In-vitro effects of Mycobacterium bovis BCG-lysate and its derived heat shock proteins on cytokines secretion by blood mononuclear cells of rheumatoid arthritis patients in comparison with healthy controls

BACKGROUND: Several studies have shown that heat shock protein (HSP)-reactive T cells have an immunoregulatory phenotype indicating that HSPs are able to trigger immunoregulatory pathways, which can suppress immune responses that occur in human inflammatory diseases, such as rheumatoid arthritis (RA). Mycobacterium bovis strain Bacillus Calmette-Guérin (BCG) is rich of HSPs which could be good resources of these regulatory proteins for modulation of immune response. PURPOSES: To study the effects of BCG-lysate and BCG-derived HSPs on secretion of T regulatory cytokines by PBMCs of RA patients in comparison with healthy controls. METHODS: BCG was heat killed and sonicated to have BCG-lysate. BCG-derived HSP65/HSP70 were detected by immunoblotting and purified by preparative SDS-PAGE. PBMCs of 18 RA patients/16 controls collected by Ficoll-paque were stimulated with BCG-lysate/BCG-derived HSP-65/HSP-70. Supernatant of stimulated PBMCs was aspirated for measuring TGF-beta, IL-10, IL-4 and IFN-gamma with sandwich ELISA. RESULTS: BCG-lysate augmented the amounts of all the mentioned cytokines as dose dependent significantly. The level of TGF-beta in controls was higher than patients (P<0.05). HSP65 and HSP70 increased TGF-beta, IL-10 as dose dependent significantly. HSP65, but not HSP70, increased IL-4. HSP65 did not increase IFN-gamma but HSP70 augmented IFN-gamma significantly. BCG-lysate increased IFN-gamma and IL-4 in RA patients more than healthy controls (P<0.05). CONCLUSION: Although BCG is able to provoke T helper 1 cell mediated immunity, its HSP proteins are able to trigger T regulatory cytokines. Healthy controls were under stronger immune regulations.     

Distinct MAPK signaling pathways, p21 up-regulation and caspase-mediated p21 cleavage establishes the fate of U937 cells exposed to 3-hydrogenkwadaphnin: differentiation versus apoptosis

Despite the depth of knowledge concerning the pathogenesis of acute myeloblastic leukemia (AML), long-term survival remains unresolved. Therefore, new agents that act more selectively and more potently are required. In that line, we have recently characterized a novel diterpene ester, called 3-hydrogenkwadaphnin (3-HK), with capability to induce both differentiation and apoptosis in various leukemia cell lines. These effects of 3-HK were mediated through inhibition of inosine 5′-monophosphate dehydrogenase, a selective up-regulated enzyme in cancerous cells, especially leukemia. However, it remains elusive to understand how cells display different fates in response to 3-HK. Here, we report the distinct molecular signaling pathways involved in forcing of 3-HK-treated U937 cells to undergo differentiation and apoptosis. After 3-HK (15 nM) treatment, a portion of U937 cells adhered to the culture plates and showed macrophage criteria while others remained in suspension and underwent apoptosis. The differentiated cells arrested in G₀/G₁ phase of cell cycle and showed early activation of ERK1/2 pathway (3 h) along with ERK-dependent p21^Cip/WAF1 (p21) up-regulation and expression of p27^Kip1 and Bcl-2. In contrast, the suspension cells underwent apoptosis through Fas/FasL and mitochondrial pathways. The occurrence of apoptosis in these cells were accompanied with caspase-8-mediated p21 cleavage and delayed activation (24 h) of JNK1/2 and p38 MAPK. Taken together, these results suggest that distinct signaling pathways play a pivotal role in fates of drug-treated leukemia cells, thus this may pave some novel therapeutical utilities.     

A Systematic Review on Overall Survival and Disease-Free Survival Following Total Pelvic Exenteration

Backgrounds: Total Pelvic Exenteration (TPE) is a radical operation for malignancies in which all of the organs inside the pelvic cavity, including the female reproductive organs, the lower urinary tract, and a part of the rectosigmoid are removed. In this study, we aimed to conduct a systematic review to assess the overall survival (OS) and disease-free survival (DFS) following TPE. Methods: This systematic review is composed of a comprehensive review of PubMed and Scopus databases with various related keywords to synthesis the overall survival and disease-free survival following TPE. The Synthesis Without Meta-analysis guideline was used to summarize the results. Results: We included the results of 39 primary studies and the results revealed that one-year OS of gynecological cancer in patients who have undergone TPE ranged from 50.0% to 72.0% and the 5-years OS ranged from 6.0% to 64.6%. The one-year survival rate of colorectal cancer patients was reported to be over 80% in almost all studies. The 3-year survival rate of patients varied from 25% to 75% and the lowest 5-year survival rate was 8% and the highest survival rate was 92%. To synthesis the disease-free survival rate in colorectal cancer, ten studies were included and one-year recurrence rate was 9.1% and the one-year DFS was reported as 61.0%. Three-year recurrence rate study was 20.4% and 3 and 5-year DFS ranged from 22.0% to 78.0%. Conclusions: The results suggested that DFS in primary advanced cancers is higher than locally recurrence tumors. This review showed that patient overall survival and disease-free survival rates have increased over time, especially at high volume centers that are more experienced and possibly better equipped. Therefore, it can be suggested that the attitude towards PE as a palliative surgery can be turned into curative surgery.     

Recurrence of the severe form of microgastria-limb reduction defect in a consanguineous family.

This report concerns two sibs from a consanguineous Sudanese family with microgastria-limb reduction defect associated with hydrocephalus and agenesis of corpus callosum. We suggest that these cases together with other previously reported cases of central nervous system (CNS) anomalies associated with microgastria-limb reduction defect could represent an autosomal recessive syndrome differing from the classical microgastria-limb reduction defect by its severity, presence of CNS anomalies and its pattern of inheritance.