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1.
Oral Oncol ; 149: 106688, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38219706

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignancy worldwide, with a significant proportion of patients developing recurrent and/or metastatic (R/M) disease. Despite recent advances in therapy, the prognosis for patients with advanced HNSCC remains poor. Here, we present the case of a patient with recurrent metastatic HNSCC harboring an HRAS G12S mutation who achieved a durable response to treatment with tipifarnib, a selective inhibitor of farnesyltransferase. The patient was a 48-year-old woman who had previously received multiple lines of therapy with no significant clinical response. However, treatment with tipifarnib resulted in a durable partial response that lasted 8 months. Serial genomic and transcriptomic analyses demonstrated upregulation of YAP1 and AXL in metastatic lesions compared with the primary tumor, the evolution of the tumor microenvironment from an immune-enriched to a fibrotic subtype with increased angiogenesis, and activation of the PI3K/AKT/mTOR pathway in tipifarnib treatment. Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven HNSCC.


Subject(s)
Head and Neck Neoplasms , Proto-Oncogene Proteins c-akt , Quinolones , Female , Humans , Middle Aged , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Neoplasm Recurrence, Local/drug therapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Cell Line, Tumor , Tumor Microenvironment , Proto-Oncogene Proteins p21(ras)/genetics
2.
Cancer Res ; 83(19): 3252-3263, 2023 10 02.
Article in English | MEDLINE | ID: mdl-37339176

ABSTRACT

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. SIGNIFICANCE: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Humans , Squamous Cell Carcinoma of Head and Neck/drug therapy , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Neoplasm Recurrence, Local/drug therapy , TOR Serine-Threonine Kinases/metabolism , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Biomarkers , Proto-Oncogene Proteins p21(ras)/genetics
4.
Cancer Res ; 83(7): 1031-1047, 2023 04 04.
Article in English | MEDLINE | ID: mdl-36753744

ABSTRACT

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression. SIGNIFICANCE: Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.


Subject(s)
Head and Neck Neoplasms , Proteomics , Humans , Transcription Factors/genetics , Transcription Factors/metabolism , Cell Line, Tumor , Signal Transduction , Head and Neck Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism
5.
Nat Commun ; 13(1): 6663, 2022 11 04.
Article in English | MEDLINE | ID: mdl-36333314

ABSTRACT

Tight control of cell fate choices is crucial for normal development. Here we show that lamin A/C plays a key role in chromatin organization in embryonic stem cells (ESCs), which safeguards naïve pluripotency and ensures proper cell fate choices during cardiogenesis. We report changes in chromatin compaction and localization of cardiac genes in Lmna-/- ESCs resulting in precocious activation of a transcriptional program promoting cardiomyocyte versus endothelial cell fate. This is accompanied by premature cardiomyocyte differentiation, cell cycle withdrawal and abnormal contractility. Gata4 is activated by lamin A/C loss and Gata4 silencing or haploinsufficiency rescues the aberrant cardiovascular cell fate choices induced by lamin A/C deficiency. We uncover divergent functions of lamin A/C in naïve pluripotent stem cells and cardiomyocytes, which have distinct contributions to the transcriptional alterations of patients with LMNA-associated cardiomyopathy. We conclude that disruption of lamin A/C-dependent chromatin architecture in ESCs is a primary event in LMNA loss-of-function cardiomyopathy.


Subject(s)
Chromatin , Lamin Type A , Humans , Lamin Type A/metabolism , Chromatin/metabolism , Cell Differentiation/genetics , Embryonic Stem Cells/metabolism , Myocytes, Cardiac/metabolism
7.
Oncogene ; 41(21): 2973-2983, 2022 05.
Article in English | MEDLINE | ID: mdl-35459782

ABSTRACT

Activating RAS mutations are found in a subset of fusion-negative rhabdomyosarcoma (RMS), and therapeutic strategies to directly target RAS in these tumors have been investigated, without clinical success to date. A potential strategy to inhibit oncogenic RAS activity is the disruption of RAS prenylation, an obligate step for RAS membrane localization and effector pathway signaling, through inhibition of farnesyltransferase (FTase). Of the major RAS family members, HRAS is uniquely dependent on FTase for prenylation, whereas NRAS and KRAS can utilize geranylgeranyl transferase as a bypass prenylation mechanism. Tumors driven by oncogenic HRAS may therefore be uniquely sensitive to FTase inhibition. To investigate the mutation-specific effects of FTase inhibition in RMS we utilized tipifarnib, a potent and selective FTase inhibitor, in in vitro and in vivo models of RMS genomically characterized for RAS mutation status. Tipifarnib reduced HRAS processing, and plasma membrane localization leading to decreased GTP-bound HRAS and decreased signaling through RAS effector pathways. In HRAS-mutant cell lines, tipifarnib reduced two-dimensional and three-dimensional cell growth, and in vivo treatment with tipifarnib resulted in tumor growth inhibition exclusively in HRAS-mutant RMS xenografts. Our data suggest that small molecule inhibition of FTase is active in HRAS-driven RMS and may represent an effective therapeutic strategy for a genomically-defined subset of patients with RMS.


Subject(s)
Rhabdomyosarcoma, Embryonal , Rhabdomyosarcoma , Farnesyltranstransferase/genetics , Genes, ras , Humans , Prenylation , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/genetics
8.
Cancers (Basel) ; 13(21)2021 Oct 22.
Article in English | MEDLINE | ID: mdl-34771475

ABSTRACT

Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)-specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.

9.
Blood Adv ; 5(24): 5588-5598, 2021 12 28.
Article in English | MEDLINE | ID: mdl-34592752

ABSTRACT

Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P < .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL.


Subject(s)
Immunoblastic Lymphadenopathy , Lymphoma, T-Cell, Peripheral , Humans , Lymphoma, T-Cell, Peripheral/diagnosis , Lymphoma, T-Cell, Peripheral/genetics , Mutation , Phenotype , Prognosis
10.
J Hepatol ; 74(2): 380-393, 2021 02.
Article in English | MEDLINE | ID: mdl-32916216

ABSTRACT

BACKGROUND & AIMS: Angiocrine signaling by liver sinusoidal endothelial cells (LSECs) regulates hepatic functions such as growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master regulator of LSEC specification during development. Herein, we studied the role of endothelial GATA4 in the adult liver and in hepatic pathogenesis. METHODS: We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC-KO) mice with LSEC-specific depletion of Gata4. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in situ hybridization, and LSECs were isolated for gene expression profiling, ChIP- and ATAC-sequencing. Partial hepatectomy was performed to assess regeneration. We used choline-deficient, l-amino acid-defined (CDAA) diet and chronic carbon tetrachloride exposure to model liver fibrosis. Human single cell RNA-seq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers. RESULTS: Genetic Gata4 deficiency in LSECs of adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch involving de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated MYC mediated angiocrine Pdgfb expression. As observed in Gata4LSEC-KO livers, CDAA diet-induced perisinusoidal liver fibrosis was associated with GATA4 repression, MYC activation and a profibrotic angiocrine switch in LSECs. Comparison of CDAA-fed Gata4LSEC-KO and control mice demonstrated that endothelial GATA4 indeed protects against dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, GATA4-positive LSECs and endothelial GATA4 target genes were reduced, while non-LSEC endothelial cells and MYC target genes including PDGFB were enriched. CONCLUSIONS: Endothelial GATA4 protects against perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling at the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRß axis offer a promising strategy for prevention and treatment of liver fibrosis. LAY SUMMARY: The liver vasculature is supposed to play a major role in the development of liver fibrosis and cirrhosis, which can lead to liver failure and liver cancer. Herein, we discovered that structural and transcriptional changes induced by genetic deletion of the transcription factor GATA4 in the hepatic endothelium were sufficient to cause liver fibrosis. Activation of the transcription factor MYC and de novo expression of the "angiocrine" growth factor PDGFB were identified as downstream drivers of fibrosis and as potential therapeutic targets for this potentially fatal disease.


Subject(s)
Endothelial Cells/metabolism , GATA4 Transcription Factor/metabolism , Liver Cirrhosis , Liver , Lymphokines , Platelet-Derived Growth Factor , Animals , Chromatin/metabolism , Drug Discovery , Gene Expression Profiling , Hepatic Stellate Cells/metabolism , Humans , Liver/blood supply , Liver/metabolism , Liver/pathology , Liver Cirrhosis/metabolism , Liver Cirrhosis/prevention & control , Liver Regeneration/physiology , Lymphokines/genetics , Lymphokines/metabolism , Mice , Platelet-Derived Growth Factor/genetics , Platelet-Derived Growth Factor/metabolism , Signal Transduction/drug effects , Zinc Fingers
11.
Cell ; 172(3): 578-589.e17, 2018 01 25.
Article in English | MEDLINE | ID: mdl-29373830

ABSTRACT

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.


Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms, Experimental/drug therapy , Piperazines/pharmacology , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Cells, Cultured , Female , HCT116 Cells , HEK293 Cells , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Docking Simulation , Mutation , Piperazines/chemistry , Piperazines/therapeutic use , Protein Binding , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Quinazolines/chemistry , Quinazolines/therapeutic use
12.
Cancer Discov ; 6(3): 316-29, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26739882

ABSTRACT

UNLABELLED: KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRAS(G12C) that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS(G12C) is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS(G12C) mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. SIGNIFICANCE: A cell-active, mutant-specific, covalent inhibitor of KRAS(G12C) is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRAS(G12C) oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , ras Proteins/antagonists & inhibitors , ras Proteins/chemistry , Biomarkers , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Ligands , Models, Biological , Models, Molecular , Molecular Conformation , Recombinant Proteins , Signal Transduction/drug effects , Structure-Activity Relationship , ras Proteins/genetics , ras Proteins/metabolism
13.
J Biol Chem ; 288(8): 5718-31, 2013 Feb 22.
Article in English | MEDLINE | ID: mdl-23275335

ABSTRACT

Class IA phosphoinositide 3-kinase (PI3K) is essential for clonal expansion, differentiation, and effector function of B and T lymphocytes. The p110δ catalytic isoform of PI3K is highly expressed in lymphocytes and plays a prominent role in B and T cell responses. Another class IA PI3K catalytic isoform, p110α, is a promising drug target in cancer but little is known about its function in lymphocytes. Here we used highly selective inhibitors to probe the function of p110α in lymphocyte responses in vitro and in vivo. p110α inhibition partially reduced B cell receptor (BCR)-dependent AKT activation and proliferation, and diminished survival supported by the cytokines BAFF and IL-4. Selective p110δ inhibition suppressed B cell responses much more strongly, yet maximal suppression was achieved by targeting multiple PI3K isoforms. In mouse and human T cells, inhibition of single class IA isoforms had little effect on proliferation, whereas pan-class I inhibition did suppress T cell expansion. In mice, selective p110α inhibition using the investigational agent MLN1117 (previously known as INK1117) did not disrupt the marginal zone B cell compartment and did not block T cell-dependent germinal center formation. In contrast, the selective p110δ inhibitor IC87114 strongly suppressed germinal center formation and reduced marginal zone B cell numbers, similar to a pan-class I inhibitor. These findings show that although acute p110α inhibition partially diminishes AKT activation, selective p110α inhibitors are likely to be less immunosuppressive in vivo compared with p110δ or pan-class I inhibitors.


Subject(s)
Class Ia Phosphatidylinositol 3-Kinase/metabolism , Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Enzymologic , Lymphocytes/cytology , Phosphoinositide-3 Kinase Inhibitors , Animals , Calcium/metabolism , Cell Line, Tumor , Cell Proliferation , Drug Design , Enzyme-Linked Immunosorbent Assay/methods , Humans , Immunosuppressive Agents/pharmacology , Lymphocytes/enzymology , Mice , Mice, Inbred BALB C , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Isoforms , Signal Transduction , Spleen/cytology , T-Lymphocytes/cytology , T-Lymphocytes/enzymology
14.
Bioorg Med Chem Lett ; 20(16): 4819-24, 2010 Aug 15.
Article in English | MEDLINE | ID: mdl-20663667

ABSTRACT

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.


Subject(s)
Amides/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Protein Kinase Inhibitors/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Administration, Oral , Allosteric Site , Amides/chemical synthesis , Amides/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Binding Sites , Cell Line , Computer Simulation , Humans , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , p38 Mitogen-Activated Protein Kinases/metabolism
15.
Nurs Leadersh (Tor Ont) ; 23 Spec No 2010: 101-12, 2010 May.
Article in English | MEDLINE | ID: mdl-20463449

ABSTRACT

Despite the growing prevalence and healthcare needs of people living with mental illness, the stigma associated with mental health nursing continues to present challenges to recruiting new nurses to this sector. As a key recruitment strategy, five mental health hospitals and three educational institutions collaborated to develop and pilot an innovative nursing residency program. The purpose of the Mental Health Nursing Residency Program was to dispel myths associated with practising in the sector by promoting mental health as a vibrant specialty and offering a unique opportunity to gain specialized competencies. The program curriculum combines protected clinical time, collaborative learning and mentored clinical practice. Evaluation results show significant benefits to clinical practice and an improved ability to recruit and retain nurses. Nursing leadership was crucial at multiple levels for success. In this paper, we describe our journey in designing and implementing a nursing residency program for other nurse leaders interested in providing a similar program to build on our experience.


