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1.
Stem Cells ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31837053

RESUMO

Osteoarthritis (OA) is a disease of an entire synovial joint characterized by clinical symptoms and distortion of joint tissues including cartilage, muscles, ligaments and bone. While OA is a disease of all joint tissues it is a defined accessible compartment and is thus amenable to topical surgical and regenerative therapies, including stem cells. All tissues arise from stem progenitor cells, and the relative capacity of different cellular compartments, and different individuals, to renew tissues into adulthood may be important in the onset of many different degenerative diseases. OA is driven by both mechanical and inflammatory factors, but how these impacts the proliferation and differentiation of cells into cartilage in vivo is largely unknown. Indeed, our very basic understanding of the physiological cellular kinetics and biology of the stem-progenitor cell unit of the articular cartilage, and how this is influenced by mechanoinflammatory injury, is largely unknown. OA seems, rather deceptively, to be the low-hanging fruit for stem cell therapy. Without the basic understanding of the stem cell and progenitor unit that generate and maintain articular cartilage in vivo, we will continue to waste opportunities to both prevent and manage this disease. In this review, we discuss the biology of chondrogenesis, the stem cell populations that support articular cartilage in health and disease and future opportunities afforded through the translation of basic articular chondrocyte stem cell biology into new clinical therapies. © AlphaMed Press 2019 SIGNIFICANCE STATEMENT: Despite much promise for stem cell-based therapy in osteoarthritis (OA), results have by far fallen short on their potential. Are our current knowledge of the stem cell biology of the articular cartilage reflective of their potential in health and disease? Can we expand on the current understanding of the promise and practice of stem cell therapy for OA? This concise review discuss about the new development in articular stem cell biology as well as the current clinical practice of stem cell-based therapy for OA.

2.
JBJS Case Connect ; 9(4): e0404, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31703012

RESUMO

CASE: A 25-year-old man presented with chronic bone and soft tissue infection of the right thigh following resection and radiation of epithelioid sarcoma. Multiple revisions and debridement procedures had failed to control the infection and left him unable to ambulate. We describe a modified Van Nes rotationplasty using a constrained, prosthetic hip between the tibia and pelvis following femur resection. With 18 months of follow-up, the patient was able to walk with a prosthetic device without evidence of recurrent infection. CONCLUSIONS: We report this rotationplasty as a potential approach to avoid hip disarticulation in cases requiring extensive debridement for incurable infection.

5.
Exp Mol Med ; 51(4): 50, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028244

RESUMO

Toll-like receptors (TLRs) recognize pathogen/damage-associated molecular patterns and initiate inflammatory signaling cascades. Occasionally, overexpression of TLRs leads to the onset of numerous inflammatory diseases, necessitating the development of selective inhibitors to allow a protective yet balanced immune response. Here, we demonstrate that a novel peptide (TIP1) derived from Toll/interleukin-1 receptor (TIR) domain-containing adapter protein inhibited multiple TLR signaling pathways (MyD88-dependent and MyD88-independent) in murine and human cell lines. TIP1 also inhibited NLRP3-mediated IL-1ß secretion, as we validated at both the protein and mRNA levels. Biophysical experiments confirmed that TIP1 specifically binds to the BB loop of the TLR4-TIR domain. Animal studies revealed that TIP1 inhibited the secretion of lipopolysaccharide (LPS)-induced proinflammatory cytokines in collagen-induced arthritis (CIA) and kaolin/carrageenan-induced arthritis (K/C) rodent models. TIP1 also rescued animals from sepsis and from LPS-induced kidney/liver damage. Importantly, TIP1 ameliorated the symptoms of rheumatoid arthritis in CIA and K/C rodent models, suggesting that TIP1 has therapeutic potential for the treatment of TLR-mediated autoimmune/inflammatory diseases.

6.
Sci Adv ; 5(2): eaav2437, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30801016

RESUMO

While a fraction of cancer patients treated with anti-PD-1 show durable therapeutic responses, most remain unresponsive, highlighting the need to better understand and improve these therapies. Using an in vivo screening approach with a customized shRNA pooled library, we identified DDR2 as a leading target for the enhancement of response to anti-PD-1 immunotherapy. Using isogenic in vivo murine models across five different tumor histologies-bladder, breast, colon, sarcoma, and melanoma-we show that DDR2 depletion increases sensitivity to anti-PD-1 treatment compared to monotherapy. Combination treatment of tumor-bearing mice with anti-PD-1 and dasatinib, a tyrosine kinase inhibitor of DDR2, led to tumor load reduction. RNA-seq and CyTOF analysis revealed higher CD8+ T cell populations in tumors with DDR2 depletion and those treated with dasatinib when either was combined with anti-PD-1 treatment. Our work provides strong scientific rationale for targeting DDR2 in combination with PD-1 inhibitors.

