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1.
Sci Transl Med ; 13(602)2021 07 14.
Article in English | MEDLINE | ID: mdl-34261798

ABSTRACT

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.


Subject(s)
Lung Neoplasms , Urinary Bladder Neoplasms , Animals , Cell Line, Tumor , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , Humans , Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mice , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics
2.
J Cell Mol Med ; 24(19): 11573-11582, 2020 10.
Article in English | MEDLINE | ID: mdl-32858764

ABSTRACT

The IKK-related kinases, IKKε and TBK1, have essential roles in innate immunity in part through modifying MYD88 signalling from the Toll-like receptors to regulate NF-κB signalling. We investigated the expression and function of IKKε and TBK1, in diffuse large B-cell lymphoma (DLBCL). DLBCL cell lines and patient-derived xenografts were used to determine their sensitivity to IKKε and TBK1 inhibitors. To understand the function of IKKε and TBK1 secreted factors were determined following administration of inhibitors. Gene expression microarrays were used to determine the transcriptional effects of inhibitors. Higher TBK1 mRNA levels associated with poorer clinical outcome but IKKε and TBK1 were expressed in both germinal centre and non-germinal centre types of DLBCL. Survival of cell lines Ly10, Ly03 and Pfeiffer, and of some primary human lymphoma cells, was suppressed by a small molecule IKKε/TBK1 inhibitor, DMX3433. DMX3433 reduced IL-10 production from Ly10 and repressed NF-κB mediated transcription. Inhibition of IKKε and TBK1 warrants further investigation as a potential therapeutic route to suppress NF-κB signalling in lymphoma.


Subject(s)
I-kappa B Kinase/metabolism , Interleukin-10/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , NF-kappa B/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Animals , Cell Line, Tumor , Chemokines/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , I-kappa B Kinase/antagonists & inhibitors , Intercellular Signaling Peptides and Proteins/metabolism , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Protein Serine-Threonine Kinases/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Messenger/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Small Molecule Libraries/pharmacology , Transcription Factor RelA/metabolism
3.
Drug Discov Today ; 2020 Aug 21.
Article in English | MEDLINE | ID: mdl-32835806

ABSTRACT

G-protein-coupled receptor (GPCR) drug research is presently hindered by the technical challenges associated with generating purified receptors. Consequently, the application of critical modern discovery technologies has been limited, and the vast untapped opportunity for new GPCR-directed medicines is not being realised. A simple but transformative solution is to purify receptors without removing them from their native phospholipid environment by using polymer lipid particle (PoLiPa) technology, with reagents such as styrene-maleic acid co-polymer (SMA). Compared with contemporary detergent-based and stabilising mutagenesis methods, the PoLiPa approach is simple and generic and, therefore, offers huge advantages, with the potential to revolutionise GPCR research by facilitating the availability of the purified receptors that are required for structural biology, biophysical, and panning technologies.

4.
Sci Rep ; 10(1): 12060, 2020 07 21.
Article in English | MEDLINE | ID: mdl-32694738

ABSTRACT

Given the poor track record to date of animal models for creating cardioprotective drugs, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been proposed as a therapeutically relevant human platform to guide target validation and cardiac drug development. Mitogen-Activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is an "upstream" member of the MAPK superfamily that is implicated in human cardiac muscle cell death from oxidative stress, based on gene silencing and pharmacological inhibition in hPSC-CMs. A further role for MAP4K4 was proposed in heart muscle cell death triggered by cardiotoxic anti-cancer drugs, given its reported activation in failing human hearts with doxorubicin (DOX) cardiomyopathy, and its activation acutely by DOX in cultured cardiomyocytes. Here, we report successful protection from DOX in two independent hPSC-CM lines, using two potent, highly selective MAP4K4 inhibitors. The MAP4K4 inhibitors enhanced viability and reduced apoptosis at otherwise lethal concentrations of DOX, and preserved cardiomyocyte function, as measured by spontaneous calcium transients, at sub-maximal ones. Notably, in contrast, no intereference was seen in tumor cell killing, caspase activation, or mitochondrial membrane dissipation by DOX, in human cancer cell lines. Thus, MAP4K4 is a plausible, tractable, selective therapeutic target in DOX-induced human heart muscle cell death.


