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Abstract Background Co-transcriptional R-loops are abundant non-B DNA structures in mammalian genomes. DNA Topoisomerase I (Top1) is often thought to regulate R-loop formation owing to its ability to resolve both positive and negative supercoils. How Top1 regulates R-loop structures at a global level is unknown. Results Here, we perform high-resolution strand-specific R-loop mapping in human cells depleted for Top1 and find that Top1 depletion results in both R-loop gains and losses at thousands of transcribed loci, delineating two distinct gene classes. R-loop gains are characteristic for long, highly transcribed, genes located in gene-poor regions anchored to Lamin B1 domains and in proximity to H3K9me3-marked heterochromatic patches. R-loop losses, by contrast, occur in gene-rich regions overlapping H3K27me3-marked active replication initiation regions. Interestingly, Top1 depletion coincides with a block of the cell cycle in G0/G1 phase and a trend towards replication delay. Conclusions Our findings reveal new properties of Top1 in regulating R-loop homeostasis in a context-dependent manner and suggest a potential role for Top1 in modulating the replication process via R-loop formation.

DNA topoisomerases are enzymes responsible for the relaxation of DNA torsional strain, as well as for the untangling of DNA duplexes after replication, and are important cancer drug targets. One class of topoisomerase inhibitors, "poisons", binds to the transient enzyme-DNA complex which occurs during the mechanism of action, and inhibits the religation of DNA. This ultimately leads to the accumulation of DNA double strand breaks and cell death. Different types of topoisomerases occur in human cells and several poisons of topoisomerase I and II are widely used clinically. However, their use is compromised by a variety of side effects. Recent studies confirm that the inhibition of the α-isoform of topoisomerase II is responsible for the cytotoxic effect, whereas the inhibition of the β-isoform leads to development of adverse drug reactions. Thus, the discovery of agents selective for topoisomerase IIα is an important strategy for the development of topoisomerase II poisons with improved clinical profiles. Here, we present a computer-aided drug design study leading to the identification of structurally novel topoisomerase IIα poisons. The study combines ligand- and structure-based drug design methods including pharmacophore models, homology modelling, docking, and virtual screening of the National Cancer Institute compound database. From the 8 compounds identified from the computational work, 6 were tested for their capacity to poison topoisomerase II in vitro: 4 showed selective inhibitory activity for the α- over the β-isoform and 3 of these exhibited cytotoxic activity. Thus, our study confirms the applicability of computer-aided methods for the discovery of novel topoisomerase II poisons, and presents compounds which could be investigated further as selective topoisomerase IIα inhibitors.

Introduction: Suicide is the third leading cause of death among US young adults, with significant racial/ethnic disparities related to the risk for suicide among Latine young adults. Despite the elevated risk for suicide, culturally relevant risk factors are not well-known. Intergenerational acculturative conflict (IAC) among Latine youth is a sociocultural factor associated with suicide ideation., Method: Although widely cited, the interpersonal theory of suicide (IPTS) lacks consistent support among Latine groups. The following cross-sectional study examined relationships between IAC categories (cultural preference, autonomy, and dating/staying out late), IPTS risk factors (i.e., thwarted belongingness and perceived burdensomeness), and suicide ideation frequency among 376 Mexican descent college students sampled using participant pools and snowball sampling (73.7% female: M age  = 19.88)., Results: Mediation analyses supported the hypotheses that IPTS risk factors partially explained the links between IAC categories and suicide ideation frequency., Conclusions: These findings advance our understanding of how sociocultural constructs, such as IAC, influence the IPTS and future advancements in culturally responsive treatments for suicide., (© 2024 The Authors. Suicide and Life‐Threatening Behavior published by Wiley Periodicals LLC on behalf of American Association of Suicidology.)

Objective: The present study examines the relationship between minority stress and academic outcomes for ethnic minority college students in the U.S. We explore to what extent anxiety functions as a potential mediating mechanism for these relationships. Participants: Data were obtained from 347 undergraduate ethnic minority college students attending a public university in West Texas. Results: Results revealed that minority stress was significantly related to anxiety symptoms when controlling for ethnic minority group membership. Additionally, it was found that anxiety symptoms significantly mediated the relationship between minority stress and major satisfaction, controlling for ethnic minority group membership. Conclusions: This study contributes to the existing psychological literature on ethnic minority college students by highlighting the extent that minority stress is related to certain academic outcomes, taking a step further to investigate anxiety as a mechanism that may explain these relationships.

Objective: Suicide is the second leading cause of death among college-age students in the U.S., with disparities in suicide ideation and attempts among Latinas. The current study aims to examine if depression severity predicts suicide ideation and attempts and to examine if caregiver intergeneration acculturation conflict (IAC) moderates this link., Participants: A sample of 246 Mexican-descent female college students., Methods: Self-reported measures for depression severity, male and female caregiver IAC, and suicide ideation and attempts in the previous 12-months were ascertained., Results: In our sample, 31.1% endorsed suicide ideation and 15.9% suicide attempts. Controlling for age, both male and female caregiver IAC moderated the relationship between depression severity and suicide ideation. A similar moderation pattern emerged for the suicide attempts outcome., Conclusions: Understanding this exacerbating contextual factor can help inform prevention/intervention efforts targeting Mexican-descent college students who are experiencing depressive symptoms by focusing on decreasing IAC with both caregivers.Suicide is the second leading cause of death among emerging adults, defined as 18-29-year-olds, 1 in the United States (U.S.) and is responsible for more deaths than any single major medical illness. 2 Significant gender and ethnic/racial disparities have been well-documented and highlight that Latina emerging adults experience some of the highest rates of suicide ideation (SI) and suicide attempts (SA) and the greatest increases in SA over time, when compared to non-Latinx White, female emerging adults. 3 , 4 In fact, recent research suggests that Latina college students report a 1.7% prevalence rate of suicide attempts compared to 1.2% among non-Latina White college students and data trends report a nearly double increase in the percent of suicide attempts from 2011 to 2015 (from 0.9% to 1.7%) for Latinas versus a minimal change (from 1.1% to 1.2%) among non-Latina White college students. 4 Key research examining this disparity have cited that elevated depressive symptoms, which are also experienced at higher levels among Latinx groups in the U.S., 5 are strongly linked to SI and SA among Latinx college students and emerging adults. 6 , 7 Developmentally, the highest risk period for the onset of SI and SA is during late adolescence or emerging adulthood 8 and deaths due to suicide increase as adolescents move into emerging adulthood. 2 , 9 Emerging adulthood is an even riskier developmental period for minoritized college students, like Latinx college students, because this period is marked by identity formation processes that are exacerbated by intercultural interactions on college campuses and cultural expectations at home. 10 These data underscore the significance of detecting how unique contextual factors may interact with elevated depressive symptoms, and importantly, how these factors are associated with the increased suicide risk among Latinx college-age youth, as they represent a high-risk developmental and ethnic group.

The COVID-19 pandemic highlighted preexisting health disparities and impacted the mental health of many Latine/x in the United States. Emerging adults are at increased risk for anxiety, depression (Ganson et al., 2021; Kujawa et al., 2020), and suicidal ideation (Tasnim et al., 2020). There is a scarcity of research that has examined sociocultural factors (i.e., racial bias, pandemic-related stress) associated with mental health outcomes (i.e., depression) and how they may be associated with self-harm resulting from the COVID-19 pandemic for Mexican-descent emerging adults. Using socioecological framework, we examined how COVID-19-related racial bias and perceived pandemic stress related to self-harm among Mexican-descent emerging adults. We used serial mediation to identify indirect effects between these factors. The present study examined the experiences of Mexican-descent college students during the COVID-19 pandemic. The participants ( N = 818) were college students (ages 18-25) and completed an online survey. Rates of self-harm were as follows: 10.5% (suicide ideation), 6.9% (nonsuicidal self-injury), and 2.9% (suicide attempts). Results showed a significant indirect effect of COVID-19-related racial bias on suicide attempts via COVID-19-related perceived stress and depression symptoms (β = .17, SE = .05, 95% CI [.10, .30]). Findings were consistent across self-harm outcomes (i.e., suicide ideation, nonsuicidal self-injury, and suicide attempts). This study elucidated novel processes from perceived COVID-19-related racial bias to self-harm outcomes via pandemic-related stress and depression symptoms. Findings inform culturally responsive interventions aimed at reducing self-harm in young adults faced with pervasive discrimination. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Hand-labelling clinical corpora can be costly and inflexible, requiring re-annotation every time new classes need to be extracted. PICO (Participant, Intervention, Comparator, Outcome) information extraction can expedite conducting systematic reviews to answer clinical questions. However, PICO frequently extends to other entities such as Study type and design, trial context, and timeframe, requiring manual re-annotation of existing corpora. In this paper, we adapt Snorkel's weak supervision methodology to extend clinical corpora to new entities without extensive hand labelling. Specifically, we enrich the EBM-PICO corpus with new entities through an example of "Study type and design" extraction. Using weak supervision, we obtain programmatic labels on 4,081 EBM-PICO documents, achieving an F1-score of 85.02% on the test set.

