Chibby drives β catenin cytoplasmic accumulation leading to activation of the unfolded protein response in BCR-ABL1+ cells

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL fusion protein. However, the phenotype of leukemic stem cells (LSC) is sustained by β catenin rather than by the BCR-ABL TK. β catenin activity in CML is contingent upon its stabilization proceeding from the BCR-ABL-induced phosphorylation at critical residues for interaction with the Adenomatous polyposis coli (APC)/Axin/glycogen synthase kinase 3 (GSK3) destruction complex or GSK3 inactivating mutations. Here we studied the impact of β catenin antagonist Chibby (CBY) on β catenin signaling in BCR-ABL1+ cells. CBY is a small conserved protein which interacts with β catenin and impairs β catenin-mediated transcriptional activation through two distinct molecular mechanisms: 1) competition with T cell factor (TCF) or lymphoid enhancer factor (LEF) for β catenin binding; and 2) nuclear export of β catenin via interaction with 14-3-3. We found that its enforced expression in K562 cell line promoted β catenin cytoplasmic translocation resulting in inhibition of target gene transcription. Moreover, cytoplasmic accumulation of β catenin activated the endoplasmic reticulum (ER) stress-associated pathway known as unfolded protein response (UPR). CBY-driven cytoplasmic accumulation of β catenin is also a component of BCR-ABL1+ cell response to the TK inhibitor Imatinib (IM). It evoked the UPR activation leading to the induction of BCL2-interacting mediator of cell death (BIM) by UPR sensors. BIM, in turn, contributed to the execution phase of apoptosis in the activation of ER resident caspase 12 and mobilization of Ca2+ stores

Cardiac sympathetic dysfunction in pulmonary arterial hypertension: Lesson from left-sided heart failure

Sympathetic nervous system hyperactivity has a well-recognized role in the pathophysiology of heart failure with reduced left ventricular ejection fraction. Alterations in sympathetic nervous system have been related to the pathophysiology of pulmonary arterial hypertension, but it is unclear whether cardiac sympathetic nervous system is impaired and how sympathetic dysfunction correlates with hemodynamics and clinical status in pulmonary arterial hypertension patients. The aim of this study was to evaluate the cardiac sympathetic nervous system activity by means of 123Iodine-metaiodobenzylguanidine nuclear imaging in pulmonary arterial hypertension patients and to explore its possible correlation with markers of disease severity. Twelve consecutive pulmonary arterial hypertension patients (nine women, median age 56.5 (17.8), eight idiopathic and four connective tissue-associated pulmonary arterial hypertension) underwent cardiac 123Iodine-metaiodobenzylguanidine scintigraphy. The results were compared with those of 12 subjects with a negative history of cardiovascular or pulmonary disease who underwent the same nuclear imaging test because of a suspected paraganglioma or pheochromocytoma, with a negative result (controls), and 12 patients with heart failure with reduced left ventricular ejection fraction. Hemodynamics, echocardiography, six-minute walking distance, cardiopulmonary exercise testing, and N-terminal pro brain natriuretic peptide were collected in pulmonary arterial hypertension patients within one week from 123Iodine-metaiodobenzylguanidine scintigraphy. Cardiac 123Iodine-metaiodobenzylguanidine uptake, assessed as early and late heart-to-mediastinum ratio, was significantly lower in pulmonary arterial hypertension compared to controls (p = 0.001), but similar to heart failure with reduced left ventricular ejection fraction. Myocardial 123Iodine-metaiodobenzylguanidine turnover, expressed as washout rate, was similar in pulmonary arterial hypertension and heart failure with reduced left ventricular ejection fraction and significantly higher compared to controls (p = 0.016). In the pulmonary arterial hypertension group, both early and late heart-to-mediastinum ratios and washout rate correlated with parameters of pulmonary arterial hypertension severity including pulmonary vascular resistance, right atrial pressure, tricuspid annular plane systolic excursion, N-terminal pro brain natriuretic peptide, and peak VO2. Although we evaluated a small number of subjects, our study showed a significant impairment in cardiac sympathetic nervous system in pulmonary arterial hypertension, similarly to that observed in heart failure with reduced left ventricular ejection fraction. This impairment correlated with indices of pulmonary arterial hypertension severity. Cardiac sympathetic dysfunction may be a contributing factor to the development of right-sided heart failure in pulmonary arterial hypertension

Recent advances in the label-free characterization of exosomes for cancer liquid biopsy: From scattering and spectroscopy to nanoindentation and nanodevices

