Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

BACKGROUND: Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels. METHODOLOGY/PRINCIPAL FINDINGS: We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05). CONCLUSIONS/SIGNIFICANCE: Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy. TRIAL REGISTRATION: (ClinicalTrials.gov) NCT00883480

Insights from the genome of the biotrophic fungal plant pathogen Ustilago maydis

Ustilago maydis is a ubiquitous pathogen of maize and a well-established model organism for the study of plant-microbe interactions. This basidiomycete fungus does not use aggressive virulence strategies to kill its host. U. maydis belongs to the group of biotrophic parasites (the smuts) that depend on living tissue for proliferation and development. Here we report the genome sequence for a member of this economically important group of biotrophic fungi. The 20.5-million-base U. maydis genome assembly contains 6,902 predicted protein-encoding genes and lacks pathogenicity signatures found in the genomes of aggressive pathogenic fungi, for example a battery of cell-wall-degrading enzymes. However, we detected unexpected genomic features responsible for the pathogenicity of this organism. Specifically, we found 12 clusters of genes encoding small secreted proteins with unknown function. A significant fraction of these genes exists in small gene families. Expression analysis showed that most of the genes contained in these clusters are regulated together and induced in infected tissue. Deletion of individual clusters altered the virulence of U. maydis in five cases, ranging from a complete lack of symptoms to hypervirulence. Despite years of research into the mechanism of pathogenicity in U. maydis, no 'true' virulence factors had been previously identified. Thus, the discovery of the secreted protein gene clusters and the functional demonstration of their decisive role in the infection process illuminate previously unknown mechanisms of pathogenicity operating in biotrophic fungi. Genomic analysis is, similarly, likely to open up new avenues for the discovery of virulence determinants in other pathogens. ©2006 Nature Publishing Group.J.K., M. B. and R.K. thank G. Sawers and U. Kämper for critical reading of the manuscript. The genome sequencing of Ustilago maydis strain 521 is part of the fungal genome initiative and was funded by National Human Genome Research Institute (USA) and BayerCropScience AG (Germany). F.B. was supported by a grant from the National Institutes of Health (USA). J.K. and R.K. thank the German Ministry of Education and Science (BMBF) for financing the DNA array setup and the Max Planck Society for their support of the manual genome annotation. F.B. was supported by a grant from the National Institutes of Health, B.J.S. was supported by the Natural Sciences and Engineering Research Council of Canada and the Canada Foundation for Innovation, J.W.K. received funding from the Natural Sciences and Engineering Research Council of Canada, J.R.-H. received funding from CONACYT, México, A.M.-M. was supported by a fellowship from the Humboldt Foundation, and L.M. was supported by an EU grant. Author Contributions All authors were involved in planning and executing the genome sequencing project. B.W.B., J.G., L.-J.M., E.W.M., D.D., C.M.W., J.B., S.Y., D.B.J., S.C., C.N., E.K., G.F., P.H.S., I.H.-H., M. Vaupel, H.V., T.S., J.M., D.P., C.S., A.G., F.C. and V. Vysotskaia contributed to the three independent sequencing projects; M.M., G.M., U.G., D.H., M.O. and H.-W.M. were responsible for gene model refinement, database design and database maintenance; G.M., J. Kämper, R.K., G.S., M. Feldbrügge, J.S., C.W.B., U.F., M.B., B.S., B.J.S., M.J.C., E.C.H.H., S.M., F.B., J.W.K., K.J.B., J. Klose, S.E.G., S.J.K., M.H.P., H.A.B.W., R.deV., H.J.D., J.R.-H., C.G.R.-P., L.O.-C., M.McC., K.S., J.P.-M., J.I.I., W.H., P.G., P.S.-A., M. Farman, J.E.S., R.S., J.M.G.-P., J.C.K., W.L. and D.H. were involved in functional annotation and interpretation; T.B., O.M., L.M., A.M.-M., D.G., K.M., N.R., V. Vincon, M. VraneŠ, M.S. and O.L. performed experiments. J. Kämper, R.K. and M.B. wrote and edited the paper with input from L.-J.M., J.G., F.B., J.W.K., B.J.S. and S.E.G. Individual contributions of authors can be found as Supplementary Notes