Caregivers' attitudes impact healthcare quality and disparities. Clinical notes contain highly specialized and ambiguous language that requires extensive domain knowledge to understand, and using negative language does not necessarily imply a negative attitude. This study discusses the challenge of detecting caregivers' attitudes from their clinical notes. To address these challenges, we annotate MIMIC clinical notes and train state-of-the-art language models from the Hugging Face platform. The study focuses on the Neonatal Intensive Care Unit and evaluates models in zero-shot, few-shot, and fully-trained scenarios. Among the chosen models, RoBERTa identifies caregivers' attitudes from clinical notes with an F1-score of 0.75. This approach not only enhances patient satisfaction, but opens up exciting possibilities for detecting and preventing care provider syndromes, such as fatigue, stress, and burnout. The paper concludes by discussing limitations and potential future work., Competing Interests: The authors declare that they have no conflict of interest., (©2023 AMIA - All rights reserved.)

Objective: The present study examines self-compassion (SC) as a potential protective factor in the relationship between value-behavior discrepancy guilt (VBDG) and the mental health outcomes of anxiety and suicide risk in a sample of Mexican-descent college students., Method: Participants consisted of 810 college students of Mexican descent. Students were recruited through a psychology participant pool and completed an online survey. Two regression analyses examined the direct effect of VBDG on anxiety symptoms and suicide risk with SC as a moderator., Results: Results indicated that high levels of SC were protective in the relationship between VBDG and mental health outcomes. On the other hand, lower levels of SC put one at risk for increased anxiety symptoms and higher suicide risk when they experience VBDG., Conclusion: The study shows the need to develop interventions that cultivate a high sense of SC in Mexican-descent college students.

Personalized support and assistance are essential for cancer survivors, given the physical and psychological consequences they have to suffer after all the treatments and conditions associated with this illness. Digital assistive technologies have proved to be effective in enhancing the quality of life of cancer survivors, for instance, through physical exercise monitoring and recommendation or emotional support and prediction. To maximize the efficacy of these techniques, it is challenging to develop accurate models of patient trajectories, which are typically fed with information acquired from retrospective datasets. This paper presents a Machine Learning-based survival model embedded in a clinical decision system architecture for predicting cancer survivors' trajectories. The proposed architecture of the system, named PERSIST, integrates the enrichment and pre-processing of clinical datasets coming from different sources and the development of clinical decision support modules. Moreover, the model includes detecting high-risk markers, which have been evaluated in terms of performance using both a third-party dataset of breast cancer patients and a retrospective dataset collected in the context of the PERSIST clinical study., (Copyright © 2023. Published by Elsevier B.V.)

