NCube/papyrus huggingface dataset:
The human organic cation transporter OCT1 mediates high affinity uptake of the anticancer drug daunorubicin

Anthracyclines such as doxorubicin and daunorubicin are hydrophilic anticancer agents that must be transported into cells.  These drugs accumulate in the nucleus where they intercalate with DNA, thereby interfering with DNA replication in turn leading to cell death.  Anthracyclines are used for treating a variety of cancers including leukemia, lymphomas, breast, lung, and ovarian. Despite evidence for active uptake of anthracyclines, the specific transporter has not been identified.  Using the ovarian cancer cell line TOV2223G, we show that substrates reported for the organic cation transporter OCT1, such as ergothioneine, thiamine and phenformin, partially compete with uptake of daunorubicin, but not of L-carnitine, i.e., a high affinity substrate transported by hCT2 and OCTN2.  These findings exclude the involvement of the L-carnitine organic cation family of transporters in anthracycline uptake.  Moreover, we show that OCT1 actively mediates high affinity (Km ~ 5 μM) transport of daunorubicin into TOV2223G cells, whereas micromolar amounts of choline completely abolish drug uptake.  shRNA-mediated downregulation of OCT1 causes defective uptake of daunorubicin, as well as significant resistance to the drug, as compared to the vector control.  Transfection of HEK293T cells with a plasmid expressing OCT1 as a GFP fusion protein revealed that OCT1-EYFP was predominantly localized to the plasma membrane.  These transfected cells manifested nearly 5-fold increased uptake of daunorubicin compared to the empty vector control.  In summary, we show for the first time that human OCT1 is a high affinity transporter for anthracyclines.  As such, we postulate that OCT1 status represents a critical determinant in the response of cancer cells to chemotherapy with anthracyclines

Keyphrases: anthracyclines, Human organic cation transporter 1(OCT1)
Trauma in critically ill children : transfusion and osmotherapy practices

Trauma is the leading cause of death of children, with the burden of mortality related both to traumatic brain injury and hemorrhagic shock. Despite the frequency of trauma in the pediatric population, the management of these patients is often based on adult literature due the sparse amount of literature in pediatric trauma. The studies presented below were intended to establish current practice, and prepare for future prospective studies in pediatric trauma. The management of raised intracranial pressure (ICP) following traumatic brain injury (TBI) involves intracranial monitoring and the escalation of care to prevent secondary insults to the brain. Hyperosmolar therapy with mannitol (20%) and hypertonic saline (3%) are standard of care for the reduction of ICP, despite little evidence for their use. Our retrospective, single center study aimed to describe the clinical practice of hyperosmolar therapy in pediatric severe TBI, and its effect on ICP. We found that both mannitol and hypertonic saline are frequently used without a clear indication for one agent over another. There was insufficient power to confirm an effect on ICP, and multiple co-interventions given after boluses of hyperosmolar therapy may have contributed this lack of effect. In order to prospectively evaluate the effect of hyperosmolar therapy on ICP, a standardized approach to TBI care and hyperosmolar agents is necessary. Red blood cell transfusion is a key component of the management of the unstable trauma patient. Literature now suggests that transfusion is associated with increased mortality, and practices have shifted toward restrictive transfusion strategies in many clinical populations.  We sought to describe the transfusion practices in pediatric trauma patients based on a secondary analysis of a large prospective study on blood loss in pediatric intensive care unit (PICU) patients. Compared to non-trauma patients, trauma patients were more likely to be transfused and transfused early in their course of stay. Younger age, higher PELOD and mechanical ventilation were associated with receiving a red blood cell transfusion in the PICU. Receiving a blood transfusion prior to PICU admission was most strongly associated with receiving a transfusion after PICU admission, suggesting ongoing bleeding in those transfused early. Future prospective studies geared specifically for trauma patients are necessary to determine whether osmotherapy for high ICP, and restrictive transfusion strategies can be applied to them, in order to improve the quality of the evidence based care provided to children.

Keyphrases: Trauma, Mannitol, Pediatrics, Traumatic Brain Injury, Hyperosmolar therapy, Mannitol, Hypertonic saline, Red blood cell transfusion, Anemia
Rôle de la qualité des tapis de cellules endométriales en co-culture autologue sur le développement embryonnaire

