Starting Day Care in Espoo from the Viewpoint of Chinese Parents

The thesis is a small-scale evaluative research. The day care start folder, which provided practical and detailed information about starting Finnish day care to support multicultural parents in Otaniemi day-care centre and Servin-Maija day-care centre, was assessed among nine Chinese parents of children in five municipal and outsourced day-care centres in the City of Espoo. The purposes of the current research were to find out how Chinese parents perceive starting day care in the City of Espoo and their difficulties and suggestions concerning starting day care in the City of Espoo; to evaluate how the day care start folder is experienced as a working method in opinion of Chinese parents living in the City of Espoo; and to further improve the day care start folder as a working method for multicultural families and personnel in Otaniemi day-care centre and possibly for other day-care centres in the similar situation. Two types of interview, namely semi-structured individual interview and focus group interview, were utilised as the primary qualitative data-collecting methods in the current research. In addition, questionnaire as an assistant quantitative data-collecting method was employed as well to ensure verification of the consistency of the data, and supplement the abundance of the narrative data collected from interviews. The qualitative data gathered from the six interviews was coded, categorised and analysed in accordance with the method of content analysis. The results showed that the participating Chinese parents basically concerned about the information on starting day care; their child’s language learning; their communication and cooperation with day-care staff; cultures, religions and festivals; playing, learning and friends; child protection and legislation and so forth. Furthermore, these Chinese parents also put forward some important problems and suggestions on Finnish day care, such as problems caused by cultural differences, different opinions on learning by playing and Finnish as a second language-teaching, difficulties to obtain enough English information about Finnish day care, and the lack of mediums for foreign families to receive help concerning Finnish day care. In addition, these Chinese parents perceived the day care start folder as useful and adequate. The results based on the questionnaires supported and verified the results generated from the qualitative data analysis

Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy

IAG933, an oral selective YAP1-TAZ/pan-TEAD protein-protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors

The YAP/TEAD protein-protein interaction is a critical event known to mediate YAP oncogenic functions downstream of the Hippo pathway. All current, advanced pharmacological agents which aim at inhibiting YAP/TEAD oncogenic function do so by engaging into the lipid pocket of TEAD. Thereby the consequences of a direct pharmacological disruption of the interface of YAP and TEADs remain largely unexplored. Here we present IAG933, the first molecule able to potently directly disrupt the YAP/TAZ-TEADs protein-protein interaction with suitable properties to enter in clinical trial. The path to drug discovery was established by careful and systematic analysis of natural sequences of YAP and TAZ binding to TEAD as well as complemented with structure-based optimization of a truncated natural YAP peptide allowing the pharmacophore mapping of the coil binding site of TEAD. Based on in silico screening, confirmed hit was optimized using structure-based and property-based lead optimization yielding IAG933. Biochemical and cellular assays demonstrated that IAG933 specifically abrogates the interaction between YAP/TAZ coactivators and all four TEAD isoforms, thus inhibiting TEAD-driven transcriptional activity and inducing cancer cell killing. Exquisite compound selectivity was shown in rescue experiments and is consistent with the correlation observed between pharmacological and genetic sensitivity profiles across a large panel of cancer cell lines. At the epigenomics level, we observe YAP eviction from chromatin and relocation to the cytoplasm upon treatment with IAG933, leaving TEADs genomic occupancy unaffected and consequently competent to engage its co-repressor VGLL4. Concomitantly, we detect a decrease in enhancer activity and accessibility upon loss of YAP occupancy, which translates to rapid and progressive changes in transcription of Hippo target genes. In preclinical experiments, IAG933 displays linear pharmacokinetics, consistent with dose proportional in vivo TEAD transcriptional inhibition and anti-tumor efficacy in orthotopic and subcutaneous mouse and rat xenograft and primary-tumor derived malignant pleural mesothelioma models. Importantly, IAG933 elicits complete tumor regression in the MSTO-211H xenograft model at doses that were well tolerated in mice and rats. In line with the current clinical strategy for IAG933, we also demonstrate robust anti-tumor efficacy in cancer models bearing NF2 loss of function or expressing TAZ-fusions. Moreover, we provide evidence for robust combination benefits of IAG933 with several MAPK/KRAS inhibitors, both in vitro and in vivo, in non-Hippo altered models including lung, pancreatic and colorectal cancer. This is also consistent with IAG933-induced YAP displacement at AP1/TEAD chromatin-binding sites. Overall, our results provide a robust rationale of progressing IAG933 as monotherapy in patients with Hippo-mutated cancers, and as a combination partner in MAPK-dependent cancers, with the potential to treat several patient populations of high unmet medical need

ROLES DES SEMAPHORINES ET DE LEURS RECEPTEURS DANS DEUX SYSTEMES DE DIFFERENCIATION (LA NEUROGENESE ET L'OSTEOCLASTOGENESE)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Deciphering mechanisms of response and resistance in large-scale mouse cancer screens

Acquired resistance is a major limitation for the successful treatment of cancer patients. Although numerous efficacious cancer therapeutics have been developed in the past decades, resistance arises due to a variety of reasons including tumoral genetic alterations, or modulation of factors in the tumor environment. Understanding the mechanistic reasons for tumor relapse supports the identification of novel combination therapies that could lead to more durable responses. Here, we will review large-scale in vivo screens in pre-clinical cancer models that employed genetic and pharmacological agents toward elucidating acquired drug resistance and informing on beneficial combinations to be tested in clinical trials

Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness

Invasiveness underlies cancer aggressiveness and is a hallmark of malignancy. Most malignant tumors have elevated levels of Tn, an O-GalNAc glycan. Mechanisms underlying Tn up-regulation and its effects remain unclear. Here we show that Golgi-to-endoplasmic reticulum relocation of polypeptide N-acetylgalactosamine-transferases (GalNAc-Ts) drives high Tn levels in cancer cell lines and in 70% of malignant breast tumors. This process stimulates cell adhesion to the extracellular matrix, as well as migration and invasiveness. The GalNAc-Ts lectin domain, mediating high-density glycosylation, is critical for these effects. Interfering with the lectin domain function inhibited carcinoma cell migration in vitro and metastatic potential in mice. We also show that stimulation of cell migration is dependent on Tn-bearing proteins present in lamellipodia of migrating cells. Our findings suggest that relocation of GalNAc-Ts to the endoplasmic reticulum frequently occurs upon cancerous transformation to enhance tumor cell migration and invasiveness through modification of cell surface proteins

Optimization of a Class of Dihydrobenzofurane Analogs Toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors

The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time