Kliničke praktične smjernice za perioperacijsku i poslijeoperacijsku skrb o arterijsko-venskim fistulama i umetcima za hemodijalizu u odraslih

Krvožilni pristup omogućuje hemodijalizu koja spašava život. Stoga je nužna dobra funkcija krvožilnog pristupa koja omogućuje prikladan krvni protok radi uklanjanja tvari koje se u uremiji zadržavaju u krvi bolesnika, uz istodobno sniženje rizika od sustavne infekcije na najmanju moguću mjeru. Godine 2007. Europske smjernice najbolje prakse (engl. European Best Practice Guidelines – EBPG), prethodnice trenutačne Europske najbolje bubrežne prakse (engl. European Renal Best Practice – ERBP), donijele su nacrt skupine preporuka – vodiča pri donošenju odluka o upućivanju na pregled radi krvožilnog pristupa, o procjeni i nadzoru izbora pristupa te o postupcima kod komplikacija. (1) Otad su se znatno razvili ne samo dokazi na kojima se temelje ove preporuke nego i procesi nastajanja smjernica. (2) Kao odgovor na to, ERBP je ažurirao prethodno djelo u suradnji s raznim stručnjacima iz tog područja uključujući i predstavnike Društva za krvožilni pristup (engl. Vascular Access Society – VAS), kirurge za krvožilni pristup, radiologe, medicinske sestre za dijalizu, znanstvenike, bolesnike i one koji se za njih brinu. Nastojanje da se pridržavaju sve strože metodike izrade smjernica nalagalo je određena odricanja u pogledu područja obuhvata ovih smjernica. Posljedično, one ne „pokrivaju” baš sve iste teme kao njihova prethodna verzija. Neka su područja zajednička, a neka su arhivirana da bi ustupila mjesto novim pitanjima kojima su prednost dali i pružatelji zdravstvene skrbi i oni za koje se skrbi. Odvojeno su objavljene pojedinosti postupka izbora djelokruga problematike koju su smjernice obuhvatile. (3) Nastajanje ovih smjernica slijedilo je strog proces pregleda i procjene dokaza koji se temeljio na sustavnim pregledima rezultata kliničkih istraživanja te opservacijskih podataka gdje je to bilo potrebno. Strukturirani pristup slijedio je model sustava GRADE (hrv. stupanj), koji svakoj preporuci pripisuje stupanj s obzirom na sigurnost sveukupnih dokaza te snagu. (4) Gdje je to bilo primjereno skupina za izradu smjernica unijela je nestupnjevan savjet za kliničku praksu, a koji nije proistekao iz pregleda sustavnih dokaza. Kliničke praktične smjernice iz 2019. godine specifično pokrivaju peritransplantacijske i poslijetransplantacijske aspekte arterijsko-venskih (AV) fistula i umetaka (graftova). Drugi dio, koji je bio u nastajanju kada su ove smjernice išle u tisak, pokrit će aspekte izbora krvožilnog pristupa, prijeoperacijske procjene krvnih žila i središnje venske katetere. Unatoč nedostatku dokaza velike sigurnosti za većinu područja krvožilnih pristupa, ERBP se posvetio izradi smjernica velike kakvoće, dajući smjernicu gdje god je moguće, a popis preporuka za istraživanje ondje gdje se nije moglo uputiti smjernicom. Nadamo se da će ove smjernice i one planirane pomoći stručnoj zajednici pri donošenju odluka o postupcima, postupnicima i skrbi vezanima s krvožilnim pristupima, pomoći bolesnicima i onima koji se za njih brinu da steknu uvid u problematiku te olakšati zajedničko donošenje odluka u tom području

The role of Doppler ultrasonography in vascular access surveillance-controversies continue

