ABSTRACT
The Wnt signalling pathway is a major pathway involved in the embryogenic development of the various organs of the body. Appropriate signalling in this pathway relies on the proper functioning of several proteins including the R-spondin family of proteins. Deactivating mutations in R-spondin 4 are associated with anonychia. We present the case of a 26-year-old man presenting with anonychia of the 20 nails, which had been present since birth. Using genetic studies, we identified a novel nonsense mutation, c.164-165TC>AA, characterized by two consecutive mismatch bases. To our knowledge, this mutation is the first to be reported in R-spondin 4 in a Lebanese population. Evaluating new patients with anonychia provides fruitful clinical and molecular findings.
Subject(s)
Codon, Nonsense , Nails, Malformed/congenital , Thrombospondins/genetics , Adult , Humans , Male , Nails, Malformed/geneticsSubject(s)
Interleukin-8 , Skin Diseases , Vasculitis, Leukocytoclastic, Cutaneous , Erythema , Humans , SkinABSTRACT
The epitranscriptome embodies many new and largely unexplored functions of RNA. A significant roadblock hindering progress in epitranscriptomics is the identification of more than one modification in individual transcript molecules. We address this with CHEUI (CH3 (methylation) Estimation Using Ionic current). CHEUI predicts N6-methyladenosine (m6A) and 5-methylcytosine (m5C) in individual molecules from the same sample, the stoichiometry at transcript reference sites, and differential methylation between any two conditions. CHEUI processes observed and expected nanopore direct RNA sequencing signals to achieve high single-molecule, transcript-site, and stoichiometry accuracies in multiple tests using synthetic RNA standards and cell line data. CHEUI's capability to identify two modification types in the same sample reveals a co-occurrence of m6A and m5C in individual mRNAs in cell line and tissue transcriptomes. CHEUI provides new avenues to discover and study the function of the epitranscriptome.
Subject(s)
5-Methylcytosine , Adenosine , Sequence Analysis, RNA , Transcriptome , Adenosine/analogs & derivatives , Adenosine/metabolism , 5-Methylcytosine/metabolism , 5-Methylcytosine/analogs & derivatives , Humans , Methylation , Sequence Analysis, RNA/methods , RNA Processing, Post-Transcriptional , RNA, Messenger/metabolism , RNA, Messenger/genetics , RNA/metabolism , RNA/geneticsABSTRACT
This case report describes a Japanese girl with systemic lupus erythematosus who had recurrent fevers and erythema nodosum. She was later found to carry the complex allele E148Q/R202Q/P369S/R408Q of MEFV, the gene responsible for familial Mediterranean fever.
Subject(s)
Familial Mediterranean Fever/complications , Lupus Erythematosus, Systemic/complications , C-Reactive Protein/analysis , Child , Cytoskeletal Proteins/genetics , Familial Mediterranean Fever/genetics , Female , Humans , Lupus Erythematosus, Systemic/genetics , PyrinABSTRACT
Optimal therapy for posttransplant lymphoproliferative disease (PTLD) remains problematic. A phase II trial adding rituximab to a low-dose cyclophosphamide and prednisone regimen was conducted for pediatric patients with Epstein-Barr virus (EBV) (+), CD20 (+) PTLD. Fifty-five patients were enrolled. Toxicity was similar for cycles of therapy containing rituximab versus those without. The complete remission (CR) rate was 69% (95% confidence interval (CI); 57%-84%). Of 12 patients with radiographic evidence of persistent disease at the end of therapy, eight were in CR 28 weeks later without further PTLD therapy. There were 10 deaths, 3 due to infections while receiving therapy and 7 from PTLD. The 2-year event-free survival (alive with functioning original allograft and no PTLD) was 71% (95% CI: 57%-82%) and overall survival was 83% (95% CI: 69%-91%) with median follow-up of 4.8 years. Due to small numbers, we were unable to determine significance of tumor histology, stage of disease, allograft type or early response to treatment on outcome. These data suggest rituximab combined with low-dose chemotherapy is safe and effective in treating pediatric with EBV (+) PTLD following solid-organ transplantation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Lymphoproliferative Disorders/drug therapy , Organ Transplantation/adverse effects , Adolescent , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Child , Child, Preschool , Confidence Intervals , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/etiology , Epstein-Barr Virus Infections/mortality , Epstein-Barr Virus Infections/pathology , Female , Follow-Up Studies , Humans , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/mortality , Lymphoproliferative Disorders/pathology , Male , Maximum Tolerated Dose , Organ Transplantation/methods , Prednisone/administration & dosage , Prednisone/adverse effects , Prospective Studies , Risk Assessment , Rituximab , Survival Analysis , Transplantation, Homologous , Treatment OutcomeSubject(s)
DNA/genetics , Genes, pX/genetics , Hyperkeratosis, Epidermolytic/genetics , Keratoderma, Palmoplantar/genetics , Membrane Proteins/metabolism , Mutation , Child , DNA Mutational Analysis , Female , Humans , Hyperkeratosis, Epidermolytic/diagnosis , Hyperkeratosis, Epidermolytic/metabolism , Iraq , Keratoderma, Palmoplantar/diagnosis , Keratoderma, Palmoplantar/metabolism , PedigreeABSTRACT
