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1.
Ann Oncol ; 31(11): 1506-1517, 2020 11.
Article in English | MEDLINE | ID: mdl-32891793

ABSTRACT

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.


Subject(s)
Sarcoma , Tropomyosin , Adult , Gene Fusion , Humans , Oncogene Proteins, Fusion/genetics , Protein Kinase Inhibitors , Receptor, trkA/genetics , Sarcoma/diagnosis , Sarcoma/drug therapy , Sarcoma/genetics
2.
Ann Oncol ; 28(6): 1230-1242, 2017 Jun 01.
Article in English | MEDLINE | ID: mdl-28184416

ABSTRACT

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.


Subject(s)
Chordoma/therapy , Practice Guidelines as Topic , Humans , Neoplasm Recurrence, Local
4.
Am J Transplant ; 16(10): 2877-2891, 2016 10.
Article in English | MEDLINE | ID: mdl-27145342

ABSTRACT

Thymic involution is associated with age-related changes of the immune system. Utilizing our innovative technique of transplantation of a thymus as an isolated vascularized graft in MHC-inbred miniature swine, we have previously demonstrated that aged thymi are rejuvenated after transplantation into juvenile swine. Here we have studied the role of insulin-like growth factor (IGF) and forkhead-box protein-N1 (FOXN1) as well as bone marrow (BM) in thymic rejuvenation and involution. We examined thymic rejuvenation and involution by means of histology and flow cytometry. Thymic function was assessed by the ability to induce tolerance of allogeneic kidneys. Aged thymi were rejuvenated in a juvenile environment, and successfully induced organ tolerance, while juvenile thymi in aged recipients involuted and had a limited ability to induce tolerance. However, juvenile BM inhibited the involution process of juvenile thymi in aged recipients. An elevated expression of both FOXN1 and IGF1 receptors (IGF-1R) was observed in juvenile thymi and rejuvenated thymi. Juvenile BM plays a role in promoting the local thymic milieu as indicated by its ability to inhibit thymic involution in aged animals. The expression of FOXN1 and IGF-1R was noted to increase under conditions that stimulated rejuvenation, suggesting that these factors are involved in thymic recovery.


Subject(s)
Bone Marrow/physiology , Forkhead Transcription Factors/metabolism , Receptor, IGF Type 1/metabolism , Rejuvenation/physiology , Thymus Gland/physiology , Aging/physiology , Animals , Cell Differentiation , Forkhead Transcription Factors/genetics , Graft Survival , Immune Tolerance , Receptor, IGF Type 1/genetics , Swine , Swine, Miniature , Thymus Gland/transplantation
7.
ESMO Open ; 9(4): 102981, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38613908

ABSTRACT

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.


Subject(s)
Neoplasms , Precision Medicine , Humans , Neoplasms/genetics , Neoplasms/drug therapy , Female , Precision Medicine/methods , Male , Middle Aged , Prospective Studies , Aged , Adult , Aged, 80 and over , Progression-Free Survival , Young Adult , Rare Diseases/genetics , Rare Diseases/drug therapy , Genomics/methods
8.
Osteoporos Int ; 22(5): 1573-9, 2011 May.
Article in English | MEDLINE | ID: mdl-20652228

ABSTRACT

SUMMARY: Postmenopausal hemodialysis patients are at risk of complications related to renal mineral and bone disorder, and postmenopausal osteoporosis. In 112 postmenopausal hemodialysis patients, free estrogen index was positively correlated with bone mineral density (BMD) Z-score and the annual percent change of BMD in multiple regression analysis. Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life. INTRODUCTION: Women on dialysis are not only at risk of developing mineral and bone disorder, but also suffer from postmenopausal osteoporosis. We assessed the effect of sex hormones on bone metabolism in postmenopausal hemodialysis patients. METHODS: We enrolled 112 postmenopausal hemodialysis patients with a mean age of 68.4 ± 10.4 years. We measured the serum levels of estradiol, testosterone, sex hormone-binding globulin (SHBG), and intact parathyroid hormone (intact-PTH), as well as bone metabolism parameters and radial bone mineral density (BMD). The free estrogen index (FEI) was calculated from the estradiol and SHBG values. After conventional dialysis was performed for 12 months, BMD was measured again and the annual percent change was calculated. Estradiol and SHBG were also measured in 25 postmenopausal women without chronic kidney disease. RESULTS: Estradiol levels were higher in the hemodialysis patients than in the postmenopausal women without chronic kidney disease. In patients with relatively normal bone turnover (intact-PTH: from 150 to 300 pg/ml), the FEI showed a positive correlation with the BMD Z-score. The annual percent change of BMD showed a positive correlation with the FEI according to multiple regression analysis. CONCLUSIONS: Endogenous estrogen may prevent bone loss in postmenopausal hemodialysis patients throughout life.


Subject(s)
Estradiol/physiology , Osteoporosis, Postmenopausal/etiology , Renal Dialysis/adverse effects , Aged , Bone Density/physiology , Bone and Bones/metabolism , Estradiol/blood , Female , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/therapy , Middle Aged , Osteoporosis, Postmenopausal/blood , Osteoporosis, Postmenopausal/physiopathology , Radius/physiopathology , Sex Hormone-Binding Globulin/metabolism
9.
Phys Chem Chem Phys ; 13(45): 20318-25, 2011 Dec 07.
Article in English | MEDLINE | ID: mdl-21997596

ABSTRACT

Photoinduced isomerization of a novel photochromic cation, [2PA-Mmim](+) (2-phenylazo-1,3-dimethylimidazolium cation), was studied by optical spectroscopic methods. The UV-Vis absorption spectra of the [2PA-Mmim](+) cation show two prominent bands starting around 410 and 520 nm, corresponding to the S(0)-S(2) (π, π*) and S(0)-S(1) (n, π*) transitions, respectively. The photoisomerization mechanism is studied by femtosecond time-resolved transient absorption experiments performed after S(0)-S(2) (π, π*) excitation in several solvents with different viscosity, including ionic liquids. The transient absorption signals at two representative wavelengths were fitted by bi-exponential functions, which yield four decay components. The photoisomerization mechanism is discussed in light of the relaxation schemes available for azobenzene. Only one of the components depends on the solvent viscosity and it changes from 1.2 ps (dichloromethane, 0.4 cP) to 5.6 ps ([Bmim][BF(4)], 93 cP). This component is assigned to a molecule at the S(1) state, which is responsible for the "rotational" isomerization. The weak dependence on the solvent viscosity of this component is explained in terms of local change in the viscosity as a result of local heating due to excess energy released at S(2)-S(1) internal conversion. The other three components of ∼0.4, 1.0 and 10 ps are attributed to relaxation processes of the molecule at S(2), S(1) and S(0) states, respectively. The quantum yields for the forward E-Z photoisomerization are ∼0.15 after S(2) excitation. The backward Z-E isomerization is slow with a lifetime of 1 hour and an activation energy of 91 kJ mol(-1) through an "inversion" mechanism.

10.
ESMO Open ; 6(3): 100170, 2021 06.
Article in English | MEDLINE | ID: mdl-34090171

ABSTRACT

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.


Subject(s)
Hemangioendothelioma, Epithelioid , Sarcoma , Adult , Child , Consensus , Hemangioendothelioma, Epithelioid/diagnosis , Hemangioendothelioma, Epithelioid/drug therapy , Humans , Medical Oncology , Patient Advocacy , Sarcoma/diagnosis , Sarcoma/drug therapy
11.
Eur J Surg Oncol ; 46(8): 1415-1422, 2020 08.
Article in English | MEDLINE | ID: mdl-32402509

ABSTRACT

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.


Subject(s)
Chordoma/radiotherapy , Chordoma/surgery , Margins of Excision , Sacrum/surgery , Humans , Proton Therapy/adverse effects , Radiotherapy Dosage
12.
J Cell Biol ; 126(2): 391-401, 1994 Jul.
Article in English | MEDLINE | ID: mdl-7518464

ABSTRACT

The ERM family members, ezrin, radixin, and moesin, localizing just beneath the plasma membranes, are thought to be involved in the actin filament/plasma membrane association. To identify the integral membrane protein directly associated with ERM family members, we performed immunoprecipitation studies using antimoesin mAb and cultured baby hamster kidney (BHK) cells metabolically labeled with [35S]methionine or surface-labeled with biotin. The results indicated that moesin is directly associated with a 140-kD integral membrane protein. Using BHK cells as antigens, we obtained a mAb that recognized the 140-kD membrane protein. We next cloned a cDNA encoding the 140-kD membrane protein and identified it as CD44, a broadly distributed cell surface glycoprotein. Immunoprecipitation with various anti-CD44 mAbs showed that ezrin and radixin, as well as moesin, are associated with CD44, not only in BHK cells, but also in mouse L fibroblasts. Furthermore, immunofluorescence microscopy revealed that in both BHK and L cells, the Triton X-100-insoluble CD44 is precisely colocalized with ERM family members. We concluded that ERM family members work as molecular linkers between the cytoplasmic domain of CD44 and actin-based cytoskeletons.


