SHP-2 deletion in CD4+ chondrocyte precursors leads to tumor development with wrist tropism

Abstract Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.

Download Full-text

SHP-2 deletion in CD4Cre expressing chondrocyte precursors leads to tumor development with wrist tropism

Scientific Reports ◽

10.1038/s41598-021-99339-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jeffrey T. McNamara ◽

Kelsey E. Huntington ◽

Samantha Borys ◽

Chathuraka T. Jayasuriya ◽

Laurent Brossay

Keyword(s):

Tyrosine Phosphatase ◽

T Cell Development ◽

Tumor Development ◽

Cell Precursor ◽

Main Site ◽

Hematopoietic Lineage ◽

Mapping System ◽

History Of ◽

Cartilage Tumors ◽

Impact On Treatment

AbstractDue to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic lineage negative CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.

Download Full-text

Cerebellar liponeurocytoma: a rare intracranial tumor with possible familial predisposition. Case report

Journal of Neurosurgery ◽

10.3171/2015.6.jns142965 ◽

2016 ◽

Vol 125 (1) ◽

pp. 57-61 ◽

Cited By ~ 5

Author(s):

Amparo Wolf ◽

Huda Alghefari ◽

Daria Krivosheya ◽

Michael D. Staudt ◽

Gregory Bowden ◽

...

Keyword(s):

Tumor Development ◽

Healthy Woman ◽

Intracranial Tumor ◽

Intracranial Tumors ◽

Histopathological Changes ◽

Biological Origin ◽

Familial Predisposition ◽

History Of ◽

Cerebellar Liponeurocytoma ◽

Supracerebellar Infratentorial Approach

The biological origin of cerebellar liponeurocytomas is unknown, and hereditary forms of this disease have not been described. Here, the authors present clinical and histopathological findings of a young patient with a cerebellar liponeurocytoma who had multiple immediate family members who harbored similar intracranial tumors. A 37-year-old otherwise healthy woman presented with a history of progressive headaches. Lipomatous medulloblastoma had been diagnosed previously in her mother and maternal grandfather, and her maternal uncle had a supratentorial liponeurocytoma. MRI revealed a large, poorly enhancing, lipomatous mass emanating from the superior vermis that produced marked compression of posterior fossa structures. An uncomplicated supracerebellar infratentorial approach was used to resect the lesion. Genetic and histopathological analyses of the lesion revealed neuronal, glial, and lipomatous differentiation and confirmed the diagnosis of cerebellar liponeurocytoma. A comparison of the tumors resected from the patient and, 22 years previously, her mother revealed similar features. Cerebellar liponeurocytoma is a poorly understood entity. This report provides novel evidence of an inheritable predisposition for tumor development. Accurate diagnosis and reporting of clinical outcomes and associated genetic and histopathological changes are necessary for guiding prognosis and developing recommendations for patient care.

Download Full-text

THE RELATIVE EFFICACY OF GENETIC ANALYSIS AND COAGULATION TESTING IN THE DIAGNOSIS OF CARRIERS OF HEMOPHILIA A

10.1055/s-0038-1644010 ◽

1987 ◽

Author(s):

D Lillicrap ◽

A R Giles ◽

J J A Holden ◽

B N White

Keyword(s):

Factor Viii ◽

Gene Deletion ◽

Hemophilia A ◽

Fragment Length Polymorphism ◽

Genetic Diagnosis ◽

Prior History ◽

Carrier Status ◽

Factor Viii Gene ◽

Coagulation Testing ◽

History Of

This study has assessed the relative benefits of restriction fragment length polymorphism (RFLP) linkage and coagulation testing in the diagnosis of carriers of hemophilia A. 221 samples from 55 families have been studied for intragenic and flanking RFLPs. All samples were tested for the Factor VIII intragenic Bell RFLP and for the flanking marker St 14. 83% of obligate carrier females were heterozygous at oneor both of these two polymorphicsites. However, only38% of these women were heterozygous at the intragenic site and might safely be offered prenatal diagnosis using this marker for the hemophilia mutation. Carrier diagnosis was obtained in 52% of 81 potential carriers tested. Diagnosis wasbased on intragenic RFLP information in only 48% of these cases. Genetic diagnosis was possible in 27 atrisk women from families with no prior history of hemophilia. Four of these women were diagnosed as carriers on the basis of a gross Factor VIII gene deletion and the remaining 23 women were identified as non-carriers by the Bell (11) and Stl4 (12) RFLP data. 39 women remained undiagnosed after gene analysis studies. 23 of these women were female relatives of sporadic hemophiliacs and thus RFLP segregation analysis was inappropriate. A further 9 potential carriers were undiagnosed because of homozygosity in key individuals in their families. In 31 potential carriers we have quantitated Factor VIII:C (one stage assay) and vWf:Ag (Laurell and ELISA) and derived probabilities for carrier status. In 3 women there was conflicting genetic and coagulation data. Meanwhile, in 12 undiagnosed women from sporadic families, carrier diagnostic probabilities of > 0.9 were obtained. These studies indicate that optimal carrier detection for hemophilia A requires more intragenic and closely linked RFLPs and the continuance of coagulation testing to assist women from sporadic families.

