Advances in "adiponcosis": Insights in the inner mechanisms at the base of adipose and tumour tissues interplay.

The epidemic spread of obesity is nowadays recognized as a global health and economic burden, arising great interest in the scientific community. The rate of adult obesity steadily increases concomitantly with the cancer incidence. As has been comprehensively reported, obesity is included among the multiple cancer risk factors and can progressively cause and/or exacerbate certain cancer types, as colorectal and breast cancers. The term adiponcosis was forged precisely to emphasize the interconnection between obesity and cancer onset and progression. The underlying mechanisms of adiponcosis have not been fully elucidated yet, may vary on cancer type, and depend on body fat distribution. It has been proposed that insulin resistance and related chronic hyperinsulinemia, increased insulin-like growth factors production, chronic inflammation or increased bioavailability of steroid hormones could be responsible of cancer hallmarks. Additionally, it has been suggested that adipose tissue-derived hormones, cytokines and adipokines, such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumorigenesis. This review summarizes the current evidence on pathways, hormones, cytokines and low-chronic inflammation subtending adiponconsis, focusing on breast and colorectal cancers. In addition, we analyzed the lifestyle interventions that could attenuate the driving forces of obesity-related cancer incidence and progression. Moreover, current targets and drugs, their pros and cons, as well as new mechanisms and targets with promising therapeutic potential in cancer are discussed. Depicting this complex interconnection will provide insights for establishing new therapeutic approaches to halt the obesity impacts and thwart cancer onset and progression.

RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC. METHODS: We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC. RESULTS: Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells. CONCLUSIONS: Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism.

Rimonabant and Cannabidiol Rewrite the Interactions between Breast Cancer Cells and Tumor Microenvironment.

The spread of breast cancer to distant sites is the major cause of death in breast cancer patients. Increasing evidence supports the role of the tumor microenvironment (TME) in breast cancers, and its pathologic assessment has become a diagnostic and therapeutic tool. In the TME, a bidirectional interplay between tumor and stromal cells occurs, both at the primary and metastatic site. Hundreds of molecules, including cytokines, chemokines, and growth factors, contribute to this fine interaction to promote tumor spreading. Here, we investigated the effects of Rimonabant and Cannabidiol, known for their antitumor activity, on reprogramming the breast TME. Both compounds directly affect the activity of several pathways involved in breast cancer progression. To mimic tumor-stroma interactions during breast-to-lung metastasis, we investigated the effect of the compounds on growth factor secretion from metastatic breast cancer cells and normal and activated lung fibroblasts. In this setting, we demonstrated the anti-metastatic potential of the two compounds, and the membrane array analyses highlighted their ability to alter the release of factors involved in the autocrine and paracrine regulation of tumor proliferation, angiogenesis, and immune reprogramming. The results enforce the antitumor potential of Rimonabant and Cannabidiol, providing a novel potential tool for breast cancer TME management.

Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells.

Cutaneous melanoma, the most aggressive form of skin cancer, is characterized by activating BRAF mutations. Despite the initial success of selective BRAF inhibitors, only few patients exhibited complete responses, whereas many showed disease progression. Melanoma is one of the few types of cancer in which p53 is not frequently mutated, but p53 inactivation can be indirectly achieved by a stable activation of MDM2 induced by a deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) locus, encoding for p16INK4A and p14ARF, two tumor suppressor genes. In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives, 8 g, 8 h and 8i, in melanoma cell lines, and we compared the effects of the most active of these, the 8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that 8i potentiates the inhibitory effect of Nutlin 3 and the combined use of 8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the 8i compound reduces p53-MDM2 interaction and induces p53-HSP90 complex formation, suggesting that the observed raise in p53 transcriptional activity could be mediated by HSP90. Because the main feature of melanoma is the resistance to most chemotherapeutics, our studies suggest that the 8i tetra-substituted pyrrole derivative, restoring p53 functions and its transcriptional activities, may have potential application, at least as adjuvant, in the treatment of human melanoma.

The Endocannabinoid System: A Target for Cancer Treatment.

