Pharmacological inhibition of CDK4/6 impairs diffuse pleural mesothelioma 3D spheroid growth and reduces viability of cisplatin-resistant cells

IntroductionDiffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results.MethodsHere, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells.ResultsSpecifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/ necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib’s cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin.DiscussionOverall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy

Bollettino Sismico Italiano: Analisys of Early Aftershocks of the 2016 MW 6.0 Amatrice, MW 5.9 Visso and MW 6.5 Norcia earthquakes in Central Italy

The Amatrice-Visso-Norcia seismic sequence is the most important of the last 30 years in Italy. The seismic sequence started on 24 August, 2016 and still is ongoing in central Apennines. At the end of February 2017 more than 57,000 events were located, 80,000 events up to the end of September 2017 (Fig. 1). The mainshocks of the sequence occurred on 24 August 2016 (Mw 6.0 and Mw 5.4), 26 October 2016 (Mw 5.4 and Mw 5.9), 30 October 2016 (Mw 6.5), 18 January 2017 (four earthquakes Mw≥ 5.0). In this seismic sequence, all the waveforms recorded by temporary stations deployed by the SISMIKO emergency group (stations T12**; Moretti et al., 2016) where available in real- time at the surveillance room of INGV. Because of the high level of seismicity and the dense seismic network installed in the region, more than 150 events per day were located at the end of February 2017; still 60 events per day were located up to the end of August 2017.The Amatrice-Visso-Norcia is the most important seismic sequence since 2015, the time when the analysis procedures of the BSI group (Bollettino Sismico Italiano) were revised (Nardi et al., 2015). BSI is now available every four months on the web: bulletins contain revised earthquakes (location and magnitude) with ML≥ 1.5, quasi-real time revision of ML≥ 3.5 earthquakes and phase arrivals from waveforms recorded on seismic stations available from the European Integrated Data Archive (EIDA), (Mazza et al., 2012). These last procedures allow the integration of signals from temporary seismic stations (Moretti et al., 2014) installed by the emergency group SISMIKO (Moretti and Sismiko working group, 2016), even when they are not in real time transmission, if they are rapidly archived in EIDA, together with real time signals from the seismic stations of the permanent INGV network. The analysis strategy of the BSI group for the Amatrice -Visso - Norcia seismic sequence (AVN.s.s in the following) was to select the earthquakes located in the box with min/max latitude: 42.2/43.2 - and min/max longitude: 12.4/14.1 to prepare a special volume of BSI on the seismic sequence.PublishedTrieste, Italy1SR. TERREMOTI - Servizi e ricerca per la Societ

Bollettino Sismico Italiano: settembre - dicembre 2015

Nel terzo quadrimestre 2015 si sono verificati 5 terremoti con M>4 nel territorio Italiano. In particolare il 14 ed il 16 ottobre si sono verificati due eventi profondi del basso Tirreno il primo con M=4.2 a 300 km di profondità, il secondo con M=4.4 a circa 250 km di profondità. Due terremoti M4.2 e M4.4 sono avvenuti il 6 dicembre nel Mar Adriatico a nord delle Isole Tremiti. Associati a questi si sono verificati alcuni eventi di magnitudo sopra a 3.5: si è trattata di una vera e propria sequenza sismica durata pochi giorni. L’ultimo evento di magnitudo superiore a 4 si è verificato a NE di Palermo nel basso Tirreno il 20 dicembre con una M=4.2. E’ infine da segnalare un terremoto con M = 4.8 che si è verificato il 1 Novembre in Slovenia, al confine con la Croazia.Istituto Nazionale di Geofisica e Vulcanologia - Dipartimento di Protezione CivilePublished4IT. Banche dat

