Cyclin dependent kinase-1 (Cdk-1) inhibition as a novel therapeutic strategy against pancreatic ductal adenocarcinoma (pdac)

The role of CDK1 in PDAC onset and development is two-fold. Firstly, since CDK1 activity regulates the G2/M cell cycle checkpoint, overexpression of CDK1 can lead to progression into mitosis even in cells with DNA damage, a potentially tumorigenic process. Secondly, CDK1 overexpression leads to the stimulation of a range of proteins that induce stem cell properties, which can contribute to the development of cancer stem cells (CSCs). CSCs promote tumor-initiation and metastasis and play a crucial role in the development of PDAC. Targeting CDK1 showed promising results for PDAC treatment in different preclinical models, where CDK1 inhibition induced cell cycle arrest in the G2/M phase and led to induction of apoptosis. Next to this, PDAC CSCs are uniquely sensitive to CDK1 inhibition. In addition, targeting of CDK1 has shown potential for combination therapy with both ionizing radiation treatment and conventional chemotherapy, through sensitizing tumor cells and reducing resistance to these treatments. To conclude, CDK1 inhibition induces G2/M cell cycle arrest, stimulates apoptosis, and specifically targets CSCs, which makes it a promising treatment for PDAC. Screening of patients for CDK1 overexpression and further research into combination treatments is essential for optimizing this novel targeted therapy

Vulnerability in acquisition, language impairments in Dutch: Creating a VALID data archive

The VALID Data Archive is an open multimedia data archive (under construction) with data from speakers suffering from language impairments. We report on a pilot project in the CLARIN-NL framework in which five data resources were curated. For all data sets concerned, written informed consent from the participants or their caretakers has been obtained. All materials were anonymized. The audio files were converted into wav (linear PCM) files and the transcriptions into CHAT or ELAN format. Research data that consisted of test, SPSS and Excel files were documented and converted into CSV files. All data sets obtained appropriate CMDI metadata files. A new CMDI metadata profile for this type of data resources was established and care was taken that ISOcat metadata categories were used to optimize interoperability. After curation all data are deposited at the Max Planck Institute for Psycholinguistics Nijmegen where persistent identifiers are linked to all resources. The content of the transcriptions in CHAT and plain text format can be searched with the TROVA search engin

Evaluation of pregnancy and delivery in 13 women who underwent resection of a sacrococcygeal teratoma during early childhood

Sacrococcygeal teratoma resection often brings changes in pelvic anatomy and physiology with possible consequences for defecation, micturition and sexual function. It is unknown, whether these changes have any gynecological and obstetric sequelae. Until now four pregnancies after sacrococcygeal teratoma resection have been described and cesarean section has been suggested to be the method of choice for delivery. We evaluated the pregnancy course and mode of delivery in women previously treated for a sacrococcygeal teratoma. The records of all patients who underwent sacrococcygeal teratoma resection after 1970 in one of the six pediatric surgical centers in the Netherlands were reviewed retrospectively. Women aged 18 years and older were eligible for participation. Patient characteristics, details about the performed operation and tumor histology were retrieved from the records. Consenting participants completed a questionnaire addressing fertility, pregnancy and delivery details. Eighty-nine women were eligible for participation; 20 could not be traced. Informed consent was received from 41, of whom 38 returned the completed questionnaire (92.7%). Thirteen of these 38 women conceived, all but one spontaneously. In total 20 infants were born, 17 by vaginal delivery and 3 by cesarean section, in one necessitated by previous intra-abdominal surgery as a consequence of sacrococcygeal teratoma resection. Conversion to a cesarean section was never necessary. None of the 25 women without offspring reported involuntary childlessness. There are no indications that resection of a sacrococcygeal teratoma in female patients is associated with reduced fertility: spontaneous pregnancy is possible and vaginal delivery is safe for mother and child, irrespective of the sacrococcygeal teratoma classification or tumor histolog

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer

Possible relevance of pigeons as an indicator species for monitoring air pollution.