In recent years, the endocannabinoid system has received great interest as a potential therapeutic target in numerous pathological conditions. Cannabinoids have shown an anticancer potential by modulating several pathways involved in cell growth, differentiation, migration, and angiogenesis. However, the therapeutic efficacy of cannabinoids is limited to the treatment of chemotherapy-induced symptoms or cancer pain, but their use as anticancer drugs in chemotherapeutic protocols requires further investigation. In this paper, we reviewed the role of cannabinoids in the modulation of signaling mechanisms implicated in tumor progression.

Multifaceted Role of PRDM Proteins in Human Cancer.

The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.

Avoidant personality disorder and social phobia: Does mindreading make the difference?

OBJECTIVE: Avoidant personality disorder (AvPD) is closely related to and partially overlaps with social phobia (SP). There is an ongoing debate as to whether AvPD and SP can be classified as separate and distinct disorders or whether these diagnoses rather reflect different degrees of severity of social anxiety. The hypothesis of this study is that in patients with AvPD and in those with AvPD and comorbid SP both interpersonal functioning and metacognitive abilities (the ability to understand mental states) are more severely impaired than they are in patients with SP only. We also hypothesise that the interpersonal and metacognitive functioning of these patients (both AvPD and AvPD+SP) is comparable to that of patients with other PD diagnoses. METHODS: To test this hypothesis, we compared four groups (22 patients with SP, 32 patients with AvPD, 43 patients with both AvPD and SP and 50 patients with other personality disorders without SP and AvPD criteria) on metacognitive abilities, interpersonal functioning and global symptomatic distress. RESULTS: Metacognitive ability showed significant variation among the four groups, with the lowest score observed in the AvPD group. As far as the interpersonal functioning is concerned, the lack of sociability was more severe in the AvPD group compared with the SP group. These differences were maintained even after controlling for global symptomatic distress. CONCLUSION: Results are in line with the alternative model of PD, proposed in the DSM-5, as dysfunction of the self and relationships. They suggest that specific impairments in critical areas of self domains and interpersonal domains of personality functioning may serve as markers distinguishing AvPD from SP.

Personality Disorders and Mindreading: Specific Impairments in Patients With Borderline Personality Disorder Compared to Other PDs.

The capacity of understanding mental states is a complex function which involves several components. Single components can be selectively impaired in specific clinical populations. It has been suggested that impairments in mindreading are central for borderline personality disorder (BPD). However, empirical findings are inconsistent, and it is debatable whether BPD presents a specific profile of mindreading impairments. The aim of this study is to compare BPD and other PDs in mindreading. Seventy-two patients with BPD and 125 patients with other PD diagnoses were assessed using the Metacognition Assessment Interview. BPD showed difficulties in two mindreading functions, differentiation and integration, even when the severity of psychopathology was controlled. These results suggest a specific mindreading impairment in BPD and a strong relationship between these impairments and the severity of psychopathology.

Modified Adenosines Sensitize Glioblastoma Cells to Temozolomide by Affecting DNA Methyltransferases.

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, and due to its unique features, its management is certainly one of the most challenging ones among all cancers. N6-isopentenyladenosine (IPA) and its analog N6-benzyladenosine (N6-BA) are modified nucleosides endowed with potent antitumor activity on different types of human cancers, including GBM. Corroborating our previous finding, we demonstrated that IPA and N6-BA affect GBM cell line proliferation by modulating the expression of the F-box WD repeat domain-containing-7 (FBXW7), a tumor suppressor with a crucial role in the turnover of many proteins, such as SREBPs and Mcl1, involved in malignant progression and chemoresistance. Luciferase assay revealed that IPA-mediated upregulation of FBXW7 translates in transcriptional inactivation of its oncogenic substrates (Myc, NFkB, or HIF-1α). Moreover, downregulating MGMT expression, IPA strongly enhances the killing effect of temozolomide (TMZ), producing a favorable sensitizing effect starting from a concentration range much lower than TMZ EC50. Through DNA methyltransferase (DNMT) activity assay, analysis of the global DNA methylation, and the histone modification profiles, we demonstrated that the modified adenosines behave similar to 5-AZA-dC, known DNMT inhibitor. Overall, our results provide new perspectives for the first time, suggesting the modified adenosines as epigenetic tools able to improve chemo- and radiotherapy efficacy in glioblastoma and potentially other cancers.

