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1.
Acta Neuropathol ; 147(1): 61, 2024 03 25.
Article in English | MEDLINE | ID: mdl-38526616

ABSTRACT

TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.


Subject(s)
Membrane Proteins , Nerve Tissue Proteins , Tauopathies , Animals , Humans , Mice , Disease Models, Animal , Membrane Proteins/genetics , Mice, Knockout , Mice, Transgenic , Mutation , Nerve Tissue Proteins/genetics , Paralysis/genetics , Polymorphism, Single Nucleotide , tau Proteins/genetics , tau Proteins/metabolism , Tauopathies/pathology
2.
Front Neurosci ; 17: 1275959, 2023.
Article in English | MEDLINE | ID: mdl-37901434

ABSTRACT

The lysosomal protein TMEM106B was identified as a risk modifier of multiple dementias including frontotemporal dementia and Alzheimer's disease. The gene comes in two major haplotypes, one associated with disease risk, and by comparison, the other with resilience. Only one coding polymorphism distinguishes the two alleles, a threonine-to-serine substitution at residue 185 (186 in mouse), that is inherited in disequilibrium with multiple non-coding variants. Transcriptional studies suggest synaptic, neuronal, and cognitive preservation in human subjects with the protective haplotype, while murine in vitro studies reveal dramatic effects of TMEM106B deletion on neuronal development. Despite this foundation, the field has not yet resolved whether coding variant is biologically meaningful, and if so, whether it has any specific effect on neuronal phenotypes. Here we studied how loss of TMEM106B or expression of the lone coding variant in isolation affected transcriptional signatures in the mature brain and neuronal structure during development in primary neurons. Homozygous expression of the TMEM106B T186S variant in knock-in mice increased cortical expression of genes associated with excitatory synaptic function and axon outgrowth, and promoted neurite branching, dendritic spine density, and synaptic density in primary hippocampal neurons. In contrast, constitutive TMEM106B deletion affected transcriptional signatures of myelination without altering neuronal development in vitro. Our findings show that the T186S variant is functionally relevant and may contribute to disease resilience during neurodevelopment.

3.
Sci Adv ; 9(18): eadd2676, 2023 05 05.
Article in English | MEDLINE | ID: mdl-37146150

ABSTRACT

TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the TMEM106B risk allele is associated with myelin loss and decreased microglial numbers in humans. Collectively, our study unveils a previously unknown role of TMEM106B in promoting microglial functionality during demyelination.


Subject(s)
Demyelinating Diseases , Microglia , Humans , Mice , Animals , Microglia/metabolism , Mice, Knockout , Brain/metabolism , Demyelinating Diseases/genetics , Demyelinating Diseases/metabolism , Cell Proliferation , Membrane Proteins/genetics , Membrane Proteins/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism
4.
bioRxiv ; 2023 Mar 25.
Article in English | MEDLINE | ID: mdl-36993574

ABSTRACT

TMEM106B is a risk modifier for a growing list of age-associated dementias including Alzheimer’s and frontotemporal dementia, yet its function remains elusive. Two key questions that emerge from past work are whether the conservative T185S coding variant found in the minor haplotype contributes to protection, and whether the presence of TMEM106B is helpful or harmful in the context of disease. Here we address both issues while extending the testbed for study of TMEM106B from models of TDP to tauopathy. We show that TMEM106B deletion accelerates cognitive decline, hindlimb paralysis, neuropathology, and neurodegeneration. TMEM106B deletion also increases transcriptional overlap with human AD, making it a better model of disease than tau alone. In contrast, the coding variant protects against tau-associated cognitive decline, neurodegeneration, and paralysis without affecting tau pathology. Our findings show that the coding variant contributes to neuroprotection and suggest that TMEM106B is a critical safeguard against tau aggregation.