Subject(s)
Cardiotonic Agents/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Anthracyclines/adverse effects , Antineoplastic Agents/adverse effects , Apoptosis/drug effects , Calcium , Cardiotoxicity/etiology , Cell Differentiation/drug effects , Cell Line , Doxorubicin/pharmacology , Humans , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/metabolism
5.
ChemMedChem ; 10(1): 69-82, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25395356

ABSTRACT

Sirtuins, NAD(+) -dependent histone deacetylases (HDACs), have recently emerged as potential therapeutic targets for the treatment of a variety of diseases. The discovery of potent and isoform-selective inhibitors of this enzyme family should provide chemical tools to help determine the roles of these targets and validate their therapeutic value. Herein, we report the discovery of a novel class of highly selective SIRT2 inhibitors, identified by pharmacophore screening. We report the identification and validation of 3-((2-methoxynaphthalen-1-yl)methyl)-7-((pyridin-3-ylmethyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (ICL-SIRT078), a substrate-competitive SIRT2 inhibitor with a Ki value of 0.62 ± 0.15 µM and more than 50-fold selectivity against SIRT1, 3 and 5. Treatment of MCF-7 breast cancer cells with ICL-SIRT078 results in hyperacetylation of α-tubulin, an established SIRT2 biomarker, at doses comparable with the biochemical IC50 data, while suppressing MCF-7 proliferation at higher concentrations. In concordance with the recent reports that suggest SIRT2 inhibition is a potential strategy for the treatment of Parkinson's disease, we find that compound ICL-SIRT078 has a significant neuroprotective effect in a lactacystin-induced model of Parkinsonian neuronal cell death in the N27 cell line. These results encourage further investigation into the effects of ICL-SIRT078, or an optimised derivative thereof, as a candidate neuroprotective agent in in vivo models of Parkinson's disease.


Subject(s)
Histone Deacetylase Inhibitors/chemistry , Neuroprotective Agents/chemistry , Pyrimidinones/chemistry , Sirtuin 2/antagonists & inhibitors , Thiophenes/chemistry , Animals , Binding Sites , Cell Line , Cell Proliferation/drug effects , Disease Models, Animal , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Drug Evaluation, Preclinical , Forkhead Box Protein O3 , Forkhead Transcription Factors/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Humans , MCF-7 Cells , Molecular Docking Simulation , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Protein Binding , Protein Structure, Tertiary , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Rats , Sirtuin 2/metabolism , Structure-Activity Relationship , Thiophenes/pharmacology , Thiophenes/therapeutic use
6.
J Med Chem ; 56(21): 8616-25, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-24099080

ABSTRACT

Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between 1 and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by 1 in vitro and has implications for the activity of ETPs against these important epigenetic targets.


Subject(s)
Chaetomium/chemistry , Enzyme Inhibitors/pharmacology , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Chaetomium/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Humans , Models, Molecular , Molecular Conformation , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Recombinant Proteins/metabolism , Structure-Activity Relationship
7.
Regul Toxicol Pharmacol ; 66(1): 88-103, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23524271

ABSTRACT

Evaluation of the safety of new chemicals and pharmaceuticals requires the combination of information from various sources (e.g. in vitro, in silico and in vivo) to provide an assessment of risk to human health and the environment. The authors have identified opportunities to maximize the predictivity of this information to humans while reducing animal use in four key areas; (i) accelerating the uptake of in vitro methods; (ii) incorporating the latest science into safety pharmacology assessments; (iii) optimizing rodent study design in biological development and (iv) consolidating approaches in developmental and reproductive toxicology. Through providing a forum for open discussion of novel proposals, reviewing current research and obtaining expert opinion in each of the four areas, the authors have developed recommendations on good practice and future strategy.