Subject(s)
Blood Proteins/metabolism , Carrier Proteins/metabolism , Cytoskeletal Proteins , Cytoskeleton/metabolism , Membrane Proteins/metabolism , Microfilament Proteins , Phosphoproteins/metabolism , Proteins/metabolism , Receptors, Cell Surface/metabolism , Receptors, Lymphocyte Homing/metabolism , Actins/metabolism , Amino Acid Sequence , Animals , Antibodies, Monoclonal , Blood Proteins/analysis , Carrier Proteins/genetics , Carrier Proteins/immunology , Carrier Proteins/isolation & purification , Cell Line , Cricetinae , Cytoskeleton/chemistry , DNA, Complementary/analysis , Epitopes/genetics , Epitopes/immunology , Hyaluronan Receptors , Membrane Proteins/analysis , Mice , Molecular Sequence Data , Phosphoproteins/analysis , Precipitin Tests , Proteins/analysis , Rabies virus/chemistry , Rabies virus/immunology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Receptors, Cell Surface/isolation & purification , Receptors, Lymphocyte Homing/genetics , Receptors, Lymphocyte Homing/immunology , Receptors, Lymphocyte Homing/isolation & purification , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/immunology , Sequence Analysis, DNA
13.
J Pathol ; 216(4): 428-39, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18855347

ABSTRACT

Synovial sarcomas account for 5-10% of all soft tissue sarcomas and the majority of synovial sarcomas display characteristic t(X;18) translocations that result in enhanced transcription of the insulin-like growth factor-2 (IGF-2) gene. IGF-2 is an essential fetal mitogen involved in the pathogenesis of different tumours, leading to cellular proliferation and inhibition of apoptosis. Here we asked whether activation of IGF signalling is of functional importance in synovial sarcomas. We screened human synovial sarcomas for expression of IGF-2 and the phosphorylated IGF-1 receptor (IGF-1R), which mainly mediates the proliferative and anti-apoptotic effects of IGF-2. Since both the phosphatidylinositol 3'-kinase (PI3K)-AKT pathway and the MAPK signalling cascade are known to be involved in the transmission of IGF-1R signals, expression of phosphorylated (p)-AKT and p-p44/42 MAPK was additionally assessed. All tumours expressed IGF-2 and 78% showed an activated IGF-1R. All tumours were found to express p-AKT and 92% showed expression of activated p44/42 MAPK. To analyse the functional and potential therapeutic relevance of IGF-1R signalling, synovial sarcoma cell lines were treated with the IGF-1R inhibitor NVP-AEW541. Growth was impaired by the IGF-1R antagonist, which was consistently accompanied by a dose-dependent reduction of phosphorylation of AKT and p44/42 MAPK. Functionally, inhibition of the receptor led to increased apoptosis and diminished mitotic activity. Concurrent exposure of selected cells to NVP-AEW541 and conventional chemotherapeutic agents resulted in positive interactions. Finally, synovial sarcoma cell migration was found to be dependent on signals transmitted by the IGF-1R. In summary, our data show that the IGF-1R might represent a promising therapeutic target in synovial sarcomas.


Subject(s)
Receptor, IGF Type 1/physiology , Sarcoma, Synovial/metabolism , Signal Transduction/physiology , Adult , Antineoplastic Agents/pharmacology , Apoptosis , Blotting, Western/methods , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Female , Fluorescent Antibody Technique , Humans , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , MAP Kinase Signaling System/physiology , Male , Middle Aged , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidines/pharmacology , Pyrroles/pharmacology , RNA, Messenger/analysis , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Sarcoma, Synovial/pathology , Signal Transduction/drug effects
14.
Bone Joint J ; 101-B(6): 745-752, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31154837

