Late-time spectral line formation in Type IIb supernovae, with application to SN 1993J, SN 2008ax, and SN 2011dh

We investigate line formation processes in Type IIb supernovae (SNe) from 100 to 500 days post-explosion using spectral synthesis calculations. The modelling identifies the nuclear burning layers and physical mechanisms that produce the major emission lines, and the diagnostic potential of these. We compare the model calculations with data on the three best observed Type IIb SNe to-date - SN 1993J, SN 2008ax, and SN 2011dh. Oxygen nucleosynthesis depends sensitively on the main-sequence mass of the star and modelling of the [O I] lambda lambda 6300, 6364 lines constrains the progenitors of these three SNe to the M-ZAMS = 12-16 M-circle dot range (ejected oxygen masses 0.3-0.9 M-circle dot), with SN 2011dh towards the lower end and SN 1993J towards the upper end of the range. The high ejecta masses from M-ZAMS greater than or similar to 17 M-circle dot progenitors give rise to brighter nebular phase emission lines than observed. Nucleosynthesis analysis thus supports a scenario of low-to-moderate mass progenitors for Type IIb SNe, and by implication an origin in binary systems. We demonstrate how oxygen and magnesium recombination lines may be combined to diagnose the magnesium mass in the SN ejecta. For SN 2011dh, a magnesium mass of 0.02-0.14 M-circle dot is derived, which gives a Mg/O production ratio consistent with the solar value. Nitrogen left in the He envelope from CNO burning gives strong [N II] lambda lambda 6548, 6583 emission lines that dominate over Ha emission in our models. The hydrogen envelopes of Type IIb SNe are too small and dilute to produce any noticeable H alpha emission or absorption after similar to 150 days, and nebular phase emission seen around 6550 angstrom is in many cases likely caused by [N II] lambda lambda 6548, 6583. Finally, the influence of radiative transport on the emergent line profiles is investigated. Significant line blocking in the metal core remains for several hundred days, which affects the emergent spectrum. These radiative transfer effects lead to early-time blueshifts of the emission line peaks, which gradually disappear as the optical depths decrease with time. The modelled evolution of this effect matches the observed evolution in SN 2011dh.

Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma:analysis of a clinic-based population

Five to ten percent of individuals with melanoma have another affected family member, suggesting familial predisposition. Germ-line mutations in the cyclin-dependent kinase (CDK) inhibitor p16 have been reported in a subset of melanoma pedigrees, but their prevalence is unknown in more common cases of familial melanoma that do not involve large families with multiple affected members. We screened for germ-line mutations in p16 and in two other candidate melanoma genes, p19ARF and CDK4, in 33 consecutive patients treated for melanoma; these patients had at least one affected first or second degree relative (28 independent families). Five independent, definitive p16 mutations were detected (18%, 95% confidence interval: 6%, 37%), including one nonsense, one disease-associated missense, and three small deletions. No mutations were detected in CDK4. Disease-associated mutations in p19ARF, whose transcript is derived in part from an alternative codon reading frame of p16, were only detected in patients who also had mutations inactivating p16. We conclude that germ-line p16 mutations are present in a significant fraction of individuals who have melanoma and a positive family history.

Characterisation of Bioresorbable Composite Performance for Validation of New On-Line Process Monitoring Technology

There is an increasing interest in the biomedical field to create implantable medical devices to provide a temporary mechanical function for use inside the human body. In many of these applications bioresorbable polymer composites using PLLA with β-TCP , are increasingly being used due to their biocompatability, biodegradability and mechanical strength.1,3 These medical devices can be manufactured using conventional plastics processing methods such as injection moulding and extrusion, however there is great need to understand and control the process due to a lack of knowledge on the influence of processing on material properties. With the addition of biocompatible additives there is also a requirement to be able to predict the quality and level of dispersion within the polymer matrix. On-line UV-Vis spectroscopy has been shown to monitor the quality of fillers in polymers. This can eliminate time consuming and costly post-process evaluation of additive dispersion. The aim of this work was to identify process and performance relationships of PLLA/β-TCP composites with respect to melt-extrusion conditions. This is part of a wider study into on-line process monitoring of bioresorbable polymers as used in the medical industry.
These results show that final properties of the PLLA/ β-TCP composite are highly influenced by the particle size and loading. UV-Vis spectroscopy can be used on-line to monitor the final product and this can be utilised as a valuable tool for quality control in an application where consistent performance is of paramount importance.

Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line

Activated protein C (APC) protects against sepsis in animal models and inhibits the lipopolysacharide (LPS)-induced elaboration of proinflammatory cytokines from monocytes. The molecular mechanism responsible for this property is unknown. We assessed the effect of APC on LPS-induced tumour necrosis factor alpha (TNF-alpha) production and on the activation of the central proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in a THP-1 cell line. Cells were preincubated with varying concentrations of APC (200 microg/ml, 100 microg/ml and 20 microg/ml) before addition of LPS (100 ng/ml and 10 microg/ml). APC inhibited LPS-induced production of TNF-alpha both in the presence and absence of fetal calf serum (FCS), although the effect was less marked with 10% FCS. APC also inhibited LPS-induced activation of NF-kappaB, with APC (200 microg/ml) abolishing the effect of LPS (100 ng/ml). The ability of APC to inhibit LPS-induced translocation of NF-kappaB is likely to be a significant event given the critical role of the latter in the host inflammatory response.

Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models

Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, is known to possess tumorigenic and proangiogenic properties. Overexpression of IL-8 has been detected in many human tumors, including colorectal cancer (CRC), and is associated with poor prognosis. The goal of our study was to determine the role of IL-8 overexpression in CRC cells in vitro and in vivo. We stably transfected the IL-8 cDNA into two human colon cancer cell lines, HCT116 and Caco2, and selected IL-8-secreting transfectants. Real-time RT-PCR confirmed that IL-8 mRNA was overexpressed in IL-8 transfectants with 45- to 85-fold higher than parental cells. The IL-8-transfected clones secreted 19- to 28-fold more IL-8 protein than control and parental cells as detected by ELISA. The IL-8 transfectants demonstrated increased cellular proliferation, cell migration and invasion based on functional assays. Growth inhibition studies showed that IL-8 overexpression lead to a significant resistance to oxaliplatin (p < 0.0001). Inhibition of IL-8 overexpression with small interfering RNA reversed the observed increases in tumorigenic functions and oxaliplatin resistance, suggesting that IL-8 not only provides a proliferative advantage but also promotes the metastatic potential of colon cancer cells. Using a tumor xenograft model, IL-8-expressing cells formed significantly larger tumors than the control cells with increased microvessel density. Together, these findings indicate that overexpression of IL-8 promotes tumor growth, metastasis, chemoresistance and angiogenesis, implying IL-8 to be an important therapeutic target in CRC.

Selecting the best targeted agent in first-line treatment of unresectable liver metastases from colorectal cancer:does the bench have the answers?

For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micrometastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent (anti-EGFR or anti-VEGF) to reach these goals. Therefore, a priori molecular identification of patients that could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the currently approved targeted therapies for metastatic colorectal cancer) is of critical importance. In this setting, the KRAS mutation status was the first identified predictive marker of response to anti-EGFR therapy. Since it has been demonstrated that tumors with KRAS mutation do not respond to anti-EGFR therapy, KRAS status must be determined prior to treatment. Thus, for KRAS wild-type patients, the choices that remain are either anti-VEGF or anti-EGFR. In this review, we present the most updated data from translational research programs dealing with the identification of biomarkers for response to targeted therapies.