Chronic hemodialysis therapy required regular entry into the patient's blood stream with adequate flow. The use of arteriovenous fistulas and grafts is linked with lower morbidity and mortality than the use of catheters. However, these types of accesses are frequently affected by stenoses, which decrease the flow and lead to both inadequate dialysis and access thrombosis. The idea of duplex Doppler ultrasound surveillance is based on the presumption that in-time diagnosis of an asymptomatic significant stenosis and its treatment prolongs access patency. Details of performed trials are conflicting, and current guidelines do not support ultrasound surveillance. This review article summarizes the trials performed and focuses on the reasons of conflicting results. We stress the need of precise standardized criteria of significant access stenosis and the weakness of the metaanalyses performed

Tarsal-less peptides control Notch signalling through the Shavenbaby transcription factor

The formation of signalling boundaries is one of the strategies employed by the Notch (N) pathway to give rise to two distinct signalling populations of cells. Unravelling the mechanisms involved in the regulation of these signalling boundaries is essential to understanding the role of N during development and diseases. The function of N in the segmentation of the Drosophila leg provides a good system to pursue these mechanisms at the molecular level. Transcriptional and post-transcriptional regulation of the N ligands, Serrate (Ser) and Delta (Dl) generates a signalling boundary that allows the directional activation of N in the distalmost part of the segment, the presumptive joint. A negative feedback loop between odd-skipped-related genes and the N pathway maintains this signalling boundary throughout development in the true joints. However, the mechanisms controlling N signalling boundaries in the tarsal joints are unknown. Here we show that the non-canonical tarsal-less (tal) gene (also known as pri), which encodes for four small related peptides, is expressed in the N-activated region and required for joint development in the tarsi during pupal development. This function of tal is both temporally and functionally separate from the tal-mediated tarsal intercalation during mid-third instar that we reported previously. In the pupal function described here, N signalling activates tal expression and reciprocally Tal peptides feedback on N by repressing the transcription of Dl in the tarsal joints. This Tal-induced repression of Dl is mediated by the post-transcriptional activation of the Shavenbaby transcription factor, in a similar manner as it has been recently described in the embryo. Thus, a negative feedback loop involving Tal regulates the formation and maintenance of a Dl+/Dl- boundary in the tarsal segments highlighting an ancient mechanism for the regulation of N signalling based on the action of small cell signalling peptide

Clinical practice guideline on peri- and postoperative care of arteriovenous fistulas and grafts for haemodialysis in adults. [Erratum]

Text has been added to the article in the ‘Study Selection’ paragraph, explaining the inclusion criteria for selecting the abstracts

Clinical practice guideline on peri- and postoperative care of arteriovenous fistulas and grafts for haemodialysis in adults

The ericoid shrub Vaccinium myrtillus is one of several deciduous boreal plants that respond to larval defoliation by compensatory production of a new set of leaves within the same growing season soon after defoliation. This new set is termed as ‘secondary leaves’. The physiological performance and longevity of secondary leaves is poorly understood. Following a multi-year larval outbreak in boreal Norway, we therefore monitored the fate of the secondary leaves from 2014 to 2016. We observed that secondary leaves were still green upon onset of snow season and that the same leaves were still attached and green when snow melted in spring. During the early growing season of 2015, the overwintering leaves were consumed by moth larvae, but the secondary leaves produced in mid-July 2015 overwintered and were not consumed by larvae the next growing season. Our monitoring shows that most of these leaves remained attached until late August, while the contents of chlorophyll and nitrogen remained high until July. The flavonoid (anthocyanin) content of overwintering leaves increased shortly after snowmelt, and this coincided with a short-lasting colour change from green to violet-bronze. This was probably a protective response to the abrupt increase in solar radiation. Overall, secondary, overwintering leaves were free of snow and physiologically active for ca 6.5 months, which is 2–3 months more than the longevity of primary leaves in the study area. We conclude that wintergreen leaves probably rendered an important carbon sequestration contribution in the critical first phase of the growing season until new side branches with new leaves were developed. Hence, the novel results reported here on the facultative wintergreen growth habit of V. myrtillus appears to be a successful strategy

Clinical practice guideline on peri- and postoperative care of arteriovenous fistulas and grafts for haemodialysis in adults [Erratum]

In the original version, reference 35 had the incorrect journal title. This has now been amended. An additional affiliation has also been added for author Tamara Jemcov