5.
Immunity ; 47(3): 421-434.e3, 2017 09 19.
Article in English | MEDLINE | ID: mdl-28930658

ABSTRACT

Environmental insults are often detected by multiple sensors that activate diverse signaling pathways and transcriptional regulators, leading to a tailored transcriptional output. To understand how a tailored response is coordinated, we examined the inflammatory response elicited in mouse macrophages by ionizing radiation (IR). RNA-sequencing studies revealed that most radiation-induced genes were strongly dependent on only one of a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, which regulated many IR-response genes, including interferon response genes, via an atypical IRF1-dependent, STING-independent mechanism. Moreover, small, defined sets of genes activated by p53 and NRF2 accounted for the selective response to radiation in comparison to a microbial inducer of inflammation. Our findings reveal that genes comprising an environmental response are activated by defined sensing mechanisms with a high degree of selectivity, and they identify distinct components of the radiation response that might be susceptible to therapeutic perturbation.


Subject(s)
Gene Expression Regulation/radiation effects , Inflammation/genetics , Inflammation/metabolism , Radiation, Ionizing , Signal Transduction , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Cluster Analysis , DNA-Activated Protein Kinase/metabolism , Dose-Response Relationship, Radiation , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Profiling , Gene Expression Regulation/drug effects , Gene Knockout Techniques , Humans , Interferons/metabolism , Interferons/pharmacology , Macrophages/metabolism , Macrophages/radiation effects , Membrane Proteins/metabolism , Mice , Myeloid Differentiation Factor 88/metabolism , NF-E2-Related Factor 2/metabolism , Reactive Oxygen Species/metabolism , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Transcription, Genetic/radiation effects , Transcriptional Activation , Transcriptional Regulator ERG/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
6.
Small ; 12(3): 294-300, 2016 Jan 20.
Article in English | MEDLINE | ID: mdl-26618498

ABSTRACT

Conditions for the dispersion of molybdenum disulfide (MoS2) in aqueous solution at concentrations up to 0.12 mg mL(-1) using a range of nonionic, biocompatible block copolymers (i.e., Pluronics and Tetronics) are identified. Furthermore, the optimal Pluronic dispersant for MoS2 is found to be effective for a range of other 2D materials such as molybdenum diselenide, tungsten diselenide, tungsten disulfide, tin selenide, and boron nitride.


Subject(s)
Biocompatible Materials/chemistry , Nanostructures/chemistry , Polymers/chemistry , Water/chemistry , Ions , Optical Phenomena , Particle Size , Poloxamer/chemistry , Spectrum Analysis
7.
J Immunol ; 195(2): 464-76, 2015 Jul 15.
Article in English | MEDLINE | ID: mdl-26071559

ABSTRACT

Systemic autoimmune diseases such as lupus affect multiple organs, usually in a diverse fashion where only certain organs are affected in individual patients. It is unclear whether the "local" immune cells play a role in regulating tissue specificity in relation to disease heterogeneity in systemic autoimmune diseases. In this study, we used skin as a model to determine the role of tissue-resident dendritic cells (DCs) in local and systemic involvement within a systemic lupus disease model. Skin-resident DCs, namely, Langerhans cells (LCs), have been implicated in regulating tolerance or autoimmunity using elegant transgenic models, however, their role in local versus systemic immune regulation is unknown. We demonstrate that although lymphocytes from skin-draining lymph nodes of autoimmune-prone MRL/MpJ-Fas(lpr/lp) (r) (MRL-lpr) mice react spontaneously to a physiological skin self-Ag desmoglein-3, epicutaneous applications of desmoglein-3 induced tolerance that is dependent on LCs. Inducible ablation of LCs in adult preclinical MRL-lpr and MRL/MpJ-Fas(+/+) mice resulted in increased autoantibodies against skin Ags and markedly accelerated lupus dermatitis with increased local macrophage infiltration, but had no effect on systemic autoantibodies such as anti-dsDNA Abs or disease in other organs such as kidneys, lung, and liver. Furthermore, skin-draining lymph nodes of LC-ablated MRL-lpr mice had significantly fewer CD4(+) T cells producing anti-inflammatory cytokine IL-10 than LC-intact controls. These results indicate that a skin-resident DC population regulates local tolerance in systemic lupus and emphasize the importance of the local immune milieu in preventing tissue-specific autoimmunity, yet have no effect on systemic autoimmunity.