Bollettino Sismico Italiano: maggio - agosto 2015

Nel secondo quadrimestre 2015 si sono verificati 7 eventi di magnitudo superiore a 4: il 9 maggio un evento di ML 4.5 è stato localizzato nel basso Tirreno ad una profondità di circa 217 km; l’11 maggio un terremoto di Mw 4.4 nel Mar Ionio a circa 47 km di profondità; il 29 maggio un Mw 4.2 nel Mar Adriatico di fronte a San Benedetto del Tronto; il 2 agosto un evento di magnitudo ML4.0 nel Mar Tirreno, al largo della costa calabra occidentale, ad una profondità di circa 247 km e il 3 agosto un terremoto di magnitudo ML 4.0 tra le province di Cosenza e Catanzaro a sud della Sila, seguito da una sequenza di oltre 80 repliche di piccola magnitudo. L’8 agosto 2015 si è verificato un terremoto di ML 4.1 alle Isole Eolie, ed infine il 29 agosto un evento di Mw 4.0 vicino al confine della Slovenia con il Friuli Venezia Giulia, seguito da una sequenza sismica che è continuata anche dopo il 31 agosto.Istituto Nazionale di Geofisica e Vulcanologia - Dipartimento di Protezione CivilePublished4IT. Banche dat

Bollettino Sismico Italiano: gennaio - aprile 2015

Nel primo quadrimestre 2015 si sono verificati 5 eventi di magnitudo superiore a 4: il 23 gennaio un Mw 4.3 è stato localizzato tra le province di Bologna e Prato, seguito da una sequenza di alcune centinaia di eventi; il 6 febbraio un Mw 4.7 al largo delle Isole Eolie, ad oltre 270 km di profondità; il 28 febbraio un Mw 4.1 nella Piana del Fucino; il 15 aprile un evento di magnitudo Mw 4.3 nel Mar Tirreno, al largo della costa calabra occidentale, ad una profondità di oltre 250 km e il 24 aprile un terremoto di magnitudo ML 4.0 tra le province di Ravenna e Forlì-Cesena,seguito da una sequenza di oltre 80 repliche.Istituto Nazionale di Geofisica e Vulcanologia e Dipartimento Protezione CivilePublished4IT. Banche dat

Bollettino Sismico Italiano: maggio - agosto 2016

Il 24 agosto 2016 un terremoto di magnitudo 6.0 ha dato inizio ad una sequenza sismica in Italia centrale, che ha generato decine di migliaia di eventi sismici. Per l’analisi e revisione di questa sequenza si rimanda ad un uscita speciale del BSI prevista per fine 2017(S_BSI_CI). In questo quadrimestre e nel successivo gli eventi nella zona della sequenza sono quelli localizzati nella sala di sorveglianza. Solo gli eventi con M>= 3.5, e pochi altri (vedi Marchetti et al. Annals of Geophys. DOI: 10.4401/ag6116) sono stati rivisti dal BSI.Nel secondo quadrimestre 2016 si sono verificati sedici eventi di magnitudo superiore a 4.0 (ML) rivisti dagli analisti del BSI uno vicino alle coste tunisine quindi fuori dal territorio nazionale; l’evento di Mw 4.1 che è avvenuto il 30 maggio in provincia di Terni vicino al Lago di Bolsena (lat=42.7, lon=11.98 ad una profondità di 8 km) e 14 eventi nella zona della sequenza nell’ultima settimana del quadrimestre: il 24 agosto 2016 si è verificato l’evento di magnitudo ML=6.0 (Mw=6.0) che ha iniziato una sequenza sismica per la quale sono stati localizzati decine di migliaia di terremoti e che alla fine di ottobre 2016 ha generato eventi persino più forti (fino a Mw=6.5) della prima scossa.Istituto Nazionale di Geofisica e Vulcanologia - Dipartimento di Protezione CivilePublished4IT. Banche dat

The emerging role of probiotics in neurodegenerative diseases: new hope for Parkinson's disease?

