Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets

Recent advances in chemotherapeutics highlight the importance of molecularlytargeted perturbagens. Although these therapies typically address dysregulated cancer cell proteins, there are increasing therapeutic modalities that take into consideration cancer cell-extrinsic factors. Targeting components of tumor stroma such as vascular or immune cells has been shown to represent an efficacious approach in cancer treatment. Cancer-associated fibroblasts (CAFs) exemplify an important stromal component that can be exploited in targeted therapeutics, though their employment in drug discovery campaigns has been relatively minimal due to technical logistics in assaying for CAF-tumor interactions. Here we report a 3-dimensional multi-culture tumor:CAF spheroid phenotypic screening platform that can be applied to high-content drug discovery initiatives. Using a functional genomics approach we systematically profiled 1,024 candidate genes for CAF-intrinsic anti-spheroid activity; identifying several CAF genes important for development and maintenance of tumor:CAF coculture spheroids. Along with previously reported genes such as WNT, we identify CAF-derived targets such as ARAF and COL3A1 upon which the tumor compartment depends for spheroid development. Specifically, we highlight the G-protein-coupled receptor OGR1 as a unique CAF-specific protein that may represent an attractive drug target for treating colorectal cancer. In vivo, murine colon tumor implants in OGR1 knockout mice displayed delayed tumor growth compared to tumors implanted in wild type littermate controls. These findings demonstrate a robust microphysiological screening approach for identifying new CAF targets that may be applied to drug discovery efforts

Relationship Between the Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) and Lung Adenocarcinoma Patterns: New Possible Insights

Introduction: This study aimed to evaluate a potential relationship between the diffusing capacity of the lung for carbon monoxide (DLCO) and the aggressiveness of lung adenocarcinoma (ADC). Methods: Patients who underwent radical surgery for lung ADC between 2001 and 2018 were retrospectively reviewed. DLCO values were dichotomized into DLCOlow (<80% of predicted) and DLCOnormal (≥80%). Relationships between DLCO and ADC histopathological features, clinical features, as well as with overall survival (OS), were evaluated. Results: Four-hundred and sixty patients were enrolled, of which 193 (42%) were included in the DLCOlow group. DLCOlow was associated with smoking status, low FEV1, micropapillary and solid ADC, tumour grade 3, high tumour lymphoid infiltrate and presence of tumour desmoplasia. In addition, DLCO values were higher in low-grade ADC and progressively decreased in intermediate and high-grade ADC (p = 0.024). After adjusting for clinical variables, at multivariable logistic regression analysis, DLCOlow still showed a significant correlation with high lymphoid infiltrate (p = 0.017), presence of desmoplasia (p = 0.065), tumour grade 3 (p = 0.062), micropapillary and solid ADC subtypes (p = 0.008). To exclude the association between non-smokers and well-differentiated ADC, the relationship between DLCO and histopathological ADC patterns was confirmed in the subset of 377 former and current smokers (p = 0.021). At univariate analysis, gender, DLCO, FEV1, ADC histotype, tumour grade, stage, pleural invasion, tumour necrosis, tumour desmoplasia, lymphatic and blood invasion were significantly related with OS. At multivariate analysis, only gender (p < 0.001), tumour stage (p < 0.001) and DLCO (p = 0.050) were significantly related with the OS. Conclusions: We found a relationship between DLCO and ADC patterns as well as with tumour grade, tumour lymphoid infiltrate and desmoplasia, suggesting that lung damage may be associated with tumour aggressiveness

Rehabilitation and release of confiscated songbirds into the wild : a pilot study

Songbirds are currently the most prevalent animals in illegal traffcking in Brazil and other countries, so they are often confiscated, and this poses legal, ethical, and conservation challenges. Returning them to nature requires complex and expensive management, a topic that is sparingly addressed in the literature. Here, we described the processes and costs associated with an attempt to rehabilitate and release confiscated songbirds into the wild. A total of 1,721 songbirds of several species were quarantined, rehabilitated, and released, primarily on two farms located within their typical geographical distribution. Health assessments were performed on samples from 370 birds. Serology revealed no antibodies against Newcastle disease, and Salmonella spp. cultures were negative. Real-time polymerase chain reactions detected M. gallisepticumin samples from seven birds. Atoxoplasma spp. and Acuaria spp. infections, sepsis, and trauma were the top causes of bird death. About 6% of the released birds were recaptured, within an average period of 249 days after release, and at a mean distance of 2,397 meters from the release sites. The majority of these birds were found with free-living mates within or close to fragments of transitional ecoregions with native or cultivated grasslands, and native groves/forests, and shrublands. However, eucalyptus plantations with rich understory regeneration provided a suitable environment for the released forest species to settle, since they were recaptured during the defense of these sites. Over half of the recaptured birds presented behavioral profiles with both dominant and tame traits. Birds with dominant traits are more likely to settle in habitats and face the live decoys during fieldwork, whereas birds with tame characteristics tend to accept close contact with humans. Ultramarine grosbeak (Cyanoloxia brissonii), the least common species among those released, at the release sites showed an almost 2-fold recapture rate in the shortest mean distances from the release sites. This suggests less territory competition, perhaps a major factor of bird re-establishment here. The total per-bird cost was USD 57. Our findings suggested suitable survival and re-establishment of confiscated songbirds in the wild, when managed as we describe

L’homme et sa diversité

Qu’est-ce que l’anthropologie biologique ? Science des interactions entre l'homme et son milieu, l'anthropologie biologique aborde les grands questionnements actuels sur notre espèce : Comment l'homme s'adapte-t-il aux changements rapides de mode de vie et d'alimentation ? Quelle est l'influence des migrations sur l'évolution des flux géniques ? À quelles modifications morphologiques ou physiologiques éventuelles du corps humain assiste-t-on à l'heure actuelle ? Des spécialistes issus des différents domaines concernés confrontent ici leurs points de vue, et ouvrent de nouvelles perspectives de recherche

Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

International audienceThe aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed