NOTCH1-mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential

IntroductionConstitutive activation of NOTCH1-wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL.MethodsWe performed a bioinformatics analysis of NOTCH1-mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca2+, and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling.Results and discussionBioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19+/CD5+ cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL

Diversity and ethics in trauma and acute care surgery teams: results from an international survey

Background Investigating the context of trauma and acute care surgery, the article aims at understanding the factors that can enhance some ethical aspects, namely the importance of patient consent, the perceptiveness of the ethical role of the trauma leader, and the perceived importance of ethics as an educational subject. Methods The article employs an international questionnaire promoted by the World Society of Emergency Surgery. Results Through the analysis of 402 fully filled questionnaires by surgeons from 72 different countries, the three main ethical topics are investigated through the lens of gender, membership of an academic or non-academic institution, an official trauma team, and a diverse group. In general terms, results highlight greater attention paid by surgeons belonging to academic institutions, official trauma teams, and diverse groups. Conclusions Our results underline that some organizational factors (e.g., the fact that the team belongs to a university context or is more diverse) might lead to the development of a higher sensibility on ethical matters. Embracing cultural diversity forces trauma teams to deal with different mindsets. Organizations should, therefore, consider those elements in defining their organizational procedures. Level of evidence Trauma and acute care teams work under tremendous pressure and complex circumstances, with their members needing to make ethical decisions quickly. The international survey allowed to shed light on how team assembly decisions might represent an opportunity to coordinate team member actions and increase performance

The psychological and cognitive predictors of adherence to social distancing behavior: data from an Italian sample

Social distancing is a widely recommended policy for limiting the COVID-19 pandemic. An internet-based survey was used to investigate the role of several psychological variables in predicting social distancing compliance in Italy. Data from 373 participants, between March and August 2021, revealed that complying with social distancing and prioritizing the benefits to society over personal costs correlated positively with emotional intelligence, extroversion, and higher risk perception of COVID-19, and negatively with age. No relationship was found between working memory capacity and social distancing compliance. The mediation analysis suggests that as the costs of social distancing are perceived to be greater than the benefits, the effect of anxiety on social distancing diminishes. Further studies are needed to better understand the characteristics of individuals who choose to practice social distancing, as this is critical for developing public service campaigns to promote these behaviors during possible future pandemics

Emotional Valence and Working Memory Performance: Effect of Concurrent Interference in a Spatial Object-Location Task

The mechanisms through which emotional stimuli are processed in working memory (WM) are still poorly understood. In a previous study we found that when emotional and neutral stimuli are presented within the same trial, visuo-spatial WM performance (evaluated in an object-relocation task) is affected by the valence dimension, but not by the arousal dimension (Costanzi et al., 2019). According to Baddeley and Hitch’s model, working memory (1974, 1986) consists of a central executive (CE) and at least two additional subsystems, specifically the “phonological loop” (PL) and the “visuo-spatial sketchpad” (VSSP). The aim of the present research was to investigate the role of the CE and the VSSP in shaping the advantage for emotionally-valenced stimuli in visuo-spatial WM. Three groups of participants watched eight black rectangles appear simultaneously on a computer screen; this was immediately followed by the sequential presentation of eight pictures selected from the International Affective Picture System superimposed onto each rectangle. Pictures differed in valence (negative vs neutral), but not in arousal levels. During encoding, one group of participants (n=30) was submitted to a concurrent task interfering with the CE; the second group (n=26) performed a concurrent tapping task known to affect the VSSP; the third one (n=26) was a control group with no concurrent tasks. Immediately after encoding, all participants had to relocate each rectangle to its original position. Results showed that rectangles that had been associated with negative pictures were better relocated than those associated with neutral ones and that interfering with the CE impaired spatial WM performance. The concurrent tapping task, on the other hand, had no statistically significant effect, although its tendency to moderate the effect of valence deserves further investigation. Taken together, results suggest that emotional valence might affect spatial working memory performance through both automatic and executive processes

