Residual tumor micro-foci and overwhelming regulatory T lymphocyte infiltration are the causes of bladder cancer recurrence

Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the presence of sporadic tumor micro-foci in the residual urothelial tissue after surgery associated with an inverted ratio between intratumoral effector and regulatory T cell subsets. Hence, surgical specimens of both tumors and autologous, macroscopically/histologically free-of-tumor tissues were collected from 28 and 20 patients affected by bladder or renal cancer, respectively. The frequencies of effector (IFN?+ and IL17+ T cells) and regulatory (CD4+CD25hiCD127lo and CD8+CD28-CD127loCD39+ Treg) T cell subpopulations among tumor infiltrating lymphocytes were analyzed by immunofluorescence, while the gene expression of MAGE-A1 and MAGE-A2 tumor-associated antigens was studied by RT-PCR. The results show that both the T cell infiltrate and the frequency of MAGE-A1/A2 gene expression were comparable in tumors and in autologous free-of-tumor tissues in bladder cancer, while the autologous free-of-tumor renal tissues showed reduced T cell infiltrate and frequency of MAGE gene expression as compared to the autologous tumors. Importantly, the intra-tumor T effector/Treg cell ratio was consistently <1 in bladder cancer patients (n. 7) who relapsed within two years, while it was always >1 in patients (n. 6) without recurrence (regardless of tumor stage) (P = 0.0006, Odds ratio = 195). These unprecedented findings clarify the pathogenic mechanism of bladder cancer recurrence and suggest that microscopically undetectable micro-foci of tumor may predispose to recurrence when associated with an inverted intratumoral T effector/Treg cell ratio

AIRE polymorphism, melanoma antigen-specific T cell immunity, and susceptibility to melanoma

AIRE is involved in susceptibility to melanoma perhaps regulating T cell immunity against melanoma antigens (MA). To address this issue, AIRE and MAGEB2 expressions were measured by real time PCR in medullary thymic epithelial cells (mTECs) from two strains of C57BL/6 mice bearing either T or C allelic variant of the rs1800522 AIRE SNP. Moreover, the extent of apoptosis induced by mTECs in MAGEB2-specific T cells and the susceptibility to in vivo melanoma B16F10 cell challenge were compared in the two mouse strains. The C allelic variant, protective in humans against melanoma, induced lower AIRE and MAGEB2 expression in C57BL/6 mouse mTECs than the T allele. Moreover, mTECs expressing the C allelic variant induced lower extent of apoptosis in MAGEB2-specific syngeneic T cells than mTECs bearing the T allelic variant (p < 0.05). Vaccination against MAGEB2 induced higher frequency of MAGEB2-specific CTL and exerted higher protective effect against melanoma development in mice bearing the CC AIRE genotype than in those bearing the TT one (p < 0.05). These findings show that allelic variants of one AIRE SNP may differentially shape the MA-specific T cell repertoire potentially influencing susceptibility to melanoma

Improving Oral Hygiene Skills by Computer-Based Training: A Randomized Controlled Comparison of the Modified Bass and the Fones Techniques

Background: Gingivitis and other plaque-associated diseases have a high prevalence in western communities even though the majority of adults report daily oral hygiene. This indicates a lack of oral hygiene skills. Currently, there is no clear evidence as to which brushing technique would bring about the best oral hygiene skills. While the modified Bass technique is often recommended by dentists and in textbooks, the Fones technique is often recommended in patient brochures. Still, standardized comparisons of the effectiveness of teaching these techniques are lacking. Methodology/Principal Findings: In a final sample of n=56 students, this multidisciplinary, randomized, examiner-blinded, controlled study compared the effects of parallel and standardized interactive computer presentations teaching either the Fones or the modified Bass technique. A control group was taught the basics of tooth brushing alone. Oral hygiene skills (remaining plaque after thorough oral hygiene) and gingivitis were assessed at baseline and 6, 12, and 28 weeks after the intervention. We found a significant group×time interaction for gingivitis (F(4/102)=3.267; p=0.016; e=0.957; ?2=0.114) and a significant main effect of group for oral hygiene skills (F(2/51)=7.088; p=0.002; ?2=0.218). Fones was superior to Bass; Bass did not differ from the control group. Group differences were most prominent after 6 and 12 weeks. Conclusions/Significance: The present trial indicates an advantage of teaching the Fones as compared to the modified Bass technique with respect to oral hygiene skills and gingivitis. Future studies are needed to analyze whether the disadvantage of teaching the Bass technique observed here is restricted to the teaching method employed. Trial Registration: German Clinical Trials Register http://www.drks.de/DRKS0000348

Vdelta1 T lymphocytes producing IFN-gamma and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans

In early HIV-1 infection, V delta 1 T lymphocytes are increased in peripheral blood and this is related to chemokine receptor expression, chemokine response, and recirculation. Herein we show that, at variance with healthy donors, in HIV-1-infected patients ex vivo-isolated V delta 1 T cells display cytoplasmic interferon-gamma (IFN-gamma). Interestingly, these cells coexpress cytoplasmic interleukin-17 (IL-17), and bear the CD27 surface marker of the memory T-cell subset. V delta 1 T cells, isolated from either patients or healthy donors, can proliferate and produce IFN-gamma and IL-17 in response to Candida albicans in vitro, whereas V delta 2 T cells respond with proliferation and IFN-gamma/IL-17 production to mycobacterial or phosphate antigens. These IFN-gamma/IL-17 double-producer gamma delta T cells express the Th17 RORC and the Th1 TXB21 transcription factors and bear the CCR7 homing receptor and the CD161 molecule that are involved in gamma delta T-cell transendothelial migration. Moreover, V delta 1 T cells responding to C albicans express the chemokine receptors CCR4 and CCR6. This specifically equipped circulating memory gamma delta T-cell population might play an important role in the control of HIV-1 spreading and in the defense against opportunistic infections, possibly contributing to compensate for the impairment of CD4(+) T cells