12-Bis-THA Cl 2 [12,12'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride] is a cationic bolalipid adapted from dequalinium chloride (DQC), a bactericidal anti-infective indicated for bacterial vaginosis (BV). Here, we used a structure-activity-relationship study to show that the factors that determine effective killing of bacterial, fungal, and mycobacterial pathogens differ, to generate new analogues with a broader spectrum of activity, and to identify synergistic relationships, most notably with aminoglycosides against Acinetobacter baumannii and Pseudomonas aeruginosa, where the bactericidal killing rate was substantially increased. Like DQC, 12-bis-THA Cl 2 and its analogues accumulate within bacteria and fungi. More hydrophobic analogues with larger headgroups show reduced potential for DNA binding but increased and broader spectrum antibacterial activity. In contrast, analogues with less bulky headgroups and stronger DNA binding affinity were more active against Candida spp. Shortening the interconnecting chain, from the most lipophilic twelve-carbon chain to six, improved the selectivity index against Mycobacterium tuberculosis in vitro , but only the longer chain analogue was therapeutic in a Galleria mellonella infection model, with the shorter chain analogue exacerbating the infection. In vivo therapy of Escherichia coli ATCC 25922 and epidemic methicillin-resistant Staphylococcus aureus 15 (EMRSA-15) infections in Galleria mellonella was also achieved with longer-chain analogues, as was therapy for an A. baumannii 17978 burn wound infection with a synergistic combination of bolaamphiphile and gentamicin. The present study shows how this class of bolalipids may be adapted further to enable a wider range of potential applications. IMPORTANCE While we face an acute threat from antibiotic resistant bacteria and a lack of new classes of antibiotic, there are many effective antimicrobials which have limited application due to concerns regarding their toxicity and which could be more useful if such risks are reduced or eliminated. We modified a bolalipid antiseptic used in throat lozenges to see if it could be made more effective against some of the highest-priority bacteria and less toxic. We found that structural modifications that rendered the lipid more toxic against human cells made it less toxic in infection models and we could effectively treat caterpillars infected with either Mycobacterium tuberculosis, methicillin resistant Staphylococcus aureus, or Acinetobacter baumannii. The study provides a rationale for further adaptation toward diversifying the range of indications in which this class of antimicrobial may be used.

Some antimicrobial peptides (AMPs) have potent bactericidal activity and are being considered as potential alternatives to classical antibiotics. In response to an infection, such AMPs are often produced in animals alongside other peptides with low or no perceivable antimicrobial activity, whose role is unclear. Here we show that six AMPs from the Winter Flounder (WF) act in synergy against a range of bacterial pathogens and provide mechanistic insights into how this increases the cooperativity of the dose-dependent bactericidal activity and potency that enable therapy. Only two WF AMPs have potent antimicrobial activity when used alone but we find a series of two-way combinations, involving peptides which otherwise have low or no activity, yield potent antimicrobial activity. Weakly active WF AMPs modulate the membrane interactions of the more potent WF AMPs and enable therapy in a model of Acinetobacter baumannii burn wound infection. The observed synergy and emergent behaviour may explain the evolutionary benefits of producing a family of related peptides and are attractive properties to consider when developing AMPs towards clinical applications., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

The pharmacodynamic profile of antimicrobial peptides (AMPs) and their in vivo synergy are two factors that are thought to restrict resistance evolution and ensure their conservation. The frog Rana temporaria secretes a family of closely related AMPs, temporins A-L, as an effective chemical dermal defense. The antibacterial potency of temporin L has been shown to increase synergistically in combination with both temporins B and A, but this is modest. Here we show that the less potent temporin B enhances the cooperativity of the in vitro antibacterial activity of the more potent temporin L against EMRSA-15 and that this may be associated with an altered interaction with the bacterial plasma membrane, a feature critical for the antibacterial activity of most AMPs. Addition of buforin II, a histone H2A fragment, can further increase the cooperativity. Molecular dynamics simulations indicate temporins B and L readily form hetero-oligomers in models of Gram-positive bacterial plasma membranes. Patch-clamp studies show transmembrane ion conductance is triggered with lower amounts of both peptides and more quickly when used in combination, but conductance is of a lower amplitude and pores are smaller. Temporin B may therefore act by forming temporin L/B hetero-oligomers that are more effective than temporin L homo-oligomers at bacterial killing and/or by reducing the probability of the latter forming until a threshold concentration is reached. Exploration of the mechanism of synergy between AMPs isolated from the same organism may therefore yield antibiotic combinations with advantageous pharmacodynamic properties.

