Toward understanding calmodulin plasticity by molecular dynamics

Aim: Calmodulin interacts in many different ways with its ligands. We aim to shed light on its plasticity analysing the changes followed by the linker region and the relative position of the lobes using conventional Molecular Dynamics (cMD), accelerated MD (aMD) and scaled MD (sMD). Materials & Methods: Three different structures of calmodulin are compared, obtaining a total of 2.5 μs of molecular dynamics, which have been analysed using the principal component analysis and clustering methodologies Results: sMD simulations reach conformations that cMD is not able to, without compromising the stability of the protein. On the other hand, aMD requires optimization of the setup parameters to be useful. Conclusion: SMD is useful to study flexible proteins, highlighting those factors that justify its promiscuit

Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials

Càncer de pròstata; Teràpia de privació d'andrògensCáncer de próstata; Terapia de privación de andrógenosProstate cancer; Androgen-deprivation therapyPURPOSE The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer–specific mortality. RESULTS Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer–specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.Funding support for this study comes from the Prostate Cancer Foundation and ASTRO to AUK. AUK also thanks generous donations from the DeSilva, McCarrick, and Bershad families. A.T. acknowledges support from Cancer Research UK (C33589/A28284 and C7224/A28724) the National Institute for Health Research (NIHR) Cancer Research Network. This project represents independent research supported by the National Institute for Health research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. N.G.Z. is supported by the American Cancer Society – Tri State CEOs Against Cancer Clinician Scientist Development Grant, CSDG‐20‐013‐01‐CCE (2020)

Follow-up care over 12months of patients with prostate cancer in Spain A multicenter prospective cohort study

The therapeutic approach is crucial to prostate cancer prognosis. We describe treatments and outcomes for a Spanish cohort of patients with prostate cancer during the first 12 months after diagnosis and identify the factors that influenced the treatment they received. This multicenter prospective cohort study included patients with prostate cancer followed up for 12 months after diagnosis. Treatment was stratified by factors such as hospital, age group (<70 and ≥70 years), and D'Amico cancer risk classification. The outcomes were Eastern Cooperative Oncology Group (ECOG) performance status, adverse events (AEs), and mortality. The patient characteristics associated with the different treatment modalities were analyzed using multivariate logistic regression. We included 470 men from 7 Spanish tertiary hospitals (mean (standard deviation) age 67.8 (7.6) years), 373 (79.4%) of which received treatment (alone or in combination) as follows: surgery (n = 163; 34.7%); radiotherapy (RT) (n = 149; 31.7%); and hormone therapy (HT) (n = 142; 30.2%). The remaining patients (n = 97) were allocated to no treatment, that is, watchful waiting (14.0%) or active surveillance (5.7%). HT was the most frequently administered treatment during follow-up and RT plus HT was the most common therapeutic combination. Surgery was more frequent in patients aged <70, with lower histologic tumor grades, Gleason scores <7, and lower prostate-specific antigen levels; while RT was more frequent in patients aged ≥70 with histologic tumor grade 4, and higher ECOG scores. HT was more frequent in patients aged ≥70, with histologic tumor grades 3 to 4, Gleason score ≥8, ECOG ≥1, and higher prostate-specific antigen levels. The number of fully active patients (ECOG score 0) decreased significantly during follow-up, from 75.3% at diagnosis to 65.1% at 12 months (P <.001); 230 (48.9%) patients had at least 1 AE, and 12 (2.6%) patients died. Surgery or RT were the main curative options. A fifth of the patients received no treatment. Palliative HT was more frequently administered to older patients with higher tumor grades and higher Gleason scores. Close to half of the patients experienced an AE related to their treatment

A new tool to screen patients with severe obstructive sleep apnea in the primary care setting : a prospective multicenter study

Altres ajuts: Sociedad Española de Neumología y Cirugía Torácica (SEPAR), Societat Catalana de Pneumologia (SOCAP).The coordination between different levels of care is essential for the management of obstructive sleep apnea (OSA). The objective of this multicenter project was to develop a screening model for OSA in the primary care setting. Anthropometric data, clinical history, and symptoms of OSA were recorded in randomly selected primary care patients, who also underwent a home sleep apnea test (HSAT). Respiratory polygraphy or polysomnography were performed at the sleep unit to establish definite indication for continuous positive airway pressure (CPAP). By means of cross-validation, a logistic regression model (CPAP yes/no) was designed, and with the clinical variables included in the model, a scoring system was established using the β coefficients (PASHOS Test). In a second stage, results of HSAT were added, and the final accuracy of the model was assessed. 194 patients completed the study. The clinical test included the body mass index, neck circumference and observed apneas during sleep (AUC 0.824, 95% CI 0.763-0.886, P < 0.001). In a second stage, the oxygen desaturation index (ODI) of 3% (ODI3% ≥ 15%) from the HSAT was added (AUC 0.911, 95% CI 0.863-0.960, P < 0.001), with a sensitivity of 85.5% (95% CI 74.7-92.1) and specificity of 67.8% (95% CI 55.1-78.3). The use of this model would prevent referral to the sleep unit for 55.1% of the patients. The two-stage PASHOS model is a useful and practical screening tool for OSA in primary care for detecting candidates for CPAP treatment. Clinical Trial Registration Registry: ClinicalTrials.gov; Name: PASHOS Project: Advanced Platform for Sleep Apnea Syndrome Assessment; URL: ; Identifier: NCT02591979. Date of registration: October 30, 2015. The online version contains supplementary material available at 10.1186/s12890-022-01827-0

