGFRA treatment as a single agent did not reduce tumor growth and did not result in significant anti-proliferative or pro-apoptotic activity. Combining doxorubicin and anti-PDGFRA did not reduce tumor burden, though a mild inhibition of proliferation was observed in UZLX-STS39 and -STS59. A pro-apoptotic effect was observed in all models except UZLX-STS22. Antitumor effects on histology were not significantly different comparing doxorubicin and the combination treatment. Moreover, anti-PDGFRA treatment, both as a single agent as well as combined with doxorubicin, did not result in inhibition of the downstream MAPK and PI3K/AKT signaling pathways.ConclusionsWe were not able to demonstrate significant antitumor effects of anti-PDGFRA treatment in selected STS PDX models, neither alone nor in combination with doxorubicin. This is in line with the very recent results of the phase III clinical trial NCT02451943 ANNOUNCE, which did not confirm the clinical benefit of olaratumab in combination with doxorubicin over single agent doxorubicin.

Abstract 1253: MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma

Abstract Liposarcoma is a rare but highly recurrent soft tissue neoplasm. Combination of surgery and radiotherapy is the main treatment for liposarcoma patients while chemotherapy remains experimental and limited depends on disease subtypes. Well-differentiated and dedifferentiated liposarcoma (WDLPS/DDLPS) represents ~50% of all diagnosed liposarcoma and their benefit from chemotherapy has been documented to be minimal. Concomitant amplifications of MDM2 and CDK4 are frequently found in WDLPS/DDLPS patients, suggesting that the combination with two targeted agents may worth further development for the treatment. APG-115 is a potent, selective, orally bioavailable small molecule inhibitor of MDM2-p53 protein-protein interaction and thus activates tumor suppression activity of p53 in p53 wild-type tumors. Currently, APG-115 is in clinical development as a single agent or in combination with PD-1 blockade immunotherapy for solid tumors, including sarcoma. To further explore the sensitive patient population and predictive biomarkers for APG-115, in this study, we evaluated the effect of the combined MDM2/CDK4 inhibition in p53 wild-type, MDM2 and CDK4 amplified liposarcoma using a preclinical xenograft tumor model derived from a dedifferentiated liposarcoma patient (PDX). Tumor-bearing mice were treated with MDM2 inhibitor APG-115, CDK4 inhibitors palbociclib/ribociclib, or their combinations. In the first experiment, APG-115 administered at 40 mg/kg as a single agent demonstrated antitumor activity in the DDLPS PDX model. In comparison with the single agents, the combination treatment with APG-115 and palbociclib or APG-115 and ribociclib exerted synergistic antitumor effects, resulting in T/C values of 16.9% and 27.1%, respectively (T/C value, average tumor volumes in treatment group vs. the vehicle control group). Partial tumor regression (PR) was achieved in 1/5 animals in both combination treatment groups but not in single arms. Another independent experiment with a higher dose of APG-115 (80 mg/kg) combined with palbociclib showed further improved antitumor activity with T/C value of 7.0% (2/5 PR). Collectively, our results suggest that the combination therapy of APG-115 and a CDK4 inhibitor may benefit WDLPS/DDLPS patients with p53 wild-type, and MDM2 and CDK4 amplifications clinically. Citation Format: Douglas D. Fang, Guoqin Zhai, Chunhua Xu, Qingyang Gu, Jingwen Wang, Saijie Zhu, Dajun Yang, Yifan Zhai. MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1253.

Abstract 3068: Synergistic effect of BCL-2 inhibitor APG-2575 and CDK9 inhibitor in acute myeloid leukemia and DLBCL preclinical tumor models

