Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in molecular and phenotypic heterogeneity within the tumor, the ...complexity of which is further amplified through specific interactions between cancer cells. We aimed to dissect the molecular mechanisms underlying the cooperation between different clones.
We produced clonal cell lines derived from the MDA-MB-231 breast cancer cell line, using the UbC-StarTrack system, which allowed tracking of multiple clones by color: GFP C3, mKO E10 and Sapphire D7. Characterization of these clones was performed by growth rate, cell metabolic activity, wound healing, invasion assays and genetic and epigenetic arrays. Tumorigenicity was tested by orthotopic and intravenous injections. Clonal cooperation was evaluated by medium complementation, co-culture and co-injection assays.
Characterization of these clones in vitro revealed clear genetic and epigenetic differences that affected growth rate, cell metabolic activity, morphology and cytokine expression among cell lines. In vivo, all clonal cell lines were able to form tumors; however, injection of an equal mix of the different clones led to tumors with very few mKO E10 cells. Additionally, the mKO E10 clonal cell line showed a significant inability to form lung metastases. These results confirm that even in stable cell lines heterogeneity is present. In vitro, the complementation of growth medium with medium or exosomes from parental or clonal cell lines increased the growth rate of the other clones. Complementation assays, co-growth and co-injection of mKO E10 and GFP C3 clonal cell lines increased the efficiency of invasion and migration.
These findings support a model where interplay between clones confers aggressiveness, and which may allow identification of the factors involved in cellular communication that could play a role in clonal cooperation and thus represent new targets for preventing tumor progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
COVID-19 has caused great devastation in the past year. Multi-organ point-of-care ultrasound (PoCUS) including lung ultrasound (LUS) and focused cardiac ultrasound (FoCUS) as a clinical adjunct has ...played a significant role in triaging, diagnosis and medical management of COVID-19 patients. The expert panel from 27 countries and 6 continents with considerable experience of direct application of PoCUS on COVID-19 patients presents evidence-based consensus using GRADE methodology for the quality of evidence and an expedited, modified-Delphi process for the strength of expert consensus. The use of ultrasound is suggested in many clinical situations related to respiratory, cardiovascular and thromboembolic aspects of COVID-19, comparing well with other imaging modalities. The limitations due to insufficient data are highlighted as opportunities for future research.
Abstract
Introduction: Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in phenotypic and molecular heterogeneity within ...the tumor, the complexity of which is further amplified through specific interactions between cancer cells and the tumor microenvironment. In this context, cancer may be perceived as an “ecomolecular” disease that involves cooperation between several neoplastic clones and their interactions with other cell types and secreted factors present in the microenvironment. Cancer is therefore analogous to complex ecosystems such as microbial consortia. We are currently aiming at dissecting the molecular mechanisms underlying the cooperation between different clones.
Methods: We produced clonal cell lines derived from the MDA-MB-231 breast cancer cell line, using UbC-StarTrack system, which allows tracking of multiple clones by color. The characteristics of each clone were determined by measuring migration, proliferation and metabolic activity. In vivo analysis by orthotopic breast injection and intravascular tail vein injection was performed to assess the tumorigenic capacity of these clones. We studied potential collaborations between clones by determining the influence of secreted factors on growth rate of different clones by medium complementation with supernatant or exosomes from different clones. In vivo, we used zebrafish as a model system to study the migration of individually or co-injected clones.
Results: Characterization of these clones in vitro revealed clear differences in proliferation, cell metabolic activity and morphology among them. In vivo, all the individually injected clones were able to form tumors but the growth rates differed among them. Injection of an equal mix of clones led to the formation of tumors where some clones displayed a growth or survival advantage. In vitro the complementation of growth medium with medium from other clone increased the proliferation rate of the other clones. Co-injection of clones in zebrafish increased the efficiency of migration.
Conclusions: These results confirm that even in stable cell lines heterogeneity is present. Malignant properties were enhanced when some clones were combined or treated with exosomes or medium from other clones. These results clearly support our hypothesis that tumor clones cooperate in cancer progression and that this cooperation is mediated by secreted factors. Finally, we are performing expression arrays of mRNA, microRNas and lncRNAs and determining epigenetic state by methylation arrays, in order to identify potential factors that are differentially expressed among clones and are therefore bona fide candidates for clonal cooperation promoting factors. It is anticipated that this knowledge will facilitate the design of new and more effective therapeutic approaches that are directed to the tumor ecosystem as a sum of different clones.
