Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18

Ultraviolet (UV) irradiation is a major mutagenic environmental agent, causing the appearance of DNA adducts that, if unrepaired, may give rise to mutations. Ultraviolet radiation has been indicated as a major risk factor in the development of nonmelanoma skin cancers; however, recent reports have suggested that infections with human papillomaviruses, a widespread family of epitheliotropic DNA viruses, may also contribute to the tumorigeneic process. Here, we investigated whether expression of the E6 protein from different HPV types interfere with the repair of thymine dimers caused by UV-B radiation. Results show that unrepaired DNA damage can be observed in UV-B-irradiated cells expressing the E6 protein of HPV types found in cervical and epithelial cancers. Moreover, such cells have the ability to overcome the G(1) cell cycle checkpoint induced as a result of unrepaired DNA. (C) 2004 Cancer Research UK

E-cadherin and α-, β- and γ-catenin expression in prostate cancers: correlation with tumour invasion

The E-cadherin–catenin complex plays an important role in establishing and maintaining intercellular connections and morphogenesis and reduced expression of its constituent molecules is associated with invasion and metastasis. In the present study, we examined E-cadherin and α-, β- and γ-catenin levels in tumour tissues obtained by radical prostatectomy in order to investigate the relationship with histopathological tumour invasion. Immunohistochemical findings for 45 prostate cancer specimens demonstrated aberrant expression of each molecule to be associated with dedifferentiation and, in addition, alteration of staining patterns for the three types of catenin was significantly correlated with capsular but not lymphatic or vascular invasion. The data thus suggest that three types of catenin may be useful predictive markers for biological aggressiveness of prostate cancer. © 1999 Cancer Research Campaig

Neogenin May Functionally Substitute for Dcc in Chicken

Dcc is the key receptor that mediates attractive responses of axonal growth cones to netrins, a family of axon guidance cues used throughout evolution. However, a Dcc homolog has not yet been identified in the chicken genome, raising the possibility that Dcc is not present in avians. Here we show that the closely related family member neogenin may functionally substitute for Dcc in the developing chicken spinal cord. The expression pattern of chicken neogenin in the developing spinal cord is a composite of the distribution patterns of both rodent Dcc and neogenin. Moreover, whereas the loss of mouse neogenin has no effect on the trajectory of commissural axons, removing chicken neogenin by RNA interference results in a phenotype similar to the functional inactivation of Dcc in mouse. Taken together, these data suggest that the chick neogenin is functionally equivalent to rodent Dcc

Molecular Evidence for a Functional Ecdysone Signaling System in Brugia malayi

Filarial parasites such as Brugia malayi and Onchocerca volvulus are the causative agents of the tropical diseases lymphatic filariasis and onchocerciasis, which infect 150 million people, mainly in Africa and Southeast Asia. Filarial nematodes have a complex life cycle that involves transmission and development within both mammalian and insect hosts. The successful completion of the life cycle includes four molts, two of which are triggered upon transmission from one host to the other, human and mosquito, respectively. Elucidation of the molecular mechanisms involved in the molting processes in filarial nematodes may yield a new set of targets for drug intervention. In insects and other arthropods molting transitions are regulated by the steroid hormone ecdysone that interacts with a specialized hormone receptor composed of two different proteins belonging to the family of nuclear receptors. We have cloned from B. malayi two members of the nuclear receptor family that show many sequence and biochemical properties consistent with the ecdysone receptor of insects. This finding represents the first report of a functional ecdysone receptor homolog in nematodes. We have also established a transgenic hormone induction assay in B. malayi that can be used to discover ecdysone responsive genes and potentially lead to screening assays for active compounds for pharmaceutical development

Cyclophosphamide Exerts Significant Immunomodulatory Function in Myeloma Patients Treated with Pomalidomide and Dexamethasone