ABSTRACT

AIMS: The purpose of this study was to clarify the clinical behaviour, prognosis, and optimum treatment of dedifferentiated low-grade osteosarcoma (DLOS) diagnosed based on molecular pathology. PATIENTS AND METHODS: We retrospectively reviewed 13 DLOS patients (six men, seven women; median age 32 years (interquartile range (IQR) 27 to 38)) diagnosed using the following criteria: the histological coexistence of low-grade and high-grade osteosarcoma components in the lesion, and positive immunohistochemistry of mouse double minute 2 homolog (MDM2) and cyclin-dependent kinase 4 (CDK4) associated with MDM2 amplification. These patients were then compared with 51 age-matched consecutive conventional osteosarcoma (COS) patients (33 men, 18 women; median age 25 years (IQR 20 to 38)) regarding their clinicopathological features. RESULTS: The five-year overall survival (OAS) rates in the DLOS and COS patients were 85.7% and 77.1% (p = 0.728), respectively, and the five-year progression-free survival (PFS) rates were 57.7% and 44.9% (p = 0.368), respectively. A total of 12 DLOS patients received chemotherapy largely according to regimens for COS. Among the nine cases with a histological evaluation after chemotherapy, eight showed a poor response, and seven of these had a necrosis rate of < 50%. One DLOS patient developed local recurrence and five developed distant metastases. CONCLUSION: Based on our study of 13 DLOS cases that were strictly defined by histological and molecular means, DLOS showed a poorer response to a standard chemotherapy regimen than COS, while the clinical outcomes were not markedly different. Cite this article: Bone Joint J 2019;101-B:745-752.


Subject(s)
Bone Neoplasms/pathology , Bone Neoplasms/therapy , Osteosarcoma/pathology , Osteosarcoma/therapy , Adult , Biomarkers, Tumor/analysis , Case-Control Studies , Combined Modality Therapy , Female , Humans , Immunohistochemistry , Male , Neoplasm Grading , Retrospective Studies , Survival Rate
15.
Transplant Proc ; 50(10): 3249-3254, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30577193

ABSTRACT

Preceding solo kidney transplantation for type 1 diabetes with end-stage renal failure is controversial because of less pancreatic graft survival in pancreas transplantation after kidney transplantation (PAK) than in simultaneous pancreas and kidney transplantation (SPK). METHODS: To study the effectiveness of preceding solo kidney transplantation for type 1 diabetes with end-stage renal failure, comparative retrospective analysis was performed between SPK (n = 232) and PAK (n = 39) that were performed until December 2016. RESULTS: At 1, 3, and 5 years, pancreatic graft survival in SPK was 87.5%, 86.4%, and 82.8%, respectively, and 87.1%, 65.0%, and 49.1%, respectively, in PAK, which showed lesser long-term graft survival than SPK. Because 10 cases out of 16 (62.5%) failed into pancreatic graft loss with rejection in PAK, which was about 3 times more than in SPK, control of rejection is very important; rejection episodes were decreased by rabbit antithymocyte globulin induction resulting in improved graft survival. Five-year patient survival was 88.0% in SPK and 96.6% in PAK. CONCLUSION: Considering patient survival, preceding solo kidney transplantation for type 1 diabetes with end-stage renal failure should be performed if a donor is available.


Subject(s)
Diabetes Mellitus, Type 1/surgery , Kidney Transplantation/methods , Pancreas Transplantation/methods , Adult , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/mortality , Female , Graft Survival , Humans , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/surgery , Male , Middle Aged , Retrospective Studies , Survival Rate , Treatment Outcome
16.
Cytogenet Genome Res ; 117(1-4): 92-102, 2007.
Article in English | MEDLINE | ID: mdl-17675849

ABSTRACT

Recent progress of chicken genome projects has revealed that bird ZW and mammalian XY sex chromosomes were derived from different autosomal pairs of the common ancestor; however, the evolutionary relationship between bird and reptilian sex chromosomes is still unclear. The Chinese soft-shelled turtle (Pelodiscus sinensis) exhibits genetic sex determination, but no distinguishable (heteromorphic) sex chromosomes have been identified. In order to investigate this further, we performed molecular cytogenetic analyses of this species, and thereby identified ZZ/ZW-type micro-sex chromosomes. In addition, we cloned reptile homologues of chicken Z-linked genes from three reptilian species, the Chinese soft-shelled turtle and the Japanese four-striped rat snake (Elaphe quadrivirgata), which have heteromorphic sex chromosomes, and the Siam crocodile (Crocodylus siamensis), which exhibits temperature-dependent sex determination and lacks sex chromosomes. We then mapped them to chromosomes of each species using FISH. The linkage of the genes has been highly conserved in all species: the chicken Z chromosome corresponded to the turtle chromosome 6q, snake chromosome 2p and crocodile chromosome 3. The order of the genes was identical among the three species. The absence of homology between the bird Z chromosome and the snake and turtle Z sex chromosomes suggests that the origin of the sex chromosomes and the causative genes of sex determination are different between birds and reptiles.


