The usage of aripiprazole as a single agent in the treatment of hyperprolactinemia associated with diogenes syndrome- a novel approach

2021 ◽  
Author(s):  
Harleen Kaur Birgi ◽  
Waleed Fawzi ◽  
Ashutosh Kapoor
Keyword(s):  
Single Agent ◽  
Novel Approach ◽  
Diogenes Syndrome

scholarly journals MBRS-17. EXAMINING THE ROLE OF LHX9 IN GROUP 3 MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii401-iii401
Author(s):  
Sarah Injac ◽  
L Frank Huang ◽  
Stephen Mack ◽  
Frank Braun ◽  
Yuchen Du ◽  
...  
Keyword(s):  
Drug Repositioning ◽  
Single Agent ◽  
Xenograft Model ◽  
Cell Killing ◽  
Rna Seq ◽  
Loss Of Function ◽  
Novel Treatments ◽  
Novel Approach ◽  
Group 3

Abstract Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite major advances in our understanding of the biology of MB, novel treatments remain urgently needed. Using a chemical-genomics driven drug repositioning strategy, we identified the cardiac glycoside family of compounds as potential treatments for Group 3 MB. We subsequently demonstrated that single-agent treatment with digoxin prolongs survival in a patient-derived xenograft model (PDOX) of Group 3 MB to a degree comparable to radiation therapy, a mainstay in the treatment of MB. Finally, we examined the mechanism of digoxin-mediated cell killing using RNA-seq. This work identified LHX9, a member of the LIM homeobox family of transcription factors, as the gene most significantly down-regulated following treatment (Huang and Injac et al, Sci Trans Medicine, 2018). Homologs of LHX9 play key roles in cerebellar development via spatially and temporally restricted expression and LHX9 has been proposed as a core transcription factor (TF) in the regulatory circuitry of Group 3 tumors. Loss of function of other core TFs has been shown to impact MB growth. The role of LHX9 in MB, however, has not been previously experimentally evaluated. We now report that knockdown of LHX9 in MB-derived cell lines results in marked growth inhibition raising the possibility that loss of LHX9 plays a major role in digoxin-mediated cell killing and that LHX9 represents a key dependency required for the growth of Group 3 MB. Clinical targeting of core TFs would represent a novel approach to targeting this devastating disease.

Targeting Aminopeptidases by Tosedostat (TST) (CHR2797), Alone and with LBH589, Induces Significant Cytotoxicity Against Human Multiple Myeloma (MM) Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1847-1847
Author(s):  
Chirag Acharya ◽  
Mike Y Zhong ◽  
Daniel Tannenbaum ◽  
Michelle Chen ◽  
Matt Ma ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Single Agent ◽  
Annexin V ◽  
Novel Approach ◽  
Human Multiple Myeloma ◽  
Induced Apoptosis ◽  
G1 Cells

Abstract Abstract 1847 Aminopeptidases (AP) are necessary for the growth and development of malignant cells and have a selectively important role in the maintenance of intracellular amino acid (AA) levels in neoplastic cells. CHR2797 is a novel, low nanomolar inhibitor of the M1 family of AP, a group of metalloenzymes containing a central Zn2+ ion. CHR2797 has antiproliferative and apoptotic effects against MM in vitro by inducing the AA deprivation response (AADR). TST, an oral, chronically administered agent with a good safety profile has demonstrated activity in patients with relapsed/refractory AML and is currently under study as part of combination therapy for untreated elderly patients with AML. At the epigenetic regulatory level, Zn-dependent histone deacetylase (HDAC) cause the deacetylation of histone and non-histone cellular proteins which are critical for gene expression, inducing apoptosis and cell cycle arrest in cancer cells. LBH589 (Panobinostat) is an established pan-HDAC inhibitor with potent in vitro anti-cancer activity in many hematological malignancies. The clinical efficacy of Panobinostat is currently being studied in several Phase II/III clinical trials with particular promise seen in the treatment of MM. Here we examined the potential therapeutic effect of CHR2797, alone and with LBH589, against MM cells. Using MTS and CTG assays, CHR2797, at clinically achievable concentrations, decreased survival and proliferation in MM1S and IL-6-dependent ANBL6 cells, in the presence or absence of bone marrow stromal cells following 72 hours incubation. CHR2797 induces apoptosis in MM cells via activation of Caspase 3/7 and 9 but not Caspase 8. Significantly, CHR2797 (10 μM) induced apoptosis in patient MM cells, as seen by % of annexin V and PI from 22 + 1.5% to 39 + 2.3% after 48h incubation. Combined treatment with CHR2797 and LBH589 in MM cells (MM1S, ANBL6, and INA6) further reduced cell viability following 72 hour incubation when compared with CHR2797 treatment alone, as determined by CTG viability luminescent assay. Both drugs together also augmented growth inhibitory effects when compared with single agent alone, after 72 hours incubation followed by MTS assay. Importantly, the combination of both drugs increased caspase 3/7- & 9-mediated apoptosis than CHR2797 alone in these MM cells following 24h-treatment. Cell cycle analysis (CHR2797 at 1μM; LBH589 at 1 nM) showed an increased growth arrest in G0/G1 cells in MM1R cells treated with both drugs versus CHR2797 alone after 24 hours: 68.5±3.3% versus 36±2.5%. Furthermore, CHR2797 inhibited anti-apoptotic protein Mcl-1 in MM1R and U266 MM cells by immunoblottings. Combined treatment with CHR2797 and LBH589 further blocked Mcl-1 when compared with either treatment alone after 24 hours incubation. Together, these results show that the combination of CHR2797 and LBH589 enhanced anti-myeloma effects when compared with either drug alone. This combination, which also has the potential of being without overlapping clinical toxicities, provides a promising novel approach to anti-myeloma therapy. Disclosures: Singer: Cell Therapeutics, Inc: Employment, Equity Ownership. Richardson:Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Novel Heterogeneous Swarm Reinforcement Learning Method for Sequential Decision Making Problems

2019 ◽  
Vol 1 (2) ◽  
pp. 590-610
Author(s):  
Zohreh Akbari ◽  
Rainer Unland
Keyword(s):  
Decision Making ◽  
Reinforcement Learning ◽  
Single Agent ◽  
Sequential Decision Making ◽  
Multi Agent Systems ◽  
Sequential Decision ◽  
Agent Systems ◽  
Novel Approach ◽  
Markov Decision ◽  
Multi Agent

Sequential Decision Making Problems (SDMPs) that can be modeled as Markov Decision Processes can be solved using methods that combine Dynamic Programming (DP) and Reinforcement Learning (RL). Depending on the problem scenarios and the available Decision Makers (DMs), such RL algorithms may be designed for single-agent systems or multi-agent systems that either consist of agents with individual goals and decision making capabilities, which are influenced by other agent’s decisions, or behave as a swarm of agents that collaboratively learn a single objective. Many studies have been conducted in this area; however, when concentrating on available swarm RL algorithms, one obtains a clear view of the areas that still require attention. Most of the studies in this area focus on homogeneous swarms and so far, systems introduced as Heterogeneous Swarms (HetSs) merely include very few, i.e., two or three sub-swarms of homogeneous agents, which either, according to their capabilities, deal with a specific sub-problem of the general problem or exhibit different behaviors in order to reduce the risk of bias. This study introduces a novel approach that allows agents, which are originally designed to solve different problems and hence have higher degrees of heterogeneity, to behave as a swarm when addressing identical sub-problems. In fact, the affinity between two agents, which measures the compatibility of agents to work together towards solving a specific sub-problem, is used in designing a Heterogeneous Swarm RL (HetSRL) algorithm that allows HetSs to solve the intended SDMPs.