Among adolescents, Latinas are at an increased risk of experiencing suicidal ideation and attempts compared to non-Hispanic, White youth. Previous research indicates that family dynamics are influential as both protective and risk factors. Although significant research has been conducted over the past several decades examining the mother-daughter relationship, few studies have examined the father-daughter relationship among Latina adolescent suicide attempters. The relationship dynamics between fathers and daughters of Latina descent are both similar and unique compared to mother-daughter relationships. Given this, an in-depth analysis is warranted. To address this gap, the present study utilized dyadic thematic analysis to describe father-daughter relationships (N = 10 dyads, 20 individual interviews) and fathers' reactions to their Latina daughters' suicide attempt(s). Three themes emerged from the results (a) dynamic proximity, which describes the variation in emotional and physical closeness between fathers and daughters; (b) father as protector, which describes fathers' roles in protecting or failing to protect their daughters; (c) responses to the suicide attempt, which describes the various ways fathers responded to daughters' suicide attempts, ranging from helpful action to apathy. Themes gleaned from in-depth interviews informed a deeper understanding of these complex, multifaceted relationships, and how they may be linked to fathers' responses to daughters' suicide attempts. Implications for future research and clinical practice with youth at risk for suicidal ideations and behaviors, along with the impact of such experiences on families, are discussed., (© 2021 Family Process Institute.)

Objective: The aims of this study are to investigate (1) how family response to acculturation (e.g., accusations of assimilation) is related to anxiety and depressive symptomatology for Latinx emerging adults. This study's goal is also to analyze (2) the extent to which ethnic identity components and gender moderate the respective associations., Method: Cross-sectional survey was completed by 200 Latinx emerging adults. Inclusion criteria involved reading English, ages 18-25, currently reside in Maricopa or Miami-Dade Counties and self-identify as Latinx. Analysis used hierarchical multiple regression and moderation analyses., Results: Findings indicate that higher familial accusations of assimilation were associated with higher symptoms of depression and anxiety. Moderation analyses indicate that gender had a statistically significant interaction with accusations of assimilation in relation to symptoms of both depression and anxiety. A significant three-way interaction between ethnic identity exploration, gender, and intracultural accusations of assimilation in relation to symptoms of depression interaction among men was found., Conclusion: Findings from the study add to literature on the effect of intragroup marginalization on Latinx mental health and highlight gender differences. The ethnic identity component of exploration is found to be a protective factor for men which wanes over increasing levels of accusation of assimilation., (© 2021 Wiley Periodicals LLC.)

Objective: To test the acculturation gap hypothesis by examining mother-youth value discrepancies (both acculturative and enculturative) and their association with mother-youth acculturative conflict and youth mental health outcomes., Method: Participants were 273 Mexican descent college students attending a large, public, Hispanic Serving Institution (HSI) in West Texas (72% women). The participants' ages ranged 18-25 years (M = 19.33 years; SD = 1.54 years)., Results: Three models assessed the relationship between mother-youth value discrepancies and mental health outcomes (suicidal ideation, non-suicidal self-injury, and depressive symptoms) as mediated by mother-youth acculturative conflict. Consistently, Mexican heritage cultural values were related to mental health outcomes while American cultural values were not., Conclusions: The study found that increased mother-youth discrepancies on Mexican cultural values were associated with increased negative mental health outcomes. Our findings suggest that adopting or learning new mainstream American values does not substitute for the Mexican cultural values that protect against negative outcomes., (© 2021 Wiley Periodicals LLC.)