Introduction: Lot's of progress has been made in the process of in vitro fertilization (IVF) in the last years. However, the pregnancy rate is still low. There are two important issues in IVF: embryo development and implantation. One answer may be the endometrial autologue co-culture which could improve the embryo development and the implantation rate in many ways. The aim of this study is to assess the effect of co-culture quality on human embryo development and implantation rate. Materials and methods: The ovogen study was a randomized, double blind trial analysis. OvoGen compared the blastulation and the pregnancy rate in two randomized groups: the study group, with autologous endometrial co-culture and the control group, with conventional media. The outcome of our study was to assess the correlation between the quality of autologous endometrial co-culture (cells confluence, rate of epithelials cells and stromals cells viability) and the embryo development. Results: FIfty patients in the co-culture group were analyzed between 2012 to 2015 at the ovo clinic (Montreal, Quebec). 291 embryos were analyzed, each cocultured on a monolayer endometrial cells. The embryo quality was not significantly linked with the co-culture quality (p=0,65 for the cells confluence, 0,25 for the epithelial cells rate and 0,92 for the stromal cells viability). On the other hand, the 11 pregnancy rate increased in correlation with the decreasing of the confluence (p=0,022) and the increase of stromal cells (p=0,001). Moreover, the moment of the biopsy had an effect on the co-culture: when the biopsy was performed seven days after the ovulation, the quality of the co-culture was better (confluence increased p=0,045, epithelials cells increased p= 0,004 and stromal cells viability increased p=0,001) than when the biopsy was done five days after the ovulation. Discussion: There were no previous study on the quality of the co-culture and its effect on the embryo development. The fact that the pregnancy rate increased with the decrease of the confluence in the co-culture is interesting. Indeed, we could easily explain why a huge confluence could be prejudicial for the dialog between embryo and endometrium. Moreover, in accordance with previous experience, the day of the biopsy in the cycle is important for the quality of the endometrium. This is why the day of the biopsy may have an effect on the co-culture quality. Conclusion: Our results show that the moment of the biopsy has an effect on the quality of the co-culture and that the quality of the co-culture has an effect on the pregnancy rate. It could be interesting to study the endometrium receptivity on the biopsy before the co-culture to optimize the quality and the benefit of the co-culture.

Keyphrases: Co-culture cellulaire autologue, In vitro fertilization, Embryo, Endometrial, Autologous endometrial coculture
Dialyse à domicile : évaluation du modèle de dialyse à domicile intégrée

Treatment of end-stage renal disease with home dialysis modalities (peritoneal dialysis [PD] and home hemodialysis [HHD]) is associated with significant patient-related benefits, including improved quality of life, greater autonomy and lower rates of medical complications. Although home dialysis is being increasingly promoted internationally, little data has been published to evaluate outcomes of patients treated with PD and HDD at time of renal replacement therapy (RRT) initiation and evaluate the optimal home dialysis treatment pattern.   The current project specifically aimed to answer the following questions: (1) what is the survival associated with initiation of RRT with PD or HDD, (2) what is the survival associated with the integrated home dialysis model (PD with subsequent transfer to HHD) compared to PD or HDD treatment initially, (3) what are the predictors associated with the integrated home dialysis model.  The first study included 11 416 incident dialysis patients from Australia and New Zealand between 2000 and 2012.  Treatment with HHD at start of RRT was associated with a lower mortality compared to initial treatment with PD (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.38-0.59). The second study assessed the integrated home dialysis model per se and showed a similar mortality among patients treated with the integrated home model (PD with transfer to HHD after PD ending) and patients treated with HHD from start of RRT (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.52-1.62). Finally, the third study assessed the predictors of the integrated home dialysis model and identified baseline characteristics such as lower age, male sex, race, cause of end-stage renal disease, comorbidities and duration of PD therapy as potential predictors of a transfer from PD to HHD.

Keyphrases: End-stage kidney disease, Home dialysis, Peritoneal dialysis, Home hemodialysis, Integrated home dialysis model, Survival
Aider sans nuire: intervention de groupe destinée aux proches de victimes d'actes criminels

Abstract: Criminal acts have severe consequences. When crimes are committed, a majority of victims will turn to their natural support network to be assisted. The social support provided to victims by their own relatives and loved ones will have positive impacts on their well-being and recovery, only when properly adapted to the victims’ needs. Providing proper social support is not an easy task for victims’ relatives. In fact, victims’ relatives also suffer repercussions of criminal acts, making it difficult for them to carry out their role in supporting the victim. Even when well intentioned, some of their actions may inflict additional pain to victims, thus negatively impacting their recovery. Given those findings, we decided to create a group intervention program designed for victims’ relatives and loved ones which we named « Aider sans nuire ». This group intervention program will attempt, in its design, to support victims’ relatives and loved ones, as well as provide them with helpful tools to assist with their supporting role towards the victims. With the assistance of intervention workers from the Victim assistance center (CAVAC) of Montreal, we evaluated the usefulness and content of the program we designed. We used various data gathering methods, including a focus group and an evaluation questionnaire, in order to get the intervention workers’ feedback on the program. We were also able to get their opinion concerning the recruiting strategies used through an online survey. The feedback we received led us to confirm the relevance of this project. We were also able to determine that our inability to recruit a sufficient number of candidates to form a group was caused by other factors independent of the program itself. The feedback provided by the intervention workers allowed us to improve the content of the original program. We believe the changes made to the original program will be beneficial to those taking part in the program in the future.

