MTR-Viewer: identifying regions within genes under purifying selection

Advances in genomic sequencing have enormous potential to revolutionize personalized medicine, however distinguishing disease-causing from benign variants remains a challenge. The increasing number of human genome and exome sequences available has revealed areas where unfavourable variation is removed through purifying selection. Here, we present the MTR-Viewer, a web-server enabling easy visualization at the gene or variant level of the Missense Tolerance Ratio (MTR), a measure of regional intolerance to missense variation calculated using variation from 240 000 exome and genome sequences. The MTR-Viewer enables exploration of MTR calculations, using different sliding windows, for over 18 000 human protein-coding genes and 85 000 alternative transcripts. Users can also view MTR scores calculated for specific ethnicities, to enable easy exploration of regions that may be under different selective pressure. The spatial distribution of population and known disease variants is also displayed on the protein's domain structure. Intolerant regions were found to be highly enriched for ClinVar pathogenic and COSMIC somatic missense variants (Mann–Whitney U test P < 2.2 × 10−16). As the MTR is not biased by known domains and protein features, it can highlight functionally important regions within genes overlooked or inaccessible by traditional methods. MTR-Viewer is freely available via a user friendly web-server at http://biosig.unimelb.edu.au/mtr-viewer/.

An invertebrate multimetric index to classify the ecological status of small coastal lagoons in the Mediterranean ecoregion (MIBIIN)

Despite the requirements of the European Water Framework Directive (WFD) to protect water bodies, suitable indices of quality designed specifically to assess coastal lagoons (transitional waters) remain absent. In the present study, we developed a multimetric index of the Balearic Island based on invertebrate communities (MIBIIN) to assess the ecological status of small coastal lagoons (i.e. up to 4-m depth and <2.5 km2), a common ecosystem within the Mediterranean ecoregion. Thirty-four coastal lagoons were sampled on six occasions between 2005 and 2008. A multimetric index for each salinity type of coastal lagoon (oligohaline-MIBIIN, mesohaline-MIBIIN and euhaline-MIBIIN) was developed. The individual metrics, and hence the MIBIINs, fulfilled the normative definitions established by the WFD (abundance, diversity and sensitive : tolerance ratio), responded to gradients of disturbance and discriminated reference from non-reference sites. Common boundary limits for the three MIBIINs were established (high/good = 0.930, good/moderate = 0.730, moderate/poor = 0.500, poor/bad = 0.250). Unlike other metrics used in coastal lagoon evaluation, the MIBIINs were developed exclusively for coastal lagoons, including oligohaline freshwater environments. Although the MIBIIN is yet to be validated with an external dataset, these findings suggest the potential for this new multimetric index to be used in similar systems in the Mediterranean ecoregion.

Navelbine (NVB) oral (o) with cisplatin (CDDP) as induction and concomitant to radiotherapy (RT): Final results of an international phase II trial in stage III non-small cell lung cancer (NSCLC)

7691 Background: NVB i.v. with CDDP has reported an optimal activity/tolerance ratio when used in combination with RT. The new oral formulation of NVB should be easier to use assuming a similar activity profile. An international phase II trial with NVBo + CDDP as induction followed by NVBo+CDDP+RT was implemented in order to evaluate the efficacy of this combination. Methods: Patients (pts) between 18 and 70 years, with histologically proven untreated locally advanced inoperable stage IIIA/IIIB (supraclavicular LN and pleural effusion excluded) NSCLC, adequate bone marrow, hepatic and renal function, KPS ≥ 80% were treated with NVBo D1,8 60 mg/m2 cycle 1 and 80 mg/m2 cycle 2 (if no haematological/non-haematological grade 3–4 toxicity) and CDDP 80 mg/m2 every 3 weeks for 2 cycles as induction. OR/NC pts received NVBo D1,8 40 mg/m2 and CDDP 80 mg/m2 every 3 weeks for 2 more cycles and RT 66 Gy in 6.5 weeks. Results: Between 12/01 and 12/03 54 pts were enrolled; stages IIIA 48%, IIIB 52%; squamous 59%; median age 57 years (range 41;71), median KPS 100% (range 80; 100%) 7% pts ≥ 5% weight loss at baseline. RDI of NVBo/CDDP were 86%/93% and 97%/98% at induction and in combination with RT, respectively. Forty-one pts (76%) during induction increased NVBo from 60 to 80 mg/m2. Reasons for non- escalation: haematological 7 pts, non-haematological 2, mistake 4. After 2 cycles of CT induction, OR (ITT) in the 54 pts was 37%. Toxicity during induction: G3–4 Neutropenia (28%), febrile neutropenia (7%), G3 nausea (11%), G3–4 vomiting (9%), G3 anorexia (4%) G4 diarrhoea (2%); G3 constipation (2%). Forty-seven out of 54 pts received CT-RT. Median RT delivered dose: 66 Gy. Tolerance: 9% G3 Neutropenia; no G3/4 oesophagitis; 2% G3 radiation dermatitis. Late pulmonary fibrosis 1 pt. One month after CT-RT completion the overall RR (ITT) in the 54 pts was 54% (95% CI: 40%; 67%). Median PFS/OS: 12.5 (95% CI: 9.6; 16.4) /23.4 (95% CI: 17.6; 29.8) months, respectively. Conclusion: NVB Oral with CDDP is effective in stage IIIA/IIIB pts. The excellent tolerance profile allowed to complete the CT/RT treatment in 94% of pts. NVB oral is a new and promising option which facilitates the concomitant administration of CT/RT. [Table: see text]