Immune Thrombocytopenia Plasma-Derived Exosomes Impaired Megakaryocyte and Platelet Production through an Apoptosis Pathway.

Reduced megakaryocyte (MK) apoptosis and insufficient platelet production play important roles in the pathogenesis of immune thrombocytopenia (ITP). The contribution of plasma-derived exosomes to the decreased platelet count in ITP has not been entirely understood. Here, we found the percentage of apoptotic MKs in patients with ITP was significantly lower than those in healthy volunteers. In the presence of ITP plasma-derived exosomes (ITP-Exo), the apoptosis of MKs was reduced during the process of MK differentiation in vitro, which contributed to the reduced platelet production by Bcl-xL/caspase signaling. Furthermore, in vivo study demonstrated that ITP-Exo administration led to significantly delayed platelet recovery in mice after 3.5 Gy of irradiation. All these findings indicated that ITP-Exo, as a regulator of platelet production, impaired MK apoptosis and platelet production through Bcl-xL/caspase signaling, unveiling new mechanisms for reduced platelet count in ITP.

Biomarkers predicting chemotherapy response in head and neck squamous cell carcinoma: a review.

BACKGROUND: Biomarkers are increasingly being used in many cancers to select patients for oncological treatment paradigms based on their inherent genetic properties. However, in head and neck cancers, there are no personalised therapies available outside the context of a clinical trial. A number of studies suggest there are intrinsic tumour properties of head and neck cancers that affect their response to chemotherapeutic agents. This paper aimed to review their evidence base. METHOD: A narrative review was conducted following a search of the PubMed database. RESULTS AND CONCLUSION: The review identified a number of biomarkers predicting response to chemotherapy in head and neck cancers. The paper discusses these in detail, and explores where future research could be directed in order to deliver personalised therapies for patients with head and neck cancers.

Role of rhIL-17 in regulating the mitochondrial pathway proteins in peripheral blood neutrophils.

BACKGROUND: IL-17, classified as an inflammatory cytokine, plays a key role in the activation of inflammatory processes involving neutrophils. METHODS: Twenty healthy voluntary blood donors were controlled in the study. The granulocyte suspensions were stimulated with rhIL-17 and fMLP. Expression of Bcl-xl, Smac/DIABLO, and Omi/HtrA2 in neutrophil lysates were assessed by Western blot. The level of cytochrome c and activity of caspase 9 was also assayed in these cells. RESULTS: The results of existing research highlight the importance of rhIL-17 in reducing the survival of neutrophils via the mitochondria, depending on the Bcl-2 protein family. Our research has indicated that rhIL-17 regulates the mutual relationships between the proteins of that family. The proapoptotic effect observed in neutrophils affected by rhIL-17 is a result of a decreased expression of Bcl-xl. Consequently, the expression of apoptogenic proteins, including cytochrome c, Smac/DIABLO, and Omi/HtrA2, is elevated. Surprisingly, there have been no observations of the cytokine influencing the activity of caspase 9. CONCLUSIONS: Results have shown for the first time that IL-17 has a direct effect on the decrease of Bcl-xl. In conclusion, the results of the research presented in this article confirm the dual action of IL-17, which, on the one hand, leads to an array of proinflammatory mechanisms regarding neutrophils and, on the other hand, reduces the survival of those cells via an immediate influence on the Bcl-2 family of proteins and apoptogenic factors.

Serum Bcl-2 values in children with pulmonary hypertension.

In this study, we aimed to assess levels of serum B cell lymphoma 2 (sBcl-2) in children, which has been implicated in the etiopathogenesis of pulmonary hypertension (PH), as well its association with tissue Doppler echocardiographic imaging (TDI) data and parameters used in the follow-up of PH. The sBcl-2 level was assessed in 35 children with PH (24 had eisenmenger syndrome, and 11 had idiopathic PH) and in 38 healthy children as controls. TDI was performed on 25 patients whose cardiac anatomy allowed the test. The respective sBcl-2 values in patients and controls were 35.69 ± 18.83 and 2.66 ± 7.95 ng/ml (p < 0.001). The sBcl-2 levels were significantly greater in the New York Heart Association (NYHA) functional class 3 patients than those in the NYHA class 2 patients (p = 0.033). The sBcl-2 value in patients who walked <475 m in the 6-min walk distance (6MWD) test was significantly greater than in those who walked ≥475 m (p = 0.038). The sBcl-2 level showed a negative correlation with ejection time measured at the septal anulus (p = 0.026) and a positive correlation with interventricular septum-Tei (p = 0.018). The results of this study showed for the first time that there is an increase in the levels of sBcl-2 as an inflammatory marker and that the sBcl-2 levels are associated with prognostic parameters in children with PH. Because sBcl-2 levels were greater in patients who walked <475 meters during the 6MWD test, we suggest 475 ms as the cut-off value for the 6MWD test to differentiate between a good and a bad prognosis.

