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1.
Immunology ; 169(1): 13-26, 2023 05.
Article in English | MEDLINE | ID: mdl-36370035

ABSTRACT

Granulomas are key histopathological features of Mycobacterium tuberculosis (Mtb) infection, with complex roles in pathogen control and dissemination. Thus, understanding drivers and regulators of granuloma formation is important for improving tuberculosis diagnosis, treatment, and prevention. Yet, molecular mechanisms underpinning granuloma formation and dynamics remain poorly understood. Here we used low-dose Mtb infection of C57BL/6 mice, which elicits structured lung granulomas composed of central macrophage clusters encased by a lymphocyte mantle, alongside the disorganized lymphocyte and macrophage clusters commonly observed in Mtb-infected mice. Using gene-deficient mice, we observed that Toll-like receptor (TLR) 2 and the TLR-related Radioprotective 105 kDa protein (RP105) contributed to the extent and spatial positioning of pathology in infected lung tissues, consistent with functional cooperation between TLR2 and RP105 in the innate immune recognition of Mtb. In mice infected with the highly virulent Mtb clinical isolate HN878, TLR2, but not RP105, positively regulated the extent of central macrophage regions within structured granulomas. Moreover, RP105, but not TLR2, promoted the formation of structured lung granulomas, suggesting that the functions of RP105 as an innate immune sensor for Mtb reach beyond its roles as TLR2 co-receptor. TLR2 and RP105 contributions to lung pathology are governed by Mtb biology, as neither receptor affected the frequency or architecture of structured granulomas in mice infected with the reference strain Mtb H37Rv. Thus, by revealing distinctive as well as cooperative functions of TLR2 and RP105 in lung pathology, our data identify TLRs as molecular determinants of TB granuloma formation and architecture, and expand understanding of how interactions between innate immune receptors and Mtb shape TB disease manifestation.


Subject(s)
Mycobacterium tuberculosis , Animals , Mice , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/metabolism , Mice, Inbred C57BL , Toll-Like Receptors , Lung , Receptors, Immunologic , Granuloma , Immunity, Innate
2.
Mol Clin Oncol ; 15(5): 240, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34650807

ABSTRACT

The combination of paclitaxel, carboplatin and cetuximab (PCC) is efficacious in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). The current study assessed the incidence of grade 3/4 (G3/4) toxicity for patients receiving weekly or 3-weekly PCC for R/M SCCHN. The present single-institution, retrospective analysis included 74 patients who received weekly [paclitaxel 45 mg/m2 and carboplatin area under the curve (AUC), 1.5] or 3-weekly (paclitaxel 175 mg/m2 and carboplatin AUC, 5) PCC. For each regimen, cetuximab was administered at 400 mg/m2 for the first week, after which the dosage was reduced to 250 mg/m2 weekly until disease progression occurred. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v4.03, and response to therapy was determined using computed tomography every 12 weeks. The results revealed that 26 patients (35%) received weekly PCC and 48 patients (65%) received PCC every 3 weeks. A total of 6 (25%) patients receiving weekly PCC experienced G3/4 toxicity compared with 30 (66%) patients that received PCC every 3 weeks (odds ratio, 0.18; 95% confidence interval, 0.05-0.64; P=0.01). The most common G3/4 side effects were neutropenia (8 vs. 53%), anemia (15 vs. 32%) and fatigue (3 vs. 10%). The incidence of G3/4 toxicity or any grade toxicity requiring dose modification or discontinuation was 74 vs. 77%, respectively. The overall response rate was 39% with weekly PCC compared with 27% in those receiving PCC every 3 weeks. The 1-year progression-free and overall survival rates were 27 and 46% for patients receiving weekly PCC, and 13 and 44% for patients receiving PCC every 3 weeks. Weekly PCC had a reduced risk of G3/4 toxicity when compared with PCC administered every 3 weeks. Considering the improved tolerance of weekly PCC, this regimen should be considered for older patients and patients being treated with second-line chemotherapy.

3.
Immunol Cell Biol ; 99(10): 1067-1076, 2021 11.
Article in English | MEDLINE | ID: mdl-34555867

ABSTRACT

The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in the host control of mycobacterial infections. Expression and release of TNF are tightly regulated, yet the molecular mechanisms that control the release of TNF by mycobacteria-infected host cells, in particular macrophages, are incompletely understood. Rab GTPases direct the transport of intracellular membrane-enclosed vesicles and are important regulators of macrophage cytokine secretion. Rab6b is known to be predominantly expressed in the brain where it functions in retrograde transport and anterograde vesicle transport for exocytosis. Whether it executes similar functions in the context of immune responses is unknown. Here we show that Rab6b is expressed by primary mouse macrophages, where it localized to the Golgi complex. Infection with Mycobacterium bovis bacille Calmette-Guérin (BCG) resulted in dynamic changes in Rab6b expression in primary mouse macrophages in vitro as well as in organs from infected mice in vivo. We further show that Rab6b facilitated TNF release by M. bovis BCG-infected macrophages, in the absence of discernible impact on Tnf messenger RNA and intracellular TNF protein expression. Our observations identify Rab6b as a positive regulator of M. bovis BCG-induced TNF trafficking and secretion by macrophages and positions Rab6b among the molecular machinery that orchestrates inflammatory cytokine responses by macrophages.


Subject(s)
Golgi Apparatus/immunology , Macrophages/immunology , Mycobacterium Infections , Tumor Necrosis Factor-alpha/immunology , rab GTP-Binding Proteins/immunology , Animals , Mice , Mycobacterium Infections/immunology , Mycobacterium bovis
4.
Drug Des Devel Ther ; 14: 1693-1704, 2020.
Article in English | MEDLINE | ID: mdl-32440095

ABSTRACT

Tenosynovial giant cell tumor (TGCT) is a rare benign tumor that involves the synovium, bursa, and tendon sheath, resulting in reduced mobility of the affected joint or limb. The current standard of care for TGCT is surgical resection. However, some patients have tumor recurrence, present with unresectable tumors, or have tumors that are in locations where resection could result in amputations or significant debility. Therefore, the development of systemic agents with activity against TGCT to expand treatment options is a highly unmet medical need. Pathologically, TGCT is characterized by the overexpression of colony-stimulating factor 1 (CSF-1), which leads to the recruitment of colony-stimulating factor-1 receptor (CSF-1R) expressing macrophages that make up the primary cell type within these giant cell tumors. The binding of CSF-1 and CSF-1R controls cell survival and proliferation of monocytes and the switch from a monocytic to macrophage phenotype contributing to the growth and inflammation within these tumors. Therefore, molecules that target CSF-1/CSF-1R have emerged as potential systemic agents for the treatment of TGCT. Given the role of macrophages in regulating tumorigenesis, CSF1/CSF1R-targeting agents have emerged as attractive therapeutic targets for solid tumors. Pexidartinib is an orally bioavailable and potent inhibitor of CSF-1R which is one of the most clinically used agents. In this review, we discuss the biology of TGCT and review the pre-clinical and clinical development of pexidartinib which ultimately led to the FDA approval of this agent for the treatment of TGCT as well as ongoing clinical studies utilizing pexidartinib in the setting of cancer.


Subject(s)
Aminopyridines/pharmacology , Antineoplastic Agents/pharmacology , Giant Cell Tumor of Tendon Sheath/drug therapy , Pyrroles/pharmacology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Clinical Trials as Topic , Dose-Response Relationship, Drug , Giant Cell Tumor of Tendon Sheath/metabolism , Humans , Molecular Structure , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Structure-Activity Relationship
5.
J Oncol Pharm Pract ; 25(4): 993-997, 2019 Jun.
Article in English | MEDLINE | ID: mdl-29651915

ABSTRACT

Methotrexate is a dihydrofolate reductase inhibitor that interferes with DNA synthesis, DNA repair, and cellular replication. We present the first adult case of a patient who received intravenous contrast prior to administration of high-dose methotrexate, who subsequently experienced delayed methotrexate clearance and renal impairment necessitating the use of glucarpidase. This case displays a possible correlation between intravenous radiographic contrast administration and resulting toxicity due to delayed methotrexate clearance.