Introduction: Little is known about the clinical performance of single-chamber leadless pacemaker (LLPM) in patients without atrial fibrillation (AF) as pacing indication. The aim of this study was to describe the clinical characteristics of patients who underwent single chamber LLPM implantation at three tertiary referral centers and to compare the safety and effectiveness of the single-chamber LLPM among patients with or without AF., Materials and Methods: All the consecutive patients who underwent LLPM implantation at three referral centers were analyzed. The indications to LLPM in a real-world setting were described. The study population was divided into two groups according to AF as pacing indication. We assessed the procedure-related complications; moreover, we compared syncope, cardiac hospitalization, pacemaker syndrome, and all-cause death recurrence during the follow-up between patients with and without AF as pacing indication., Results: A total of 140 consecutive patients (mean age, 76.7 ± 11.24 years, men 64.3%) were included in the study. The indication to implantation of LLPM was permanent AF with slow ventricular response ( n : 67; 47.8%), sinus node dysfunction ( n : 25; 17.8%), third atrioventricular block (AVB) ( n : 20; 14.2%), second-degree AVB ( n : 18; 12.8%), and first degree AVB ( n : 10; 7.1%). A total of 7 patients (5%) experienced perioperative complications with no differences between the AF vs. non-AF groups. During a mean follow-up of 606.5 ± 265.9 days, 10 patients (7.7%) died and 7 patients (5.4%) were reported for cardiac hospitalization; 5 patients (3.8%) experienced syncope; no patients showed pacemaker syndrome. No significant differences in the clinical events between the groups were shown. The Kaplan-Meier analysis for the combined endpoints did not show significant differences between the AF and non-AF groups [hazard ratio (HR): 0.94, 95% CI: 0.41-2.16; p = 0.88]., Conclusion: Our real-world data suggest that LLPM may be considered a safe and reasonable treatment in patients without AF in need of pacing. Further studies are needed to confirm these preliminary results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Russo, D'Andrea, De Vivo, Rago, Manzo, Bocchetti, Papa, Giordano, Ammendola, Sarubbi, Golino, D'Onofrio and Nigro.)

Healthcare providers need indicators to monitor the quality of ambulatory care by making the best use of routinely collected data ; the goal is to provide high-value, patient-centered, evidence-based, and data-informed health care. While it may seem simple to produce indicators via the electronic medical record (EMR), these data do not speak by themselves. Indeed, it is necessary to : a) make the data usable ; b) define relevant indicators ; and c) ensure the dissemination of these indicators to patients and healthcare providers. In this article, we explain how the EMR can be used to produce indicators of quality of ambulatory care, using the example of hypertension and diabetes., Competing Interests: Le Dr Gaillard et M. Alves sont actifs au sein de Logival qui produit le DMI MediWay. Les autres auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

In the past decades, the incidence rate of cancer has steadily risen. Although advances in early and accurate detection have increased cancer survival chances, these patients must cope with physical and psychological sequelae. The lack of personalized support and assistance after discharge may lead to a rapid diminution of their physical abilities, cognitive impairment, and reduced quality of life. This paper proposes a personalized support system for cancer survivors based on a cohort and trajectory analysis (CTA) module integrated within an agent-based personalized chatbot named EREBOTS. The CTA module relies on survival estimation models, machine learning, and deep learning techniques. It provides clinicians with supporting evidence for choosing a personalized treatment, while allowing patients to benefit from tailored suggestions adapted to their conditions and trajectories. The development of the CTA within the EREBOTS framework enables to effectively evaluate the significance of prognostic variables, detect patient's high-risk markers, and support treatment decisions., (© 2021. The Author(s).)

Reliable antimicrobial susceptibility testing is essential in informing both clinical antibiotic therapy decisions and the development of new antibiotics. Mammalian cell culture media have been proposed as an alternative to bacteriological media, potentially representing some critical aspects of the infection environment more accurately. Here, we use a combination of NMR metabolomics and electron microscopy to investigate the response of Escherichia coli and Pseudomonas aeruginosa to growth in differing rich media to determine whether and how this determines metabolic strategies, the composition of the cell wall, and consequently susceptibility to membrane active antimicrobials including colistin and tobramycin. The NMR metabolomic approach is first validated by characterizing the expected E. coli acid stress response to fermentation and the accompanying changes in the cell wall composition, when cultured in glucose rich mammalian cell culture media. Glucose is not a major carbon source for P. aeruginosa but is associated with a response to osmotic stress and a modest increase in colistin tolerance. Growth of P. aeruginosa in a range of bacteriological media is supported by consumption of formate, an important electron donor in anaerobic respiration. In mammalian cell culture media, however, the overall metabolic strategy of P. aeruginosa is instead dependent on consumption of glutamine and lactate. Formate doping of mammalian cell culture media does not alter the overall metabolic strategy but is associated with polyamine catabolism, remodelling of both inner and outer membranes, and a modest sensitization of P. aeruginosa PAO1 to colistin. Further, in a panel of P. aeruginosa isolates an increase between 2- and 3-fold in sensitivity to tobramycin is achieved through doping with other organic acids, notably propionate which also similarly enhances the activity of colistin. Organic acids are therefore capable of nonspecifically influencing the potency of membrane active antimicrobials.