Abstract Effective treatments are urgently needed for elderly acute myeloid leukemia (AML) and relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients as only 10-25% of the population respond to standard therapies and resistance often occurred. Concurrent overexpression of anti-apoptotic BCL-2 gene and proto-oncogene MYC are frequently found in AML and DLBCL and this molecular characteristic is associated with poor prognosis of patients. CDK9 controls non-ribosomal transcription of genes including MYC and MCL-1. Dysregulation in the CDK9 pathway had been reported in AML and DLBCL, making it an attractive target for the combination with BCL-2 inhibitor to achieve more effective therapy. To test the above hypothesis, in this study, we applied the combination of APG-2575 with a CDK9 inhibitor (alvocidib or dinaciclib) to preclinical tumor models. APG-2575 is a novel, orally bioavailable BH3-mimetic that selectively inhibits BCL-2, but not BCL-xL or MCL-1. After the treatment, synergistic effect of the combination treatment was demonstrated in mice bearing xenograft tumors of human AML or DLBCL. Specifically, in xenograft tumor models derived from human DLBCL cell line U2932, the treatment with APG-2575, alvocidib, or dinaciclib single agent for 22 days exhibited antitumor activity with T/C values of 20-50% (T/C value, average tumor volumes in treatment group vs. the vehicle control group). The combination treatment achieved substantial antitumor activity with T/C value of 5%. All animals in the combination groups showed either partial or complete tumor regression whereas none in the single arms. Similar synergistic antitumor activity of the combination treatment was consistently observed in the myelodysplastic syndrome SKM-1 and AML OCI-AML-3 xenograft models. Taken together, our data suggest that APG-2575 and CDK9 inhibition combination has a potential therapeutic application in treatment of patients with AML and DLBCL. Citation Format: Douglas D. Fang, Ran Tao, Qiuqiong Tang, Shoulai Gu, Guoqin Zhai, Jiajun Li, Qixin Wang, Xu Fang, Na Li, Dajun Yang, Yifan Zhai. Synergistic effect of BCL-2 inhibitor APG-2575 and CDK9 inhibitor in acute myeloid leukemia and DLBCL preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3068.

Abstract 2134: Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wt prostate tumors

Abstract Patients with metastatic prostate cancer may initially respond well to first- and second-generation androgen receptor (AR)-targeted therapies, but many will experience disease progression, indicating a need for alternative therapies. A subset of these patients bears prostate tumors that harbor deleterious mutations in DNA damage repair (DDR) pathway genes, such as BRCA2. These DDR mutations render the tumors sensitive to drugs that inhibit poly (ADP-ribose) [PAR] polymerase-1 (PARP1), inducing synthetic lethality. Studies indicate that there are interactions between AR signaling pathways and DDR pathways in prostate cancer cells, supporting the hypothesis that dual AR/PARP inhibition could inhibit prostate tumor growth more potently than single agents, regardless of the DDR status of the tumor. This hypothesis was tested using well-known human and mouse prostate tumor models that are sensitive to androgen deprivation. Genotyping of the models confirmed that none of them carried homozygous pathogenic mutations in DDR genes, including BRCA1, BRCA2, and ATM. When the cell lines were incubated in vitro with niraparib, a potent and highly selective PARP1/2 inhibitor, PAR formation was significantly inhibited, and there was induction of γH2AX in treated cells, indicating the drug induced DNA double-stranded breaks. In addition, the cytotoxicity IC50 values for niraparib were in the range of 1-10 µM, as expected for cells that are DDRwt. In vivo efficacy studies demonstrated that the VCaP and Myc-CaP tumor models were insensitive or modestly sensitive to single agent treatment with niraparib or abiraterone acetate (AA). In contrast, the combination treatment of niraparib plus AA significantly reduced tumor growth and increased survival (p<0.05) as compared with control or single agent arms. Studies are ongoing to understand the mechanisms of tumor growth control mediated by the combination of these two agents. The results support the hypothesis that prostate tumors may respond to a combination treatment with niraparib, a PARP inhibitor, and AA, an androgen synthesis inhibitor, even in the absence of DDR anomalies. A Phase 3 study is planned to evaluate this hypothesis and the safety and efficacy of this combination in humans. Citation Format: Rajendra N. Damle, Rebecca Hawkins, Jennifer Hosbach, Georges Habineza Ndikuyeze, Jenny Driscoll, Natalie L. Fulton, David Derosa, Anna Hughes, Gerald Chu, Karl Calara-Nielsen, Denis Smirnov, Dong Shen, Linda A. Snyder. Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wt prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2134.

No relevant activity of olaratumab in patient-derived soft tissue sarcoma xenografts selected for expression of platelet-derived growth factor receptor a.

e22556 Background: Soft tissue sarcoma (STS) comprises a heterogeneous family of rare tumors of mesenchymal origin. Single-agent doxorubicin (DOX) remains the standard-of-care for advanced and inoperable STS, but response rates are < 15% and survival is generally poor. In 2016, Tap et al. reported impressive results of a phase Ib/II trial combining DOX and the platelet-derived growth factor receptor a (PDGFRA)-directed antibody olaratumab (OLA), suggesting an unprecedented survival advantage of the combination over DOX alone, without providing a mechanistic rationale for the observed activity (Lancet 2016;388:488-97). We decided to evaluate the efficacy of OLA in a panel of patient-derived STS xenografts (PDX). Methods: NMRI nu/nu mice were transplanted bilaterally with tumor tissue of models expressing PDGFRA, including PDX of leiomyosarcoma (UZLX-STS22), malignant peripheral nerve sheath tumor (STS39), myxofibrosarcoma (STS59) and undifferentiated pleomorphic sarcoma (STS84). Mice were randomly divided into 4 treatment groups: (1) control, (2) DOX (3 mg/kg once weekly), (3) anti-PDGFRA [OLA (60 mg/kg twice weekly) + mouse anti-PDGFRA antibody 1E10 (20 mg/kg twice weekly)] and (4) the combination of DOX and anti-PDGFRA (same dose/schedule as single treatment arms). Tumor volume, histopathology and Western blotting were used to assess treatment efficacy. Results: Anti-PDGFRA treatment as single agent did not reduce tumor growth and did not result in significant anti-proliferative or pro-apoptotic activity. Combining DOX and anti-PDGFRA did not reduce tumor burden, though a mild inhibition of proliferation was observed in models STS39 and STS59 and a pro-apoptotic effect was seen in all models except STS22. Antitumor effects on histology were not significantly different comparing DOX and the combination treatment. Anti-PDGFRA treatment, both as a single agent as well as with DOX, did not inhibit downstream MAPK and PI3K/AKT signaling pathways. Conclusions: In vivo findings in PDX models selected for PDGFRA expression support negative findings of the phase III trial NCT02451943 with OLA reported at this meeting.

Sensitivity of treatment-free survival (TFS), a novel outcome, to subgroup analyses of patients (pts) with advanced melanoma (MEL) treated with immune checkpoint inhibitors (ICI).

9550 Background: Many pts treated with ICIs can discontinue treatment and experience ongoing disease control and toxicity. We previously proposed a novel outcome, TFS, as the time between ICI therapy cessation and subsequent therapy initiation or death, with integrated graphical analysis to better characterize the unique effects of ICIs (ASCO 2018 #9531). In the CheckMate 067 and 069 trials of ipilimumab (IPI) and nivolumab (NIVO) alone or in combination (NIVO+IPI) in pts with MEL, the 36-month restricted mean TFS was 8.7, 4.6 and 11.1 mo, respectively. We explored the sensitivity of TFS to be informative of overall survival (OS) differences through subgroup analysis. Methods: Data from MEL pts in the CheckMate 067 and 069 trials were pooled and analyzed. TFS was defined as the area between the Kaplan-Meier curves for two endpoints, from randomization: (A) time to ICI therapy cessation; and (B) time to subsequent therapy initiation or death. TFS was estimated by restricted mean survival time until 36 mo since randomization. Differences in restricted mean TFS between subgroups of pts (such as PD-L1 status, lactate dehydrogenase [LDH], performance status [PS], gender) were calculated with bootstrapped 95% CIs. OS from randomization was also estimated. Results: Among 407 pts treated with NIVO+IPI, restricted mean TFS ranged from 8-13 mo across subgroups (Table). Subgroup differences in mean TFS were larger for prognostic factors LDH and PS and smaller in non-prognostic PD-L1 status and gender subgroups. Conclusions: Clinically meaningful TFS was seen across all subgroups. TFS was sensitive to prognostic subgroup differences. These results provide further support for TFS as a relevant clinical endpoint. Additional subgroups and comparisons with single agent NIVO and IPI arms will be presented at the meeting. [Table: see text]

Efficacy and safety of direct-acting antiviral therapy for chronic hepatitis C genotype 6: A meta-analysis.

Because of the heterogeneity of hepatitis C virus (HCV) distribution of different genotypes, large-scale clinical trials on direct-acting antiviral (DAA) mainly included patients with genotype 1 and genotype 3 infection. Data on the efficacy of direct-acting antiviral agents in patients with chronic genotype 6 HCV infection are limited. The PubMed, Embase, and the Cochrane Libraries were searched comprehensively. All published clinical trials assessing the efficacy of DAA therapy for patients with chronic genotype 6 HCV infection were included. Sustained virological response (SVR) and rapid virological response (RVR) were pooled. Additional meta-analyses were also performed to compare the efficacy of DAA therapy in HCV-6 versus HCV-1 or HCV-3 patients. Seventeen studies met the inclusion criteria and were included in our meta-analysis. The pooled SVR of all single arms was 95% [95% confidence interval (CI): 0.90-0.97]. The pooled RVR of all single arms was 97% (95% CI: 0.95-0.99). The SVR and RVR were both similar between HCV-6 and HCV-1 or HCV-3. Adverse events were common but rarely caused treatment interruption. Based on the available data, our results indicate that DAA treatment is effective and safe for patients with genotype 6 HCV infection, and the efficacy was similar compared to patients with genotype 1 HCV or genotype 3 HCV infection.

The Role of Great Britain in the Military-technical Cooperation of the Countries of European Union

In the article the Great Britain’s contribution to the development of military-technical cooperation between the countries of the European Union is analyzed. It was found that the British leadership conducted ambiguous policies on military-technical cooperation (MTC) of the European integration. The desire to win the priority in the European MTC was combined with the provision of British companies the benefits of cooperation with American partners. British military-industrial complex became a rival of the military-industrial complex of the states of continental Europe. The position of Great Britain has become one of the obstacles to the formation of a single European arms market. The exit of the kingdom from the EU can stimulate the process of creating a single European militaryindustrial complex, in which France and Germany, supported by other influential industrial states (Italy, Spain, etc.) will dominate. The British military-industrial complex will continue to have a significant impact on the European MTC machinery, which relatively successfully operates outside the EU.

Slip signal analysis on a Baxter robot

Abstract The Baxter robot by ReThink Robotics is a dual arm collaborative platform, which can perform multiple tasks and is designed for use in an unstructured environment. Such robotic manipulators working in tandem have certain advantages over single arms when manipulating heavy or large, awkwardly shaped objects. With the attachment of two custom 3D-printed end-effectors, the robot gains the ability to push and hold objects of this kind. This paper deals with the preliminary steps in creating a reliable controller feedback signal using the robot’s on-board torque and positioning sensors. Determining the best joint signal and designing a suitable filter are two challenges that are addressed. The paper concludes that the torque values from the centre wrist joint undergo the largest increase in value caused by vibrations during slip. A filtering array technique is also proposed, successfully removing unwanted noise from the torque signal, allowing slip events to be effectively isolated.

Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis

ObjectiveTo assess the effectiveness and safety of dual agent antiplatelet therapy combining clopidogrel and aspirin to prevent recurrent thrombotic and bleeding events compared with aspirin alone in patients with acute...

Analysis of vibration of pendulum arm under bursting oscillation excitation

We investigate numerically the responses of the single pendulum and double pendulum arms coupled to a nonlinear RLC-circuit shaker through a magnetic field. These systems can be used to build a robotic device or an automat. The nonlinear RLC circuit is a Duffing oscillator that generates electric bursting oscillations. We first examine the dynamical behaviour of the single pendulum arm. Time series shows that the pendulum arm exhibits bursting oscillation. When the natural frequency $$w_2 <1$$ , the shape of the bursting in the electrical part is different from that observed in the pendulum arm and if $$w_2 >1$$ , the shape is the same. We then explore the behaviour of a double pendulum arm powered by electric bursting oscillations. Time series are also used to explore the behaviour of each pendulum arm. The results show that the displacement of each pendulum arm undergoes bursting oscillations resulting from the transfer of the electronic signal. The shape of bursting of the first pendulum is different from that of the second pendulum for some values of $$w_1 $$ . The shape, period and amplitude of the bursting oscillations depend on various control parameters.

