ABSTRACT
BACKGROUND: Alterations in connexin 43 (Cx43) expression and/or gap junction (GJ)-mediated intercellular communication are implicated in cancer pathogenesis. Herein, we have investigated the role of Cx43 in melanoma cell proliferation and apoptosis sensitivity in vitro, as well as metastatic capability and tumour growth in vivo. METHODS: Connexin 43 expression levels, GJ coupling and proliferation rates were analysed in four different human melanoma cell lines. Furthermore, tumour growth and lung metastasis of high compared with low Cx43-expressing FMS cells were evaluated in vivo using a melanoma xenograft model. RESULTS: Specific inhibition of Cx43 channel activity accelerated melanoma cell proliferation, whereas overexpression of Cx43 increased GJ coupling and reduced cell growth. Moreover, Cx43 overexpression in FMS cells increased basal and tumour necrosis factor-α-induced apoptosis and resulted in decreased melanoma tumour growth and lower number and size of metastatic foci in vivo. CONCLUSIONS: Our findings reveal an important role for Cx43 in intrinsically controlling melanoma growth, death and metastasis, and emphasise the potential use of compounds that selectively enhance Cx43 expression on melanoma in the future chemotherapy and/or immunotherapy protocols.
Subject(s)
Cell Proliferation , Connexin 43/physiology , Melanoma/pathology , Animals , Apoptosis , Calcium/metabolism , Cell Communication , Cell Line, Tumor , Gap Junctions/physiology , Humans , Melanoma/secondary , Mice , Mice, Inbred NOD , Neoplasm MetastasisABSTRACT
BACKGROUND: Recently, we produced a tumour antigen-presenting cells (TAPCells) vaccine using a melanoma cell lysate, called TRIMEL, as an antigen source and an activation factor. Tumour antigen-presenting cells induced immunological responses and increased melanoma patient survival. Herein, we investigated the effect of TAPCells loaded with prostate cancer cell lysates (PCCL) as an antigen source, and TRIMEL as a dendritic cell (DC) activation factor; which were co-injected with the Concholepas concholepas haemocyanin (CCH) as an adjuvant on castration-resistant prostate cancer (CRPC) patients. METHODS: The lysate mix capacity, for inducing T-cell activation, was analysed by flow cytometry and Elispot. Delayed-type hypersensitivity (DTH) reaction against PCCL, frequency of CD8(+) memory T cells (Tm) in blood and prostate-specific antigen (PSA) levels in serum were measured in treated patients. RESULTS: The lysate mix induced functional mature DCs that were capable of activating PCCL-specific T cells. No relevant adverse reactions were observed. Six out of 14 patients showed a significant decrease in levels of PSA. DTH(+) patients showed a prolonged PSA doubling-time after treatment. Expansion of functional central and effector CD8(+) Tm were detected. CONCLUSION: Treatment of CRPC patients with lysate-loaded TAPCells and CCH as an adjuvant is safe: generating biochemical and memory immune responses. However, the limited number of cases requires confirmation in a phase II clinical trial.
Subject(s)
Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Dendritic Cells/immunology , Immunotherapy, Adoptive/methods , Prostatic Neoplasms, Castration-Resistant/immunology , Prostatic Neoplasms, Castration-Resistant/therapy , Aged , Aged, 80 and over , Cell Line, Tumor , Humans , Lymphocyte Activation , Male , Middle Aged , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
A new paradigm has emerged relating the pathogenesis of rheumatoid arthritis (RA), focused on the balance between T helper type 17 cells and regulatory T cells (T(regs) ). In humans, both subpopulations depend on transforming growth factor (TGF)-ß for their induction, but in the presence of inflammatory cytokines, such as interleukin (IL)-6, the generation of Th17 is favoured. Tocilizumab is a therapeutic antibody targeting the IL-6 receptor (IL-6R), which has demonstrated encouraging results in RA. The aim of this study was to evaluate the effect of tocilizumab on Th1 cells, Th17 cells, IL-17 and interferon (IFN)-γ double secretors Th17/Th1 cells, and T(regs) in RA patients. Eight RA patients received tocilizumab monthly for 24 weeks and blood samples were obtained every 8 weeks to study T cell populations by flow cytometry. The frequency of Th17 cells, Th1 cells and Th17/Th1 cells was evaluated in peripheral blood mononuclear cells (PBMCs) activated in vitro with a polyclonal stimulus. T(regs) were identified by their expression of forkhead box protein 3 (FoxP3) and CD25 by direct staining of PBMCs. Although no changes were detected in the frequency of Th1 or Th17 cells, the percentages of peripheral T(regs) increased after therapy. In addition, the infrequent Th17/Th1 subpopulation showed a significant increment in tocilizumab-treated patients. In conclusion, tocilizumab was able to skew the balance between Th17 cells and T(regs) towards a more protective status, which may contribute to the clinical improvement observed in RA patients.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Arthritis, Rheumatoid/immunology , Receptors, Interleukin-6/antagonists & inhibitors , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Th17 Cells/drug effects , Th17 Cells/immunology , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Arthritis, Rheumatoid/drug therapy , Female , Humans , Middle Aged , Th1 Cells/immunologyABSTRACT
Internal consistency reliabilities were calculated for the Tactual Performance Test blocks-per-minute scores for the Preferred Hand (n=298), Nonpreferred Hand (n=302), and Both Hands (n=314) trials, and Total Time. Reliabilities are reported for the total sample and three groups of normal, alcoholic, and undiagnosed patients sent for assessment. The reliabilities ranged from .6102 to .9232. Only three of the discriminate indexes were poor.
Subject(s)
Memory/physiology , Surveys and Questionnaires , Touch/physiology , Humans , Psychometrics , Reaction Time , Reproducibility of ResultsABSTRACT
Exact probabilities for a variety of F scale cutoffs are presented for detecting examinees who respond randomly to the MMPI-2 items.
Subject(s)
MMPI/standards , Humans , Psychometrics , Sensitivity and SpecificityABSTRACT
Using the Kuder-Richardson formula 20 (KR-20) corrected for item difficulty, the internal consistency reliability of the Halstead Category Test (HCT) was calculated for a sample (N = 398) of normal patients and volunteers, diffusely brain-damaged patients, and undiagnosed patients sent for neuropsychological assessment. The HCT Total Score reliability was.9716 and the subtest reliabilities ranged from.4587 to.9590. An item analysis found that most of the test items, except for those from Subtests I and II, were within established criteria for item difficulty and the discrimination index.
Subject(s)
Brain Diseases/diagnosis , Neuropsychological Tests/standards , Adult , Aged , Aged, 80 and over , Brain Diseases/psychology , Case-Control Studies , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Psychometrics , Reproducibility of Results , Retrospective StudiesABSTRACT
An analysis of the types of error (Initial, Terminal, and Both) made on the Speech-Sounds Perception Test was conducted on data collected from 104 normal controls and 56 diffusely brain-damaged patients. The brain-damaged group made more Terminal and Both errors than the normal group. A logistic regression analysis showed that knowing the types of error did not produce a higher percentage of correctly classified subjects than knowing only the total score.