Subject(s)
Immune Tolerance , Langerhans Cells/immunology , Lupus Erythematosus, Cutaneous/immunology , Skin/immunology , Animals , Autoantibodies/biosynthesis , Autoantigens/genetics , Autoantigens/immunology , Autoimmunity , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Cell Movement , Desmoglein 3/administration & dosage , Desmoglein 3/genetics , Desmoglein 3/immunology , Disease Models, Animal , Female , Gene Expression , Interleukin-10/genetics , Interleukin-10/immunology , Langerhans Cells/drug effects , Langerhans Cells/pathology , Lupus Erythematosus, Cutaneous/drug therapy , Lupus Erythematosus, Cutaneous/genetics , Lupus Erythematosus, Cutaneous/pathology , Lymph Nodes/drug effects , Lymph Nodes/immunology , Lymph Nodes/pathology , Macrophages/drug effects , Macrophages/immunology , Macrophages/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred MRL lpr , Skin/drug effects , Skin/pathology
8.
Arthritis Res Ther ; 15(2): R47, 2013 Mar 27.
Article in English | MEDLINE | ID: mdl-23531237

ABSTRACT

INTRODUCTION: ß2-microglobulin (ß2m) is required for the surface expression of MHC class I and class I-like proteins such as CD1d, Qa1 and neonatal Fc receptor (FcRn), all of which may impact the development of autoimmunity. Since CD1d is known to bind and present phospholipid antigens to T cells, we asked if the deficiency of ß2m or CD1d will impact the development of anti-phospholipid antibodies as compared to other aspects of lupus autoimmunity. METHODS: We introgressed the ß2m-null genotype onto the NZB and NZW backgrounds for 12 to 14 generations to generate genetically lupus-susceptible (NZB/NZW)F1 (BWF1) mice that are ß2m-deficient (ß2m°). Circulating immunoglobulins (Ig), rheumatoid factor (RF), anti-DNA and anti-cardiolipin (anti-CL) antibodies, and renal disease were analyzed in these and CD1d-deficient (CD1d°) BWF1 mice that we had previously generated. RESULTS: Whereas ß2m° BWF1 mice had reduced serum IgG, they had increased mortality, nephritis, serum IgG anti-DNA antibody and RF as compared to heterozygous and wild-type littermates. These effects were recapitulated in CD1d° BWF1 mice, except that they also had increased serum IgG as compared to control littermates. Intriguingly, both ß2m° and CD1d° mice had lower serum anti-CL antibody levels than in control littermates. Such CD1d dependence of anti-CL antibody production is not mediated by CD1d/glycolipid-reactive iNKT cells, as these cells reduced the production of RF and anti-DNA antibodies but had no effect on anti-CL antibodies. CONCLUSIONS: We report a novel dichotomous role of ß2m and CD1d, whereby these molecules differently regulate autoimmunity against phospholipid versus non-phospholipid autoantigens.