In Vitro Evidence of Statins' Protective Role against COVID-19 Hallmarks.

Despite the progressions in COVID-19 understanding, the optimization of patient-specific therapies remains a challenge. Statins, the most widely prescribed lipid-lowering drugs, received considerable attention due to their pleiotropic effects, encompassing lipid metabolism control and immunomodulatory and anti-thrombotic effects. In COVID-19 patients, statins improve clinical outcomes, reducing Intensive Care Unit admission, the onset of ARDS, and in-hospital death. However, the safety of statins in COVID-19 patients has been debated, mainly for statins' ability to induce the expression of the ACE2 receptor, the main entry route of SARS-CoV-2. Unfortunately, the dynamic of statins' mechanism in COVID-19 disease and prevention remains elusive. Using different in vitro models expressing different levels of ACE2 receptor, we investigated the role of lipophilic and hydrophilic statins on ACE2 receptor expression and subcellular localization. We demonstrated that the statin-mediated increase of ACE2 receptor expression does not necessarily coincide with its localization in lipid rafts domains, particularly after treatments with the lipophilic atorvastatin that disrupt lipid rafts' integrity. Through a proteomic array, we analyzed the cytokine patterns demonstrating that statins inhibit the release of cytokines and factors involved in mild to severe COVID-19 cases. The results obtained provide additional information to dissect the mechanism underlying the protective effects of statin use in COVID-19.

Metacognitive mastery dysfunctions in personality disorder psychotherapy.

Individuals with personality disorders (PDs) have difficulties in modulating mental states and in coping with interpersonal problems according to a mentalistic formulation of the problem. In this article we analyzed the first 16 psychotherapy sessions of 14 PD patients in order to explore whether their abilities to master distress and interpersonal problems were actually impaired and how they changed during the early therapy phase. We used the Mastery Section of the Metacognition Assessment Scale, which assesses the use of mentalistic knowledge to solve problems and promote adaptation. We explored the hypotheses that a) PD patients had problems in using their mentalistic knowledge to master distress and solve social problems; b) the impairments were partially stable and only a minimal improvement could be observed during the analyzed period; c) patients' mastery preferences differed from one another; d) at the beginning of treatment the more effective strategies were those involving minimal knowledge about mental states. Results seemed to support the hypotheses; the patients examined had significant difficulties in mastery abilities, and these difficulties persisted after 16 sessions. Moreover, the attitudes towards problem-solving were not homogenous across the patients. Lastly, we discuss implications for assessment and treatment of metacognitive disorders in psychotherapy.

Emotion Regulation, Physical Diseases, and Borderline Personality Disorders: Conceptual and Clinical Considerations.

This perspective paper aims at discussing theoretical principles that could explain how emotion regulation and physical diseases mutually influence each other in the context of borderline personality disorder (BPD). Furthermore, this paper discusses the clinical implications of the functional relationships between emotion regulation, BPD and medical conditions considering dialectical behavior therapy (DBT) as a well-validated therapeutic intervention, which encompasses these issues. The inflexible use of maladaptive emotion regulation strategies (e.g., suppression, experiential avoidance, and rumination) might directly increase the probability of developing physical diseases through a physiological pathway, or indirectly through a behavioral pathway. Some metabolic and chronic medical conditions could significantly impact emotional functioning through biological alterations involved in emotion regulation. Several empirical studies have shown high co-occurrence rates between BPD and several chronic physical diseases, especially ones linked to emotion-based maladaptive behaviors. DBT addresses physical diseases reported by individuals with BPD reducing problematic behaviors functionally associated to emotion dysregulation and identifying physical health as a goal for Building a Life Worth Living.

Lipid homeostasis and mevalonate pathway in COVID-19: Basic concepts and potential therapeutic targets.

Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic. Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection. In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality. Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected.

Impaired decentration in personality disorder: a series of single cases analysed with the Metacognition Assessment Scale.

BACKGROUND: There is growing support for the idea that an impaired understanding of others' mental states is an underlying feature of personality disorder (PD). Only recently has there begun to be evidence of impairments to subjects' ability to infer and reason about others' intentions and emotions, and detach from their own perspective when doing so. METHOD: We analysed the transcripts from the first 16 psychotherapy sessions of 14 PD patients. Scales for understanding others' minds from the Metacognition Assessment Scale were used. RESULTS: Patients were generally able to describe others' mental states, although, at times, they had problems. There was, on the other hand, an inability to decentre while reasoning about others, and this was common to all the patients. CONCLUSIONS: PDs indeed feature a poor decentration, which is not easily identified with the usual lab tasks. Implications for further research and treatment are discussed. KEY PRACTITIONER MESSAGE: *Patients with personality disorders have substantial difficulties in adopting others' point of view and standing back from their own, and grasping that they are not the center of other peoples' thoughts.

N6-Isopentenyladenosine Inhibits Colorectal Cancer and Improves Sensitivity to 5-Fluorouracil-Targeting FBXW7 Tumor Suppressor.

N6-isopentenyladenosine has been shown to exert potent in vitro antitumor activity on different human cancers, including colorectal cancer. Although some potential biochemical targets have been identified, its precise mechanism of action remains unclear. We found that N6-isopentenyladenosine affects colorectal cancer proliferation in in vitro models carrying different mutational status of FBXW7 and TP53 genes, and in HCT116 xenografts in SCID mice, by increasing the expression of the well-established tumor suppressor FBXW7, a component of the SCF-E3 ubiquitin ligase complex that promotes degradation of various oncoproteins and transcription factors, such as c-Myc, SREBP and Mcl1. Corroborating our previous studies, we identified for the first time the FBXW7/SREBP/FDPS axis as a target of the compound. Pull down of ubiquitinated proteins, immunoprecipitation and luciferase assays, reveal that through the increase of FBXW7/c-Myc binding, N6-isopentenyladenosine induces the ubiquitination of c-Myc, inhibiting its transcriptional activity. Moreover, in FBXW7- and TP53-wild type cells, N6-isopentenyladenosine strongly synergizes with 5-Fluorouracil to inhibit colon cancer growth in vitro. Our results provide novel insights into the molecular mechanism of N6-isopentenyladenosine, revealing its multi-targeting antitumor action, in vitro and in vivo. Restoring of FBXW7 tumor-suppressor represents a valid therapeutic tool, enabling N6-isopentenyladenosine as optimizable compound for patient-personalized therapies in colorectal cancer.

N6-Isopentenyladenosine Enhances the Radiosensitivity of Glioblastoma Cells by Inhibiting the Homologous Recombination Repair Protein RAD51 Expression.

Glioblastoma is among the most common malignant brain tumors and has a dismal prognosis due to the poor response to therapeutic regimens such as ionizing radiation and DNA-alkylating agents. In our study, we investigated the radiosensitizing activity of the N6-isopentenyladenosine (iPA), an naturally modified adenosine harboring an isopenenyl moiety, which shows antiproliferative effects on glioblastoma cell lines. We observed that co-treatment with ionizing radiation and iPA at micromolar concentration inhibited colony formation and viability of glioblastoma cell lines but not of non-malignant human cells. The combined treatment significantly attenuated the repair of radiation-induced DNA damage by inhibiting both the expression and irradiation-induced foci formation of RAD51, a key player in the homologous recombination repair process, leading to persistent DNA damage, as reflected by an increase of γ-H2AX foci. The radiosensitizing effect relied also on the inhibition of STAT5a/b activation, which is crucial for RAD51 expression, suggesting that iPA modulates the STAT5a/b-RAD51 axis following exposure to ionizing radiation. Overall, these data suggest that iPA, by acting through RAD51 inhibition at the mechanistic level, could function as a promising radiosensitizing agent and warrants further evaluation in prospective clinical trials.