Subject(s)
Animal Testing Alternatives/methods , Drug-Related Side Effects and Adverse Reactions , Toxicology/methods , Animals , Humans , Research Design , Risk Assessment/methods , Rodentia , Species Specificity , Translational Research, Biomedical/methods
9.
Biochim Biophys Acta ; 1828(2): 535-42, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23088915

ABSTRACT

This study involves the structural and functional properties of the recombinant melanocortin 4 receptor (MC(4)R) expressed in the HEK-293 cell line. Using co-immuno-purification approaches, the receptor appears to be an oligomer, which can be crosslinked through disulphide bonds involving a native cysteine residue (84) to give a dimeric species. This position is located near the cytosolic region of transmembrane segment 2 and it is suggested that this is an interacting interface between MC(4)R monomers. Using co-expression of the native protein and a C84A mutant, it appears that the receptor also forms higher order oligomers via alternative interfaces. Interestingly, disulphide crosslink formation does not occur if the receptor is uncoupled from its G-protein, even though the oligomeric state is preserved. This suggests that the conformational changes, which occur on activation, affect the TM2 interface. The pharmacology of the agonist, NDP-MSH, indicates that the MC(4)R retains high affinity for the ligand in the absence of the G-protein but occupancy for the ligand is increased. The data can be interpreted to suggest that the G-protein exerts a negative allosteric effect on the receptor. Co-expression of one receptor lacking the ability to signal with another, which cannot bind the agonist, restored ligand-dependent activation of the G-protein to situations in which neither receptor on its own could activate the G-protein. Such transactivation suggests meaningful cross talk between the receptor subunits in the oligomeric complex. These studies demonstrate further unique features of the MC(4)R.


Subject(s)
Receptor, Melanocortin, Type 4/chemistry , Allosteric Site , Amino Acid Sequence , Binding Sites , Cell Membrane/metabolism , Cross-Linking Reagents/chemistry , Cyclic AMP Response Element Modulator/metabolism , Dimerization , Disulfides/chemistry , Dose-Response Relationship, Drug , GTP-Binding Proteins/chemistry , HEK293 Cells , Humans , Ligands , Mutagenesis , Mutation , Protein Binding , Receptor, Melanocortin, Type 4/metabolism , alpha-MSH/analogs & derivatives , alpha-MSH/pharmacology
10.
Regul Toxicol Pharmacol ; 62(2): 347-54, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22100994

ABSTRACT

The changing environment of monoclonal antibody (mAb) development is impacting on the cost of drug development and the use of experimental animals, particularly non-human primates (NHPs). The drive to reduce these costs is huge and involves rethinking and improving nonclinical studies to make them more efficient and more predictive of man. While NHP use might be unavoidable in many cases because of the exquisite specificity and consequent species selectivity of mAbs, our increasing knowledge base can be used to improve drug development and maximise the output of experimental data. Data on GLP regulatory toxicology studies for 58mAbs were obtained from 10 companies across a wide range of therapeutic indications. These data have been used to investigate current practice and identify study designs that minimise NHP use. Our analysis shows that there is variation in the number of animals used for similar studies. This information has been used to develop practical guidance and make recommendations on the use of science-based rationale to design studies using fewer animals taking into account the current regulatory guidance. There are eight recommendations intended to highlight areas for consideration. They include guidance on the main group size, the inclusion of recovery groups and the number of dose groups used in short and long term chronic toxicology studies.