Enrichment of Allogeneic Tumor Antigen-Specific T Cells From Bone Marrow (BM) of Patients Treated with High-Dose Post-Transplant Cyclophoshamide (Cy) – A Novel Approach to Adoptive Immunotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 647-647
Author(s):  
Kimberly Noonan ◽  
Leo Luznik ◽  
Ivan M. Borrello
Keyword(s):  
T Cells ◽  
Adoptive Immunotherapy ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
High Dose ◽  
Post Transplant ◽  
Novel Approach ◽  
Tumor Specificity

Abstract Abstract 647 Background: Donor lymphocyte infusions (DLI) has limited efficacy and is associated with substantial graft vs host disease (GVHD) in treating relapse after allogeneic BMT (alloBMT) in large part due to the absence of significant tumor specificity. Thus, novel strategies are required that increase the tumor specificity with reduced alloreactivity. High-dose Cy post-BMT effectively reduces GVHD through early elimination of allo-reactive T cells and enables immune reconstitution free of ongoing pharmacologic immunosuppression. Since the BM is both the site of disease in most hematologic malignancies and a reservoir of tumor specific T cells, we hypothesized that marrow infiltrating lymphocytes (MILs) collected after alloBMT in patients treated with high-dose Cy could be a source of tumor-specific T cells for adoptive immunotherapy. Methods: BM was obtained from patients 2 –12 months after HLA-matched alloBMT on the clinical trial using high-dose post-transplant Cy as a single agent GVHD prophylaxis. The MILs were activated and expanded with CD3/CD28 antibody-coated beads. Results: Allo-MILs can be reproducibly expanded (574-fold avg expansion; 14–2000) at all time points tested. The activated allo-MILs are not anergic, exhibit anti-HLA-reactivity against third party allo-antigens but do not respond to recipient allo-antigens. Tumor-specific MILs were significantly expanded as determined by reactivity to HL60/K562 myeloid cell lysates (P<0.0001; pre- vs. post-activation). In contrast, no change was observed in cultures pulsed with irrelevant antigens, thus suggesting the specificity of the response. The ability to expand allogeneic antigen-specific MILs was also confirmed with a 15.5 fold expansion of PR-1 specific (HLA) A*0201-restricted CD8+ T-cells using tetramers. Conclusions: We can augment the tumor-specificity of MILs obtained post-transplant with minimal allo-reactivity in patients treated with post-BMT high-dose Cy. This could represent a novel approach to highly tumor-specific DLI. A phase I/II trial is planned to assess the safety and feasibility of administering ex vivo expanded post-transplant, allogeneic MILs to patients with relapsed hematologic malignancies after alloHSCT. Disclosures: No relevant conflicts of interest to declare.

Training Coordination Proxy Agents Using Reinforcement Learning

2009 ◽  
pp. 158-172 ◽  
Author(s):  
Myriam Abramson
Keyword(s):  
Reinforcement Learning ◽  
Single Agent ◽  
Machine Learning Techniques ◽  
Multi Agent Systems ◽  
Adjustable Autonomy ◽  
Novel Approach ◽  
Learning Techniques ◽  
Multi Agent ◽  
Mixed Initiative ◽  
Learning Team

In heterogeneous multi-agent systems, where human and non-human agents coexist, intelligent proxy agents can help smooth out fundamental differences. In this context, delegating the coordination role to proxy agents can improve the overall outcome of a task at the expense of human cognitive overload due to switching subtasks. Stability and commitment are characteristics of human teamwork, but must not prevent the detection of better opportunities. In addition, coordination proxy agents must be trained from examples as a single agent, but must interact with multiple agents. We apply machine learning techniques to the task of learning team preferences from mixed-initiative interactions and compare the outcome results of different simulated user patterns. This chapter introduces a novel approach for the adjustable autonomy of coordination proxies based on the reinforcement learning of abstract actions. In conclusion, some consequences of the symbiotic relationship that such an approach suggests are discussed.

Distributed Identity Management for Semantic Entities Based on Graph Signatures and owl:sameAs

2021 ◽  
Vol 15 (01) ◽  
pp. 57-92
Author(s):  
Falko Schönteich ◽  
Ansgar Scherp ◽  
Andreas Kasten
Keyword(s):  
Concurrency Control ◽  
Process Model ◽  
Identity Management ◽  
Single Agent ◽  
Formal Reasoning ◽  
Professional Networks ◽  
Modular Software ◽  
Web Architecture ◽  
Novel Approach ◽  
First Time

Distributed Identity Management (DIM) refers to the ability of defining distributed identities of agents and roles, i.e. a single agent is represented using multiple unique identifiers managed in different namespaces and may have various roles across those namespaces. We propose semDIM, a novel approach for Semantic DIM based on a Semantic Web architecture. For the first time, semDIM provides a framework for a distributed definition and management of entities such as persons being part of an organization, groups, and roles across namespaces. It is suitable for informal, i.e. social networks, as well as for professional networks such as cross-organizational collaborations. In addition, the framework ensures authenticity, authorization and integrity for such distributed identities by featuring certificate-based graph signatures. Beyond the capabilities of existing Identity Management solutions, we allow distributed identifiers and management of groups (consisting of agents and sub-groups) and roles as “first-class entities”. semDIM uses owl:sameAs relations to represent and verify distributed identities via formal reasoning. This concept enables novel functionalities for DIM, as these entities can be identified, related to one another, as well as be managed across namespaces. Our semDIM approach consists of a modular software architecture, a process model using a novel approach for pattern-based concurrency control, as well as a set of state-of-the-art formal OWL ontology patterns. The use of formal patterns ensures semantic interoperability, and extensibility for future requirements. Thereby, our approach can be combined with other applications based on the same or related patterns. We evaluate semDIM in the context of a real-world scenario of securely exchanging DIM information across organizations.

Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity

2019 ◽  
Vol 476 (24) ◽  
pp. 3705-3719 ◽  
Author(s):  
Avani Vyas ◽  
Umamaheswar Duvvuri ◽  
Kirill Kiselyov
Keyword(s):  
Oxidative Stress ◽  
Head And Neck ◽  
Transcriptional Activation ◽  
Platinum Resistance ◽  
Mrna Levels ◽  
Strong Positive Correlation ◽  
Platinum Compounds ◽  
Copper Chelation ◽  
Novel Approach ◽  
Cancer Models

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.

Collecting Words: A Clinical Example of a Morphology-Focused Orthographic Intervention

2020 ◽  
Vol 51 (3) ◽  
pp. 544-560 ◽  
Author(s):  
Kimberly A. Murphy ◽  
Emily A. Diehm
Keyword(s):  
Written Language ◽  
Morphological Knowledge ◽  
English Orthography ◽  
Word Level ◽  
Novel Approach ◽  
Language Pathology ◽  
The One ◽  
Critical Intervention ◽  
Reading And Spelling ◽  
Reading And Spelling Difficulties

Purpose Morphological interventions promote gains in morphological knowledge and in other oral and written language skills (e.g., phonological awareness, vocabulary, reading, and spelling), yet we have a limited understanding of critical intervention features. In this clinical focus article, we describe a relatively novel approach to teaching morphology that considers its role as the key organizing principle of English orthography. We also present a clinical example of such an intervention delivered during a summer camp at a university speech and hearing clinic. Method Graduate speech-language pathology students provided a 6-week morphology-focused orthographic intervention to children in first through fourth grade ( n = 10) who demonstrated word-level reading and spelling difficulties. The intervention focused children's attention on morphological families, teaching how morphology is interrelated with phonology and etymology in English orthography. Results Comparing pre- and posttest scores, children demonstrated improvement in reading and/or spelling abilities, with the largest gains observed in spelling affixes within polymorphemic words. Children and their caregivers reacted positively to the intervention. Therefore, data from the camp offer preliminary support for teaching morphology within the context of written words, and the intervention appears to be a feasible approach for simultaneously increasing morphological knowledge, reading, and spelling. Conclusion Children with word-level reading and spelling difficulties may benefit from a morphology-focused orthographic intervention, such as the one described here. Research on the approach is warranted, and clinicians are encouraged to explore its possible effectiveness in their practice. Supplemental Material https://doi.org/10.23641/asha.12290687

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