DNA methylation profiling of myelodysplastic syndromes and clinical response to azacitidine: A multicentre retrospective study.

Real-world data have revealed that a substantial portion of patients with myelodysplastic syndromes (MDS) does not respond to epigenetic therapy with hypomethylating agents (HMAs). The cellular and molecular reasons for this resistance to the demethylating agent and biomarkers that would be able to predict the treatment refractoriness are largely unknown. In this study, we shed light on this enigma by characterizing the epigenomic profiles of patients with MDS treated with azacitidine. Our approach provides a comprehensive view of the evolving DNA methylation architecture of the disease and holds great potential for advancing our understanding of MDS treatment responses to HMAs.

Podophyllic Aldehyde, a Podophyllotoxin Derivate, Elicits Different Cell Cycle Profiles Depending on the Tumor Cell Line: A Systematic Proteomic Analysis.

When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis.

Psychometric analysis of the Psychiatric Diagnostic Screening Questionnaire (PDSQ) and determinants of psychopathology in two outpatient clinics in Navarre (Spain).

BACKGROUND: The self-report Psychiatric Diagnostic Screening Questionnaire PDSQ is designed to screen Axis I psychiatric disorders. We aim to determine its psychometric properties in Spanish outpatients and assess its relationship with two interviews (for psychopathology and for personality disorders) and clinical/demographic variables. METHODOLOGY: We administered the study questionnaire, the Mini International Neuropsychiatric Interview Plus (MINI-Plus), the Standardised Assessment of Personality Abbreviated Scale (SAPAS), and the List of Threatening Experiences Questionnaire (LTE-Q) to 375 patients at two public outpatient centres. Reliability of the study questionnaire was evaluated (Cronbach's alpha, ?) and known-group validity measured by comparing groups based on demographic and clinical variables (binary logistic regression analysis) and MINI-Plus diagnoses (Mann-Whitney U). The diagnostic accuracy of the study questionnaire score was analysed taking the MINI-Plus diagnoses as the gold standard (ROC analysis). RESULTS: Internal consistency was adequate across all PDSQ scales (? >0.7; mean ?=0.85). Known-group comparisons were satisfactory. Female and male patients showed higher prevalence of internalizing and externalizing diagnoses, respectively. Younger age, more life events and limitations, higher SAPAS scores, and lower economic levels were linked to a greater number of PDSQ diagnoses. Inter-group differences were found for all PDSQ scales based on the corresponding MINI-Plus diagnoses. Mean values of sensitivity, AUC, and negative predictive value were 88.7, 0.82, and 96.7, respectively. CONCLUSIONS: When applied to a sample of Spanish outpatients, the PDSQ exhibits satisfactory psychometric properties and adequate relationships with the psychopathology and personality interviews, and clinical and demographic variables. The study questionnaire is suitable for assessing comorbidity and psychopathology dimensions.