7.
Am J Clin Oncol ; 42(3): 231-237, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30811352

RESUMO

BACKGROUND: Historically, nontargeted adjuvant therapies such as liquid nitrogen, phenol, argon beam, and alcohol have been applied locally after curettage of giant cell tumors (GCT) in the extremities. Systemic bisphosphonates (BP) and denosumab have emerged as osteoclast-targeting therapies because osteoclast-like giant cells, responsible for aggressive bone resorption, are susceptible to BP or denosumab. However, such drugs may cause systemic side effects. We examined the effects of an alternative intraoperative local delivery of BP on GCTs. MATERIALS AND METHODS: In total, 17 patients with GCTs underwent extended surgical curettage procedures consisting of high-speed burring, traditional adjuvant therapy, and application of BP-loaded polymethylmethacrylate bone cement. Clinical data and follow-up radiographs were reviewed to investigate local recurrence (LR) rate and complications in a retrospective manner. RESULTS: There were 6 males and 11 females (mean age, 33.7 y). There were no cases of pulmonary metastases. Patient follow-up ranged from 1 to 12 years. There was 1 LR during the follow-up period for an LR rate of 5.9%. The mean final Musculoskeletal Tumor Society (MSTS) score was 29. There were no systemic or localized avascular necrosis or atypical fractures related to BPs noted. CONCLUSIONS: BP-loaded polymethylmethacrylate is a targeted local adjuvant therapy that is feasible, safe, and may reduce LRs while alleviating the risk of systemic side effects of BPs such as avascular necrosis of jaw and atypical femur fractures. Future prospective randomized clinical trials will strengthen the level of evidence of this proposed targeted therapy. LEVEL OF EVIDENCE: Therapeutic level IV-see instructions for authors for a complete description of evidence.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Cimentos para Ossos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/uso terapêutico , Tumor de Células Gigantes do Osso/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Neoplasias Ósseas/patologia , Feminino , Seguimentos , Tumor de Células Gigantes do Osso/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Adulto Jovem
8.
Instr Course Lect ; 68: 547-556, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32032068

RESUMO

Metastatic bone disease is a substantial driver of morbidity and mortality in many cancers. The presence of bone metastases often indicates a worse prognosis for patients. The mechanisms underlying bone metastases and bone loss are complex and involve interaction between the local factors controlling bone remodeling, systemic regulators, cancer cells, the immune system, and pharmaceutical agents. Cancer cells hone to and initiate interactions with bone cells, thereby resulting in an increase or decrease of local bone mass. Osteolytic metastases are clinically important because they place patients at risk of skeletally related events. In the era of precision medicine and targeted therapies, several pathways have been identified that can serve as targets for new drugs. Therefore, it becomes necessary to understand the molecular mechanisms governing normal bone homeostasis and cancer-induced bone loss to optimally use available and emerging therapeutic modalities for the benefit of patients with skeletal metastases. When pharmacologic or radiation therapies do not block the pathogenesis of metastatic cancer-induced bone loss, surgical stabilization and reinforcement procedures are performed based on size of the lesion, location, degree of osteolysis, and pain. These interventions are performed with the goal of improving patient function and overall outcome.

9.
Instr Course Lect ; 68: 557-566, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32032067

RESUMO

Advancements in medical and radiation oncology have improved the prognosis for many cancers during the past few decades. As a result, physicians are challenged with managing a greater burden of disease for a longer time. In orthopaedics, bone loss secondary to metastatic tumor places patients at risk of impending and pathologic fractures. These events limit functional independence, lessen the quality of life, and place a financial burden on patients and their families. Thus, it is important for clinicians to be aware of measures capable of mitigating cancer-induced bone loss.