Keyphrases: crime victims' relatives, crime victims' loved ones, crime victims' social network, social support provided by victims' network, group intervention, program evaluation
Caractérisation de l’activité transcriptionnelle antivirale et immunorégulatrice dépendante de STAT2 et IRF9, mais indépendante de STAT1, induite par la costimulation par TNF𝛼�+IFN𝛽�

Lung epithelial cells are the first line of defense against respiratory viruses via mucus secretion, peptides, cytokines and chemokines that determine the progression of the infection. The main antiviral cytokines produced by alveolar epithelial cells (AEC) are the interferons (IFN) type I (α / β) and III (λ). IFNβ binding to its receptor induces an antiviral pathway that is well characterized and leads to activation of the ISGF3 complex (STAT1, STAT2 and IRF9) which allows the transcription of multiple genes encoding proteins with antiviral and immunoregulatory activity. It has recently been shown that the costimulation of lung epithelial cells by IFNβ and Tumor Necrosis Factor α (TNFα), also produced during infection, induces a separate and late antiviral state, through synergy. On the other hand, it has been shown that the synergy between IFNβ+TNFα induces a signaling pathway involving STAT2 and IRF9 independently of STAT1 permitting the expression of the DUOX2 gene. Our goal is to determine the importance of this new signaling pathway induced by costimulation of TNFα+IFNβ involving STAT2 and IRF9 regardless of STAT1 in regulating the antiviral immunoregulatory and late transcriptional program.  Our first objective is to determine whether antiviral and immunomodulatory genes that are induced by costimulation TNFα+IFNβ are dependent on the STAT2/IRF9 way, indenpant of STAT1. Using the technique of qRT-PCR, we identified 3 immunoregulatory genes, CXCL10, IDO and APOBEC3G, synergistically induced in response to TNFα+IFNβ in A549 cells, a model of pulmonary epithelial cells. To confirm that these genes are induced independantly of STAT1, we validated their expression in the STAT1 deficient cell line, U3A. By the use of interfering RNA (siRNA) directed against STAT2 and IRF9, we confirmed that the induction of these genes is dependent STAT2 and IRF9. Finally, the analysis of the activity of CXCL10 promoter in response to TNFα+IFNβ by luciferase reporter assays has shown that the regulation is at the transcriptional level.  Our second objective is to determine whether STAT6 could replace the STAT1 in the signaling pathway induced by TNFα+IFNβ. Indeed, STAT6 is a known inducer of the expression of DUOX2 in response to IL4+IL13. Contrarily to our hypothesis, inhibition of STAT6 by RNAi increases the expression of DUOX2 in response to TNFα+IFNβ suggesting that STAT6 is a negative regulator.  Our results allow the understanding of the mechanisms in the development of an antiviral response in more detail. On the other hand, the study of the effect of IFNβ and TNFα is also relevant for chronic inflammatory and autoimmune diseases. In addition, our results illustrate a new paradigm for cell signaling mechanisms involved in the synergy between two cytokines that may be applicable to combinations of cytokines other than TNFα+IFNβ.

Keyphrases: Cytokines, TNFα, IFNβ, Synergy, Antiviral response
Déterminer le rôle de C1orf106, un gène associé aux maladies inflammatoires de l’intestin

The Inflammatory bowel diseases (IBD, [MIM 266600]) involve chronic inflammation of the digestive tract and include ulcerative colitis (UC) and Crohn’s disease (CD). IBD may result from defects in the homeostasis of immune system and intestinal epithelium. The latter forms a physical and biochemical barrier to commensal and pathogenic microorganisms. A dysfunction in the epithelial barrier may lead to a sustained immune response against the gut flora. Genome wide association studies (GWAS) have identified 200 susceptibility regions in IBD. Among these, the 1q32 region associated with risk of both CD (p<2x10-11) and UC (p<6x10-7), contains the gene C1orf106. Our targeted re-sequencing study has identified a low-frequency variant, Y333F (p=0.009) in C1orf106, a protein of unknown function and in which tyrosine333 is predicted to be phosphorylated. We demonstrated that its substitution by a phenylalanine may have an effect on C1orf106 protein stability as shown by cycloheximide treatment experiments. Our RNA expression analyses of human tissues and cell lines demonstrated that C1orf106 is mostly expressed in the small intestine and colon. It is also detectable in monocytic cell lines but more highly expressed in colonic epithelial cell lines. Furthermore, its expression is increased by 40% during differentiation of colonic epithelial Caco-2 cells into polarized epithelium. To provide further biological context, we generated colorectal LS174T cells that stably overexpress the Y333F alleles and demonstrated that it is partially localized with ZO-1, used as a tight junction (TJ) marker. We did observe tighter colocalization with E-cadherin, a canonical marker for adherens junctions (AJ), typically located below the TJ complex. AJ and TJ play an essential role in the establishment of epithelial barrier. The localization of C1orf106 at these regions suggests its possible implication in epithelial barrier homeostasis. Using trans-epithelial measurement of ions movement across epithelium, we demonstrated an increased in permeability of an epithelium formed by C1orf106 knock-down Caco-2 cells. Our results suggest that C1orf106 could be the causal gene of the 1q32 susceptibility region.