Subject(s)
Antigens, CD1d/genetics , Autoantibodies/immunology , Autoantigens/immunology , Histocompatibility Antigens Class I/genetics , Lupus Erythematosus, Systemic/immunology , Animals , Antibodies, Antiphospholipid/immunology , Antigens, CD1d/immunology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Germ-Line Mutation , Histocompatibility Antigens Class I/immunology , Lupus Erythematosus, Systemic/genetics , Mice , Mice, Inbred BALB C , Mice, Mutant Strains , Mice, SCID
9.
Eur J Pharmacol ; 701(1-3): 176-80, 2013 Feb 15.
Article in English | MEDLINE | ID: mdl-23276666

ABSTRACT

Although the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is often described as a selective serotonergic neurotoxin, some research has challenged this view. The objective of this study was to determine the influence of MDMA on subsequent levels of two different markers of dopaminergic function, the dopamine transporter (DAT) as well as dopamine and its major metabolites. In experiment I, adult male Sprague-Dawley rats were administered either a low or moderate dose MDMA binge (2.5 or 5.0mg/kg×4 with an inter-dose interval of 1h) or saline, and were killed 1 week later. The moderate dose dramatically reduced [(3)H]WIN 35,428 binding to striatal DAT by 73.7% (P≤0.001). In experiment II, animals were binged with a higher dose of MDMA (10mg/kg×4) to determine the drug's effects on concentrations of serotonin (5-HT), dopamine, and their respective major metabolites 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the striatum and frontal cortex 1 week later. As expected, MDMA significantly reduced 5-HT and 5-HIAA (≥50%) in these structures, while only a marginal decrease in dopamine was noted in the striatum. In contrast, levels of DOPAC (34.3%, P<0.01) and HVA (33.5%, P<0.001) were reduced by MDMA treatment, suggesting a decrease in dopamine turnover. Overall, these findings indicate that while serotonergic markers are particularly vulnerable to MDMA-induced depletion, significant dopaminergic deficits may also occur under some conditions. Importantly, DAT expression may be more vulnerable to perturbation by MDMA than dopamine itself.


Subject(s)
Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , Animals , Hydroxyindoleacetic Acid/metabolism , Male , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Time Factors
10.
J Clin Immunol ; 32(1): 106-13, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22002593

ABSTRACT

CD1d presents glycolipid antigens such as α-galactosylceramide (αGalCer) to invariant natural killer T cells (iNKT). We have reported that activated iNKTs inhibit IL-10-producing autoreactive B cells, while promoting or leaving intact the normal B cell responses, making iNKT modulation an attractive therapeutic modality. Here, we report that a brief treatment of young lupus-prone (NZB/NZW)F1 (BWF1) mice with two injections of αGalCer conferred a long-term protection against lupus. Long-term repeated administrations of αGalCer, however, afforded no clinical benefit. These disparate clinical effects correlated with iNKT responsiveness. While a brief treatment with αGalCer enhanced iNKT responses upon in vitro recall, the long-term αGalCer treatment resulted in reduced iNKT responses in BWF1 mice. The improvement in disease with αGalCer treatment was associated with the reduced IL-10 production. Furthermore, iNKTs directly inhibited IL-10-secreting cells in vivo in reconstituted SCID mice and inhibited IL-10-secreting B cells in vitro in co-cultures. Thus, a brief treatment with a CD1d-binding glycolipid enhances iNKT responses, reduces IL-10 production, and delays the onset of lupus, whereas long-term repeated treatments induce marked iNKT hyporesponsiveness and do not affect disease outcome in BWF1 mice. Identifying glycolipid regimens that can modulate iNKT responsiveness will have important implications for developing iNKT-based therapies for autoimmune diseases.


Subject(s)
Galactosylceramides/therapeutic use , Lupus Nephritis/prevention & control , Natural Killer T-Cells/immunology , Animals , Cytokines/metabolism , Disease Models, Animal , Female , Galactosylceramides/administration & dosage , Interleukin-10/biosynthesis , Ligands , Lupus Nephritis/drug therapy , Mice , Mice, Inbred BALB C , Mice, Inbred NZB , Mice, Knockout , Mice, SCID , Proteinuria/metabolism
11.
PLoS One ; 6(10): e26536, 2011.
Article in English | MEDLINE | ID: mdl-22046304