Metacognition as a Predictor of Improvements in Personality Disorders.

Personality Disorders (PDs) are particularly hard to treat and treatment drop-out rates are high. Several authors have agreed that psychotherapy is more successful when it focuses on the core of personality pathology. For this reason, therapists dealing with PDs need to understand the psychopathological variables that characterize this pathology and exactly what contributes to maintaining psychopathological processes. Moreover, several authors have noted that one key problem that characterizes all PDs is an impairment in understanding mental states - here termed metacognition - which could also be responsible for therapy failures. Unfortunately, a limited number of studies have investigated the role of mentalization in the process of change during psychotherapy. In this paper, we assume that poor metacognition corresponds to a core element of the general pathology of personality, impacts a series of clinical variables, generates symptoms and interpersonal problems, and causes treatment to be slower and less effective. We explored whether changes in metacognition predicted an improvement among different psychopathological variables characterizing PDs; 193 outpatients were treated at the Third Center of Cognitive Psychotherapy in Rome, Italy, and followed a structured path tailored for the different psychopathological variables that emerged from a comprehensive psychodiagnostic assessment that considered patients' symptoms, metacognitive abilities, interpersonal relationships, personality psychopathology, and global functioning. The measurements were repeated after a year of treatment. The results showed that changes in metacognitive abilities predicted improvements in the analyzed variables.

Attachment disorganization and borderline patients' metacognitive responses to therapists' expressed understanding of their states of mind: A pilot study.

This study explores the relationship between psychotherapists' validation interventions and patients' metacognitive responses at the beginning of treatment of borderline personality disorder (BPD). A model of BPD based on disorganized attachment provides the hypothesis that, before patients' internal working model of attachment has been corrected within the therapeutic relationship, therapist interventions that are likely to activate patients' attachment system are also likely to induce temporary disorganization of patients' metacognitive functions. Any validation intervention implies that therapists openly display an understanding and accepting attitude when they comment on patients' reported experiences and is, therefore, likely to activate the patients' attachment system. Linehan's (1993) manual of dialectic-behavioral therapy (DBT) was used as a guideline to assess validation interventions adopted by therapists. The transcripts of the second individual session in the psychotherapy of 19 consecutive patients were analyzed. Checklists based on the DBT manual were used to identify therapists' validating, supportive, and neutral interventions. The Metacognitive Assessment Scale was used to assess changes in specific aspects of patients' metacognitive processes during therapeutic dialogues. Following validation interventions, patients' responses revealed significantly higher rates of temporary metacognitive failure in comparison to the responses solicited by neutral intervention.

An intensive case analysis of client metacognition in a good-outcome psychotherapy: Lisa's case.

The authors analyzed the successful case of Lisa, a client with major depression, using the Metacognitive Assessment Scale (MAS). Consistently with the literature on depression, the authors hypothesize that Lisa's ability to reflect on mental states--here metacognition--is marginally affected. The authors found that Lisa was better at describing her own mind rather than understanding the mind of the others. Furthermore, the most severe impairment was in using metacognition to cope with mental state source of distress and to enact strategies to solve interpersonal problems. During the therapy such difficulties improved progressively. Limitations and implications of these findings are discussed.

States of minds in narcissistic personality disorder: three psychotherapies analyzed using the grid of problematic states.

The subjective experience of patients suffering from narcissistic personality disorder (NPD) has been studied using various methods. However, there has not been an analysis of psychotherapy session transcripts. It is much more likely that the facets of experience surface in this context than during a single interview or in a self-administered questionnaire. Using the Grid of Problematic States, designed to assess contents emerging in patients' transcripts, the authors analyzed the first 18 psychotherapy sessions with three female patients suffering from NPD and treated by therapists of the cognitive-constructivist school specializing in personality disorders. The three patients' dominant states of mind were characterized by anger, feeling excluded from groups, feelings of being harmed, and distrust toward others. The authors discuss the results and their implications for future research and for the definition of NPD in future editions of the Diagnostic and Statistical Manual of Mental Disorders.