Differential expression of genes related to mitochondrial biogenesis and bioenergetics in fatigued prostate cancer men receiving external beam radiation therapy.

OBJECTIVES: This prospective study explored relationships between expression changes of genes related to mitochondrial biogenesis/bioenergetics and fatigue in men with prostate cancer receiving external beam radiation therapy (EBRT). METHODS: Fatigue and gene expression were measured before (Day 0), at midpoint (Days 19-21), and at completion (Days 38-42) of EBRT using the seven-item Patient-Reported Outcomes Measurement Information System-Fatigue short form and from whole blood cell RNA, respectively. The human mitochondria RT2 Profiler PCR Array System was used to identify differential expression of mitochondrial biogenesis/bioenergetics-related genes. Mixed linear modeling estimated the changes in fatigue and gene expression over time and determined significant associations between gene expression and fatigue. RESULTS: Subjects were 50 men with prostate cancer (scheduled for EBRT = 25, active surveillance as matched controls = 25). The mean Patient-Reported Outcomes Measurement Information System-Fatigue T-score (mean = 50 ± 10 in a general population) for study subjects was 44.87 ± 5.89 and for controls was 43.5 ± 2.8 at baseline. Differential expression of two genes inside the mitochondria involved in critical mitochondrial complexes: BCS1L (ß = 1.30), SLC25A37 (ß = -2.44), and two genes on the outer mitochondrial membrane vital for mitochondrial integrity: BCL2L1 (ß = -1.68) and FIS1 (ß = -2.35) were significantly associated with changes in fatigue scores of study subjects during EBRT. CONCLUSION: Genes related to oxidative phosphorylation, energy production, and mitochondrial membrane integrity are associated with worsening fatigue during EBRT. Further investigation of the pathways involved with this association may explain mechanisms behind the development of fatigue in this population.

Extramedullary hematopoietic pleural effusion accompanied by follicular lymphoma.

Extramedullary hematopoietic effusion (EHE) is recognized to be an unusual phenomenon accompanied by hematologic disorders. Only a few reports are available of EHE occurring in patients with lymphoma. We herein report the case of a 54-year-old man with follicular lymphoma. Bone marrow aspirates and biopsied specimens showed diffuse invasion of small cleaved atypical lymphoid cells that were positive for CD10, 20, bcl2, immunoglobulin lambda and Bcl-2-IgH rearrangement. The pleural effusion aspirates and a biopsied specimen obtained via thoracoscopy revealed megakaryocytes and immature myeloid cells in addition to lymphoma cells. To the best of our knowledge, this is the first report of EHE accompanied by lymphoma according to the World Health Organization classification.

TNFα cooperates with IFN-γ to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis.

BACKGROUND: TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo. CONCLUSIONS/SIGNIFICANCE: TNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer.

Circulating gamma delta T cells in response to Salmonella enterica serovar enteritidis exposure in chickens.

gammadelta T cells are considered crucial to the outcome of various infectious diseases. The present study was undertaken to characterize gammadelta (T-cell receptor 1(+) [TCR1(+)]) T cells phenotypically and functionally in avian immune response. Day-old chicks were orally immunized with Salmonella enterica serovar Enteritidis live vaccine or S. enterica serovar Enteritidis wild-type strain and infected using the S. enterica serovar Enteritidis wild-type strain on day 44 of life. Between days 3 and 71, peripheral blood was examined flow cytometrically for the occurrence of gammadelta T-cell subpopulations differentiated by the expression of T-cell antigens. Three different TCR1(+) cell populations were found to display considerable variation regarding CD8alpha antigen expression: (i) CD8alpha(+high) TCR1(+) cells, (ii) CD8alpha(+dim) TCR1(+) cells, and (iii) CD8alpha(-) TCR1(+) cells. While most of the CD8alpha(+high) TCR1(+) cells expressed the CD8alphabeta heterodimeric antigen, the majority of the CD8alpha(+dim) TCR1(+) cells were found to express the CD8alphaalpha homodimeric form. After immunization, a significant increase of CD8alphaalpha(+high) gammadelta T cells was observed within the CD8alpha(+high) TCR1(+) cell population. Quantitative reverse transcription-PCR revealed reduced interleukin-7 receptor alpha (IL-7Ralpha) and Bcl-x expression and elevated IL-2Ralpha mRNA expression of the CD8alphaalpha(+high) gammadelta T cells. Immunohistochemical analysis demonstrated a significant increase of CD8alpha(+) and TCR1(+) cells in the cecum and spleen and a decreased percentage of CD8beta(+) T cells in the spleen after Salmonella immunization. After infection of immunized animals, immune reactions were restricted to intestinal tissue. The study showed that Salmonella immunization of very young chicks is accompanied by an increase of CD8alphaalpha(+high) gammadelta T cells in peripheral blood, which are probably activated, and thus represent an important factor for the development of a protective immune response to Salmonella organisms in chickens.