Subject(s)
Antibodies, Monoclonal/toxicity , Research Design , Toxicity Tests, Chronic/methods , Animals , Dose-Response Relationship, Drug , Female , Male , No-Observed-Adverse-Effect Level , Primates
11.
Regul Toxicol Pharmacol ; 61(2): 222-9, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21855593

ABSTRACT

Toxicity studies in animals are carried out to identify the intrinsic hazard of a substance to support risk assessment for humans. In order to identify opportunities to minimise animal use in regulatory toxicology studies, a review of current study designs was carried out. Pharmaceutical companies and contract research organisations in the UK shared data and experience of standard toxicology studies (ranging from one to nine months duration) in rodents and non-rodents; and carcinogenicity studies in the rat and mouse. The data show that variation in study designs was primarily due to (i) the number of animals used in the main study groups, (ii) the use of animals in toxicokinetic (TK) satellite groups, and (iii) the use of animals in off-treatment recovery groups. The information has been used to propose a series of experimental designs where small adjustments could reduce animal use in practice, while maintaining the scientific objectives.


Subject(s)
Animal Experimentation , Animal Use Alternatives/methods , Toxicity Tests/methods , Animals , Drug Industry , Humans , Research Design , Risk Assessment/methods
12.
J Pain Symptom Manage ; 41(2): 374-82, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21236629

ABSTRACT

CONTEXT: The literature predominately describes hospice utilization among Medicare recipients, with a limited number of reports describing use among all age groups. OBJECTIVES: This study aimed to describe and compare patterns of hospice use among decedents of all ages in Alabama using a population-based approach. METHODS: We obtained death certificates for Alabama residents who died from January 1, 2002 to December 31, 2005 (n=178,420). To ascertain hospice use, we linked death certificates to the hospice administering care using state-mandated listings of deaths reported by hospices. Additionally, each decedent's residence at death was geocoded and area-level socioeconomic status (SES) measures were added. RESULTS: From 2002 to 2005, a total of 43,638 Alabamians died while under hospice care, representing a quarter (24.5%) of all deaths in the state. During this four-year span, the rate of hospice use increased by nearly 15% (22.2%-25.6%). As expected, rates of hospice use increased with age at death. For the SES indicators for poverty, education, and income, rates of hospice use increased as SES improved. However, this pattern was found to vary by race and metro/nonmetro status. CONCLUSIONS: In addition to revealing racial, geographic, and other disparities in hospice care across Alabama, our results indicate usage rates in Alabama trail behind those observed nationally. We also identified previously unreported interactions between race, urbanization level, and poverty classification. Future studies should explore whether such relationships exist elsewhere and the rationale for their occurrence.


Subject(s)
Hospice Care/statistics & numerical data , Hospices/statistics & numerical data , Alabama , Death Certificates , Hospice Care/economics , Hospices/economics , Humans , Medicare/economics , Medicare/statistics & numerical data , United States
13.
Am J Hosp Palliat Care ; 28(3): 153-60, 2011 May.
Article in English | MEDLINE | ID: mdl-20801920

ABSTRACT

Few studies have evaluated barriers to hospice from a hospice provider perspective. We assessed such views via a postal survey to all licensed hospices in Alabama (N = 193)-response = 55.4%. Most providers considered physicians and health care professionals to be somewhat knowledgeable of hospice, but also indicated a lack of knowledge constituted the barrier with the most impact in their communities. Respondents also cited physician difficulties with discussing end of life with patients and prognosticating death within 6 months as leading barriers. Providers also described Medicare reimbursement cap issues that have resulted in barriers to hospice. Our findings were similar to previous investigations assessing provider perceptions. Future studies should explore how reimbursement cap issues affect the receipt and delivery of hospice care.


Subject(s)
Attitude of Health Personnel , Health Personnel/psychology , Hospice Care/organization & administration , Professional-Patient Relations , Alabama , Communication , Health Knowledge, Attitudes, Practice , Humans , Medicare/economics , Physicians , Residence Characteristics , Time Factors , Trust , United States
14.
Eur J Pharmacol ; 652(1-3): 1-6, 2011 Feb 10.
Article in English | MEDLINE | ID: mdl-21114972