ABSTRACT

Marginal zone B cells (MZB) mount a rapid antibody response, potently activate naïve T cells, and are enriched in autoreactive B cells. MZBs express high levels of CD1d, the restriction element for invariant natural killer T cells (iNKT). Here, we examined the effect of iNKT cells on MZB cell activation and numbers in vitro and in vivo in normal and autoimmune mice. Results show that iNKT cells activate MZBs, but restrict their numbers in vitro and in vivo in normal BALB/c and C57/BL6 mice. iNKT cells do so by increasing the activation-induced cell death and curtailing proliferation of MZB cells, whereas they promote the proliferation of follicular B cells. Sorted iNKT cells can directly execute this function, without help from other immune cells. Such MZB regulation by iNKTs is mediated, at least in part, via CD1d on B cells in a contact-dependent manner, whereas iNKT-induced proliferation of follicular B cells occurs in a contact- and CD1d-independent manner. Finally, we show that iNKT cells reduce 'autoreactive' MZB cells in an anti-DNA transgenic model, and limit MZB cell numbers in autoimmune-prone (NZB×NZW)F1 and non-obese diabetic mice, suggesting a potentially new mechanism whereby iNKT cells might regulate pathologic autoimmunity. Differential regulation of follicular B cells versus potentially autoreactive MZBs by iNKT cells has important implications for autoimmune diseases as well as for conditions that require a rapid innate B cell response.


Subject(s)
B-Lymphocyte Subsets/cytology , Homeostasis/immunology , Natural Killer T-Cells/physiology , Animals , Autoimmune Diseases/immunology , B-Lymphocyte Subsets/immunology , Cell Death , Cell Proliferation , Immunity, Innate , Lymphocyte Activation , Mice
12.
J Immunol ; 186(3): 1512-20, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21209282

ABSTRACT

Autoantibody production is a hallmark of autoimmune diseases, such as lupus and rheumatoid arthritis. Accumulating evidence suggests a role of invariant NKT (iNKT) cells in their pathogenesis. Mechanisms underlying the role of iNKT cells in these diseases, however, remain unclear. In this study, we show that iNKT cells suppress IgG anti-DNA Ab and rheumatoid factor production and reduce IL-10-secreting B cells in a contact-dependent manner, but increase total IgG production and enhance activation markers on B cells via soluble factors. In vivo reconstitution with iNKT cells also reduces autoantibody production in iNKT-deficient mice and in SCID mice implanted with B cells. Using an anti-DNA transgenic model, we found that autoreactive B cells spontaneously produce IL-10 and are activated in vivo. In the presence of activated iNKT cells, these autoreactive B cells are selectively reduced, whereas nonautoreactive B cells are markedly activated. Because iNKTs recognize CD1d, we reasoned that CD1d might play a role in the differential regulation of autoreactive versus nonautoreactive B cells by iNKT cells. Indeed, autoreactive B cells express more CD1d than nonautoreactive B cells, and CD1d deficiency in lupus mice exacerbates autoantibody production and enhances Ab response to a self-peptide but not to a foreign peptide. Importantly, iNKT cells fail to inhibit autoantibody production by CD1d-deficient B cells. Thus, iNKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner but activate nonautoreactive B cells via cytokines. Such ability of iNKTs to suppress autoantibody production, without causing global suppression of B cells, has important implications for the development of iNKT-based therapy for autoimmune diseases.


Subject(s)
Antigens, CD1d/physiology , Autoantibodies/metabolism , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Cell Adhesion/immunology , Natural Killer T-Cells/immunology , Animals , Antigens, CD1d/genetics , Antigens, CD1d/metabolism , Autoantibodies/biosynthesis , Cell Adhesion/genetics , Galactosylceramides/pharmacology , Immunoglobulin G/metabolism , Immunosuppressive Agents/pharmacology , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Lymphocyte Depletion , Mice , Mice, Inbred BALB C , Mice, Inbred NZB , Mice, Knockout , Mice, SCID , Mice, Transgenic , Natural Killer T-Cells/metabolism
13.
J Arthroplasty ; 26(3): 354-9, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21167676