Subject(s)
Chickens/genetics , Evolution, Molecular , Physical Chromosome Mapping , Reptiles/genetics , Sex Chromosomes/genetics , Animals , Base Sequence , Cells, Cultured , Cloning, Molecular , DNA, Complementary/genetics , Female , Karyotyping , Male , Metaphase/genetics , RNA, Ribosomal/genetics , Sequence Homology, Nucleic Acid
17.
Mol Cell Biol ; 18(7): 4324-36, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9632816

ABSTRACT

Rat PEX12 cDNA was isolated by functional complementation of peroxisome deficiency of a mutant CHO cell line, ZP109 (K. Okumoto, A. Bogaki, K. Tateishi, T. Tsukamoto, T. Osumi, N. Shimozawa, Y. Suzuki, T. Orii, and Y. Fujiki, Exp. Cell Res. 233:11-20, 1997), using a transient transfection assay and an ectopic, readily visible marker, green fluorescent protein. This cDNA encodes a 359-amino-acid membrane protein of peroxisomes with two transmembrane segments and a cysteine-rich zinc finger, the RING motif. A stable transformant of ZP109 with the PEX12 was morphologically and biochemically restored for peroxisome biogenesis. Pex12p was shown by expression of bona fide as well as epitope-tagged Pex12p to expose both N- and C-terminal regions to the cytosol. Fibroblasts derived from patients with the peroxisome deficiency Zellweger syndrome of complementation group III (CG-III) were also complemented for peroxisome biogenesis with PEX12. Two unrelated patients of this group manifesting peroxisome deficiency disorders possessed homozygous, inactivating PEX12 mutations: in one, Arg180Thr by one point mutation, and in the other, deletion of two nucleotides in codons for 291Asn and 292Ser, creating an apparently unchanged codon for Asn and a codon 292 for termination. These results indicate that the gene encoding peroxisome assembly factor Pex12p is a pathogenic gene of CG-III peroxisome deficiency. Moreover, truncation and site mutation studies, including patient PEX12 analysis, demonstrated that the cytoplasmically oriented N- and C-terminal parts of Pex12p are essential for biological function.


Subject(s)
Membrane Proteins/genetics , Mutation , Zellweger Syndrome/genetics , Zinc Fingers , Amino Acid Sequence , Animals , Base Sequence , CHO Cells , Cell Line , Cell Line, Transformed , Cloning, Molecular , Cricetinae , Cytosol , DNA, Complementary , Fibroblasts , Humans , Microbodies/metabolism , Molecular Sequence Data , Mutagenesis , Peroxisomal Disorders/veterinary , Rats , Sequence Homology, Amino Acid
18.
J Bone Joint Surg Br ; 89(5): 659-63, 2007 May.
Article in English | MEDLINE | ID: mdl-17540754

ABSTRACT

We evaluated the construct validity of the Musculoskeletal Tumour Society rating scale (Enneking score) as a functional measure for patients with sarcoma involving the upper limb. We compared the Enneking score by examining the correlation between two patient-derived outcome measures, the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire and the Medical Outcomes Study Short Form-36 (SF-36) as indicators of functional status in 40 patients with malignant or aggressive benign bone and soft-tissue tumours of the upper limb who had undergone surgical treatment. The frequency distributions were similar among the three scoring systems. As for the validity, Spearman's rank correlation coefficient of the Enneking score to the DASH questionnaire was -0.79 and that of the Enneking to the SF-36 subscales ranged from 0.38 to 0.60. Despite being a measure from the surgeon's perspective, the Enneking score was shown to be a valid indicator of physical disability in patients with malignant or aggressive benign tumours of the upper limb and reflected their opinion.