Nivolumab for Treating Metastatic or Unresectable Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Bristol-Myers Squibb) of nivolumab (Opdivo®) to submit evidence of its clinical and cost effectiveness for metastatic or unresectable urothelial cancer. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG), which produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. Nivolumab was compared with docetaxel, paclitaxel, best supportive care and retreatment with platinum-based chemotherapy (cisplatin plus gemcitabine, but only for patients whose disease has had an adequate response in first-line treatment). Two ongoing, phase I/II, single-arm studies for nivolumab were identified, but no studies directly compared nivolumab with any specified comparator. Evidence from directly examining the single arms of the trial data indicated little difference between the outcomes measured from the nivolumab and comparator studies. A simulated treatment comparison (STC) analysis was used in an attempt to reduce the bias induced by naïve comparison, but there was no clear evidence that risk of bias was reduced. Multiple limitations in the STC were identified and remained. The effect of an analysis based on different combinations of covariates in the prediction model remains unknown. The ERG's concerns regarding the economic analysis included the use of a non-established response-based survival analysis method, which introduced additional uncertainty. The use of time-dependent hazard ratios produced overfitting and was not represented in the probabilistic sensitivity analysis. The use of a treatment stopping rule to cap treatment cost left treatment effectiveness unaltered. A relevant comparator was excluded from the base-case analysis. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's Appraisal Consultation Document response were £58,791, £78,869 and £62,352 per quality-adjusted life-year gained versus paclitaxel, docetaxel and best supportive care, respectively. Nivolumab was dominated by cisplatin plus gemcitabine in the ERG base case. Substantial uncertainties about the relative treatment effectiveness comparing nivolumab against all comparators remained. NICE did not recommend nivolumab, within its marketing authorisation, as an option for treating locally advanced, unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy, and considered that nivolumab was not suitable for use within the Cancer Drugs Fund.

Efficacy and Safety of a Single Dose versus a Multiple Dose Regimen of Mebendazole against Hookworm Infections in Children: A Randomised, Double-blind Trial

BackgroundSingle-dose mebendazole is widely used in preventive chemotherapy against the soil-transmitted helminths (STHs) Ascaris lumbricoides, hookworm and Trichuris trichiura, yet it shows limited efficacy against hookworm and T. trichiura infections. The use of adapted treatment regimens might provide a strategy to control and eliminate STH infections in STH-persistent settings. We evaluated the safety and efficacy of the multiple dose mebendazole regimen (3 days 100 mg bid) versus a single dose of 500 mg mebendazole in a setting with high STH prevalence and high drug pressure. MethodsThis randomised, double-blind clinical trial took place in a primary school on Pemba Island, Tanzania, in school-aged children (6–12 years). Using a computer random number generator (block size 10), hookworm-positive children were randomly assigned (1:1) to either a single or multiple dose regimen of mebendazole by an independent statistician. Two stool samples were collected at baseline and follow-up (18 to 22 days after treatment) for Kato-Katz analysis. The primary outcome was cure rate (CR) against hookworm. Secondary outcomes were egg reduction rate (ERR) against hookworm, CRs and ERRs against A. lumbricoides and T. trichiura, and tolerability assessed 3, 24 and 48 h post-treatment. Participants, investigators, caregivers, outcome assessors and the trial statistician were blinded. This trial is registered with ClinicalTrials.gov, number NCT03245398. Findings93 children were assigned to each treatment arm. 185 children completed treatment and provided follow-up stool samples. CR against hookworm was significantly higher in the multiple dose (98%) than in the single dose arm (13%, OR 389.1, 95% CI 95.2 to 2885.7%, p < 0.001). 34 and 42 children reported mild adverse events in the single and multiple dose arms, respectively. The most common events were abdominal pain, headache and diarrhoea. InterpretationThe poor performance of single dose mebendazole against hookworm infections was confirmed, but the multiple dose treatment regimen of mebendazole showed high efficacy. Hence, multiple dose mebendazole might provide a treatment strategy in given epidemiological situations to boost control and elimination of STH infections. FundingPATH.