Citation Format: Ana Martín-Pardillos, Angeles Valls-Chiva, Eva Bejar Serrano, Roberto Piñeiro Cid, Pablo Hurtado Blanco, Angel Días-Lagares, María Magdalena Castro, Juan Antonio Juan Antonio Cámara Serrano, Santiago Ramon y Cajal. Clonal cooperation in cancer progression: A new paradigm in cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2183.
In the context of COVID-19 pandemic, we aimed to analyze the epidemiology, clinical characteristics, risk factors for mortality and impact of COVID-19 on outcomes of solid organ transplant (SOT) ...recipients compared to a cohort of non transplant patients, evaluating if transplantation could be considered a risk factor for mortality. From March to May 2020, 261 hospitalized patients with COVID-19 pneumonia were evaluated, including 41 SOT recipients. Of these, thirty-two were kidney recipients, 4 liver, 3 heart and 2 combined kidney-liver transplants. Median time from transplantation to COVID-19 diagnosis was 6 years. Thirteen SOT recipients (32%) required Intensive Care Unit (ICU) admission and 5 patients died (12%). Using a propensity score match analysis, we found no significant differences between SOT recipients and non-transplant patients. Older age (OR 1.142; 95% CI 1.08-1.197) higher levels of C-reactive protein (OR 3.068; 95% CI 1.22-7.71) and levels of serum creatinine on admission (OR 3.048 95% CI 1.22-7.57) were associated with higher mortality. The clinical outcomes of SARS-CoV-2 infection in our cohort of SOT recipients appear to be similar to that observed in the non-transplant population. Older age, higher levels of C-reactive protein and serum creatinine were associated with higher mortality, whereas SOT was not associated with worse outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVERituximab in combination with chemotherapy has been proven to increase progression-free and overall survival in follicular lymphoma (FL), but there is considerable interindividual ...variability in the response. Extrinsic pathway apoptosis triggered by death receptors seems to be involved in the mechanism of action of monoclonal antibodies. This study aimed to assess the association between TRAILR1/TRAIL polymorphisms (rs20575, rs20576, rs2230229, rs12488654) and rituximab response and the relationship with FASL rs763110, previously found to be associated with rituximab response.
PATIENTS AND METHODSPolymorphisms were determined in a study cohort of 125 FL patients treated with rituximab as first-line treatment and correlated with response, which was scored according to the International Working Group Consensus Revised as complete response, partial response, stable disease, and progressive disease.
RESULTSNo significant association with response was found for rs20576, rs2230229, and rs12488654 polymorphisms. In contrast, rs20575 GC/GG carriers were more partial/nonresponders (88.2%) than complete responders (72.5%), showing a trend toward statistical significance (P=0.064). In a multivariable setting, we found that female sex odds ratio=0.355, 95% confidence interval (CI)0.137–0.922, P=0.033 and the TRAILR1 rs20575 CC genotype (odds ratio=0.162, 95% CI0.035–0.757, P=0.021) were independent positive predictive factors of complete clinical response to rituximab, constructing a parsimonious model with good calibration χ of 5.719 (d.f.=6, P=0.455) and discrimination (C-statistic=0.739, 95% CI0.636–0.842).
CONCLUSIONAfter studying the pharmacogenetic role of TRAILR1/TRAIL polymorphisms in rituximab-treated FL patients, we found that the rs20575 CC genotype is an independent predictive factor of better rituximab response, indicating the possible involvement of death receptors in anti-CD20 mechanisms of action.
The present Spanish laws on the procedure to evaluate the environmental impact of wind farms are ambiguous, especially those pertaining to visual impact. There is no specific national law but only ...regional laws. The main targets of these laws are the conservation of the environment (protected animals and plants), and the noise generated. The focus of this paper, the visual impact, is not taken into account in a direct way in these laws.
This work develops a methodology to predict, before its construction, the visual impact that a wind farm can have. This could be used as a consulting tool to analyze and evaluate wind projects, both government-run and private.
The developed methodology is quick, concise and clear.
The knowledge acquired during university education about organ donation and transplantation (ODT) decisively influences the information future health professionals transmit. This is important in ODT ...where the participation of the general public is essential to obtain organs.