Subject(s)
Bone Neoplasms/physiopathology , Sarcoma/physiopathology , Severity of Illness Index , Soft Tissue Neoplasms/physiopathology , Upper Extremity/physiopathology , Adolescent , Adult , Aged , Aged, 80 and over , Bone Neoplasms/rehabilitation , Bone Neoplasms/surgery , Disability Evaluation , Female , Humans , Male , Middle Aged , Pain Measurement/methods , Recovery of Function , Sarcoma/rehabilitation , Sarcoma/surgery , Soft Tissue Neoplasms/rehabilitation , Soft Tissue Neoplasms/surgery , Treatment Outcome
19.
Transplant Proc ; 48(4): 1315-9, 2016 May.
Article in English | MEDLINE | ID: mdl-27320612

ABSTRACT

BACKGROUND: Clinical intestinal transplantation (Int-Tx) is associated with some problems such as rejection, infection, graft-versus-host disease, and ischemia-reperfusion injury (IRI). To determine mechanisms of rejection as well as to develop treatment strategies for Int-Tx, this study was designed to establish both heterotopic and orthotropic Int-Tx models using major histocompatibility antigen complex (MHC) inbred CLAWN miniature swine. MATERIALS AND METHODS: Eleven CLAWN miniature swine received MHC matched but minor antigen mismatched allogenic intestinal grafts. Four animals received intestinal grafts heterotopically and kept host intestine intact. The remaining 7 animals received intestinal grafts orthotopically and resected host small intestine. Continuous infusion of tacrolimus was given from day 0 for 12 days. RESULTS: Heterotopically transplanted small intestine were well perfused after revascularization; however, grafts easily underwent ischemic changes during or soon after abdomen closure due to oppression of the grafts in the limited abdominal space. In contrast, all of 7 orthotopically transplanted intestinal grafts in which recipients' small intestine was removed from the jejunum to the ileum had no signs of severe ischemia associated with compartment syndrome. Elevation of the serum concentration of inflammatory cytokines and the progression of lethal acidosis seen in recipients of heterotipic transplantation were markedly less in the case of orthotopic transplantation. Two recipients survived more than 30 days, and 1 long-term survivor showed no evidence of rejection at day 90 despite the fact that tacrolimus was stopped at day 12. CONCLUSIONS: In this study, we demonstrated the establishment of a clinically relevant orthotopic Int-Tx model with long survival in MHC inbred CLAWN miniature swine. We believe that this unique MHC inbred swine Int-Tx model is useful for developing treatment strategies for clinical Int-Tx.


Subject(s)
Disease Models, Animal , Intestine, Small/transplantation , Animals , Graft Rejection/prevention & control , Graft vs Host Disease/prevention & control , Ileum/surgery , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacology , Infusions, Intravenous , Jejunum/surgery , Major Histocompatibility Complex/physiology , Reperfusion Injury/prevention & control , Swine , Swine, Miniature , Tacrolimus/administration & dosage , Transplantation, Heterotopic/methods , Transplantation, Homologous/methods
20.
Oncogene ; 35(48): 6177-6188, 2016 12 01.
Article in English | MEDLINE | ID: mdl-27157622

ABSTRACT

Myxoid/round cell (RC) liposarcomas (MLS) were originally classified into two distinct populations based on histological differences; a myxoid component and a RC component. It is notable that, depending on an increase of the RC component, the prognosis significantly differs. Hence, the RC component is associated with metastasis and poor prognosis. However, the molecular mechanisms that contribute to the malignancy of the RC component still remain largely unknown. Here, we report microRNA-135b (miR-135b), a key regulator of the malignancy, highly expressed in the RC component and promoting MLS cell invasion in vitro and metastasis in vivo through the direct suppression of thrombospondin 2 (THBS2). Decreased THBS2 expression by miR-135b increases the total amount of matrix metalloproteinase 2 (MMP2) and influences cellular density and an extracellular matrix structure, thereby resulting in morphological change in tumor. The expression levels of miR-135b and THBS2 significantly correlated with a poor prognosis in MLS patients. Overall, our study reveals that the miR-135b/THBS2/MMP2 axis is tightly related to MLS pathophysiology and has an important clinical implication. This work provides noteworthy evidence for overcoming metastasis and improving patient outcomes, and sheds light on miR-135b and THBS2 as novel molecular targets for diagnosis and therapy in MLS.


Subject(s)
Gene Expression Regulation, Neoplastic , Liposarcoma, Myxoid/genetics , Liposarcoma, Myxoid/mortality , MicroRNAs/genetics , 3' Untranslated Regions , Animals , Cell Line, Tumor , Cell Movement/genetics , Disease Models, Animal , Gene Expression Profiling , Gene Silencing , High-Throughput Nucleotide Sequencing , Humans , Liposarcoma, Myxoid/pathology , Lung Neoplasms/secondary , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Mice , Mice, Knockout , Neoplasm Metastasis , Prognosis , RNA Interference , Thrombospondins/genetics , Tumor Burden
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