Background and aims Existing evidence regarding the effect of low-dose cyclophosphamide on immune cells in myeloma patients, in particular in combination with the IMiD® compound pomalidomide is limited. We present here for the first time changes in immune cell sub-group composition associated with the addition of cyclophosphamide to pomalidomide in the randomised MUKseven clinical trial. Material and Methods MUKseven is a randomised phase II study for relapsed or refractory myeloma (RRMM) patients comparing cyclophosphamide (500 mg po d1, 15, 21), pomalidomide and dexamethasone (CPd) versus standard pomalidomide and dex (Pd). Patients with ≥2 prior lines of therapy were randomised 1:1 to CPd or Pd and treated until disease progression. All patients underwent bone marrow sampling and peripheral blood collection, the latter for immune cell immunophenotyping at Cycle 1 Day 1 (C1D1; Baseline), C1D14 (on-treatment), C4D14 (on-treatment) and at disease progression. Peripheral blood (PB) T-cell populations were profiled using multicolor flow cytometry (MFC) designed to assess baseline and pharmacodynamic changes in subpopulations including helper, cytotoxic, naïve, memory, and activated/proliferating phenotypes (CD3, CD4, CD8, CD45RA, CD62L, HLA-DR, Ki67. T-cell sub-populations were defined and their respective % of total lymphocyte population used for downstream analyses. Results In total 102 evaluable RRMM patients were randomised, 51 each to CPd and Pd treatment arms, with comparable clinical baseline characteristics. Patients had received a median of 3 prior lines of treatment. Evaluable PB immune profiling data was available for 93 (91%) patients at Baseline, 83 (81%) at C1D14, 55 (54%) at C4D14 and 26 (25%) at progression. We observed trends for changes in baseline T-cell population composition with increasing numbers of prior lines of therapy. Specifically, mean % CD4+ T-cells decreased from 35% for patients with 2 prior lines (n=18) to 30% with 3 (n=33), 23% with 4 and 20% with ≥5 prior lines of treatment (n=27), whilst the % of CD8+ cells were similar, indicating potential differential cumulative effects of anti-myeloma therapy on T-cell populations. We compared changes in T-cell profiles longitudinally over trial treatment from baseline to C1D14 and C4D14 with summary statistics. Overall, there was a marked increase in activated (HLA-DR+) T-cells with therapy, with a 2-fold increase in mean proportion of activated CD4+ and CD8+ from 3.9% and 10.2% at baseline to 7.8% and 19.9% at C1D14 and 7.2% and 28.2% at C4D14, respectively (Figure 1). Trial treatment was associated with a shift in sub-populations within CD8+ T-cells in particular, with a relative % decrease in naïve (CD45RA+) sub-populations and increase in memory (CD45RA-) populations. To identify differences associated with cyclophosphamide treatment a regression analysis was conducted on the C1D14 time point accounting for the treatment a patient received and incorporating their baseline (C1D1) measurement. The mean% estimates for total T-cells (CD3+) at C1D14 were significantly higher for the CPd arm in comparison to Pd: 72.1% [95% CI: 66.5 - 73.6] vs. 64.2% [58.2 - 66.1] (P=0.004). Estimates for the Pd arm appeared similar to baseline [mean C1D1: 61.7%]. Mean% estimates for CD8+ and CD4+ cells were also significantly higher with CPd treatment at C1D14 compared to Pd: 37.2% [32.6 - 38.0] vs. 33.1% [28.5 - 33.7] (P=0.03) and 26.2% [21.6 - 27.0] vs. 21.8% [21.6 - 27.0] (P=0.016), respectively. Importantly, mean% estimates for activated (HLA-DR+) CD4+ cells were significantly higher for the CPd arm 10.1% [6.9 - 9.4] vs 8.1% [5.1 - 7.2] in the Pd arm (P =0.02). There was a trend for additional increase of activated CD8+ cells by addition of cyclophosphamide to Pd therapy (P=0.06). Discussion We demonstrate for the first time in a randomised trial using systematic longitudinal immune profiling that addition of cyclophosphamide to pomalidomide and dexamethasone is significantly associated with altered T-cell profiles and an increased proportion of activated T-cells. MUKseven clinical endpoint data are reported separately, with improved response rates observed for CPd vs. Pd. Correlation of immune profiles with clinical outcomes and tumour genetics will be presented at the conference when PFS outcome data will be mature