Methods of limb elongation with congenital inequality in children

During the period 1973-1978 elongation with a distraction-compression apparatus was performed on 78 children with congenital limb length inequality. The length of follow-up ranged from 2 to 6 years. Inequality in limb length measured 4 to 6.5 cm in 51 children, 6.5 to 8 cm in 24, and more than 8 cm in three. The final results in 72 children were judged satisfactory in that equal limb length was obtained. Equalization was accomplished with lengthening up to 6 cm in a one-stage procedure; lengthening greater than 6 cm was accomplished in two stages. During distraction two fractures and six pin tract infections occurred; four patients with joint stiffness adjacent to the segment under elongation required additional measures.     

The form of NY-ESO-1 antigen has an impact on the clinical efficacy of anti-tumor vaccination

Anti-tumor vaccination is being evaluated as a prophylactic and therapeutic strategy against cancer growth, dissemination (spreading) or recurrence. Although a large number of studies investigate in detail the identity of antigens to be used for efficacious immune intervention, there have been few studies investigating the optimal form for antigen to be used in the vaccine. Here we show in a mouse H-2^d MHC background and for NY-ESO-1 that genetic (plasmid DNA) but not full length protein vaccine is capable of inducing a protective prophylactic anti-tumor cytotoxic T-cell immune response in vivo. Peptide vaccination using nominal MHC class I epitope adjuvanted with a Toll Like Receptor agonist such as stabilized RNA can also provide some anti-tumor protection. Our results highlight the idea that when evaluating the clinical efficacy of a cancer vaccine, not only the identity of the antigen but also the format of the vaccine is of the utmost importance.     

Immunogenicity of attenuated measles virus engineered to express Helicobacter pylori neutrophil-activating protein

Helicobacter pylori is a Gram-negative, spiral-shaped microorganism associated with acute and chronic gastritis, peptic ulcer, gastric cancer and gastric lymphomas in humans. H. pylori neutrophil-activating protein (NAP) is a major virulence factor playing a central role in pathogenesis of mucosal inflammation by immune cell attraction and Th1 cytokine response polarization. NAP is protective antigen and promising vaccine candidate against H. pylori infection. Here we present the development of measles virus (MV) vaccine strain encoding the NAP antigen. In order to facilitate the extracellular transport and detection, NAP was inserted in the human lambda immunoglobulin chain replacing a major part of the variable domain. We generated two MV vectors expressing secretory NAP forms: MV-lambda-NAP encoding the full-length constant lambda light chain domain and MV-s-NAP encoding only the N-terminus of the lambda light chain with the leader peptide. Immunization of MV permissive Ifnarko-CD46Ge transgenic mice by a single intraperitoneal injection of the NAP-expressing strains induced a robust, long-term humoral and cellular immune response against MV. Nine months post vaccination measles-neutralizing antibody titers were above the serum level considered protective for humans. Furthermore, all animals immunized with MV strains expressing the secretory NAP antigen developed strong humoral immunity against NAP, reaching titers >1:10,000 within 2-4 weeks. IFN-γ ELISpot assay confirmed that NAP-encoding MV vectors can also stimulate NAP-specific cell-mediated immunity. Our data demonstrate that MV is an excellent vector platform for expression of bacterial antigens and development of vaccines for H. pylori immunoprophylaxis in humans.     

p63 cytoplasmic aberrance is associated with high prostate cancer stem cell expression

Introduction: Prostate cancer in Indonesia is the 3rd ranking cancer among males and the 5th rank for theircancer mortality. Prognostic markers that can identify aggressive prostate cancer in early stages and helpselect appropriate therapy to finally reduce the mortality are therefore urgently needed. It has been suggestedthat stem cells in the prostate gland have a role in initiation, progression, and metastasis of cancer, althoughcontroversy continues to exist. Maintenance of normal stem cell or reserve cell populations in several epitheliaincluding prostate has been shown to be regulated by p63 and alteration of p63 expression is considered to havean oncogenic role in prostate cancer. We hypothesize that the expression of cytoplasmic aberrance of p63 isassociated with high ALDH1A1 expression as a cancer stem cell marker, thus leading to progression of prostatecancer. Methods: Using a cross-sectional study during two years (2009-2010), a total of 79 paraffin embeddedtissues of benign prostatic hyperplasia, PIN prostatic intraepithelial neoplasia, low and high Gleason scoreprostate cancer were investigated using immunohistochemistry. Associations between cytoplasmic p63 andALDH1A1, as well as with pathological diagnosis, were analyzed by Chi-Square test using SPSS 15.0. Links ofboth markers with cell proliferation rate (KI-67) and apoptotic rate (cleaved caspase 3) were also analyzed byKruskal-Wallis test. Results: The mean age of patient at the diagnosis is 70.0 years. Cytoplasmic aberrance ofp63 was associated with ALDH1A1 expression (p<0.001) and both were found to have significant relationshipswith pathological diagnosis (including Gleason score), (p=0.006 and p<0.001 respectively). Moreover, it was alsofound that higher levels of cytoplasmic p63 were significantly associated with the frequency of proliferatingcells and cells undergoing apoptosis in prostate cancers (p=0.001 and p=0.016 respectively). Conclusion: p63cytoplasmic aberrance is associated with high ALDH1A1 expression. These components are suggested to havean important role in prostate cancer progression and may be used as molecular markers.     

Polyploidy road to therapy‐induced cellular senescence and escape

Therapy‐induced cellular senescence (TCS), characterized by prolonged cell cycle arrest, is an in vivo response of human cancers to chemotherapy and radiation. Unfortunately, TCS is reversible for a subset of senescent cells, leading to cellular reproliferation and ultimately tumor progression. This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer. We report the findings of a clinicopathological study in patients with locally advanced non‐small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome. In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape, we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry. We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS. These polyploid senescent cells represent important transition states through which escape preferentially occurs. The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin‐dependent kinase inhibitor family during TCS. Altogether, these studies underscore the importance of TCS in cancer therapeutics.