Exosomes (EXOs) are nano-sized vesicles secreted by most cell types. They are abundant in bio-fluids and harbor specific molecular constituents from their parental cells. Due to these characteristics, EXOs have a great potential in cancer diagnostics for liquid biopsy and personalized medicine. Despite this unique potential, EXOs are not yet widely applied in clinical settings, with two main factors hindering their translational process in diagnostics. Firstly, conventional extraction methods are time-consuming, require large sample volumes and expensive equipment, and often do not provide high-purity samples. Secondly, characterization methods have some limitations, because they are often qualitative, need extensive labeling or complex sampling procedures that can induce artifacts. In this context, novel label-free approaches are rapidly emerging, and are holding potential to revolutionize EXO diagnostics. These methods include the use of nanodevices for EXO purification, and vibrational spectroscopies, scattering, and nanoindentation for characterization. In this progress report, we summarize recent key advances in label-free techniques for EXO purification and characterization. We point out that these methods contribute to reducing costs and processing times, provide complementary information compared to the conventional characterization techniques, and enhance flexibility, thus favoring the discovery of novel and unexplored EXO-based biomarkers. In this process, the impact of nanotechnology is systematically highlighted, showing how the effectiveness of these techniques can be enhanced using nanomaterials, such as plasmonic nanoparticles and nanostructured surfaces, which enable the exploitation of advanced physical phenomena occurring at the nanoscale level

Status psicopatologico, eventi di vitya stressanti e modalità relazionali di un campione di pazienti affetti da alopecia areata in comorbidità con disturbi psichiatrici

Introduzione: L ' A l o p e c i a A r e a t a è u n a f o r m a d i a l o p e c i a n on c i c a t r i z i a l e c a r a t t e r i z z a t a d a l l a c o m p a r s a , n e l l a r e g i o n e d e l c a p o , d i c h i a z z e c i r c o l a r i c i r c o s c r i t t e p r i v e d i p e l i . L ' e z i o l o g i a è m u l t i f a t t o r i a l e , c o m p r e n d e n d o f a t t o r i a u l o i m m u n i , suscettibilità g e n e t i c a l e g a t a a l s i s t e m a H L A e f a t t o r i a m b i e n t a l i , t r a c u i l o s t r e s s . I n a l c u n i s l u d i è s t a t a e v i d e n z i a t a u n a comorbidità p s i c h i a t r i c a . Obiettivi: D e s c r i v e r e l e p r i n c i p a l i c a r a t t e r i s t i c h e s o c i o - d e m o gr a f i c h e e v a l u t a r e l o s t a t u s p s i c o p a t o l o g i c o , l ' e v e n t u a l e p r e s e n z a d i e v e n t i d i v i t a s t r e s s a n t i e l e modalità r e l a z i o n a U i n u n a p o p o l a z i o n e d i p a z i e n t i a f f e t t i d a A A i n comorbidità c o n u n o o p i t i d i s t u r b i p s i c h i a t r i c i ; i n d a g a r e l e p o s s i b i l i c o r r e l a z i o n i t r a q u e s t i d i v e r s i f a t t o r i . Materiali e metodi: V e n t u n o p a z i e n t i c o n d i a g n o s i i n A s s e I d e l D S M I V - T R , e f f e t t u a t a m e d i a n t e S C I D - I , h a n n o c o m p i l a t o l a s c a l a S C L 9 0 - R e s o n o s t a t i s o t t o p o s t i a d u n a v a l u t a z i o n e p s i c o d i n a m i c a m e d i a n te i l s i s t e m a O P D ; l a ricorrenza di e v e n t i d i v i t a s t r e s s a n t i è s t a t a i n d a g a ta m e d i a n t e S c a l a d i P a y k e l . È s t a t a c o n d o t t a u n ' a n a l i s i d e s c r i t t i v a d e l c a m p i o n e e d è s t a t a v a l u t a t a l a c o r r e l a z i o n e t r a l e v a r i a b i l i i n d a g a t e. Risultati: L e d i a g n o s i più f r e q u e n t i s o n o s t a t e q u e l l e r e l a t i v e a i D i s t u r b i d e l l ' U m o r e e d a i D i s t u r b i d ' A n s i a . L e d i m e n s i o n i d e l l a s c a la S C L 9 0 –R h a n n o m o s t r a t o u n p u n t e g g i o m e d i o i n f e r i o r e a 6 0 p u n t i T . i l 5 7 . 1 % d e l c a m p i o n e h a riferito d i a v e r a v u t o a l m e n o u n e v e n to s t r e s s a n t e n e i s e i m e s i a n t e c e d e n t i l a c o m p a r s a d i A A . L a modalità r e l a z i o n a l e d i q u e s t i p a z i e n t i è p r e v a l e n t e m e n t e c a r a t t e r i z z a t a d a l la t e n d e n z a a d i f f e n d e r s i f a c i l m e n t e . L ' a n a l i s i d e l l a c o r r e l a z i o n e h a m o s t r a t o c o r r e l a z i o n i s t a t i s t i c a m e n t e s i g n i f i c a t i v e t r a a l c u n e d i m e n s i o n i d e l l a s c a l a S C L 9 0 - R e g l i e v e n t i d i v i t a s t r e s s a n t i. Conclusioni: U l t e r i o r i s t u d i s o n o n e c e s s a r i p e r c o n f e r m a r e t a li risultati