Sibling Rivalry among Paralogs Promotes Evolution of the Human Brain

Geneticists have long sought to identify the genetic changes that made us human, but pinpointing the functionally relevant changes has been challenging. Two papers in this issue suggest that partial duplication of SRGAP2, producing an incomplete protein that antagonizes the original, contributed to human brain evolution

Protein p16 as a marker of dysplastic and neoplastic alterations in cervical epithelial cells

BACKGROUND: Cervical carcinomas are second most frequent type of women cancer. Success in diagnostics of this disease is due to the use of Pap-test (cytological smear analysis). However Pap-test gives significant portion of both false-positive and false-negative conclusions. Amendments of the diagnostic procedure are desirable. Aetiological role of papillomaviruses in cervical cancer is established while the role of cellular gene alterations in the course of tumor progression is less clear. Several research groups including us have recently named the protein p16(INK4a )as a possible diagnostic marker of cervical cancer. To evaluate whether the specificity of p16(INK4a )expression in dysplastic and neoplastic cervical epithelium is sufficient for such application we undertook a broader immunochistochemical registration of this protein with a highly p16(INK4a)-specific monoclonal antibody. METHODS: Paraffin-embedded samples of diagnostic biopsies and surgical materials were used. Control group included vaginal smears of healthy women and biopsy samples from patients with cervical ectopia. We examined 197 samples in total. Monoclonal antibody E6H4 (MTM Laboratories, Germany) was used. RESULTS: In control samples we did not find any p16(INK4a)-positive cells. Overexpression of p16(INK4a )was detected in samples of cervical dysplasia (CINs) and carcinomas. The portion of p16(INK4a)-positive samples increased in the row: CIN I – CIN II – CIN III – invasive carcinoma. For all stages the samples were found to be heterogeneous with respect to p16(INK4a)-expression. Every third of CINs III and one invasive squamous cell carcinoma (out of 21 analyzed) were negative. CONCLUSIONS: Overexpression of the protein p16(INK4a )is typical for dysplastic and neoplastic epithelium of cervix uteri. However p16(INK4a)-negative CINs and carcinomas do exist. All stages of CINs and carcinomas analyzed are heterogeneous with respect to p16(INK4a )expression. So p16(INK4a)-negativity is not a sufficient reason to exclude a patient from the high risk group. As far as normal cervical epithelium is p16(INK4a)-negative and the ratio p16(INK4a)-positive/ p16(INK4a)-negative samples increases at the advanced stages application of immunohisto-/cytochemical test for p16(INK4a )may be regarded as a supplementary test for early diagnostics of cervical cancer

Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor

Bortezomib inhibits nuclear factor-κB (NF-κB). Cetuximab is a chimeric mouse–human antibody targeted against epidermal growth factor receptor (EGFR). We hypothesised that concomitant blockade of NF-κB and EGFR signalling would overcome EGFR-mediated resistance to single-agent bortezomib and induce apoptosis through two molecular pathways. The aim of this phase I trial was to establish the maximum tolerated dose (MTD) for bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumours. The 21-day treatment cycle consisted of bortezomib administered on days 1 and 8 through dose escalation (1.3–2 mg m−2). Cetuximab was delivered at a dose of 250 mg m−2 on days 1, 8 and 15 (400 mg m−2 day 1 cycle 1). A total of 37 patients were enroled and given a total 91 cycles. No grade ⩾3 haematological toxicity was noted. Non-hematological grade ⩾3 toxicities included fatigue (22% of patients), dyspnoea (16%) and infection (11%). The MTD was not reached at the highest tested bortezomib dose (2.0 mg m−2). Efficacy outcomes included disease progression in 21 patients (56.7%) and stable disease (SD) at 6 weeks in 16 patients (43.3%). Five of the six patients with SD at 12 weeks were diagnosed with cancers of the lungs or head and neck. This combination therapy was moderately effective in extensively pretreated patients with non-small cell lung or head and neck cancers and warrants further investigation

Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for the prognosis of non-small-cell lung cancers

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs. © 1999 Cancer Research Campaig

Oncolytic measles viruses encoding interferon β and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy

Mesothelioma usually leads to death within 8–14 months of diagnosis. To increase the potency of oncolytic measles viruses (MVs) for mesothelioma therapy, we inserted the interferon β (IFNβ) gene alone or with the human thyroidal sodium iodide symporter (NIS) gene into attenuated MV of the Edmonston lineage. The corresponding mouse IFNβ (mIFNβ) viruses, MV-mIFNβ and MV-mIFNβ-NIS, successfully propagated in human mesothelioma cells, leading to intercellular fusion and cell death. High levels of mIFNβ were detected in the supernatants of the infected cells, and radioiodine uptake was substantial in the cells infected with MV-mIFNβ-NIS. MV with mIFNβ expression triggered CD68-positive immune cell infiltration 2–4 times higher than MV-GFP injected into the tumor site. The numbers of CD31-positive vascular endothelial cells within the tumor were decreased at day 7 after intratumoral injection of MV-mIFNβ or MV-mIFNβ-NIS, but not after MV-GFP and PBS administration. Immunohistochemical analysis showed that MV-mIFNβ changed the microenvironment of the mesothelioma by increasing innate immune cell infiltration and inhibiting tumor angiogenesis. Oncolytic MVs coding for IFNβ effectively retarded growth of human mesotheliomas and prolonged survival time in several mesothelioma tumor models. The results suggest that oncolytic MVs that code for IFNβ and NIS will be potent and versatile agents for the treatment of human mesothelioma

Engineering Cloud-based Applications: Towards an Application Lifecycle

The adoption of cloud computing by organizations of all sizes and types in the recent years has created multiple opportunities and challenges for the development of software to be used in this environment. In this work-in-progress paper, the focus is on the latter part, providing a view on the main research challenges that are created for software engineering by cloud computing. These challenges stem from the inherent characteristics of the cloud computing paradigm, and require a multi-dimensional approach to address them. Towards this goal, a lifecycle for cloud-based applications is presented, as the foundation for further work in the area

The Smiling Abbot: Rediscovering a Unique Medieval Effigial Slab

This is an Accepted Manuscript of an article published by Taylor & Francis in Archaeological Journal on 06/11/2017, available online: http://www.tandfonline.com/doi/full/10.1080/00665983.2017.1366705The article reports on a newly re-discovered fragment of a recumbent effigial slab commemorating Abbot Hywel (‘Howel’), most likely an abbot of the Cistercian house of Valle Crucis, near Llangollen (Denbighs.). The slab was probably carved very early in the fourteenth century, and could have covered the abbot’s burial place. The stone was dislocated and fragmented at an unknown point in the abbey’s history, and most likely removed from the site during the nineteenth-century clearance of the abbey ruins. It was briefly reported on in 1895 and has been lost to scholarship subsequently. If indeed from Valle Crucis, the stone is the only known effigial slab commemorating a Cistercian abbot from Wales, and a rare example from Britain. Given that few similar Cistercian abbatial monuments have been identified from elsewhere, the ‘Smiling Abbot’, although only a fragment, is a significant addition to the known corpus of later medieval mortuary monuments. The article discusses the provenance, dating, identification and significance of the monument, including the abbot’s distinctive smile. The stone sheds new light on mortuary and commemorative practice at Valle Crucis Abbey in the early fourteenth century

La mise en charge immédiate en prothèse implanto-portée

MONTROUGE-BUFR Odontol.PARIS5 (920492101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF