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Introduction: Borderline personality disorder (BPD) is a severe mental disorder characterized by emotion dysregulation, impulsivity, neuropsychological impairment, and interpersonal instability, presenting with multiple psychiatric comorbidities, functional disability and reduced life expectancy due suicidal behaviors., Areas Covered: In this perspective, the authors explore the application of noninvasive brain stimulation (NIBS) (rTMS, tDCS, and MST) in BPD individuals by considering a symptom-based approach, focusing on general BPD psychopathology, impulsivity and neuropsychological impairments, suicidality and depressive/anxious symptoms, and emotion dysregulation., Expert Opinion: According to a symptoms-based approach, NIBS interventions (particularly rTMS and tDCS) are promising treatment options for BPD individuals improving core symptoms such as emotional and behavioral dysregulation, neuropsychological impairments and depressive symptoms. However, the heterogeneity of stimulation protocols and of assessment tools used to detect these changes limits the possibility to provide definitive recommendations according to a symptom-based approach. To implement such armamentarium in clinical practice, future NIIBS studies should further consider a lifespan perspective due to clinical variability over time, the role of psychiatric comorbidities affecting BPD individuals and the need to combine NIBS with specialized psychotherapeutic approaches for BPD patients and with functional neuroimaging studies.

Background: Treating depressive symptoms in patients with schizophrenia is challenging. While transcranical Dicrect Current Stimulation (tDCS) improved other core symptoms of schizophrenia, conflicting results have been obtained on depressive symptoms. Thus, we aimed to expand current evidence on tDCS efficacy to improve depressive symptoms in patients with schizophrenia., Methods: A double-blind RCT was performed with patients randomized to 2 mA active-tDCS or sham-tDCS (15 daily sessions) with a bilateral bipolar-nonbalanced prefrontal placement (anode: left Dorsolateral prefrontal cortex; cathode: right orbitofrontal region). Clinical outcomes included variations of Calgary Depression Scale for Schizophrenia total score (CDSS) and of Depression-hopelessness and Guilty idea of reference-pathological guilt factors. Analysis of covariance was performed evaluating between-group changes over time. The presence/absence of probable clinically significant depression was determined when CDSS > 6., Results: As 50 outpatients were included (both groups, n = 25), significant improvements following active-tDCS were observed for CDSS total score (p = 0.001), Depression-hopelessness (p = 0.001) and Guilty idea of reference-pathological guilt (p = 0.03). Considering patients with CDSS>6 (n = 23), compared to sham, active-tDCS significantly improved CDSS total score (p < 0.001), Depression-hopelessness (p = 0.001) but Guilty idea of reference-pathological guilt only marginally improved (p = 0.051). Considering response rates of clinically significant depression, important reductions of CDSS score were observed (78 % of the sample scored ≤6; active-tDCS, n = 23; sham-tDCS, n = 16; p = 0.017). Early wakening item did not significantly change in any group., Limitations: The study lacks a follow-up period and evaluation of tDCS effects on psychosocial functioning., Conclusions: Bilateral bipolar-nonbalanced prefrontal tDCS is a successful protocol for the treatment of depressive symptoms in patients with schizophrenia., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, underlining a need to characterize the effects of CDK4/6 inhibitors beyond pRb. Our study demonstrates how palbociclib impairs origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA while showing no cell cycle arrest. Furthermore, this CDK4/6 inhibitor treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of the Pre-initiation complex (Pre-IC) proteins on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and of its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib in combination with other drugs to target genomic instability in pRB-deficient cancers.

