Global Gene Expression Characterization of Circulating Tumor Cells in Metastasic Castration-Resistant Prostate Cancer Patients

BACKGROUND: Current therapeutic options in the course of metastatic castration-resistant prostate cancers (mCRPC) reinforce the need for reliable tools to characterize the tumor in a dynamic way. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem, whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis. The biomarker characterization in CTCs could provide insights into the current state of the disease and an overall picture of the intra-tumor heterogeneity. METHODS: in the present study, we applied a global gene expression characterization of the CTC population from mCRPC (n = 9), with the goal to better understand the biology of these cells and identify the relevant molecules favoring this tumor progression. RESULTS: This analysis allowed the identification of 50 genes specifically expressed in CTCs from patients. Six of these markers (HOXB13, QKI, MAOA, MOSPD1, SDK1, and FGD4), were validated in a cohort of 28 mCRPC, showing clinical interest for the management of these patients. Of note, the activity of this CTC signature was related to the regulation of MYC, a gene strongly implicated in the biology of mCRPC. CONCLUSIONS: Overall, our results represent new evidence on the great value of CTCs as a non-invasive biopsy to characterize PC

The burden of injury in Central, Eastern, and Western European sub-region : a systematic analysis from the Global Burden of Disease 2019 Study

Background Injury remains a major concern to public health in the European region. Previous iterations of the Global Burden of Disease (GBD) study showed wide variation in injury death and disability adjusted life year (DALY) rates across Europe, indicating injury inequality gaps between sub-regions and countries. The objectives of this study were to: 1) compare GBD 2019 estimates on injury mortality and DALYs across European sub-regions and countries by cause-of-injury category and sex; 2) examine changes in injury DALY rates over a 20 year-period by cause-of-injury category, sub-region and country; and 3) assess inequalities in injury mortality and DALY rates across the countries. Methods We performed a secondary database descriptive study using the GBD 2019 results on injuries in 44 European countries from 2000 to 2019. Inequality in DALY rates between these countries was assessed by calculating the DALY rate ratio between the highest-ranking country and lowest-ranking country in each year. Results In 2019, in Eastern Europe 80 [95% uncertainty interval (UI): 71 to 89] people per 100,000 died from injuries; twice as high compared to Central Europe (38 injury deaths per 100,000; 95% UI 34 to 42) and three times as high compared to Western Europe (27 injury deaths per 100,000; 95%UI 25 to 28). The injury DALY rates showed less pronounced differences between Eastern (5129 DALYs per 100,000; 95% UI: 4547 to 5864), Central (2940 DALYs per 100,000; 95% UI: 2452 to 3546) and Western Europe (1782 DALYs per 100,000; 95% UI: 1523 to 2115). Injury DALY rate was lowest in Italy (1489 DALYs per 100,000) and highest in Ukraine (5553 DALYs per 100,000). The difference in injury DALY rates by country was larger for males compared to females. The DALY rate ratio was highest in 2005, with DALY rate in the lowest-ranking country (Russian Federation) 6.0 times higher compared to the highest-ranking country (Malta). After 2005, the DALY rate ratio between the lowest- and the highest-ranking country gradually decreased to 3.7 in 2019. Conclusions Injury mortality and DALY rates were highest in Eastern Europe and lowest in Western Europe, although differences in injury DALY rates declined rapidly, particularly in the past decade. The injury DALY rate ratio of highest- and lowest-ranking country declined from 2005 onwards, indicating declining inequalities in injuries between European countries.Peer reviewe

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Deposition and characterization of BiVO4 thin films and evaluation as photoanodes for methylene blue degradation

Thin films of bismuth vanadate (BiVO4) are deposited through the solution combustion synthesis technique coupled with the dip-coating process. Thermal gravimetric analyis shows a total mass loss of 71 % besides the formation of the monoclinic phase, about 300 A degrees C, which is also revealed by X-ray diffraction. UV-Vis optical absorption spectra show direct bandgap transition about 2.5 eV for films, in good agreement with semiconducting monoclinic phase. Scanning electron microscopic images reveal that thermal annealing time at 500 A degrees C is a very important parameter to control the thickness and shape of the particles and yields an average thickness of about 800 nm for 10 dip-coated deposited layers, with round-shaped nanometric-sized particles, homogeneously distributed on the film surface. Photoelectrochemical degradation of methylene blue by a bismuth vanadate film deposited on fluor-doped tin oxide substrate shows up as a very efficient process. The first-order rate constant for the photoinduced process is about five times the rate constant for degradation in the dark, showing the capacity of the BiVO4/fluorine-doped tin oxide film for electrochemical degradation, mainly in the presence of light.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Protective effects of yacon (Smallanthus sonchifolius) intake on experimental colon carcinogenesis

Yacon (Smallanthus sonchifolius), a tuberous root native to the Andean region of South America, contains high concentration of fructans with potential for colon cancer prevention. This study investigated the potential beneficial of yacon intake on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) in male Wistar rats. After 4 weeks of DMH-initiation, groups were fed basal diet (Cl and G6) or basal diet containing dried extract of yacon root at 0.5% (G2), 1.0% (G3 and G5) or a synbiotic formulation (G4) (1.0% yacon plus Lactobacillus casei at 2.5 x 10(10) CFU per g diet) for 13 weeks. At week 20, a significant reduction in number and multiplicity of aberrant crypt foci (ACF) and in number of invasive adenocarcinomas was observed in the groups orally treated with 1.0% yacon (G3) or the synbiotic formulation (G4) (0.05 < p < 0.001). Tumor multiplicity (noninvasive plus invasive) was significantly lower in the group fed synbiotic formulation (p < 0.02). A significant reduction in cell proliferation in colonic crypts and tumors and short chain fatty acids (SCFA) caecal contents was observed in the groups orally treated with 1.0% yacon (G3) or the synbiotic formulation (G4). Therefore, the findings this study indicate that yacon and yacon plus L casei intake may reduce the development of chemically-induced colon cancer. (C) 2012 Elsevier Ltd. All rights reserved