ABSTRACT

We have used selective muscarinic receptor antagonists and M(2) and M(4) receptor knockout (KO) mouse tissue to define the functional muscarinic acetylcholine receptor populations in rodent striatum. [(3)H] NMS binding studies in rat and mouse striatum demonstrated that approximately 30% of muscarinic acetylcholine receptors expressed are M(1) receptors. Radioligand binding studies suggest that the remaining muscarinic acetylcholine receptor population is largely M(4) with small levels of M(2). In agreement, carbachol-induced GTPγS binding studies in M(2) and M(4) receptor KO mouse striatum implicated the M(4) receptor as the predominant functional receptor subtype. Based on these data we have developed a novel, native tissue M(4) receptor [(35)S] GTPγS binding assay. Pharmacological assessment of M(4) receptor agonist and positive 3modulators revealed clear differences in the potencies observed in a human recombinant CHO-M(4) receptor [(35)S] GTPγS binding assay as compared to the native tissue [(35)S] GTPγS binding assay. These differences are believed to reflect differences in receptor reserve between the assay systems as well as differences in compound pharmacology (relative contribution of compound affinity and efficacy to observed potency). These studies have demonstrated the importance of understanding the pharmacology of test compounds in a native environment when predicting in vivo response.


Subject(s)
Corpus Striatum/metabolism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Muscarinic Antagonists/pharmacology , Receptor, Muscarinic M4/metabolism , Sulfur Radioisotopes , Animals , Cell Membrane/metabolism , Cricetinae , Humans , Male , Mice , Mice, Knockout , Protein Binding/drug effects , Radioligand Assay , Rats , Receptor, Muscarinic M4/agonists , Receptors, Muscarinic/metabolism
15.
J Mol Biol ; 401(3): 433-50, 2010 Aug 20.
Article in English | MEDLINE | ID: mdl-20600126

ABSTRACT

Melanocortin-4 receptor (MC4R) has an important regulatory role in energy homeostasis and food intake. Peptide agonists of the MC4R are characterized by the conserved sequence His(6)-Phe(7)-Arg(8)-Trp(9), which is crucial for their interaction with the receptor. This investigation utilized the covalent attachment approach to identify receptor residues in close proximity to the bound ligand [Nle(4),D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), thereby differentiating between residues directly involved in ligand binding and those mutations that compromise ligand binding by inducing conformational changes in the receptor. Also, recent X-ray structures of G-protein-coupled receptors were utilized to refine a model of human MC4R in the active state (R(*)), which was used to generate a better understanding of the binding mode of the ligand NDP-MSH at the atomic level. The mutation of residues in the human MC4R--such as Leu106 of extracellular loop 1, and Asp122, Ile125, and Asp126 of transmembrane (TM) helix 3, His264 (TM6), and Met292 (TM7)--to Cys residues produced definitive indications of proximity to the side chains of residues in the core region of the peptide ligand. Of particular interest was the contact between D-Phe(7) on the ligand and Ile125 of TM3 on the MC4R. Additionally, Met292 (TM7) equivalent to Lys(7.45) (Ballesteros numbering scheme) involved in covalently attaching retinal in rhodopsin is shown to be in close proximity to Trp(9). For the first time, the interactions between the terminal regions of NDP-MSH and the receptor are described. The amino-terminus appears to be adjacent to a series of hydrophilic residues with novel interactions at Cys196 (TM5) and Asp189 (extracellular loop 2). These interactions are reminiscent of sequential ligand binding exhibited by the beta(2)-adrenergic receptor, with the former interaction being equivalent to the known interaction involving Ser204 of the beta(2)-adrenergic receptor.


