Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL

In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is an incurable B-cell neoplasm characterized by highly variable clinical outcomes. In recent years, genomic and molecular studies revealed a remarkable heterogeneity in CLL, which mirrored the clinical diversity of this disease. These studies profoundly enhanced our understanding of leukemia cell biology and led to the identification of new biomarkers with potential prognostic and therapeutic significance. Accumulating evidence indicates a key role of deregulated NOTCH1 signaling and NOTCH1 mutations in CLL. This review highlights recent discoveries that improve our understanding of the pathophysiological NOTCH1 signaling in CLL and the clinical impact of NOTCH1 mutations in retrospective and prospective trials. In addition, we discuss the rationale for a therapeutic strategy aiming at inhibiting NOTCH1 signaling in CLL, along with an overview on the currently available NOTCH1-directed approaches

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy

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

The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19)

SARS-CoV-2 virus, infecting human cells via its spike protein, causes Coronavirus disease 2019 (COVID-19). COVID-19 is characterized by shortness of breath, fever, and pneumonia and is sometimes fatal. Unfortunately, to date, there is still no definite therapy to treat COVID-19. Therefore, the World Health Organization (WHO) approved only supportive care. During the COVID-19 pandemic, the need to maintain a correct intake of nutrients to support very weakened patients in overcoming disease arose. The literature available on nutrient intake for COVID-19 is mainly focused on prevention. However, the safe intake of micro- and/or macro-nutrients can be useful either for preventing infection and supporting the immune response during COVID-19, as well as in the post-acute phase, i.e., “long COVID”, that is sometimes characterized by the onset of various long lasting and disabling symptoms. The aim of this review is to focus on the role of nutrient intake during all the different phases of the disease, including prevention, the acute phase, and finally long COVID

Chemical composition, antimicrobial and antioxidant activities of anethole-rich oil from leaves of selected varieties of fennel [Foeniculum vulgare Mill. ssp. vulgare var. azoricum (Mill.) Thell]

The chemical composition and biological activity of the essential oils obtained from the leaves of two different cultivars of Florence fennel cropped under three different fertilization treatments (Control not fertilized; Mineral Fertilization; Compost from Municipal Solid Wastes) have been analyzed. All the oils were characterized by high anethole concentration and some showed also a good percentage of limonene. Thus, the leaves of Florence fennel, which are agricultural wastes, could be used for the recovery of anethole to be used for its flavoring and biomedical properties. The antimicrobial activity expressed by assays on the examined oils indicates an appreciable effect, generally higher on Gram-positive bacteria. The various samples of Florence fennel analyzed did not show any results with FRAP test. The DPPH test showed a weak capacity of the samples to catch the free radicals from the solution, attributable to their content in anethole

Valorization of Olive Mill Wastewater by Membrane Processes to Recover Natural Antioxidant Compounds for Cosmeceutical and Nutraceutical Applications or Functional Foods

Olive oil boasts numerous health benefits due to the high content of the monounsaturated fatty acid (MUFA) and functional bioactives including tocopherols, carotenoids, phospholipids, and polyphenolics with multiple biological activities. Polyphenolic components present antioxidant properties by scavenging free radicals and eliminating metabolic byproducts of metabolism. The objective of this research project was to recover the biologically active components rich in polyphenols, which include treatment of olive oil mills wastewater, and, at the same time, to remove the pollutant waste component resulting from the olive oil manufacturing processes. With specific focus on using technologies based on the application of ultra and nanofiltration membranes, the polyphenols fraction was extracted after an initial flocculation step. The nano-filtration permeate showed a reduction of about 95% of the organic load. The polyphenols recovery after two filtration steps was about 65% w/v. The nanofiltration retentate, dried using the spray dryer technique, was tested for cell viability after oxidative stress induction on human keratinocytes model in vitro and an improved cell reparation in the presence of this polyphenolic compound was demonstrated in scratch assays assisted through time lapse video-microscopy. The polyphenols recovered from these treatments may be suitable ingredients in cosmeceuticals and possibly nutraceutical preparations or functional foods

A novel microdeletion in the IGF2/H19 imprinting centre region defines a recurrent mutation mechanism in familial Beckwith–Wiedemann syndrome

The overgrowth disorder Beckwith–Wiedemann syndrome (BWS) is associated with dysregulation of imprinted genes at chromosome 11p15.5. The molecular defects are heterogeneous but most of the cases are associated with defective DNA methylation at either one of two Imprinting Control Regions (IC1 and IC2) or Uniparental paternal Disomy (UPD) at 11p15.5. In rare cases, the BWS phenotype has been found associated with maternal transmission of IC1 microdeletions. We describe a family with a novel 1.8 kb deletion that is associated with hypermethylation at IC1. The mutation results from recombination between highly homologous sequences containing target sites for the zinc-finger protein CTCF (CTSs). This finding supports the hypothesis that the function of IC1 and the penetrance of the clinical phenotype depend on the spacing of the CTSs resulting from recombination in the mutant allele