Keyphrases: C1orf106, Inflammatory bowel diseases, Intestinal epithelium, Tight and adherence junctions, Protein stability
L'activité tonique diaphragmatique chez les enfants avec et sans support respiratoire

Background: Infants have to actively maintain their end expiratory lung volume (EELV) due to their high rib cage compliance. Mechanisms such as high respiratory rate, short expiratory time and laryngeal braking are implicated. In mechanically ventilated infants, the diaphragm stays activated until the end of expiration (tonic activity), contributing to EELV maintenance. It is unclear whether tonic activity compensates for the lack of laryngeal braking due to intubation or if it is normally present.  Objective: To determine if tonic diaphragm activity remains after extubation in infants, and if it can be observed in older children.   Methods: Prospective observational study of pediatric patients 1 week to 18 years-old ventilated for >24 hr with parental consent. Diaphragm electrical activity (EAdi) was recorded using a specific nasogastric catheter during four periods: (i) the acute phase, (ii) pre-extubation, (iii) postextubation, and (iv) at PICU discharge. EADi was analyzed in a semi-automatic manner. Tonic EAdi was defined as the EAdi in the last quartile of expiration.   Results: Fifty-five patients, median age 10 months (Interquartile range: 1–48) were studied. In infants (<1 year, n=28), tonic EAdi as a percentage of inspiratory activity was 48% (30-56) in acute phase, 38% (25-44) pre-extubation, 28% (17-42) post-extubation et 33% (22-43) at PICU discharge (p<0.05, ANOVA, with statistically significant difference between recordings 1 and 3-4).  No significant change was observed between pre- and post-extubation periods. In older patients (n=27), tonic activity was negligible as a whole (0.6mcv). However, significant tonic EAdi (>1mcv and >10%) was observed in 10 patients (37%). Bronchiolitis was the only independent factor associated with tonic EAdi.  Conclusions: In infants, tonic EAdi remains involved in ventilatory control after extubation and restoration of laryngeal braking. Tonic EAdi can be reactivated in older patients. The interest of tonic EAdi as a tool to titrate mechanical ventilation warrants further evaluation.

Keyphrases: Expiration, Mechanical ventilation, Pediatric intensive care, Diaphragm function, End expiratory lung volume, Positive end expiratory pressure
Étude de mortalité de cinq cancers : mélanome cutané, cancer broncho-pulmonaire, leucémie myéloïde chronique, maladie de Hodgkin et cancer de l’endomètre

For each of the five cancers, we made an epidemiologic summary in North America, and we recalled classifications and prognosis factors; then we made a description of the studies retained, we made a mortality analysis and added comments, and a conclusion. The study of cutaneous melanoma showed that melanomas are insurable in the early years for stages IA, IB, IIA, and IIIA, after five years for stages IIB, IIC and IIIB and after 15 years for stage IIIC. The study of lung cancer showed that small cell cancer is not insurable; non-small cells bronchopulmonary cancers could be insured under 65 years after ten years for stages IA to IIIA; patients 65 years and older could be insured in the early years for stage IA, after five years for stages IB and IIA and after ten years for stages IIB and IIIA.  The study of chronic myeloid leukemia showed insurability in the early years for those over 65 years and after 5 years for the patients aged 60 to 65years. The study of Hodgkin lymphoma showed that subjects under 45 years are insurable in the early years for stage IA, after 5 years for stages IB and IIA, and after 10 years for stage IIB to IVA; the subjects of 45-64 years are insurable in the first years for stages IA and IIA and after 5 years for other stages; and subjects aged 65 and over are insurable in the first years for stages IA to IIIA and after 5 years at other stages. The study of endometrial cancer shows that insurability could be offered for type 1 during the first five years for  stage I only for women aged 45 years and over;  for women at stage II only women  55 years and over; for stage III only for women  65 years and over;  for Type II cancers, insurability could be offered only for Stage I for 65 years and over and stage II for women 75 years and over;  for malignant mixed Mullerian insurability could be offered only for tumors at stage I for 65 years and older.

Keyphrases: Lung cancer, Chronic Myelocytic leukemia, Hodgkin Lymphoma, Endometrial Cancer, Mortality, Survival, Prognosis, Skin melanoma