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1.
Cancer Discov ; 6(12): 1366-1381, 2016 12.
Article in English | MEDLINE | ID: mdl-27683557

ABSTRACT

Programmed death-1 (PD-1) is a coinhibitory receptor that downregulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TILs have not been fully investigated. We demonstrate that TGFß1 enhances antigen-induced PD-1 expression through SMAD3-dependent, SMAD2-independent transcriptional activation in T cells in vitro and in TILs in vivo The PD-1hi subset seen in CD8+ TILs is absent in Smad3-deficient tumor-specific CD8+ TILs, resulting in enhanced cytokine production by TILs and in draining lymph nodes and antitumor activity. In addition to TGFß1's previously known effects on T-cell function, our findings suggest that TGFß1 mediates T-cell suppression via PD-1 upregulation in the tumor microenvironment (TME). They highlight bidirectional cross-talk between effector TILs and TGFß-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit antitumor immunity. SIGNIFICANCE: Engagement of the coinhibitory receptor PD-1 or its ligand, PD-L1, dramatically inhibits the antitumor function of TILs within the TME. Our findings represent a novel immunosuppressive function of TGFß and demonstrate that TGFß1 allows tumors to evade host immune responses in part through enhanced SMAD3-mediated PD-1 expression on TILs. Cancer Discov; 6(12); 1366-81. ©2016 AACRThis article is highlighted in the In This Issue feature, p. 1293.


Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Neoplasms/immunology , Programmed Cell Death 1 Receptor/genetics , Smad3 Protein/metabolism , Transforming Growth Factor beta1/metabolism , Animals , Cell Line, Tumor , Cytokines/metabolism , Drug Resistance, Neoplasm , Humans , Jurkat Cells , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Neoplasms/metabolism , Programmed Cell Death 1 Receptor/metabolism , Signal Transduction , Tumor Microenvironment
2.
J Appl Physiol (1985) ; 120(6): 592-8, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26769954

ABSTRACT

Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit muscle mass. In adult animals, MSTN is made almost exclusively by skeletal muscle and circulates in the blood. A critical question is whether this circulating MSTN protein can enter the active pool to regulate muscle growth or whether all of the activity of MSTN results from locally produced protein. Here, we addressed this question in mice by using a Cdx2-Cre transgene in conjunction with a conditional Mstn-flox allele to generate mice in which Mstn was targeted in a regionally restricted manner. Specifically, we generated mosaic mice in which MSTN production was eliminated in posteriorly located muscles but not in anteriorly located muscles, resulting in mice in which circulating levels of MSTN were reduced roughly by half. Analysis of posteriorly located vs. anteriorly located muscles of these mice revealed clear differential effects indicative of an important paracrine role for MSTN in regulating muscle mass. Significant, albeit more subtle, effects consistent with an endocrine mode of MSTN action were also seen in these mice. These findings have important implications not only for the understanding of the physiological control of muscle mass but also for therapeutic strategies to target MSTN to treat patients with muscle loss.


Subject(s)
Endocrine Cells/physiology , Muscle, Skeletal/physiology , Myostatin/metabolism , Paracrine Communication/physiology , Alleles , Animals , CDX2 Transcription Factor/genetics , Endocrine Cells/metabolism , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic/genetics , Mice, Transgenic/physiology , Muscle, Skeletal/metabolism , Myostatin/genetics , Paracrine Communication/genetics , Signal Transduction/genetics , Signal Transduction/physiology
3.
Proc Natl Acad Sci U S A ; 109(35): E2353-60, 2012 Aug 28.
Article in English | MEDLINE | ID: mdl-22869749

ABSTRACT

Myostatin and activin A are structurally related secreted proteins that act to limit skeletal muscle growth. The cellular targets for myostatin and activin A in muscle and the role of satellite cells in mediating muscle hypertrophy induced by inhibition of this signaling pathway have not been fully elucidated. Here we show that myostatin/activin A inhibition can cause muscle hypertrophy in mice lacking either syndecan4 or Pax7, both of which are important for satellite cell function and development. Moreover, we show that muscle hypertrophy after pharmacological blockade of this pathway occurs without significant satellite cell proliferation and fusion to myofibers and without an increase in the number of myonuclei per myofiber. Finally, we show that genetic ablation of Acvr2b, which encodes a high-affinity receptor for myostatin and activin A specifically in myofibers is sufficient to induce muscle hypertrophy. All of these findings are consistent with satellite cells playing little or no role in myostatin/activin A signaling in vivo and render support that inhibition of this signaling pathway can be an effective therapeutic approach for increasing muscle growth even in disease settings characterized by satellite cell dysfunction.