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Contrast Media/adverse effects , Kidney/drug effects , Methotrexate/adverse effects , gamma-Glutamyl Hydrolase/therapeutic use , Drug Interactions , Female , Humans , Infusions, Intravenous , Methotrexate/pharmacokinetics , Middle Aged , Tomography, X-Ray Computed
6.
J Leukoc Biol ; 103(2): 311-319, 2018 02.
Article in English | MEDLINE | ID: mdl-29345364

ABSTRACT

Radioprotective 105 kDa (RP105, CD180) is a member of the Toll-like receptor (TLR) family that interacts with TLR2 and facilitates recognition of mature lipoproteins expressed by Mycobacterium tuberculosis and Mycobacterium bovis BCG. In this study, we used synthetic lipopeptide analogs of the M. tuberculosis 19 kDa lipoprotein to define structural characteristics that promote RP105-mediated host cell responses. A tripalmitoylated lipopeptide composed of the first 16 N-terminal amino acids of the M. tuberculosis 19 kDa lipoprotein induced RP105-dependent TNF and IL-6 production by macrophages. Di- and tripalmitoylated variants of this lipopeptide elicited an equivalent RP105-dependent response, indicating that while the lipid moiety is required for macrophage activation, it is not a determinant of RP105 dependency. Instead, substitution of two polar threonine residues at positions 7 and 8 with nonpolar alanine residues resulted in reduced RP105 dependency. These results strongly suggest that the amino acid composition of the M. tuberculosis 19 kDa lipoprotein, and likely other mycobacterial lipoproteins, is a key determinant of RP105 agonism.


Subject(s)
Antigens, CD/metabolism , Bacterial Proteins/pharmacology , Host Microbial Interactions/drug effects , Lipopeptides/pharmacology , Mycobacterium tuberculosis/immunology , Tuberculosis/immunology , Alanine/genetics , Animals , Antigens, CD/chemistry , Antigens, CD/genetics , Bacterial Proteins/chemical synthesis , Lipopeptides/chemical synthesis , Lipopeptides/chemistry , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/genetics , Primary Cell Culture , Threonine/genetics , Toll-Like Receptor 2/chemistry , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/metabolism , Tuberculosis/microbiology
7.
Front Immunol ; 8: 1633, 2017.
Article in English | MEDLINE | ID: mdl-29230217

ABSTRACT

Tuberculosis (TB) remains a major global health threat. Urgent needs in the fight against TB include improved and innovative treatment options for drug-sensitive and -resistant TB as well as reliable biological indicators that discriminate active from latent disease and enable monitoring of treatment success or failure. Prominent interferon (IFN) inducible gene signatures in TB patients and animal models of Mycobacterium tuberculosis infection have drawn significant attention to the roles of type I IFNs in the host response to mycobacterial infections. Here, we review recent developments in the understanding of the innate immune pathways that drive type I IFN responses in mycobacteria-infected host cells and the functional consequences for the host defense against M. tuberculosis, with a view that such insights might be exploited for the development of targeted host-directed immunotherapies and development of reliable biomarkers.

8.
J Leukoc Biol ; 101(1): 183-192, 2017 01.
Article in English | MEDLINE | ID: mdl-27067450

ABSTRACT

Radioprotective 105 kDa (CD180) is an unusual TLR that lacks an intracellular Toll-IL-1R signaling domain and exhibits unconventional homodimerization behavior. Differential expression and functions of radioprotective 105 kDa have been associated with immune-mediated pathologies, including infection, chronic inflammation, and autoimmune disorders. Radioprotective 105 kDa activates macrophages and B cells independently of canonical TLR signaling. Current understanding of the functional consequences of radioprotective 105 kDa signaling in B cells, macrophages, and dendritic cells indicates overlapping, but also some apparent opposing, cell-specific roles for radioprotective 105 kDa in shaping cellular functions. This review compares interactions of radioprotective 105 kDa with its coreceptors, CD19, TLR4, and TLR2; integrates recent, novel findings on radioprotective 105 kDa-mediated molecular signaling mechanisms; and summarizes current understanding of its contributions to infectious, inflammatory, and autoimmune disease.