BACKGROUND: we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). PATIENTS AND METHODS: treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. RESULTS: forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. CONCLUSIONS: TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Head and Neck Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cisplatin/administration & dosage , Cisplatin/adverse effects , Docetaxel , Dose-Response Relationship, Drug , Drug Combinations , Female , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Oxonic Acid/administration & dosage , Oxonic Acid/adverse effects , Taxoids/administration & dosage , Taxoids/adverse effects , Tegafur/administration & dosage , Tegafur/adverse effects , Young AdultABSTRACT
Downregulation of major histocompatibility complex (MHC) class I expression is an important mechanism by which tumors evade classical T cell-dependent immune responses. Therefore, a system was designed to evaluate parameters for active immunization against MHC class I- tumors. Mice were capable of rejecting a MHC class I- tumor challenge after immunization with an irradiated granulocyte/macrophage colony-stimulating factor (GM-CSF) transduced MHC class I- tumor vaccine. This response was critically dependent on CD4+ T cells and natural killer (NK) cells, but minimally on CD8+ T cells. A strong protective response against MHC class I+ variants of the tumor could be elicited when mice were immunized with irradiated MHC class I+ GM-CSF-secreting tumor cells. This response required CD4+ and CD8+ T cells, and in addition, elimination of NK cells resulted in outgrowth of tumors that had lost expression of at least one MHC class I gene. Finally, class I MHC expression on the vaccinating cells inhibited the response generated against a MHC class I- tumor challenge. These results demonstrate that the host is capable of being immunized against a tumor that has lost MHC class I expression and reveal conditions under which distinct effector cells play a role in the systemic antitumor immune response.
Subject(s)
Histocompatibility Antigens Class I/immunology , Neoplasms, Experimental/immunology , T-Lymphocytes/immunology , Animals , Base Sequence , CD4-Positive T-Lymphocytes/immunology , DNA , Down-Regulation , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Histocompatibility Antigens Class I/biosynthesis , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Molecular Sequence Data , Neoplasm Transplantation , T-Lymphocytes, Regulatory/immunology , Transduction, Genetic , Tumor Cells, Cultured , VaccinationABSTRACT
Hyperimmunization of BALB/c mice with concanavalin A-stimulated blasts from the Ig allotype-congenic strain, C.B20, results in the production of antibodies reactive with T cells in an allotype-restricted manner. Spleen cells from these hyperimmune BALB/c mice were used to generate a panel of hybridomas that secrete monoclonal antibodies, reactive, in an allotype-restricted manner, exclusively with T cells subpopulations, and in particular, reactive with suppressor T cell hybridomas and their secreted soluble factors. Two functional classes of antibodies were identified: those that react with single polypeptide-chain suppressor T cell factors (TsF1) and the suppressor T cell hybridomas that produce such factors, and those that react with two polypeptide-chain suppressor T cell factors (TsF2) and their corresponding suppressor T cell hybridomas. These two classes of antibody were used to isolate molecules from the membranes of the respective suppressor T cell hybrids that are functionally and structurally related to the secreted suppressor T cell factors, suggesting a receptor function for these molecules.
Subject(s)
Epitopes/immunology , Peptides/immunology , Receptors, Antigen, T-Cell/isolation & purification , T-Lymphocytes, Regulatory/immunology , Animals , Antibodies, Monoclonal/immunology , Chromosome Mapping , Epitopes/genetics , Hybridomas/immunology , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Lymphokines/metabolism , Mice , Mice, Inbred Strains/immunology , Polymers , Receptors, Antigen, T-Cell/immunology , Suppressor Factors, Immunologic , T-Lymphocytes, Regulatory/analysis , T-Lymphocytes, Regulatory/metabolismABSTRACT
The induction of optimal systemic antitumor immunity involves the priming of both CD4(+) and CD8(+) T cells specific for tumor-associated antigens. The role of CD4(+) T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8(+) cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4(+) T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4(+) T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.
Subject(s)
Cytokines/immunology , Eosinophils/immunology , Macrophages/immunology , Melanoma, Experimental/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Antigens, CD/genetics , Antigens, CD/immunology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Cell Movement , Cytokines/genetics , Cytotoxicity, Immunologic , Eosinophils/cytology , Female , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Injections, Subcutaneous , Lymphocyte Cooperation , Macrophages/cytology , Macrophages/enzymology , Macrophages/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , NADPH Oxidases/genetics , NADPH Oxidases/metabolism , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type IIABSTRACT
Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21(ras) in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21(Asn-17) (Ha-ras) was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21(ras) activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21(ras) activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangement and progressing to immature B cells. These results suggest that p21(ras) mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.