Subject(s)
Activins/metabolism , Muscle Fibers, Skeletal/cytology , Myostatin/metabolism , Satellite Cells, Skeletal Muscle/cytology , Signal Transduction/physiology , Activin Receptors, Type II/genetics , Activin Receptors, Type II/metabolism , Animals , Follistatin/genetics , Follistatin/metabolism , Hypertrophy , Membrane Fusion/physiology , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/cytology , Muscle, Skeletal/physiology , Organ Size , PAX7 Transcription Factor/genetics , PAX7 Transcription Factor/metabolism , Regeneration/physiology , Satellite Cells, Skeletal Muscle/metabolism , Syndecan-4/genetics , Syndecan-4/metabolism
4.
BMC Dev Biol ; 9: 24, 2009 Mar 19.
Article in English | MEDLINE | ID: mdl-19298661

ABSTRACT

BACKGROUND: Myostatin (Mstn) and growth/differentiation factor 11 (Gdf11) are highly related transforming growth factor beta (TGFbeta) family members that play important roles in regulating embryonic development and adult tissue homeostasis. Despite their high degree of sequence identity, targeted mutations in these genes result in non-overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of Gdf11 in mice causes dramatic anterior homeotic transformations of the axial skeleton, kidney agenesis, and an increase in progenitor cell number in several tissues. In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules. RESULTS: We show that Mstn-/- Gdf11-/- mice have more extensive homeotic transformations of the axial skeleton than Gdf11-/- mice in addition to skeletal defects not seen in single mutants such as extra forelimbs. We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn+/+ or Mstn-/- mice does not affect muscle size, fiber number, or fiber type. CONCLUSION: These results provide evidence that myostatin and Gdf11 have redundant functions in regulating skeletal patterning in mice but most likely not in regulating muscle size.


Subject(s)
Bone Development , Bone Morphogenetic Proteins/metabolism , Gene Expression Regulation, Developmental , Growth Differentiation Factors/metabolism , Muscle, Skeletal/embryology , Myostatin/metabolism , Animals , Bone Morphogenetic Proteins/genetics , Female , Growth Differentiation Factors/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myostatin/genetics
5.
Hawaii Med J ; 66(12): 328-30, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18269092

ABSTRACT

This paper focuses on a promising health care intervention--mindfulness meditation--that is the subject of considerable and increasing interest. The authors describe what mindfulness means, how it has been applied in patient and non-patient populations, and current activities in Hawai'i.


Subject(s)
Attention , Awareness , Meditation/methods , Stress, Psychological/therapy , Buddhism , Education, Medical/methods , Hawaii , Humans , Medical Oncology/methods , Patient Education as Topic/methods
6.
J Neurosurg Spine ; 3(2): 159-64, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16370306

ABSTRACT

Osteoradionecrosis is a process of dysvascular bone necrosis and fibrous replacement following exposure to high doses of radiation. The poorly vascularized necrotic tissue may cause pain and/or instability, and it cannot resist infection well, which may result in secondary osteomyelitis. When these processes affect the cervical spine, the resulting instability and neurological deficits can be devastating, and immediate reestablishment of spinal stability is paramount. Reconstruction of the cervical spine can be particularly challenging in this subgroup of patients in whom the spine is poorly vascularized after radical surgery, high-dose irradiation, and infection. The authors report three cases of cervical spine osteoradionecrosis following radiotherapy for primary head and neck malignancies. Two patients suffered secondary osteomyelitis, severe spinal deformity, and spinal cord compression. These patients underwent surgery in which a vascularized fibular graft and instrumentation were used to reconstruct the cervical spine; subsequently hyperbaric oxygen (HBO) therapy was instituted. Fusion occurred, spinal stability was restored, and neurological dysfunction resolved at the 2- and 4-year follow-up examinations, respectively. The third patient experienced pain and dysphagia but did not have osteomyelitis, spinal instability, or neurological deficits. He underwent HBO therapy alone, with improved symptoms and imaging findings. Hyperbaric oxygen is an essential part of treatment for osteoradionecrosis and may be sufficient by itself for uncomplicated cases, but surgery is required for patients with spinal instability, spinal cord compression, and/or infection. A vascularized fibular bone graft is a very helpful adjunct in these patients because it adds little morbidity and may increase the rate of spinal fusion.


Subject(s)
Carcinoma, Squamous Cell/radiotherapy , Cervical Vertebrae/radiation effects , Head and Neck Neoplasms/radiotherapy , Osteoradionecrosis/etiology , Radiation Injuries/complications , Aged , Cervical Vertebrae/pathology , Cervical Vertebrae/surgery , Epidural Abscess/diagnosis , Epidural Abscess/etiology , Humans , Hyperbaric Oxygenation , Kyphosis/diagnostic imaging , Kyphosis/etiology , Magnetic Resonance Imaging , Male , Middle Aged , Osteomyelitis/etiology , Osteomyelitis/surgery , Osteoradionecrosis/diagnostic imaging , Osteoradionecrosis/therapy , Radiography , Spinal Cord Compression/etiology , Spinal Cord Compression/surgery , Spinal Fusion
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