Design of three-direction strain sensor with big measurement range for structural health monitoring

A design method of a three-direction double-loop strain sensor for two-dimensional (2-D) strain is proposed and analyzed. The strain sensor is made up of three sensing arms and each arm is made of fiber Bragg gratings (FBG) sensor surface glued on titanium alloy substrate. The substrate has double loops to improve the sensor’s measurement range. The strain sensor is unique in that by designing three single arms of strain sensors in different direction, a 2-D strain’s maximum strain value and direction can be precisely determined. In comparison with common unidirectional strain sensor, this has great value for structural health monitoring. With finite element analysis and measurement demonstration, it is shown the measurement range of the strain sensor is increased by seven times compared with normal FBG sensor. The strain sensor’s measurement range can reach 1% (±5000 μϵ) with accuracy of 0.6%. An accurate and real-time monitoring system based on the sensor is presented, which demonstrated the sensor’s fast speed and high reliability.

Use Rate and Outcome in Bilateral Internal Thoracic Artery Grafting: Insights From a Systematic Review and Meta-Analysis.

BackgroundThis meta‐analysis was designed to assess whether center experience affects the short‐ and long‐term results and the relative benefits of bilateral internal thoracic artery grafting (BITA) for coronary artery bypass grafting.Methods and ResultsMEDLINE and EMBASE were searched to identify all articles reporting the outcome of BITA in patients undergoing coronary artery bypass grafting. The BITA center experience was gauged according to the percentage use of BITA in the institutional overall coronary artery bypass grafting population (%BITA). The primary outcome was long‐term all‐cause mortality. Secondary outcomes were operative mortality, perioperative myocardial infarction, perioperative stroke, deep sternal wound infections (DSWIs), and major postoperative adverse event. The rates of the primary and secondary outcomes were calculated after adjusting for %BITA. Primary and secondary outcomes were also compared between the BITA and the single internal thoracic artery arms in the adjusted studies. Meta‐regression was used to evaluate the effect of %BITA on the primary and secondary outcomes. Thirty‐four studies (27 894 patients undergoing BITA) were included. In the pooled analysis, the incidence rate for long‐term mortality was 2.83% (95% confidence interval, 2.21%–3.61%). %BITA was significantly and inversely associated with long‐term mortality and the rate of DSWI. In the pairwise comparison, %BITA was significantly and inversely associated with the risk of long‐term mortality and DSWI in the group undergoing BITA.ConclusionsBITA series with higher %BITA report significantly lower long‐term mortality and DSWI rate as well as higher long‐term survival advantage and lower relative risk of DSWI in their BITA cohort. These findings suggest that a specific volume‐outcome relationship exists for BITA grafting.