Download Full-text

The History of Dissociation and Trauma in the UK and Its Impact on Treatment

Trauma and Dissociation in a Cross-Cultural Perspective ◽

10.4324/9780203051801-28 ◽

2013 ◽

pp. 327-344

Keyword(s):

History Of ◽

Impact On Treatment ◽

The Uk

Download Full-text

Insights into the ontogeny and activation of T cells

Clinical Chemistry ◽

10.1093/clinchem/40.11.2128 ◽

1994 ◽

Vol 40 (11) ◽

pp. 2128-2131 ◽

Cited By ~ 5

Author(s):

T W Mak

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Cell Surface ◽

Immune Responses ◽

Tyrosine Phosphatase ◽

T Cell Development ◽

Cell Development ◽

Mutant Mice ◽

Target Cells

Abstract T lymphocytes recognize antigen peptides and major histocompatibility complex products through their T-cell antigen receptors (TcR), consisting of alpha and beta chains. The interaction between T cells and their target cells or antigen-presenting cells is also assisted by a series of other cell-surface polypeptides, most notably CD4 and CD8, which are selectively expressed on mature helper/inducer and killer/suppressor T cells, respectively. Upon engagement of their ligands, a series of signals is transduced intracytoplasmically via some of these molecules and their associated proteins. Perhaps the most important enzyme in this signal transduction process is the lymphocyte-specific tyrosine kinase lck. Another important component is the cell-surface tyrosine phosphatase CD45. This molecule is alternatively spliced and the different isoforms are expressed on the various hematopoietic and lymphopoietic cells. Signaling through the TcR-CD4 D8-lck-CD45 complex is thought to be insufficient to activate T lymphocytes. A costimulatory signal is believed to be essential, and many investigators have suggested that CD28, a ligand for B7/BB1, is such a signal. Immune responses are also controlled by a number of cytokines and soluble factors. Signaling through the tumor necrosis factor receptor p55 is required for clearance of intracellular pathogens. Transcriptional factors involved in controlling interferon production are also important in T-cell development and immune responses. In an attempt to gain a better understanding of the roles of these molecules in T-lymphocyte functions and ontogeny, we generated a series of mutant mice with disruptions in the genes coding for these molecules. We are analyzing the mutant mice to evaluate the importance of these genes in T-cell development.

Download Full-text

Primary Pure Angiosarcoma of the Testis: A Case Report

Translation: The University of Toledo Journal of Medical Sciences ◽

10.46570/utjms.vol1-2014-82 ◽

2014 ◽

Vol 1 ◽

Author(s):

Samay Jain ◽

Richard Cantley ◽

Justus Philip

Keyword(s):

Germ Cell ◽

Molecular Genetic ◽

Malignant Neoplasm ◽

Cell Precursor ◽

Cell Component ◽

Genetic Studies ◽

Spindle Cell Neoplasm ◽

Primary Angiosarcoma ◽

History Of ◽

Vascular Channels

Angiosarcoma is a rare and aggressive, malignant neoplasm of endothelial-cell origin. A primary angiosarcoma originating in the testicle is extremely rare, with only five previous cases reported in the current literature. We report a case of primary, pure angiosarcoma of the testis in a 63-year-old patient with no history of previous chemotherapy or radiation therapy. By histology, the tumor was a high-grade spindle cell neoplasm, arranged in sheets and poorly-formed vascular channels. The tumor cells were positive for vascular markers (CD31, CD34) by immunohistochemical staining. No evidence of a germ cell component was seen by morphology, immunohistochemistry, or molecular genetic studies. This finding is unique in that it is one of only three reported cases of primary angiosarcomas of the testicle without a germ cell precursor or component.