Subject(s)
Receptor, Melanocortin, Type 4/agonists , alpha-MSH/analogs & derivatives , Catalytic Domain , Crystallography, X-Ray , Humans , Ligands , Mutation , Peptides , Protein Conformation , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/metabolism , Static Electricity , alpha-MSH/metabolism
16.
Drug Discov Today ; 15(5-6): 235-42, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20096369

ABSTRACT

It has been predicted that the use of non-human primates (NHPs) is going to increase considerably in the development of monoclonal antibodies (mAbs). Opportunities exist to focus on a rigorous, science-based approach to drug development, however, which will minimize this increase. In this article, the authors review current and future NHP use in mAb development based on surveys, experience and expert opinion and propose a framework that will minimize future NHP use and continue to support science and innovation.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Disease Models, Animal , Drug Discovery/trends , Animals , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/trends , Forecasting , Humans , Macaca fascicularis
17.
Prev Chronic Dis ; 6(4): A119, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19754995

ABSTRACT

INTRODUCTION: Most studies that describe hospice use among cancer patients use the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, which has known limitations. We used vital records data to describe patterns of hospice use among cancer decedents in Alabama. METHODS: To ascertain hospice use, we linked death certificates from 2002 through 2005 for people who died from cancer to listings of deaths reported by hospices. To evaluate accessibility of care, we calculated straight-line distances between decedent residence at death and the hospice providing care. We used these distances to estimate the reach of each hospice and identify the number of hospice nonusers residing in these areas. RESULTS: During the study period, 52.0% of cancer decedents in Alabama received hospice care from 165 hospices. Nearly two-thirds of Alabama counties contain at least 1 hospice. Whites (53.6%) used hospice at a significantly higher rate than blacks (47.0%), but the rate of use was similar for women (53.2%) and men (51.0%). For people who were eligible for Medicare, 53.0% received hospice care. The median distance between decedent's residence and the hospice providing care was 9.8 miles. This distance was slightly shorter for blacks than whites and roughly equal by sex. CONCLUSION: Alabamians use hospice at lower rates than observed elsewhere. Barriers to hospice care in Alabama must be identified and addressed.


Subject(s)
Cause of Death , Hospice Care/statistics & numerical data , Neoplasms/mortality , Adult , Black or African American , Aged , Aged, 80 and over , Alabama/epidemiology , Demography , Female , Humans , Male , Middle Aged , Neoplasms/epidemiology , White People
18.
Pediatr Pathol Mol Med ; 22(1): 53-75, 2003.
Article in English | MEDLINE | ID: mdl-12687890

ABSTRACT

This review reports on multiple epiphyseal dysplasia (MED), first described clinically in the early part of the 20th century. Over 50 years later, we are now beginning to unravel the mystery behind the genetic mutations involved in triggering the changes in cartilage observed in this condition. In the past decade considerable progress has been made in identifying the underlying genetic defect in some forms of MED. Understanding the precise effect that these molecular changes have on the integrity of the cartilage extracellular matrix will lead the way in identifying the complex disease pathophysiology that defines MED. In addition, a greater understanding of the role and interactions of specific cartilage molecules may reveal the basis of more widespread cartilage disorders such as osteoarthritis.


Subject(s)
Osteochondrodysplasias/diagnostic imaging , Osteochondrodysplasias/genetics , Animals , Anion Transport Proteins , Carrier Proteins/genetics , Cartilage/pathology , Cartilage/ultrastructure , Cartilage Oligomeric Matrix Protein , Collagen Type IX/genetics , Collagen Type IX/ultrastructure , Extracellular Matrix/genetics , Extracellular Matrix/pathology , Extracellular Matrix/ultrastructure , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/ultrastructure , Glycoproteins/genetics , Glycoproteins/ultrastructure , Humans , Matrilin Proteins , Membrane Transport Proteins , Molecular Biology , Mutation , Osteochondrodysplasias/pathology , Radiography , Sulfate Transporters
19.
Hum Mutat ; 19(5): 465-78, 2002 May.
Article in English | MEDLINE | ID: mdl-11968079

ABSTRACT

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dysplasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias.


Subject(s)
Achondroplasia/genetics , Mutation/genetics , Osteochondrodysplasias/genetics , Amino Acid Sequence , Base Sequence , Cartilage Oligomeric Matrix Protein , Collagen Type IX/genetics , Extracellular Matrix Proteins/genetics , Genotype , Glycoproteins/genetics , Humans , Matrilin Proteins , Molecular Sequence Data , Phenotype
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