Neurodegenerative disease etiology is still unclear, but different contributing factors, such as lifestyle and genetic factors are involved. Altered components of the gut could play a key role in the gut-brain axis, which is a bidirectional system between the central nervous system and the enteric nervous system. Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic, autoimmune, cancer, and, notably, neurodegenerative disorders. Diet can alter the microbiota composition, affecting the gut-brain axis function. Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions, including the use of probiotics. Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry, modulating different pathways. This review will discuss the potential use of probiotics for Parkinson's disease prevention or treatment or as adjuvant therapy, confirming that gut microbiota modulation influences different pro-survival pathways. Future investigations in Parkinson's disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary

The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death

Simple SummarySeveral current therapies fail to eradicate tumors due to the ability of cancer stem cells (CSCs) to escape different programmed cell deaths. In fact, apoptosis, autophagy, and necroptosis are deregulated in CSCs. Over the years, it has emerged that CSCs play a key role in tumor formation, progression, and recurrence. Thus, developing CSC-selective and programmed death-inducing therapeutic approaches appears of primary importance. In this review, we focus on signaling pathways involved in CSCs' escape-death ability and the variety of CSC-targeting agents developed in recent years.Cancer is one of the primary causes of death worldwide. Tumour malignancy is related to tumor heterogeneity, which has been suggested to be due to a small subpopulation of tumor cells named cancer stem cells (CSCs). CSCs exert a key role in metastasis development, tumor recurrence, and also epithelial-mesenchymal transition, apoptotic resistance, self-renewal, tumorigenesis, differentiation, and drug resistance. Several current therapies fail to eradicate tumors due to the ability of CSCs to escape different programmed cell deaths. Thus, developing CSC-selective and programmed death-inducing therapeutic approaches appears to be of primary importance. In this review, we discuss the main programmed cell death occurring in cancer and the promising CSC-targeting agents developed in recent years. Even if the reported studies are encouraging, further investigations are necessary to establish a combination of agents able to eradicate CSCs or inhibit their growth and proliferation

Potential Approaches Versus Approved or Developing Chronic Myeloid Leukemia Therapy

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, continued use of these inhibitors has contributed to the increase in clinical resistance and the persistence of resistant leukemic stem cells (LSCs). So, there is an urgent need to introduce additional targeted and selective therapies to eradicate quiescent LSCs, and to avoid the relapse and disease progression. Here, we focused on emerging BCR-ABL targeted and non-BCR-ABL targeted drugs employed in clinical trials and on alternative CML treatments, including antioxidants, oncolytic virus, engineered exosomes, and natural products obtained from marine organisms that could pave the way for new therapeutic approaches for CML patients

S-Carboxymethyl Cysteine Protects against Oxidative Stress and Mitochondrial Impairment in a Parkinson’s Disease In Vitro Model

The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated metabolites generated upon night-time administration. It has been indicated that this drug behaves like a free radical scavenger and that, in this regard, the sulfide is the active species with sulphoxide metabolites (already oxidized) being inactive. Consequently, a night-time consumption of the drug should be more effective upon daytime administration. Still, this diurnal variation in biotransformation (deactivation) is dependent on the genetic polymorphism on which relies the patient population capacities of S-carboxymethyl-L-cysteine sulphoxidation. It has been reported that those cohorts who are efficient sulfur oxidizers will generate inactive oxygenated metabolites. In contrast, those who have a relative deficiency in this mechanism will be subjected to the active sulfide for a more extended period. In this regard, it is noteworthy that 38–39% of Parkinson’s disease patients belong to the poor sulphoxide cohort, being exposed to higher levels of active sulfide, the active antioxidant metabolite of S-carboxymethyl-L-cysteine. Parkinson’s disease is a neurodegenerative disorder that affects predominately dopaminergic neurons. It has been demonstrated that oxidative stress and mitochondrial dysfunction play a crucial role in the degeneration of dopaminergic neurons. Based on this evidence, in this study, we evaluated the effects of S-carboxymethyl cysteine in an in vitro model of Parkinson’s disease in protecting against oxidative stress injury. The data obtained suggested that an S-carboxymethylcysteine-enriched diet could be beneficial during aging to protect neurons from oxidative imbalance and mitochondrial dysfunction, thus preventing the progression of neurodegenerative processes