Wild city pigeons were caught at four different locations in the Netherlands to represent areas of high (Amsterdam-high), moderate (Amsterdam-medium), and low (Maastricht and Assen) traffic density. It is assumed that local ambient air pollution decreases as a function of traffic density. In these pigeons levels of polycyclic aromatic hydrocarbon (PAH)-DNA adducts, oxidative DNA damage, and heavy metal residues were determined in kidney, lung, liver, and blood (no adduct analysis in blood). The contribution of leaded gasoline to total body lead content was estimated by measuring concentrations of Pb and its isotopes in blood. We also analyzed samples of ambient air particulate matter for PAH and heavy metal concentrations at the four different locations. Interregional differences in heavy metals in ambient air particulate matter were reflected relatively well by pigeon body loads. The higher lead and cadmium concentrations in blood, kidney, liver, and lung were found in the Amsterdam high traffic density area, followed by Amsterdam medium, Assen, and Maastricht. A high Pb concentration in blood coincided with relatively low 206Pb/207Pb values, indicating a high contribution of leaded gasoline to total blood Pb concentrations in pigeons from the Amsterdam high traffic density area. Significantly enhanced blood zinc values were found in pigeons from both locations in Amsterdam compared to pigeons from the other two areas. However, no differences in Zn tissue levels between the four different groups were found. Oxidative DNA damage, determined as the ratio of 7-Hydro-8-oxo-2'-deoxyguanosine/ deoxyguanosine, in pigeon liver was highest in Amsterdam-high, followed by Assen (low traffic density). Pb content, but not the Cd content, was positively associated with oxidative DNA damage in liver tissue. In lung tissue, a negative correlation was found between oxidative DNA damage and Zn content. These results indicate that the carcinogenic potential of Pb might be ascribed to oxygen radical formation, whereas Zn plays a protective role against oxidative DNA damage. Places with high and medium traffic density could be clearly discriminated on the basis of PAH levels in the ambient air. The PAH content in particulate air samples was not, however, reflected in total PAH-related DNA adduct levels because no differences could be observed in tissue adduct levels in pigeons from the four different locations. Our results indicate that wild city pigeons can be used as biological indicators of exposure to heavy metal pollution in outdoor air

Characterizing speech heterogeneity in schizophrenia-spectrum disorders

Schizophrenia-spectrum disorders (SSD) are highly heterogeneous in risk factors, symptom characteristics, and disease course outcome. Although speech anomalies have long been recognized as a core symptom of SSD, speech markers are an unexplored source of symptom heterogeneity that may be informative in recognizing relevant subtypes. This study investigated speech heterogeneity and its relation to clinical characteristics in a large sample of patients with SSD and healthy controls. Speech samples were obtained from 142 patients with SSD and 147 healthy controls by means of open-ended interviews. Speech was analyzed using standardized open-source acoustic speech software. Hierarchical clustering was conducted using acoustic speech markers. Symptom severity was rated with the Positive and Negative Syndrome Scale, and cognition was assessed with the Brief Assessment of Cognition for Schizophrenia. Three speech clusters could be distinguished in the patient group that differed regarding speech properties, independent of medication use. One cluster was characterized by mild speech disturbances, while two severely impaired clusters were recognized (fragmented speakers and prolonged pausers). Both clusters with severely impaired speech had more severe cognitive dysfunction than the mildly impaired speakers. Prolonged pausers specifically had difficulties with memory-related tasks. Prolonged pausing, as opposed to fragmented speaking, related to chronic active psychosis and refractory psychotic symptoms. Based on speech clustering, subtypes of patients emerged with distinct disease trajectories, symptomatology, and cognitive functioning. The identification of clinically relevant subgroups within SSD may help to characterize distinct profiles and benefit the tailoring of early intervention and improvement of long-term functional outcome. (PsycInfo Database Record (c) 2022 APA, all rights reserved).</p

Towards a synthetic tutor assistant: The EASEL project and its architecture

Robots are gradually but steadily being introduced in our daily lives. A paramount application is that of education, where robots can assume the role of a tutor, a peer or simply a tool to help learners in a specific knowledge domain. Such endeavor posits specific challenges: affective social behavior, proper modelling of the learner’s progress, discrimination of the learner’s utterances, expressions and mental states, which, in turn, require an integrated architecture combining perception, cognition and action. In this paper we present an attempt to improve the current state of robots in the educational domain by introducing the EASEL EU project. Specifically, we introduce the EASEL’s unified robot architecture, an innovative Synthetic Tutor Assistant (STA) whose goal is to interactively guide learners in a science-based learning paradigm, allowing us to achieve such rich multimodal interactions