Subject(s)
Community Mental Health Services/supply & distribution , Mental Health , Personnel Selection , Prejudice , Psychiatric Nursing/education , Adult , Clinical Competence , Cooperative Behavior , Curriculum , Education, Nursing , Educational Status , Female , Focus Groups , Humans , Leadership , Male , Mental Disorders/nursing , Mentors , Middle Aged , Nurse Administrators , Personnel Turnover , Pilot Projects , Prevalence , Qualitative Research , Specialties, Nursing/education , Surveys and Questionnaires , Technology Transfer , Young Adult
16.
Eur J Pharmacol ; 632(1-3): 93-102, 2010 Apr 25.
Article in English | MEDLINE | ID: mdl-20132813

ABSTRACT

The tumor necrosis factor-alpha (TNF-alpha) cytokine, secreted by activated monocytes/macrophages and T lymphocytes, is implicated in several diseases, including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, and osteoporosis. Monocyte/macrophage production of TNF-alpha is largely driven by p38alpha mitogen-activated protein kinase (MAP kinase), an intracellular soluble serine-threonine kinase. p38alpha MAP kinase is activated by growth factors, cellular stresses, and cytokines such as TNF-alpha and interleukin-l (IL-I). The primary contribution of p38alpha activation to excess TNF-alpha in settings of both chronic and acute inflammation has instigated efforts to find inhibitors of this enzyme as possible therapies for associated disease states. Analogue design, synthesis, and structure-activity studies led to the identification of 5-tert-butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetylamino}-benzamide (KR-003048) as a potent inhibitor of the p38 MAP kinase signaling pathway in vitro and in vivo. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide (LPS)-induced p38 activation and subsequent TNF-alpha release is described. KR-00348 was demonstrated to be a potent inhibitor of inflammatory cytokine production ex vivo in rat and human whole blood, and showed good oral bioavailability. Additionally, efficacy in mouse and rat models of acute and chronic inflammation was obtained. KR-003048 possessed therapeutic activity in acute models, demonstrating substantial inhibition of carrageenan-induced paw edema and in vivo LPS-induced TNF release at 30mg/kg p.o. Collagen-induced arthritis in mice was significantly inhibited by 10 and 30mg/kg doses of KR-003048. Evidence for disease-modifying activity in this model was indicated by histological evaluation of joints.


Subject(s)
Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Administration, Oral , Animals , Arthritis, Rheumatoid/drug therapy , Benzamides/antagonists & inhibitors , Benzamides/chemistry , Cells, Cultured , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Inflammation/drug therapy , Lipopolysaccharides/antagonists & inhibitors , Macrophages/metabolism , Male , Models, Chemical , Models, Immunological , Models, Molecular , Monocytes/metabolism , Morpholines/antagonists & inhibitors , Morpholines/chemistry , Osteoporosis/drug therapy , Osteoporosis/immunology , Osteoporosis/metabolism , Phosphorylation/drug effects , Rats , Rats, Inbred Lew , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism
17.
Gerontol Geriatr Educ ; 30(1): 1-20, 2009.
Article in English | MEDLINE | ID: mdl-19214843

ABSTRACT

This article explores facilitators and barriers to the impact and sustainability of a learning initiative to increase capacity of long-term care (LTC) homes to manage the mental health needs of older persons, through development of in-house Psychogeriatric Resource Persons (PRPs). Twenty interviews were conducted with LTC staff. Management support, particularly designation of time for PRP activities, development of PRP teams, and supportive learning strategies were significant factors affecting sustained knowledge transfer. Continuing education that is provided and evaluated on an ongoing basis, secures management commitment, is integrated within a broader system strategy, and provides on-the-job support has the greatest potential to affect care.


Subject(s)
Diffusion of Innovation , Homes for the Aged/organization & administration , Learning , Long-Term Care/organization & administration , Mental Health , Nursing Homes/organization & administration , Aged , Consumer Behavior , Education, Continuing/organization & administration , Health Services Research , Humans , Interviews as Topic , Quality of Health Care/organization & administration , Quality of Life , Staff Development/organization & administration
20.
Bioorg Med Chem Lett ; 18(6): 1772-7, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18325768

ABSTRACT

We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design which due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME and in vivo PK studies show these compounds to have drug-like characteristics which could result in the development of an oral treatment for inflammatory conditions.


Subject(s)
Amides/chemical synthesis , Drug Design , Protein Kinase Inhibitors/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Allosteric Site , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Animals , Binding Sites , Cells, Cultured , Crystallography, X-Ray , Humans , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Structure , Monocytes/cytology , Monocytes/drug effects , Phosphorylation/drug effects , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
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