Long-Term Neuropsychological Outcome in Preterm Twins

Few long-term studies have yet described neuropsychological outcome in preterm twins. Our aim was to assess, by long-term evaluation, neuropsychological outcome in preterm twins in order to define a correct follow-up program. Our study was a cohort one, with an index and a comparison group. Neonatal medical records of all preterm newborns admitted to our centre between 1991 and 1997 were reviewed and selected patients were recalled. The sample population included two matched groups of children aged 6—12 years, 86 twins and 86 singletons, submitted to paediatric, neurological, psychological, and ophthalmological examinations. Inclusion criteria were twin pregnancy and gestational age 27—36 weeks for index group; same gestational age, but single pregnancy, for the comparison group. All children underwent paediatric and neuropsychiatric examinations, cognitive assessment, and psychological evaluation by standardized tests for screening of learning specific disorders and language difficulties, and finally, ophthalmological examination. In order to study their role in predicting neuropsychological outcome, we examined some perinatal prognostic factors by statistical analysis. Unfavourable neuropsychological outcome was observed in 55/172 (32%) children, with different prevalence in the two groups, 42/172 (24%) in twins and 13/172 (8%) in singletons. Statistical analysis performed for examined prognostic factors showed significant differences in neuropsychological outcome with regard only to gestational age < 32 weeks, low birth weight, intraventricular haemorrhage, and periventricular leukomalacia. The incidence of neuropsychological diseases in the two groups showed significant difference about language and learning difficulties. Our data suggest that preterm twins represent a particular high-risk category of premature babies, mostly regarding the risk of so-called “minimal brain dysfunction”, so a careful follow-up is recommended

The role of bisphenol A on puberty: a critical review of the medical lierature

Introduction: Many scientific studies have revealed a trend towards anticipation of the age of puberty and disclosed an increasing number of children displaying a precocious puberty. As explanation, some authors have considered the global socio-economic improvement across different populations, but also claimed the action of many endocrine disrupting chemicals (ECDs). Among these, bisphenol A (BPA), an aromatic compound largely used worldwide as a precursor of some plastic stuff and chemical additives, is well-known for its molecular estrogen-like and obesogenic actions. Methods: We have reviewed the medical literature containing studies published in the previous 20 years that examined any associations between BPA exposure and age of puberty in humans, considering only the ones referring clinical or epidemiological data. Discussion: Out of 19 studies found, only 7 showed a correlation between BPA and puberty. In particular, the possible disrupting role on puberty of BPA may be seen in those with central precocious puberty or isolated premature breast development aged 2 months-4 years old, even if the mechanism is undefined. Some studies have also found a close relationship between urinary BPA, body weight, and early puberty, which can be explained by the obesogenic effect of BPA itself. Conclusions: Data currently available do not allow to establish a clear role of BPA on the pubertal development because of conflicting results of all clinical and epidemiological studies examined. Further researches are needed to fully understand the potential role of exposure to ECDs and their adverse endocrine health outcomes

Timing of surgery and elective perioperative management of patients with previous SARS-CoV-2 infection: a SIAARTI expert consensus statement

Background The appropriate timing of surgery and perioperative management of patients with previous SARS-CoV-2 infection are open issues. The purpose of this document is to support the clinical decision-making process regarding the patient with previous Sars-CoV-2 infection to undergo elective surgery. The recipients of this document are physicians, nurses, healthcare personnel, and other professionals involved in the patient’s surgical process. Methods The Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) selected 11 experts to reach a consensus on key aspects of this theme in adult and pediatric population. The methods of this process document were in accordance to the principles of rapid review of the scientific literature and modified Delphi method. The experts produced statements and supporting reasons in the form of an informative text. The overall list of statements was subjected to a vote in order to express the degree of consent. Results Patients should not undergo elective surgery within 7 weeks of infection unless there is the risk of a negative evolution of the disease. To mitigate the risk of postsurgical mortality, a multidisciplinary approach seemed useful in addition to the use of validated algorithms to estimate the risk of perioperative morbidity and mortality; the risk related to SARS-CoV-2 infection should be added. The risk of potential nosocomial contagion from a positive patients should also be considered when deciding to proceed with surgery. Most of the evidence came from previous SARS-CoV-2 variants, so the evidence should be considered indirect. Conclusion A balanced preoperative multidisciplinary risk–benefit evaluation is needed in patients with previous infection by SARS-CoV-2 for elective surgery