Abstract OT3-06-07: A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer

Abstract Background: Advanced or metastatic ER+BC (estrogen receptor positive breast cancer) is an incurable illness that will prove fatal for most afflicted women. Current standards of care include endocrine, targeted, and chemotherapy. Preclinical data suggest that altering the expression of the estrogen receptor (ER) as well as other ER-responsive genes may provide therapeutic benefit for women for whom endocrine therapy alone has proven inadequate. The bromodomain (BRD) and extra-terminal (BET) family of proteins (BRD2, BRD3, BRD4 and BRDT) bind to acetyl-histone residues and epigenetically control transcription of genes driving cell survival and proliferation. BET proteins have been implicated in carcinogenesis and treatment resistance in multiple tumors including ER+BC, and are a novel target for therapy in breast cancer. GSK525762 is a pan-BET inhibitor that has shown strong synergistic activity with fulvestrant in killing ER+BC cells in vitro and in xenograft models. The combination of BET agents with endocrine therapy may provide therapeutic benefit and restore sensitivity to ER targeting agents like fulvestrant. Trial Design &amp; Specific Aims: This study is a Phase I/II dose-escalation, expansion (Phase I) and randomized control (Phase II) study with oral administration of GSK525762 in combination with fulvestrant in advanced or metastatic ER+BC subjects, whose disease has progressed on prior treatment with at least one line of endocrine therapy. Phase I of the study is designed as parallel single arms to determine a recommended Phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetic, and efficacy profiles in two distinct populations of ER+ breast cancer: Subjects with disease that relapsed during treatment or within 12 months of adjuvant therapy with an AI, OR disease that progressed during treatment with an AI for advanced/metastatic disease. OR Subjects with disease that progressed during treatment with the combination of a CDK4/6 inhibitor plus letrozole for advanced or metastatic disease. Phase II of the study is a randomized, double-blind, placebo-controlled cohort, designed to evaluate the efficacy of the combination. Key Eligibility Criteria: Patients must have received &amp;lt;3 lines of systemic anti-cancer therapy (≤1 line of chemo), measurable disease, and PS 0-1. Statistical Methods: A modified toxicity probability interval (mTPI) design will be used to monitor safety. A Bayesian adaptive design will be used to evaluate efficacy in Phase 1. Present and Target Accrual: Target enrolment will be ˜300 subjects across ˜50 sites worldwide. To date, 2 subjects have been enrolled. Contact Information: Elizabeth Cunningham, Elizabeth.A.Cunningham@GSK.com. NCT02964507 Funding: GSK Citation Format: Pluard T, Oh SY, Oliveira M, Cescon D, Tan-Chiu E, Wu Y, Carpenter C, Cunningham E, Ballas M, Dhar A, Sparano J. A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer [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 OT3-06-07.

Abstract 1101: Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia

Abstract Background/Aims: Acute myeloid leukemia (AML) is an aggressive cancer with limited treatment options outside of chemotherapy. Improved therapies with novel mechanisms of action are desperately needed to fill this need. Both hTERT, the catalytic subunit of telomerase, and BCL-2, an apoptotic regulator, are overexpressed in AML, correlating with disease severity and poor prognosis respectively. Imetelstat is a novel, first-in-class competitive inhibitor of telomerase with clinical activity in hematologic malignancies. Venetoclax, an approved BCL-2 inhibitor for CLL, has shown a promising clinical benefit in AML patients. Preclinical evidence shows that downregulation of hTERT induces apoptosis via disruptions of hTERT and BCL-2 interaction; we hypothesize that inhibiting both targets would yield greater anti-tumor activity in AML compared to treatment with either agent alone. Methods: AML cell lines and AML patient’s PBMC samples were treated with imetelstat or venetoclax alone, or in combination, and viable and apoptotic populations of cells were evaluated by flow cytometry. Telomerase activity, hTERT expression and mitochondrial dysfunction were investigated for mechanism of action. Furthermore, an in vivo study in the MOLM-13 AML disseminated model was conducted to assess efficacy and survival. Results: A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax. In the MOLM-13 cell line, single-agent imetelstat and venetoclax had modest apoptotic activity after 48 hours (22% and 30% respectively), but the combination achieved 88% at 48 hours and nearly 100% at 96 hours. Similarly enhanced apoptotic activity was also observed in PBMCs purified from 4 AML patient whole blood samples. Molecular analyses showed combining imetelstat with venetoclax reduced hTERT expression and telomerase activity much more strongly than either agent alone. Furthermore, in vivo studies showed all mice tolerated the combination of imetelstat with ABT-199 well, with increased life span as compared to the vehicle control (68.1%, p=0.0001), to imetelstat (39.6%, p=0.0011) alone, or to venetoclax (23.3%, p=0.0001) alone. In the combination group, 40% of treated mice were alive 77-days after treatment discontinued whereas all mice of the other single agent arms died within two weeks, demonstrating a significant survival benefit. Conclusions: To our knowledge, this is the first investigation combining imetelstat with venetoclax in AML, and the results demonstrated a synergistic effect on induction of apoptosis in cell lines and patient samples in vitro, which translated into prolonged survival in xenograft models, thus providing a strong rationale for clinical exploration of this combination. Citation Format: Joshua J. Rusbuldt, Leopoldo Luistro, Diana Chin, Melissa Smith, Amy Wong, Margarita Romero, Aleksandra Rizo, Jacqueline Bussolari, Fei Huang, Amy (Kate) Sasser. Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1101. doi:10.1158/1538-7445.AM2017-1101