I have recently theorized that several similarities exist between the tumor process and embryo development. Starting from an initial cancer stem cell (CSC 0 ), similar to an embryonic stem cell (ESC), after implantation in a niche, primary self-renewing CSCs (CSC 1 s) would arise, which then generate secondary proliferating CSCs (CSC 2 s). From these epithelial CSCs, tertiary mesenchymal CSCs (CSC 3 s) would arise, which, under favorable stereotrophic conditions, by asymmetric proliferation, would generate cancer progenitor cells (CPCs) and then cancer differentiated cells (CDCs), thus giving a defined cell heterogeneity and hierarchy. CSC 1 s-CSC 2 s-CSC 3 s-CPCs-CDCs would constitute a defined "tumor growth module," able to generate new tumor modules, forming a spherical avascular mass, similar to a tumor sphere. Further growth in situ of this initial tumor would require implantation in the host and vascularization through the overexpression of some aspecific checkpoint molecules, such as CD44, ID, LIF, HSP70, and HLA-G. To expand and spread in the host tissues, this vascularized tumor would then carry on a real growth strategy based on other specific checkpoint factors, such as those contained in the extracellular vesicles (EVs), namely, microRNAs, messenger RNAs, long non-coding RNAs, and integrins. These EV components would be crucial in tumor progression because they can mediate intercellular communications in the surrounding microenvironment and systemically, dictating to recipient cells a new tumor-enslaved phenotype, thus determining pre-metastatic conditions. Moreover, by their induction properties, the EV contents could also frustrate in time the effects of cytolytic tumor therapies, where EVs released by killed CSCs might enter other cancer and non-cancer cells, thus giving chemoresistance, non-CSC/CSC transition (recurrence), and metastasis. Thus, antitumor cytotoxic treatments, "shielded" from the EV-specific checkpoints by suitable adjuvant agents, simultaneously targeting the aforesaid aspecific checkpoints should be necessary for dismantling the hierarchic tumor structure, avoiding recurrence and preventing metastasis., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Manzo.)