Negative symptoms (NS), conceived as Avolition-Apathy (AA) and Expressive Deficit (EXP) domains, and neurocognitive impairments represent unmet therapeutic needs for patients with schizophrenia. The present study investigated if bilateral bipolar-nonbalanced frontal transcranial Direct Current Stimulation (tDCS) could improve these psychopathological dimensions. This randomized, double-blind, sham-controlled study (active-tDCS versus sham-tDCS, both, n = 25) included 50 outpatients diagnosed with schizophrenia clinically stabilized. Patients received 20-min 2 mA active-tDCS or sham-tDCS (anode: left Dorsolateral Prefrontal Cortex; cathode: right orbitofrontal region). Primary outcomes included: PANSS-Negative subscale, Negative Factor (Neg-PANSS), AA and EXP domains; neurocognitive performance at Brief Assessment of Cognition in Schizophrenia. Secondary outcomes included: PANSS subscales and total score, Disorganized/Concrete (DiscC-PANSS) and Positive Factors, Clinical Global Impression (CGI) scores, clinical insight at Scale to Assess Unawareness of Mental Disorder (SUMD). Analysis of covariance (ANCOVA) was performed evaluating between-group changes over time. Significant improvements following active-tDCS were observed for all NS measures (all, p < 0.001; d > 0.8) and for working memory (p = 0.025, d = 0.31). Greater variations following to active treatment emerged also for PANSS-General Psychopathology subscale (p < 0.001; d = 0.54), PANSS total score (p < 0.001; d = 0.69), CGI indexes (all, p < 0.001; d > 0.6), DiscC-PANSS (p < 0.001; d = 0.80) and SUMD-general Unawareness index (p = 0.005; d = 0.15) but not for positive symptoms and others insight measures. Good safety/tolerability profiles were found. Bilateral bipolar-nonbalanced frontal-tDCS is a non-pharmacological approach in schizophrenia effectively improving NS, particularly the AA and EXP domains, probably acting by modulating dysfunctional cortical-subcortical networks. Preliminary results also suggest working memory improvements following tDCS. Further studies are needed to confirm the neurobiological basis of these results., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in the present study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The present narrative review has covered the current evidence regarding the role of cognitive impairments during the early phase of major depressive disorder (MDD), attempting to describe the cognitive features in childhood, adolescence and in at-risk individuals. These issues were analyzed considering the trait , scar and state hypotheses of MDD by examining the cold and hot dimensions, the latter explained in relation to the current psychological theoretical models of MDD. This search was performed on several electronic databases up to August 2022. Although the present review is the first to have analyzed both cold and hot cognitive impairments considering the trait , scar and state hypotheses, we found that current evidence did not allow to exclusively confirm the validity of one specific hypothesis since several equivocal and discordant results have been proposed in childhood and adolescence samples. Further studies are needed to better characterize possible cognitive dysfunctions assessing more systematically the impairments of cold , hot and social cognition domains and their possible interaction in a developmental perspective. An increased knowledge on these topics will improve the definition of clinical endophenotypes of enhanced risk to progression to MDD and, to hypothesize preventive and therapeutic strategies to reduce negative influences on psychosocial functioning and well-being.

Treating Borderline Personality Disorder (BPD) is a major challenge for psychiatrists. As Brain Stimulation represents an alternative approach to treat psychiatric disorders, our systematic review is the first to focus on both invasive and Non-Invasive Brain Stimulation (NIBS) interventions in people living with BPD, examining clinical effects over core features and comorbid conditions. Following PRISMA guidelines, out of 422 original records, 24 papers were included regarding Deep Brain Stimulation (n = 1), Electroconvulsive therapy (n = 5), Transcranial Magnetic Stimulation (n = 13) and transcranial Direct Current Stimulation (n = 5). According to impulsivity and emotional dysregulated domain improvements, NIBS in BPD appears to restore frontolimbic network deficiencies. NIBS seems also to modulate depressive features. Safety and tolerability profiles for each technique are discussed. Despite encouraging results, definitive recommendations on Brain Stimulation in BPD are mitigated by protocols heterogeneity, lack of randomized controlled trials and poor quality of included studies, including high risk of methodological biases. To serve as guide for future systematic investigations, protocols optimization proposals are provided, focusing on alternative stimulation sites and suggesting a NIBS symptom-based approach., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The DNA polymerase zeta (Polζ) plays a critical role in bypassing DNA damage. REV3L, the catalytic subunit of Polζ, is also essential in mouse embryonic development and cell proliferation for reasons that remain incompletely understood. In this study, we reveal that REV3L protein interacts with heterochromatin components including repressive histone marks and localizes in pericentromeric regions through direct interaction with HP1 dimer. We demonstrate that Polζ/REV3L ensures progression of replication forks through difficult-to-replicate pericentromeric heterochromatin, thereby preventing spontaneous chromosome break formation. We also find that Rev3l-deficient cells are compromised in the repair of heterochromatin-associated double-stranded breaks, eliciting deletions in late-replicating regions. Lack of REV3L leads to further consequences that may be ascribed to heterochromatin replication and repair-associated functions of Polζ, with a disruption of the temporal replication program at specific loci. This is correlated with changes in epigenetic landscape and transcriptional control of developmentally regulated genes. These results reveal a new function of Polζ in preventing chromosome instability during replication of heterochromatic regions., (© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)