Parallel declines in species and genetic diversity driven by anthropogenic disturbance: a multispecies approach in a French Atlantic dune system.

Numerous studies assess the correlation between genetic and species diversities, but the processes underlying the observed patterns have only received limited attention. For instance, varying levels of habitat disturbance across a region may locally reduce both diversities due to extinctions, and increased genetic drift during population bottlenecks and founder events. We investigated the regional distribution of genetic and species diversities of a coastal sand dune plant community along 240 kilometers of coastline with the aim to test for a correlation between the two diversity levels. We further quantify and tease apart the respective contributions of natural and anthropogenic disturbance factors to the observed patterns. We detected significant positive correlation between both variables. We further revealed a negative impact of urbanization: Sites with a high amount of recreational infrastructure within 10 km coastline had significantly lowered genetic and species diversities. On the other hand, a measure of natural habitat disturbance had no effect. This study shows that parallel variation of genetic and species diversities across a region can be traced back to human landscape alteration, provides arguments for a more resolute dune protection, and may help to design priority conservation areas

Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis.

Background Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas.Patients and methods A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed.Results Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively.Conclusion The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation

BMJ Open

INTRODUCTION: The prevalence of postnatal depression (PND) is significant: reaching up to 20% in the general population. In mechanistic terms, the risk of PND lies in an interaction between a maternal psychophysiological vulnerability and a chronic environmental context of stress. On the one hand, repetition of stressor during pregnancy mimics a chronic stress model that is relevant to the study of the allostatic load and the adaptive mechanisms. On the other hand, vulnerability factors reflect a psychological profile mirroring mindfulness functioning (psychological quality that involves bringing one's complete and non-judgemental attention to the present experience on a moment-to-moment basis). This psychological resource is linked to protective and resilient psychic functioning. Thus, PND appears to be a relevant model for studying the mechanisms of chronic stress and vulnerability to psychopathologies.In this article, we present the protocol of an ongoing study (started in May 2017). METHODS AND ANALYSIS: The study is being carried out in five maternities and will involve 260 women. We aim to determine the predictive psychobiological factors for PND emergence and to provide a better insight into the mechanisms involved in chronic stress during pregnancy. We use a multidisciplinary approach that encompasses psychological resources and biophysiological and genetic profiles in order to detect relevant vulnerability biomarkers for chronic stress and the development of PND. To do so, each woman will be involved in the study from her first trimester of pregnancy until 12 months postdelivery. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ile de France III Ethics Committee, France (2016-A00887-44). We aim to disseminate the findings through international conferences and international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03088319; Pre-results

Prognostic factors in metastatic renal cell carcinoma: metastasectomy as independent prognostic variable

Prognostic and predictive factors in patients with metastatic renal cell carcinoma (MRCC) have been evaluated from untreated patients or patients on several different treatment approaches. The aim of this analysis was to define prognostic and predictive factors in patients treated uniformly with a low-dose outpatient cytokine combination. The relationship between patient-, tumour-, and treatment-related factors was analysed in 99 patients with MRCC. These features were first examined in univariate analyses, then a stepwise modelling approach based on Cox regression was used to form a multivariate model. Nuclear grade, metastasectomy – even incomplete – C-reactive protein and lactate dehydrogenase were identified as independent prognostic factors for survival. Patients assigned to three different risk groups had statistically significant survival differences (30, 22 and 6 months, respectively). A total of 43.4% had undergone metastasectomy, mostly incomplete. Risk group affiliation was correlated with response to treatment. Our findings strongly suggest the consideration of metastasectomy in the management of patients with metastatic renal cell cancer undergoing either immunotherapy or targeted treatment

Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study

To assess the efficacy of the combination of long-acting release (LAR) octreotide and tamoxifen (TMX) for the treatment of advanced hepatocellular carcinoma (HCC). A total of 109 patients with advanced HCC were randomised to receive octreotide LAR combined with TMX (n=56) (experimental treatment group) or TMX alone (n=53; control group). The clinical, biological and tumoural parameters were recorded every 3 months until death. Primary end point was patient survival; secondary end points were the impact of therapy on tumour response, quality of life and variceal bleeding episodes. Univariate and multivariate analyses were performed for assessment of specific prognostic factors. The median survival was 3 months (95% CI 1.4–4.6) for the experimental treatment group and 6 months (CI 95% 2–10) for the control group (P=0.609). There was no difference in terms of α-foetoprotein (α-FP) decrease, tumour regression, improvement of quality of life and prevention of variceal bleeding between the two groups. Variables associated with a better survival in the multivariate analysis were: presence of cirrhosis, α-FP level <400 ng ml−1 and Okuda stage I. The combination of octreotide LAR and TMX does not influence survival, tumour progression or quality of life in patients with advanced HCC

EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer

Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations

Activity and safety of crizotinib in patients with advanced clear cell sarcoma with MET alterations. European Organization for Research and Treatment of Cancer phase 2 trial 90101 "CREATE"

BACKGROUND: Clear cell sarcoma (CCSA) is an orphan malignancy, characterised by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor (TKI) crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary endpoint was objective response rate (ORR), secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), overall survival rate (OSR) and safety. The study design focused on MET + disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization (FISH). RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and evaluable. 26/28 patients had MET + disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval:0.1-19.6). Further efficacy endpoints in MET + CCSA were DCR:69.2% (48.2-85.7%), median PFS:131 days (49-235), median OS:277 days (232-442). The 3, 6, 12 and 24 month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two evaluable MET - patients, one had SD and one had progression. The most common treatment-related adverse events were nausea (18/34[52.9%]), fatigue (17/34[50.0%]), vomiting (12/34[35.3%]), diarrhea (11/34[32.4%]), constipation (9/34[26.5%] and blurred vision (7/34[20.6%]). CONCLUSIONS: The PFR with crizotinib in MET + CCSA is similar to results achieved first-line in metastatic soft tissue sarcomas with single-agent doxorubicin. In further lines, the PFS is similar to pazopanib in previously treated sarcoma patients

Flanking signal and mature peptide residues influence signal peptide cleavage

<p>Abstract</p> <p>Background</p> <p>Signal peptides (SPs) mediate the targeting of secretory precursor proteins to the correct subcellular compartments in prokaryotes and eukaryotes. Identifying these transient peptides is crucial to the medical, food and beverage and biotechnology industries yet our understanding of these peptides remains limited. This paper examines the most common type of signal peptides cleavable by the endoprotease signal peptidase I (SPase I), and the residues flanking the cleavage sites of three groups of signal peptide sequences, namely (i) eukaryotes (Euk) (ii) Gram-positive (Gram+) bacteria, and (iii) Gram-negative (Gram-) bacteria.</p> <p>Results</p> <p>In this study, 2352 secretory peptide sequences from a variety of organisms with amino-terminal SPs are extracted from the manually curated SPdb database for analysis based on physicochemical properties such as p<it>I</it>, aliphatic index, GRAVY score, hydrophobicity, net charge and position-specific residue preferences. Our findings show that the three groups share several similarities in general, but they display distinctive features upon examination in terms of their amino acid compositions and frequencies, and various physico-chemical properties. Thus, analysis or prediction of their sequences should be separated and treated as distinct groups.</p> <p>Conclusion</p> <p>We conclude that the peptide segment recognized by SPase I extends to the start of the mature protein to a limited extent, upon our survey of the amino acid residues surrounding the cleavage processing site. These flanking residues possibly influence the cleavage processing and contribute to non-canonical cleavage sites. Our findings are applicable in defining more accurate prediction tools for recognition and identification of cleavage site of SPs.</p