ABSTRACT

Distorted proximal femoral anatomy can pose a great technical challenge during total hip arthroplasty. Fifty-eight total hip arthroplasty were performed in 51 patients with proximal femoral deformity from 1998 to 2006. All hips except 2 were treated with cementless prosthesis. Twenty-three patients had a retained hardware that had to be removed. Nonprimary cementless components were used in 22 (25%) femurs. In 21 (23%) hips, osteotomy was required to properly fit the cementless stem in the femur. At the time of latest follow-up (4 years on average), functional scores showed significant improvement. Radiographically, all femoral components showed stable bone ingrowth except 2 hips (3.5%) with stable fibrous ingrowth and 1 hip (2%) with loosening. There were 2 (3.5%) revisions in 2 patients for periprosthetic fracture and femoral loosening. The mechanical failure rate was 9% (5 hips). Despite technical difficulties, cementless femoral reconstruction provides a reliable and durable result in patients with proximal femoral deformity.


Subject(s)
Arthroplasty, Replacement, Hip/methods , Bone Cements , Femur/abnormalities , Femur/surgery , Hip Prosthesis , Joint Diseases/surgery , Congenital Abnormalities/diagnostic imaging , Congenital Abnormalities/etiology , Congenital Abnormalities/surgery , Femur/diagnostic imaging , Humans , Joint Diseases/diagnostic imaging , Osteotomy , Prosthesis Failure , Radiography , Retrospective Studies , Treatment Outcome
14.
J Clin Oncol ; 25(12): 1476-81, 2007 Apr 20.
Article in English | MEDLINE | ID: mdl-17442990

ABSTRACT

PURPOSE: Peroxisome proliferator-activated receptor gamma (PPARgamma) mediates cell cycle arrest and adipocyte differentiation; has tumor suppressor activity in liposarcoma, lung, and prostate cancers; and suppresses colonic polyp formation in adenomatous polyposis coli (APC)min/+ mice. To assess the influence of thiazolidinediones (TZDs), which are PPAR ligands used to treat diabetes mellitus, a retrospective analysis of a database from 10 Veteran Affairs medical centers was conducted. PATIENTS AND METHODS: Data on male patients 40 years and older diagnosed to have diabetes mellitus between 1997 and 2003 were obtained from the Veterans Integrated Services Network 16 (VISN 16) data warehouse. Subsequent diagnoses of colorectal, lung, and prostate cancer and use of TZD, other antidiabetic agents, and insulin were identified. Cox regression with time-dependent covariates was used to estimate the association between TZD use and cancer risk. Relative risks were adjusted for confounders (age, race/ethnicity, body mass index, use of insulin, and other oral antidiabetic agents). RESULTS: Of 87,678 individuals, 1,137 had colorectal cancer, 3,246 had prostate cancer, and 1,371 had lung cancer. We observed a 33% reduction in lung cancer risk among TZD users compared with nonusers after adjusting for confounder interactions (relative risk, 0.67; 95% CI, 0.51 to 0.87). The risk reduction for colorectal and prostate cancers did not reach statistical significance. CONCLUSION: TZD use was associated with reduced risk of lung cancer. Further studies are warranted to confirm our findings.


Subject(s)
Colonic Neoplasms/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Lung Neoplasms/epidemiology , Prostatic Neoplasms/epidemiology , Thiazolidinediones/therapeutic use , Adolescent , Adult , Age Distribution , Aged , Causality , Comorbidity , Confidence Intervals , Diabetes Mellitus, Type 2/diagnosis , Dose-Response Relationship, Drug , Humans , Incidence , Male , Middle Aged , Probability , Prognosis , Registries , Retrospective Studies , Risk Assessment , Survival Analysis
15.
J Immunol ; 177(10): 6650-9, 2006 Nov 15.
Article in English | MEDLINE | ID: mdl-17082577