Thirty-day suicidal thoughts and behaviours in the Spanish adult general population during the first wave of the Spain COVID-19 pandemic

To investigate the prevalence of suicidal thoughts and behaviours (STB; i.e. suicidal ideation, plans or attempts) in the Spanish adult general population during the first wave of the Spain coronavirus disease 2019 (COVID-19) pandemic (March−July, 2020), and to investigate the individual- and population-level impact of relevant distal and proximal STB risk factor domains. Cross-sectional study design using data from the baseline assessment of an observational cohort study (MIND/COVID project). A nationally representative sample of 3500 non-institutionalised Spanish adults (51.5% female; mean age = 49.6 [ = 17.0]) was taken using dual-frame random digit dialing, stratified for age, sex and geographical area. Professional interviewers carried out computer-assisted telephone interviews (1-30 June 2020). Thirty-day STB was assessed using modified items from the Columbia Suicide Severity Rating Scale. Distal (i.e. pre-pandemic) risk factors included sociodemographic variables, number of physical health conditions and pre-pandemic lifetime mental disorders; proximal (i.e. pandemic) risk factors included current mental disorders and a range of adverse events-experiences related to the pandemic. Logistic regression was used to investigate individual-level associations (odds ratios [OR]) and population-level associations (population attributable risk proportions [PARP]) between risk factors and 30-day STB. All data were weighted using post-stratification survey weights. Estimated prevalence of 30-day STB was 4.5% (1.8% active suicidal ideation; n = 5 [0.1%] suicide attempts). STB was 9.7% among the 34.3% of respondents with pre-pandemic lifetime mental disorders, and 1.8% among the 65.7% without any pre-pandemic lifetime mental disorder. Factors significantly associated with STB were pre-pandemic lifetime mental disorders (total PARP = 49.1%) and current mental disorders (total PARP = 58.4%), i.e. major depressive disorder (OR = 6.0; PARP = 39.2%), generalised anxiety disorder (OR = 5.6; PARP = 36.3%), post-traumatic stress disorder (OR = 4.6; PARP = 26.6%), panic attacks (OR = 6.7; PARP = 36.6%) and alcohol/substance use disorder (OR = 3.3; PARP = 5.9%). Pandemic-related adverse events-experiences associated with STB were lack of social support, interpersonal stress, stress about personal health and about the health of loved ones (PARPs 32.7-42.6%%), and having loved ones infected with COVID-19 (OR = 1.7; PARP = 18.8%). Up to 74.1% of STB is potentially attributable to the joint effects of mental disorders and adverse events−experiences related to the pandemic. STB at the end of the first wave of the Spain COVID-19 pandemic was high, and large proportions of STB are potentially attributable to mental disorders and adverse events−experiences related to the pandemic, including health-related stress, lack of social support and interpersonal stress. There is an urgent need to allocate resources to increase access to adequate mental healthcare, even in times of healthcare system overload. NCT0455656

Ribonucleoprotein HNRNPA2B1 interacts with and regulates oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells.

BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDAC) involves activation of c-Ki-ras2 Kirsten rat sarcoma oncogene homolog (KRAS) signaling, but little is known about the roles of proteins that regulate the activity of oncogenic KRAS. We investigated the activities of proteins that interact with KRAS in PDAC cells. METHODS: We used mass spectrometry to demonstrate that heterogeneous nuclear ribonucleoproteins (HNRNP) A2 and B1 (encoded by the gene HNRNPA2B1) interact with KRAS G12V. We used co-immunoprecipitation analyses to study interactions between HNRNPA2B1 and KRAS in KRAS-dependent and KRAS-independent PDAC cell lines. We knocked down HNRNPA2B1 using small hairpin RNAs and measured viability, anchorage-independent proliferation, and growth of xenograft tumors in mice. We studied KRAS phosphorylation using the Phos-tag system. RESULTS: We found that interactions between HRNPA2B1 and KRAS correlated with KRAS-dependency of some human PDAC cell lines. Knock down of HNRNPA2B1 significantly reduced viability, anchorage-independent proliferation, and formation of xenograft tumors by KRAS-dependent PDAC cells. HNRNPA2B1 knock down also increased apoptosis of KRAS-dependent PDAC cells, inactivated c-akt murine thymoma oncogene homolog 1 signaling via mammalian target of rapamycin, and reduced interaction between KRAS and phosphatidylinositide 3-kinase. Interaction between HNRNPA2B1 and KRAS required KRAS phosphorylation at serine 181. CONCLUSIONS: In KRAS-dependent PDAC cell lines, HNRNPA2B1 interacts with and regulates the activity of KRAS G12V and G12D. HNRNPA2B1 is required for KRAS activation of c-akt murine thymoma oncogene homolog 1-mammalian target of rapamycin signaling, interaction with phosphatidylinositide 3-kinase, and PDAC cell survival and tumor formation in mice. HNRNPA2B1 might be a target for treatment of pancreatic cancer

Thirty-day suicidal thoughts and behaviours in the Spanish adult general population during the first wave of the Spain COVID-19 pandemic

Aims: To investigate the prevalence of suicidal thoughts and behaviours (STB; i.e. suicidal ideation, plans or attempts) in the Spanish adult general population during the first wave of the Spain coronavirus disease 2019 (COVID-19) pandemic (March-July, 2020), and to investigate the individual- and population-level impact of relevant distal and proximal STB risk factor domains. Methods: Cross-sectional study design using data from the baseline assessment of an observational cohort study (MIND/COVID project). A nationally representative sample of 3500 non-institutionalised Spanish adults (51.5% female; mean age = 49.6 [s.d. = 17.0]) was taken using dual-frame random digit dialing, stratified for age, sex and geographical area. Professional interviewers carried out computer-assisted telephone interviews (1-30 June 2020). Thirty-day STB was assessed using modified items from the Columbia Suicide Severity Rating Scale. Distal (i.e. pre-pandemic) risk factors included sociodemographic variables, number of physical health conditions and pre-pandemic lifetime mental disorders; proximal (i.e. pandemic) risk factors included current mental disorders and a range of adverse events-experiences related to the pandemic. Logistic regression was used to investigate individual-level associations (odds ratios [OR]) and population-level associations (population attributable risk proportions [PARP]) between risk factors and 30-day STB. All data were weighted using post-stratification survey weights. Results: Estimated prevalence of 30-day STB was 4.5% (1.8% active suicidal ideation; n = 5 [0.1%] suicide attempts). STB was 9.7% among the 34.3% of respondents with pre-pandemic lifetime mental disorders, and 1.8% among the 65.7% without any pre-pandemic lifetime mental disorder. Factors significantly associated with STB were pre-pandemic lifetime mental disorders (total PARP = 49.1%) and current mental disorders (total PARP = 58.4%), i.e. major depressive disorder (OR = 6.0; PARP = 39.2%), generalised anxiety disorder (OR = 5.6; PARP = 36.3%), post-traumatic stress disorder (OR = 4.6; PARP = 26.6%), panic attacks (OR = 6.7; PARP = 36.6%) and alcohol/substance use disorder (OR = 3.3; PARP = 5.9%). Pandemic-related adverse events-experiences associated with STB were lack of social support, interpersonal stress, stress about personal health and about the health of loved ones (PARPs 32.7-42.6%%), and having loved ones infected with COVID-19 (OR = 1.7; PARP = 18.8%). Up to 74.1% of STB is potentially attributable to the joint effects of mental disorders and adverse events-experiences related to the pandemic. Conclusions: STB at the end of the first wave of the Spain COVID-19 pandemic was high, and large proportions of STB are potentially attributable to mental disorders and adverse events-experiences related to the pandemic, including health-related stress, lack of social support and interpersonal stress. There is an urgent need to allocate resources to increase access to adequate mental healthcare, even in times of healthcare system overload.This study was supported by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación/FEDER (grant number COV20/00711), (PM, grant number ISCIII, CD18/00049), (grant number ISCIII, FI18/00012), (VPS, grant number PI19/00236); Ayudas para la Formación de Profesorado Universitario, Ministerio de Ciencia, Innovación y Universidades (grant number FPU15/05728); Generalitat de Catalunya (grant number 2017SGR452). The funding institutions had no role in the design, analysis, interpretation or submission of publication of the data. No payment was made for writing this article by a pharmaceutical company or other agency. Corresponding authors had full access to all the data in the study and the final responsibility for the decision of submitting for publication.S