10.
Instr Course Lect ; 68: 607-612, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32032089

RESUMO

Skeletal metastases of the femur and tibia leading to pathologic fractures or large skeletal defects can be managed with surgical reconstruction, resulting in improved patient outcomes and functionality. The indications for femoral and tibial reconstruction are dependent on several factors, including goals of management, age, comorbidities, site and extent of the lesion, soft-tissue involvement, and history of radiation or other systemic therapy. The goal of reconstruction of large bone defects is to restore anatomy and function while minimizing the risk of complications, implant failure, and subsequent revision procedure. Common reconstructive options include fixation with plates and screws, intramedullary nails, and endoprosthesis implantation.

11.
J Nutr Biochem ; 52: 54-61, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29149648

RESUMO

Dried plum (DP), a rich source of polyphenols has been shown to have bone-preserving properties in both animal models of osteoporosis and postmenopausal women. We evaluated if DP alleviated the destruction of joints in transgenic mice (TG) that overexpress human tumor necrosis factor (TNF), a genetic model of rheumatoid arthritis (RA). A four-week treatment of 20% DP diet in TG slowed the onset of arthritis and reduced bone erosions in the joints compared to TG on a regular diet. This was associated with fewer tartrate-resistant acid phosphatase (TRAP) positive cells, suggesting decreased osteoclastogenesis. A DP diet also produced significant protection of articular cartilage and reduction of synovitis. Cultures of human synovial fibroblast in the presence of TNF showed a significant increase in inflammatory interleukin (IL)-1ß, chemokines (monocyte chemoattractant protein-1: MCP1 & macrophage inflammatory protein-1 alpha: MIP1α), cartilage matrix metalloproteinases (MMP1&3), and an osteoclastogenic cytokine (receptor activator of nuclear factor-κB ligand: RANKL) compared to controls. Addition of neochlorogenic acid (NC), a major polyphenol in DP to these cultures resulted in down-regulation of these genes. In the cultures of mouse bone marrow macrophage, NC also repressed TNF-induced formation of osteoclasts and mRNA levels of cathepsin K and MMP9 through inhibition of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression and nuclear factor kappa B (NF-κB) activation. Our data suggested that dietary supplementation with DP inhibited TNF singling; leading to decreased erosions of bone and articular cartilage as well as synovitis.


Assuntos
Artrite Reumatoide/dietoterapia , Ácido Clorogênico/análogos & derivados , Prunus domestica , Ácido Quínico/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Reumatoide/fisiopatologia , Reabsorção Óssea/dietoterapia , Reabsorção Óssea/tratamento farmacológico , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Ácido Clorogênico/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteogênese/efeitos dos fármacos , Prunus domestica/química , Ácido Quínico/farmacologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Sinovite/dietoterapia , Sinovite/prevenção & controle
12.
Mol Cancer Ther ; 16(12): 2759-2769, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28978720

RESUMO

Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin [mean combination index (CI) value, 0.54 and 0.85, respectively, P = 0.01]. On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI, 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line- and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel and that wild-type KRAS and BRAF status may predict better patient response to the combination therapy. Mol Cancer Ther; 16(12); 2759-69. ©2017 AACR.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos Fitogênicos/uso terapêutico , Benzodiazepinonas/uso terapêutico , Paclitaxel/uso terapêutico , Adenocarcinoma , Adenocarcinoma de Pulmão , Animais , Antineoplásicos Fitogênicos/farmacologia , Benzodiazepinonas/farmacologia , Feminino , Humanos , Neoplasias Pulmonares , Camundongos , Camundongos Endogâmicos NOD , Paclitaxel/farmacologia , Transfecção
13.
J Orthop Res ; 35(12): 2658-2666, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28460421

RESUMO

Osteoclasts play key roles in bone remodeling and pathologic osteolytic disorders such as inflammation, infection, bone implant loosening, rheumatoid arthritis, metastatic bone cancers, and pathological fractures. Osteoclasts are formed by the fusion of monocytes in response to receptor activators of NF-κB-ligand (RANKL) and macrophage colony stimulating factor 1 (M-CSF). Calreticulin (CRT), a commonly known intracellular protein as a calcium-binding chaperone, has an unexpectedly robust anti-osteoclastogenic effect when its recombinant form is applied to osteoclast precursors in vitro or at the site of bone inflammation externally in vivo. Externally applied Calreticulin was internalized inside the cells. It inhibited key pro-osteoclastogenic transcription factors such as c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-in osteoclast precursor cells that were treated with RANKL in vitro. Recombinant human Calreticulin (rhCRT) inhibited lipopolysaccharide (LPS)-induced inflammatory osteoclastogenesis in the mouse calvarial bone in vivo. Cathepsin K molecular imaging verified decreased Cathepsin K activity when rhCalreticulin was applied at the site of LPS application in vivo. Recombinant forms of intracellular proteins or their derivatives may act as novel extracellular therapeutic agents. We anticipate our findings to be a starting point in unraveling hidden extracellular functions of other intracellular proteins in different cell types of many organs for new therapeutic opportunities. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2658-2666, 2017.