Preliminary characterization of Vulnerable Marine Ecosystems and associated communities of Chella Bank (Alboran Sea, W Mediterranean)

Poster presentation at ATLAS 3rd General Assembly. Seamounts may promote the presence of vulnerable marine ecosystems (VMEs) worldwide. In the Alboran Sea (W Mediterranean Sea), the Chella Bank (locally known as “Seco de los Olivos”) is a seamount that covers ca. 100 km2 and is under the influence of different water masses in this important Atlanto-Mediterranean biogeographical transition zone. During the MEDWAVES expedition (September-October 2016) within the frame of the H2020 ATLAS project, biological and sediment samples collected with Van Veen dredge and ROV underwater videos were obtained in sedimentary and coral rubble bottoms of Chella Bank. The analyses have revealed a diverse invertebrate community associated with these bottoms containing abundant cold-water coral (CWC) remains (mainly Madrepora oculata and Lophelia pertusa), which provide complex heterogeneous microhabitats to many different taxa. The community associated with the coral rubble bottoms is mainly composed of different genera of bivalves (Mendicula, Limopsis, Asperarca), gastropods (Gibberula, Epitonium), small crustaceans (class Malacostraca), polychaetes (Eunice), ophiuroideans (Ophiothrix), bryozoans (order Cyclostomata), hydrozoans (Cryptolaria), poriferans (Terpios, Haliclona) and brachiopods (Megathiris, Megerlia), among other taxa. Furthermore, the megafauna include cnidarians (Bebryce, Acanthogorgia, Dendrophyllia), sponges (Pachastrella) and dense shoals of the carangid fish Caranx rhonchus. Unlike coral rubble bottoms, macro- and micro-fauna inhabiting close sandy, muddy or hemipelagic muddy habitats seems less diverse (up to four times in terms of abundance and species richness). These communities are mainly composed of polychaetes, small crustaceans and bivalves (Abra, Ennucula, Yoldiella), together with shoals of the ammodytid fish Gymnammodytes cicerelus. Coral rubble bottoms of Chella Bank may therefore represent an interesting habitat for conservation, harboring a good representation of the biodiversity linked to CWC communities. This study increases the scarce information on biodiversity and biogeography (WP3) for this area that probably favors the connectivity of CWC associated fauna (WP4) between the Atlantic and Mediterranean basins

Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease.

International audienceThere is a paucity of information regarding the factors that affect nonrelapse mortality (NRM) and overall survival among children that develop chronic graft-versus-host disease (cGVHD). We performed multivariate analyses using data from the Center for International Blood and Marrow Transplant Research to identify risk factors for NRM and survival in 1117 pediatric subjects with leukemia or myelodysplastic syndrome, transplanted from related donors, unrelated donors (URD), or unrelated cord blood between 1995 and 2004. We identified 4 variables associated with higher NRM: HLA partially matched or mismatched URD, peripheral blood cell graft, Karnofsky/Lansky score 10 years, transplantation from HLA partially matched or mismatched URD, advanced disease at transplantation, Karnofsky/Lansky < 80; and platelets < 100 × 10(9)/L. Cumulative incidence of discontinuation of systemic immune suppression at 1, 3, and 5 years after diagnosis of cGVHD were 22% (20%-25%), 34% (31%-37%), and 37% (34%-40%), respectively. This is the largest study elucidating variables affecting outcome after diagnosis of cGVHD in pediatric allograft recipients. These variables may be useful for risk stratification, development of future clinical trials, and family counseling in children with cGVHD

Impact of Chronic Graft-versus-Host Disease on Late Relapse and Survival on 7,489 Patients after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Leukemia

PURPOSE: Malignancy relapse remains a major obstacle for successful allogeneic hematopoietic cell transplantation (HCT). Chronic graft-versus-host disease (cGVHD) is associated with fewer relapses. However, when studying effects of cGVHD on relapse it is difficult to separate from acute GVHD effects as most cases of cGVHD occur within the first year post-transplant at the time when acute GVHD is still active. EXPERIMENTAL DESIGN: The current study based on CIBMTR registry data investigated cGVHD and its association with the incidence of late relapse and survival in 7489 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) who were leukemia-free at12 months after myeloablative allogeneic HCT. RESULTS: Forty-seven percent of the study population was diagnosed with cGVHD at 12 months after transplant. The protective effect of cGVHD on relapse was present only in patients with CML (RR: 0.47, 95% CI: 0.37-0.59, P <0.0001). cGVHD was significantly associated with higher risk of treatment related mortality, (RR: 2.43, 95% CI: 2.09-2.82, P <0.0001) and inferior overall survival (RR: 1.56, 95% CI: 1.41-1.73, P <0.0001) for all diseases. In patients with CML all organ sites and presentation types of cGVHD were equally associated with lower risk of late relapse. CONCLUSIONS: These results indicate that clinically relevant anti-leukemia effects of cGVHD on late relapses are present only in CML but not in AML, ALL or MDS. Chronic GVHD in patients who are one year survivors after myeloablative allogeneic HCT is primarily associated with higher TRM and inferior survival