To determine notions of Spanish medicine and nursing students on ODT and its relationship with attitude toward ODT.
and design. We conducted a sociologic, multicenter, and observational study. The population for our study consisted of medical and nursing students in Spanish universities. Our database was the Collaborative International Donor Project, stratified by geographic area and academic course. A validated questionnaire (PCID-DTO-RIOS) was self-administered and completed anonymously. Our sample consisted of 9598 medical and 10,566 nursing students (99% confidence interval; precision of ±1%), stratified by geographic area and year of study.
The completion rate for our study was 90%. Only 20% (n=3640) of students thought their notions on ODT were good; 41% (n=7531) thought their notions were normal; 36% (n=6550) thought their notions were scarce. Comparing groups, there were differences between those who believed that their notions on ODT were good (44% nursing vs 56% medical students; P < .000), and those who believed it scarce (54% nursing vs 46% medical students; P < .000). Notions on ODT were related with attitude toward the donation of one's own organs: those who considered their notions were good were more in favor then those who considered it scarce (88% vs 72%; P < .000).
Only 20% of Spanish medical and nursing students thought their notions on ODT were good. Having good knowledge is related to a favorable attitude towards ODT. Receiving specific information on the subject could improve their knowledge about ODT during their training.
•Only 20% of Spanish medical and nursing students thought their notions on ODT were good.•Attitude toward ODT is related with having specific knowledge on the subject.•For improvement in health science students’ curriculum, it is necessary that the curriculum should include topics on basic and ethical aspects of ODT.
A primary care physician (PCP) not only accompanies the patient in the process of an illness, but throughout his or her life. The confidence we have in these health professionals is fundamental, and ...their favorable attitude toward organ donation and transplantation (ODT) has a significant influence on the population.
To analyze trust in PCPs among Spanish medical and nursing students, the relationship with their attitude toward ODT, and the factors that condition it.
A sociologic, multicenter, and observational study. Population: medical and nursing students in Spanish universities. Database: Collaborative International Donor Project, stratified by geographic area and academic course. A validated questionnaire (PCID-DTO-RIOS) was self-administered and completed anonymously. A sample of 9598 medical and 10,566 nursing students (99% confidence and precision of ±1%), stratified by geographic area and year of study.
Completion rate: 90%. With respect to students’ trust in their physician, 18% (n = 3267) of them totally trust (completely), 45% (n = 8101) trust enough, 30% (n = 5478) of them have not enough trust, and 7% not at all. Comparing groups, medical students totally trust more in PCPs than nursing students (55% vs 45%; P < .000), however, nursing students have less than enough trust in their PCP than medical students (53% vs 47%; P < .000). Students that totally trust in their PCP were more in favor toward ODT than students with not enough trust (83% vs 77%; P < .000).
Only 18% of Spanish medical and nursing students totally trust in their PCP. Attitude toward ODT is related to a higher level of trust in PCPs among these students.
•Only 18% of Spanish medical and nursing students have total trust in their primary care physician.•Attitude toward ODT is related to a higher level of trust in primary care physicians among these students.•Information about ODT given by primary care physicians is of great significance in the population.
Health care professionals and the information that they provide to the public on organ donation and transplantation (ODT) influence attitudes toward this option.
The objective was to analyze the ...knowledge of university nursing students at Spanish universities toward ODT and the factors affecting it.
The methods and design included a multicenter, sociologic, and observational study including university nursing diploma students in a complete academic year.
A sample of 10,566 students was selected stratified by geographic area and year. Instrument. A validated questionnaire of knowledge toward ODT (PCID-DTO RIOS), self-administered and completed anonymously.
Questionnaire completion rate: 85% (n = 9001). Only 18% (n = 1580) believed that their knowledge about ODT was good, 40% (n = 3578) believed that the information they had was normal, and 39% believed that their knowledge was sparse. Of the students, 96% believed that organ needs are not covered and 79% that they might need a transplant in the future. Only 39% (n = 3493) had attended a talk about ODT. Furthermore, 83% (n = 7435) believed that attending a talk would be interesting. The following variables were associated with having a more adequate knowledge: gender (62% men vs 57% women; P < .001); academic year (P < .001); knowing a donor (P < .001); knowing a transplant patient (P < .001); believing the possibility of needing a transplant oneself in the future (P < .001); attitude toward deceased donation (P < .001); and interest in receiving an informative talk about ODT (P < .001).
Only 18% of nursing students in Spain believed that their knowledge about ODT was adequate. These results must be considered for possible training plans for these future professionals.
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