Assuntos
Reabsorção Óssea/prevenção & controle , Calreticulina/uso terapêutico , Osteogênese/efeitos dos fármacos , Clorometilcetonas de Aminoácidos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Calreticulina/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fatores de Transcrição NFATC/antagonistas & inibidores , Proteômica
14.
FASEB J ; 31(9): 3991-3998, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28533328

RESUMO

Tendon stem/progenitor cells (TSCs) have been found in different anatomic locations and showed a promising regenerative potential. We identified a role of TSCs in the regulation of inflammation during healing of acute tendon injuries. Delivery of connective tissue growth factor (CTGF) into full-transected rat patellar tendons significantly increased the number of CD146+ TSCs, leading to enhanced healing. In parallel, CTGF delivery significantly reduced the number of iNOS+ M1 macrophages and increased the expression of anti-inflammatory IL-10 at 2 d after surgery, with over 85% CD146+ TSCs expressing IL-10. By 1 wk, the elevated IL-10 expression remained, and IL-6 expression was significantly attenuated in CTGF-delivered tendon healing. Matrix metalloproteinase (MMP)-3 expression in CTGF-delivered tendon was organized along with the reorienting collagen fibers by 1 wk after surgery, in comparison with the control group showing the abundant MMP-3 expression localized at healing junction. Tissue inhibitor of metalloprotease (TIMP)-3 was expressed in CD146+ TSCs at 1 wk with CTGF, in contrast to control with no TIMP-3 expression. In vitro, IL-10 expression was detected only when tendon cells were stimulated with IL-1ß, and CTGF and significantly higher in CD146+ TSCs than CD146- tendon cells. Similarly, TIMP-3 expression was detected only when treated with CTGF or CTGF and IL-1ß that is significantly higher in CD146+ TSCs compared to CD146- tendon cells. Signaling study with specific inhibitors and Western blot analysis demonstrated that CTGF-induced expression of IL-10 and TIMP-3 in CD146+ TSCs are regulated by JNK/signal transducer and activator of transcription 3 signaling. Taken together, these findings suggest anti-inflammatory roles of CTGF-stimulated TSCs that are likely associated with improved tendon healing.-Tarafder, S., Chen, E., Jun, Y., Kao, K., Sim, K. H., Back, J., Lee, F. Y., Lee, C. H. Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling.


Assuntos
Inflamação/metabolismo , MAP Quinase Quinase 4/metabolismo , Fator de Transcrição STAT3/metabolismo , Tendões/citologia , Animais , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/fisiologia , MAP Quinase Quinase 4/genética , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Transdução de Sinais , Células-Tronco , Traumatismos dos Tendões , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismo
15.
Cancer Immunol Res ; 5(2): 157-169, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28073775

RESUMO

Dasatinib, a broad-range tyrosine kinase inhibitor, induces rapid mobilization of lymphocytes and clonal expansion of cytotoxic cells in leukemia patients. Here, we investigated whether dasatinib could induce beneficial immunomodulatory effects in solid tumor models. The effects on tumor growth and on the immune system were studied in four different syngeneic mouse models (B16.OVA melanoma, 1956 sarcoma, MC38 colon, and 4T1 breast carcinoma). Both peripheral blood (PB) and tumor samples were immunophenotyped during treatment. Although in vitro dasatinib displayed no direct cytotoxicity to B16 melanoma cells, a significant decrease in tumor growth was observed in dasatinib-treated mice compared with vehicle-treated group. Further, dasatinib-treated melanoma-bearing mice had an increased proportion of CD8+ T cells in PB, together with a higher amount of tumor-infiltrating CD8+ T cells. Dasatinib-mediated antitumor efficacy was abolished when CD4+ and CD8+ T cells were depleted with antibodies. Results were confirmed in sarcoma, colon, and breast cancer models, and in all cases mice treated daily with dasatinib had a significant decrease in tumor growth. Detailed immunophenotyping of tumor tissues with CyTOF indicated that dasatinib had reduced the number of intratumoral regulatory T cells in all tumor types. To conclude, dasatinib is able to slow down the tumor growth of various solid tumor models, which is associated with the favorable blood/tumor T-cell immunomodulation. The assessment of synergistic combinatorial therapies with other immunomodulatory drugs or targeted small-molecule oncokinase inhibitors is warranted in future clinical trials. Cancer Immunol Res; 5(2); 157-69. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Dasatinibe/farmacologia , Imunomodulação/efeitos dos fármacos , Neoplasias/imunologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos
16.
Sci Robot ; 2(2)2017 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31289767

RESUMO

Implantable microdevices often have static components rather than moving parts, and exhibit limited biocompatibility. This paper demonstrates a fast manufacturing method which can produce features in biocompatible materials down to tens of microns in scale, with intricate and composite patterns in each layer. By exploiting unique mechanical properties of hydrogels, we developed a "locking mechanism" for precise actuation and movement of freely moving parts, which can provide functions such as valves, manifolds, rotors, pumps, and delivery of payloads. Hydrogel components could be tuned within a wide range of mechanical and diffusive properties, and can be controlled after implantation without a sustained power supply. In a mouse model of osteosarcoma, triggering of release of doxorubicin from the device over ten days showed high treatment efficacy and low toxicity, at one-tenth of a standard systemic chemotherapy dose. Overall, this platform, called "iMEMS", enables development of biocompatible implantable microdevices with a wide range of intricate moving components that can be wirelessly controlled on demand, in a manner that solves issues of device powering and biocompatibility.

17.
Acta Pharm Sin B ; 6(5): 460-467, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27709015

RESUMO

To assess targeting of an epothilone folate conjugate (BMS-753493) to the folate receptor (FR)-overexpressed tumor in mice bearing both FR+ and FR- tumors, a series of experiments were conducted by quantitative whole-body autoradiography (QWBA) and LC-MS/MS following i.v. administration of BMS-753493 or its active moiety, BMS-748285 in mice bearing FR+ (98M109) and FR- (M109) tumors. QWBA showed [3H]BMS-753493-derived radioactivity was extensively distributed to various tissues. The FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors (i.e., M109 tumors) up to 48 h post dose of [3H]BMS-753493, despite the magnitude of difference between the tumors is relatively small (generally 3~5-fold). The radioactivity level in 98M109 tumors was 2~12-fold of normal tissues except intestine/content at 48 h post dose. No selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after i.v. administration of the active epothilone, [3H]BMS-748285. LC-MS/MS measurements demonstrated that the concentrations of BMS-748285, presumably from hydrolysis of the folate conjugate, in 98M109 tumors were greater than those in M109 tumors after i.v. administration of BMS-753493 (2-3-fold) whereas no differential uptake in the tumors following BMS-748285 administration. Those data were consistent with radioactivity determinations. Those results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR over-expressing 98M109 tumors, thereby supporting targeted delivery of cytotoxics through the folate receptor.

18.
Regen Med ; 11(2): 211-22, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26877156

RESUMO

Autograft, while currently the gold standard for bone grafting, has several significant disadvantages including limited supply, donor site pain, hematoma formation, nerve and vascular injury, and fracture. Bone allografts have their own disadvantages including reduced osteoinductive capability, lack of osteoprogenitor cells, immunogenicity and risk of disease transmission. Thus demand exists for tissue-engineered constructs that can produce viable bone while avoiding the complications associated with human tissue grafts. This review will focus on recent advancements in tissue-engineered bone graft substitutes utilizing nanoscale technology in spine surgery applications. An evaluation will be performed of bone graft substitutes, biomimetic 3D scaffolds, bone morphogenetic protein, mesenchymal stem cells and intervertebral disc regeneration strategies.