Subject(s)
Antigens, CD/metabolism , Autoimmune Diseases/immunology , Autoimmune Diseases/physiopathology , Signal Transduction , Animals , B-Lymphocytes/immunology , Humans , Lymphocyte Activation/immunology , Toll-Like Receptors/metabolism
9.
J Immunol ; 195(8): 3890-900, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26371254

ABSTRACT

Cytokines are key regulators of adequate immune responses to infection with Mycobacterium tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR family member RP105 (CD180) in promoting mycobacteria-induced cytokine production by macrophages. Our data show that the significantly reduced release of TNF and IL-6 by RP105(-/-) macrophages during mycobacterial infection was not accompanied by diminished mRNA or protein expression. Mycobacteria induced comparable activation of NF-κB and p38 MAPK signaling in wild-type (WT) and RP105(-/-) macrophages. In contrast, mycobacteria-induced phosphorylation of Akt was abrogated in RP105(-/-) macrophages. The p110δ-specific inhibitor, Cal-101, and small interfering RNA-mediated knockdown of p110δ diminished mycobacteria-induced TNF secretion by WT but not RP105(-/-) macrophages. Such interference with p110δ activity led to reduced surface-expressed TNF in WT but not RP105(-/-) macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton's tyrosine kinase was required for RP105-mediated activation of Akt phosphorylation and TNF release by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine responses of macrophages and provide molecular insight into the functions of RP105 as an innate immune receptor for mycobacteria.


Subject(s)
Antigens, CD/immunology , Class I Phosphatidylinositol 3-Kinases/immunology , MAP Kinase Signaling System/immunology , Mycobacterium tuberculosis/immunology , Tuberculosis/immunology , Tumor Necrosis Factor-alpha/immunology , Animals , Antigens, CD/genetics , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/genetics , Enzyme Inhibitors/pharmacology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Knockout , Protein Transport/drug effects , Protein Transport/genetics , Protein Transport/immunology , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/immunology , Purines/pharmacology , Quinazolinones/pharmacology , Tuberculosis/genetics , Tuberculosis/pathology , Tumor Necrosis Factor-alpha/genetics , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/immunology
10.
AANA J ; 76(3): 189-91, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18567322

ABSTRACT

The obligatory use of fluoroscopy for placement of epidural steroids is controversial. Proponents of the use of fluoroscopy cite studies that report up to 35% rates of inaccurate placement of epidural needles without the aid of fluoroscopic imaging. This case study presents a situation in which a loss-of-resistance technique resulted in an inadvertent discogram.


Subject(s)
Fluoroscopy/methods , Injections, Epidural/adverse effects , Intervertebral Disc/injuries , Low Back Pain/drug therapy , Medication Errors/adverse effects , Radiography, Interventional/methods , Aged , Anti-Inflammatory Agents/administration & dosage , Betamethasone/administration & dosage , Female , Humans , Injections, Epidural/methods , Low Back Pain/diagnosis , Low Back Pain/etiology , Lumbar Vertebrae , Magnetic Resonance Imaging , Medication Errors/methods , Myelography , Pain Measurement , Spinal Stenosis/complications , Spinal Stenosis/diagnosis
11.
AANA J ; 73(1): 35-6, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15727281

ABSTRACT

This case report describes the use of sevoflurane in a 26-year-old woman who presented to a rural critical access hospital emergency department in status asthmaticus and subsequently failed conventional therapy. Although the use of potent inhalation agents in the treatment of refractory status asthmaticus has been documented, there is little written about the use of sevoflurane in this situation. Sevoflurane was administered for approximately 2(1/2) hours, stabilizing the patient's condition enough to allow fixed-wing air transport to a tertiary facility.


Subject(s)
Anesthetics, Inhalation/therapeutic use , Methyl Ethers/therapeutic use , Status Asthmaticus/drug therapy , Adult , Female , Humans , Sevoflurane
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