Download Full-text

Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2012.03.003 ◽

2012 ◽

Vol 52 (6) ◽

pp. 1257-1264 ◽

Cited By ~ 31

Author(s):

Elodie Gomez ◽

Magali Vercauteren ◽

Baptiste Kurtz ◽

Antoine Ouvrard-Pascaud ◽

Paul Mulder ◽

...

Keyword(s):

Heart Failure ◽

Protein Tyrosine Phosphatase ◽

Gene Deletion ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Pharmacological Inhibition ◽

Or Gene

Download Full-text

Multiple extrathymic precursors contribute to T-cell development with different kinetics

Blood ◽

10.1182/blood-2009-07-230821 ◽

2010 ◽

Vol 115 (6) ◽

pp. 1137-1144 ◽

Cited By ~ 35

Author(s):

Namita Saran ◽

Marcin Łyszkiewicz ◽

Jens Pommerencke ◽

Katrin Witzlau ◽

Ramin Vakilzadeh ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Cell Fate ◽

T Cell Development ◽

Cell Development ◽

Cell Precursor ◽

Lineage Differentiation ◽

Multipotent Cells ◽

Kinetics Of

Abstract T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches.

Download Full-text

Ajmaline‐Induced Abnormalities in Brugada Syndrome: Evaluation With ECG Imaging

Journal of the American Heart Association ◽

10.1161/jaha.121.024001 ◽

2022 ◽

Author(s):

Luigi Pannone ◽

Cinzia Monaco ◽

Antonio Sorgente ◽

Pasquale Vergara ◽

Paul‐Adrian Calburean ◽

...

Keyword(s):

Brugada Syndrome ◽

Recovery Time ◽

Area Under The Curve ◽

Electrocardiographic Imaging ◽

Mapping System ◽

Before And After ◽

History Of ◽

Noninvasive Mapping ◽

The Difference ◽

The Right

Background The rate of sudden cardiac death (SCD) in Brugada syndrome (BrS) is ≈1%/y. Noninvasive electrocardiographic imaging is a noninvasive mapping system that has a role in assessing BrS depolarization and repolarization abnormalities. This study aimed to analyze electrocardiographic imaging parameters during ajmaline test (AJT). Methods and Results All consecutive epicardial maps of the right ventricle outflow tract (RVOT‐EPI) in BrS with CardioInsight were retrospectively analyzed. (1) RVOT‐EPI activation time (RVOT‐AT); (2) RVOT‐EPI recovery time, and (3) RVOT‐EPI activation‐recovery interval (RVOT‐ARI) were calculated. ∆RVOT‐AT, ∆RVOT‐EPI recovery time, and ∆RVOT‐ARI were defined as the difference in parameters before and after AJT. SCD‐BrS patients were defined as individuals presenting a history of aborted SCD. Thirty‐nine patients with BrS were retrospectively analyzed and 12 patients (30.8%) were SCD‐BrS. After AJT, an increase in both RVOT‐AT [105.9 milliseconds versus 65.8 milliseconds, P <0.001] and RVOT‐EPI recovery time [403.4 milliseconds versus 365.7 milliseconds, P <0.001] was observed. No changes occurred in RVOT‐ARI [297.5 milliseconds versus 299.9 milliseconds, P =0.7]. Before AJT no differences were observed between SCD‐BrS and non SCD‐BrS in RVOT‐AT, RVOT‐EPI recovery time, and RVOT‐ARI ( P =0.9, P =0.91, P =0.86, respectively). Following AJT, SCD‐BrS patients showed higher RVOT‐AT, higher ∆RVOT‐AT, lower RVOT‐ARI, and lower ∆RVOT‐ARI ( P <0.001, P <0.001, P =0.007, P =0.002, respectively). At the univariate logistic regression, predictors of SCD‐BrS were the following: RVOT‐AT after AJT (specificity: 0.74, sensitivity 1.00, area under the curve 0.92); ∆RVOT‐AT (specificity: 0.74, sensitivity 0.92, area under the curve 0.86); RVOT‐ARI after AJT (specificity 0.96, sensitivity 0.58, area under the curve 0.79), and ∆RVOT‐ARI (specificity 0.85, sensitivity 0.67, area under the curve 0.76). Conclusions Noninvasive electrocardiographic imaging can be useful in evaluating the results of AJT in BrS.

Download Full-text