Aims: Following coronavirus disease (COVID-19) outbreak, the Italian government adopted strict rules of lockdown and social distancing. The aim of our study was to assess the admission rate for cardiac implantable electronic devices (CIEDs) replacement procedures in Campania, the 3rd-most-populous region of Italy, during COVID-19 lockdown., Methods and Results: Data were sourced from 16 referral hospitals in Campania from 10 March to 4 May 2020 (lockdown period) and during the same period in 2019. We retrospectively evaluated consecutive patients hospitalized for CIEDs replacement procedures during the two observational periods. The number and type of CIEDs replacement procedures among patients followed by remote monitoring (RM), the admission rate, and the type of hospital admission between the two observational periods were compared. In total, 270 consecutive patients were hospitalized for CIEDs replacement procedures over the two observation periods. Overall CIEDs replacement procedures showed a reduction rate of 41.2% during COVID-19 lockdown. Patients were equally distributed for sex ( P = 0.581 ), and both age [median 76 years (IQR: 68-83) vs. 79 years (IQR: 68-83); P =  0.497]. Cardiac implantable electronic devices replacement procedures in patients followed by RM significantly increased (IR: +211%; P <  0.001), mainly driven by the remarkable increase rate trend of both PM (IR: +475%; P <  0.001) and implantable cardiac defibrillator replacement procedures (IR: +67%, P =  0.01), during COVID-19 lockdown compared with 2019 timeframe., Conclusions: We showed a significant increase trend rate of replacement procedures among CIEDs patients followed by RM, suggesting the hypothesis of its increased use to closely monitoring and to optimize the hospital admission time during COVID-19 lockdown., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objetivo: Determinar la tasa de recurrencia del cáncer de próstata localizado después de la prostatectomía radical según la clasificación D'Amico., Métodos: Estudio de cohorte retrospectivo comparativo de 5 años. Se obtuvieron datos de registros clínicos de pacientes con cáncer de próstata localizado, que se sometieron a prostatectomía radical y se evaluó la tasa de recurrencia de la enfermedad. Se analizó con pruebas estadísticas descriptivas y comparativas. Una p < 0.05 se consideró significativo., Resultados: Se analizó 108 pacientes, la edad promedio 65.3 años. Acerca de la clasificación de riesgo de D'Amico, 33.33% de bajo riesgo, 55.56% riesgo intermedio y 11.11% alto riesgo. La tasa de recurrencia de APE fue 14,81%. Los pacientes de bajo riesgo tuvieron recurrencia del 13.89%, riesgo intermedio 18.33% y alto riesgo no tuvieron recurrencia. Sobre piezas quirúrgicas, el 25.93% presentaron características adversas. La escala de Gleason postoperatoria muestra un aumento de 44.44% en bajo riesgo, 26.67% en riesgo intermedio y 41.67% en alto riesgo., Conclusiones: La prostatectomía radical ofrece un control adecuado del cáncer de próstata localizado. La tasa de recurrencia del APE fue menor que otros informes internacionales. Asimismo, la recurrencia bioquímica del riesgo bajo, intermedio y alto fue similar a la tendencia global., Objective: The objective of the study was to determine the recurrence rate of localized prostate cancer after radical prostatectomy according to the D’Amico classification., Methods: This was a observational and 5-year comparative retrospective cohort study. Data were obtained from clinical records of patients with localized prostate cancer who underwent radical prostatectomy and the recurrence rate of the disease was evaluated. It was analyzed with descriptive and comparative statistical tests, p<0.05 was considered significant., Results: One hundred and eight patients were analyzed, and the average age was 65.3 years. About D’Amico’s risk classification, 33.33% low risk, 55.56% intermediate risk, and 11.11% high risk. The prostate-specific antigen (PSA) recurrence rate was 14.81%. Low-risk patients had recurrence of 13.89%, intermediate risk 18.33%, and high risk had no recurrence. Regarding surgical pieces, 25.93% presented adverse characteristics. The post-operative Gleason scale shows an increase of 44.44% in low risk, 26.67% in intermediate risk, and 41.67% in high risk., Conclusions: Radical prostatectomy offers adequate control of localized prostate cancer. The PSA recurrence rate was lower than other international reports. Likewise, the biochemical recurrence of low, intermediate, and high risk was similar to the global trend., (Copyright: © 2021 Permanyer.)

Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide-lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising D-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.

Because of particular properties of SARS-Cov-2, such as an high infection speed, its antigenic nature, evolutionarily unknown to the human immune system, and/or a viral interference on the immune response mechanisms, this virus would determine in the subjects a delayed anomalous (slow and/or low) immune response, ineffective and, finally, self-damaging. The hypothetical pathogenetic process for covid-19 could occur in three phases: a) Viral phase, asymptomatic or weakly symptomatic, with an a-specific innate immune response; b) Immunological phase, intermediately symptomatic, with an anomalous specific immune response (delayed, slow and/or low synthesis of IgM and IgG) in antigen excess conditions, immune complex formation and complement activation with tissue damages; c) Hemo-vascular phase, severely symptomatic, where complement-mediated tissue damages would induce vascular inflammation and systemic alteration of the coagulation homeostasis. This hypothesis is well supported by the immune-histochemical and microscopic demonstration in severe patient lungs of co-localized spike viral proteins, terminal components of the activated complement system (C5b-9 membrane attack complex) and microvascular deposits of small fibrin thrombi. This picture could be aggravated by the involvement of neutrophils and macrophages, releasing additional lytic and inflammatory factors. Thus, covid-19 would arise as a simple viral infection, develop as a diffuse immune complex hypersensitivity and explode as a systemic hemo-vascular pathology. If this hypothesized process would be real, suitable therapeutic interventions might be carried out, able to interfere with or block the critical factors in the various phases., (Copyright © 2020 Manzo.)