Fenomeni dissociativi in un campione di pazienti Borderline La patologia dissociativa come processo patogenetico nucleare del Disturbo Borderline di Personalità

Obiettivi. Scopi di tale studio sono: indagare il rapporto tra fenomeni dissociativi e Disturbo Borderline di Personalità, indagare rispetto a quale fattore sintomatologico dissociativo sia più forte il legame con il DBP e, infine, indagare se la presenza di fenomeni dissociativi sia legata al numero di tratti (sintomi) di DBP o alla diagnosi dello stesso. Metodi. Al campione (n = 1033), estratto dalla popolazione di pazienti di un ambulatorio di salute mentale privato della provincia di Napoli, sono stati somministrati gli strumenti DES e SCID II. Le valutazioni inferenziali sono state effettuate applicando il test T di Student, la regressione logistica e l’anova ad una via. Le variabili continue sono state standardizzate prima di effettuare il test di regressione. I dati raccolti sono stati trattati statisticamente attraverso l’ausilio del pacchetto SPSS per le analisi statistiche. Risultati. Il punteggio medio alla DES totale è significativamente più alto (t = -3,11) nei soggetti con DBP (μ = 17,38) rispetto a quello dei soggetti senza DBP (μ = 10,72). Dalla regressione logistica emerge che il legame tra fenomeni dissociativi e DBP è forte in relazione al Fattore III della DES (depersonalizzazione/derealizzazione) e che all’aumentare di un punto standard del Fattore III della DES aumenta del 50% la probabilità di riscontrare un DBP. L’analisi della varianza evidenzia che all’aumentare del numero di tratti di DBP si manifestano punteggi medi più alti alla DES totale. Discussione e conclusioni. Si evidenzia che i fenomeni dissociativi sono più frequenti nei pazienti con DBP rispetto ai pazienti senza DBP. Si evidenzia, inoltre, che il legame tra fenomeni dissociativi e DBP è più forte per quanto riguarda il fattore sintomatologico di depersonalizzazione/derealizzazione. Si rileva, infine, che i punteggi medi alla DES TOT aumentano all’aumentare del numero di tratti di DBP ma che, in particolare, tali punteggi sono più alti alla presenza di 4 tratti. Questa evidenza ci consente di concludere che il legame tra fenomeni dissociativi e DBP si collega al numero di tratti di DBP e non necessariamente alla diagnosi dello stesso.Aims. This study aims to investigate the relationship between dissociative phenomena and the Borderline Personality Disorder, in order to identify which one of dissociative symptoms factor has a stronger tie with Borderline Personality Disorder. Moreover, this study aims to find out if the presence of dissociative symptoms is linked to the number of Borderline Personality Disorder traits (symptoms), or the Borderline Personality Disorder diagnosis itself. Methods. A representative sample (n = 1033) was selected from patients visiting a private mental health clinical center in Naples. Inclusion criteria provided both Borderline Personality Disorder and non-Borderline Personality Disorder patients. The Dissociative Experiences Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV Axis II Disorders were used in order to collect data. Statistical Analysis involved the Student’s T-test, logistic regression and one-way Analysis of Variance. Continuous variables were standardized before the regression test. In addition, collected data were analyzed by the software Statistical Package of Social Science. Results. The mean of DES-Total scores in Borderline Personality Disorder patients (μ = 17,38) was significantly higher (t = -3,11) than in non-Borderline Personality Disorder patients (μ = 10,72). Logistic regression showed a strong link between dissociative phenomena and Borderline Personality Disorder respect to DES Factor III (depersonalization/derealization). Furthermore, it shows how increasing one standard point in DES Factor III increases by 50% the chance to detect a Borderline Personality Disorder. Lastly, the Analysis of Variance highlighted that more the number of Borderline Personality Disorder traits increase, the higher average are shown on DES-Total scores. Discussion and conclusions. The study has shown that Dissociative phenomena are more frequent in Borderline Personality Disorder patients rather than non-Borderline Personality Disorder patients. Moreover, it shows that the link between dissociative phenomena and Borderline Personality Disorder is stronger in relation to symptom factor depersonalization/derealisation. Finally, results show that DES-Total mean scores increase as Borderline Personality Disorder traits number increases, with higher scores when four specific traits are detected. This evidence confirms that the relationship between dissociative phenomena and Borderline Personality Disorder depends on the number of Borderline Personality Disorder traits detected, but not necessarily on the Borderline Personality Disorder diagnosis