Assuntos
Materiais Biomiméticos , Osso e Ossos , Coluna Vertebral/cirurgia , Engenharia Tecidual/métodos , Tecidos Suporte , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Humanos , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia
19.
Endocrinology ; 157(1): 112-26, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26488807

RESUMO

Protein kinase A (PKA) regulates osteoblast cell function in vitro and is activated by important bone mass modulating agents. We determined whether PKA activation in osteoblasts is sufficient to mediate a bone anabolic response. Thus, a mouse model conditionally expressing a constitutively active PKA (CA-PKA) in osteoblasts (CA-PKA-OB mouse) was developed by crossing a 2.3-kb α1 (I)-collagen promoter-Cre mouse with a floxed-CA-PKA mouse. Primary osteoblasts from the CA-PKA-OB mice exhibited higher basal PKA activity than those from control mice. Microcomputed tomographic analysis revealed that CA-PKA-OB female mice had an 8.6-fold increase in femoral but only 1.16-fold increase in lumbar 5 vertebral bone volume/total volume. Femur cortical thickness and volume were also higher in the CA-PKA-OB mice. In contrast, alterations in many femoral microcomputed tomographic parameters in male CA-PKA-OB mice were modest. Interestingly, the 3-dimensional structure model index was substantially lower both in femur and lumbar 5 of male and female CA-PKA-OB mice, reflecting an increase in the plate to rod-like structure ratio. In agreement, femurs from female CA-PKA-OB mice had greater load to failure and were stiffer compared with those of control mice. Furthermore, the CA-PKA-OB mice had higher levels of serum bone turnover markers and increased osteoblast and osteoclast numbers per total tissue area compared with control animals. In summary, constitutive activation of PKA in osteoblasts is sufficient to increase bone mass and favorably modify bone architecture and improve mechanical properties. PKA activation in mature osteoblasts is, therefore, an important target for designing anabolic drugs for treating diseases with bone loss.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fêmur/citologia , Vértebras Lombares/citologia , Osteócitos/enzimologia , Osteogênese , Mutação Puntual , Regulação para Cima , Proteínas Quinases Ativadas por AMP/genética , Animais , Densidade Óssea , Células Cultivadas , Metabolismo Energético , Ativação Enzimática , Feminino , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoblastos/citologia , Osteoblastos/enzimologia , Osteoblastos/metabolismo , Osteócitos/citologia , Osteócitos/metabolismo , Regiões Promotoras Genéticas , Caracteres Sexuais , Microtomografia por Raio-X
20.
Clin Biomech (Bristol, Avon) ; 30(10): 1114-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26386637

RESUMO

BACKGROUND: Large segmental bone defects following tumor resection, high-energy civilian trauma, and military blast injuries present significant clinical challenges. Tissue engineering strategies using scaffolds are being considered as a treatment, but there is little research into optimal fixation of such scaffolds. METHODS: Twelve fresh-frozen paired cadaveric legs were utilized to simulate a critical sized intercalary defect in the tibia. Poly-ε-caprolactone and hydroxyapatite composite scaffolds 5 cm in length with a geometry representative of the mid-diaphysis of an adult human tibia were fabricated, inserted into a tibial mid-diaphyseal intercalary defect, and fixed with a 14-hole large fragment plate. Optimal screw fixation comparing non-locking and locking screws was tested in axial compression, bending, and torsion in a non-destructive manner. A cyclic torsional test to failure under torque control was then performed. FINDINGS: Biomechanical testing showed no significant difference for bending or axial stiffness with non-locking vs. locking fixation. Torsional stiffness was significantly higher (P=0.002) with the scaffold present for both non-locking and locking compared to the scaffold absent. In testing to failure, angular rotation was greater for the non-locking compared to locking constructs at each torque level up to 40 N-m (P<0.05). The locking constructs survived a significantly higher number of loading cycles before reaching clinical failure at 30 degrees of angular rotation (P<0.02). INTERPRETATION: The presence of the scaffold increased the torsional stiffness of the construct. Locking fixation resulted in a stronger construct with increased cycles to failure compared to non-locking fixation.


Assuntos
Placas Ósseas , Parafusos Ósseos , Substitutos Ósseos/química , Transplante Ósseo , Fixação Interna de Fraturas/métodos , Tíbia/patologia , Idoso , Fenômenos Biomecânicos , Cadáver , Durapatita/química , Feminino , Humanos , Masculino , Poliésteres/metabolismo , Estresse Mecânico , Engenharia Tecidual , Tecidos Suporte
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