ABSTRACT

Although invariant NKT (iNKT) cells participate in many aspects of immune responses, the molecular mechanisms regulating their development, maturation, and activation are still poorly understood. GATA-3 is a T cell-specific transcription factor that is also expressed in iNKT cells. The critical role of GATA-3 in conventional alphabeta T cells has been well documented, but whether GATA-3 also regulates the development and function of iNKT cells is unknown. In the present study, we report that deficiency of GATA-3 results in cell-intrinsic defects in the thymic development and peripheral maturation of murine iNKT cells. In addition, GATA-3 is also required for survival, activation, and effector functions of this unique population of T cells. Our data also reveal a previously unidentified peripheral maturation step that is GATA-3 dependent.


Subject(s)
Cell Differentiation/immunology , GATA3 Transcription Factor/physiology , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation/genetics , Cell Survival/genetics , Cell Survival/immunology , Cytokines/biosynthesis , Cytokines/blood , GATA3 Transcription Factor/biosynthesis , GATA3 Transcription Factor/deficiency , GATA3 Transcription Factor/genetics , Galactosylceramides/administration & dosage , Injections, Intravenous , Interferon-gamma/biosynthesis , Killer Cells, Natural/metabolism , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Antigen, T-Cell/physiology , Signal Transduction/immunology , Spleen/cytology , Spleen/immunology , Spleen/metabolism , T-Lymphocyte Subsets/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Thymus Gland/cytology , Thymus Gland/immunology , Thymus Gland/metabolism
16.
Endocr Pract ; 12(1): 48-53, 2006.
Article in English | MEDLINE | ID: mdl-16524863

ABSTRACT

OBJECTIVE: To report 3 cases of bisphosphonate-induced hypocalcemia and review the relevant literature. METHODS: We present the clinical and laboratory findings in 3 cases of bisphosphonate-induced hypocalcemia, and discuss the pathophysiologic mechanisms and the pertinent literature. RESULTS: In our first patient (case 1), symptomatic hypocalcemia developed after intravenous administration of pamidronate for management of multiple myeloma. He had vitamin D insufficiency and impaired renal function at the time of pamidronate therapy. Our second patient (case 2) presented with symptomatic hypocalcemia 12 weeks after initiation of alendronate therapy for osteoporosis. Her serum 25-hydroxyvitamin D level was low (3 ng/mL), attributable to a combination of poor vitamin D intake, limited exposure to sunlight, use of phenytoin, and previous intestinal resections. In our third patient (case 3), hypocalcemia developed on 2 different occasions, each episode occurring after intravenous administration of pamidronate for hypercalcemia of malignancy. All 3 patients had underlying conditions that impaired the homeostatic response to bisphosphonates and contributed to the severe hypocalcemia. Review of published reports on symptomatic bisphosphonate-induced hypocalcemia disclosed that hypocalcemia develops in patients with unrecognized hypoparathyroidism, impaired renal function, or vitamin D deficiency. Overall, the rate of the development of hypocalcemia was related to the potency of the bisphosphonate administered. CONCLUSION: The increasing use of bisphosphonates and the introduction of more potent agents impose a considerable risk for bisphosphonate-induced hypocalcemia in a substantial number of patients. Greater awareness of this complication, a better understanding of the underlying mechanisms, and proper assessment of patients in whom bisphosphonate therapy is contemplated should reduce the frequency of occurrence of this potentially life-threatening complication.


Subject(s)
Bone Density Conservation Agents/adverse effects , Diphosphonates/adverse effects , Hypocalcemia/chemically induced , Aged , Bone Density Conservation Agents/therapeutic use , Calcium Compounds/therapeutic use , Diphosphonates/therapeutic use , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Hypocalcemia/drug therapy , Hypocalcemia/physiopathology , Male , Middle Aged , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Risk Assessment , Severity of Illness Index
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