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Chronic lymphocytic leukemia (CLL) is characterized by an extremely variable clinical course. Although several parameters have been shown to be associated with clinical outcomes in patients with CLL, there remains substantial intragroup clinical heterogeneity in otherwise molecularly and staging homogeneous CLL subgroups. We have recently shown that high catalase (CAT) expression identifies patients with an aggressive clinical course and that higher CAT expression is associated with the presence of the rs1001179 single nucleotide polymorphism (SNP) T allele in the CAT promoter. Herein, we genotyped CLL patients for CAT rs1001179 SNP in an exploratory study (n = 235) and in a sequential independent validation study (n = 531). Time‐to‐event modeling analyses for time‐to‐first‐treatment (TTFT) from the two patients' cohorts showed that TT genotype was associated with a shorter TTFT, independently of other currently used prognostic parameters in CLL. Moreover, the TT genotype identifies CLL patients with a faster clinical progression even within subgroups of patients with low‐risk biological and clinical hallmarks. In conclusion, our data show that the TT genotype identifies CLL patients with a shorter TTFT, pointing to this SNP as a possible prognostic factor, which can improve patients' risk stratification leading to better patient management and personalized therapeutic choices. [ABSTRACT FROM AUTHOR]

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated. [ABSTRACT FROM AUTHOR]

Aim: Force expression is characterized by an interplay of biological and molecular determinants that are expected to differentiate males and females in terms of maximal performance. These include muscle characteristics (muscle size, fiber type, contractility), neuromuscular regulation (central and peripheral factors of force expression), and individual genetic factors (miRNAs and gene/protein expression). This research aims to comprehensively assess these physiological variables and their role as determinants of maximal force difference between sexes. Methods: Experimental evaluations include neuromuscular components of isometric contraction, intrinsic muscle characteristics (proteins and fiber type), and some biomarkers associated with muscle function (circulating miRNAs and gut microbiome) in 12 young and healthy males and 12 females. Results: Male strength superiority appears to stem primarily from muscle size while muscle fiber‐type distribution plays a crucial role in contractile properties. Moderate‐to‐strong pooled correlations between these muscle parameters were established with specific circulating miRNAs, as well as muscle and plasma proteins. Conclusion: Muscle size is crucial in explaining the differences in maximal voluntary isometric force generation between males and females with similar fiber type distribution. Potential physiological mechanisms are seen from associations between maximal force, skeletal muscle contractile properties, and biological markers. [ABSTRACT FROM AUTHOR]

Overexpression of the Runt-related transcription factor 2 (RUNX2) has been reported in several cancer types, and the C-X-C motif chemokine receptor 4 (CXCR4) has an important role in tumour progression. However, the interplay between CXCR4 and RUNX2 in melanoma cells remains poorly understood. In the present study, we used melanoma cells and a RUNX2 knockout (RUNX2-KO) in vitro model to assess the influence of RUNX2 on CXCR4 protein levels along with its effects on markers associated with cell invasion and autophagy. Osteotropism was assessed using a 3D microfluidic model. Moreover, we assessed the impact of CXCR4 on the cellular levels of key cellular signalling proteins involved in autophagy. We observed that melanoma cells express both RUNX2 and CXCR4. Restored RUNX2 expression in RUNX2 KO cells increased the expression levels of CXCR4 and proteins associated with the metastatic process. The protein markers of autophagy LC3 and beclin were upregulated in response to increased CXCR4 levels. The CXCR4 inhibitor WZ811 reduced osteotropism and activated the mTOR and p70-S6 cell signalling proteins. Our data indicate that the RUNX2 transcription factor promotes the expression of the CXCR4 chemokine receptor on melanoma cells, which in turn promotes autophagy, cell invasiveness, and osteotropism, through the inhibition of the mTOR signalling pathway. Our data suggest that RUNX2 promotes melanoma progression by upregulating CXCR4, and we identify the latter as a key player in melanoma-related osteotropism. [ABSTRACT FROM AUTHOR]

The hyperpolarization-activated cyclic-nucleotide-gated (HCN) proteins are voltage-dependent ion channels, conducting both [Na.sup.+] and [K.sup.+], blocked by millimolar concentrations of extracellular [Cs.sup.+] and modulated by cyclic nucleotides (mainly cAMP) that contribute crucially to the pacemaker activity in cardiac nodal cells and subsidiary pacemakers. Over the last decades, much attention has focused on HCN current, [I.sub.f], in non-pacemaker cardiac cells and its potential role in triggering arrhythmias. In fact, in addition to pacemakers, HCN current is constitutively present in the human atria and has long been proposed to sustain atrial arrhythmias associated to different cardiac pathologies or triggered by various modulatory signals (catecholamines, serotonin, natriuretic peptides). An atypical [I.sub.f] occurs in diseased ventricular cardiomyocytes, its amplitude being linearly related to the severity of cardiac hypertrophy. The properties of atrial and ventricular [I.sub.f] and its modulation by pharmacological interventions has been object of intense study, including the synthesis and characterization of new compounds able to block preferentially HCN1, HCN2, or HCN4 isoforms. Altogether, clues emerge for opportunities of future pharmacological strategies exploiting the unique properties of this channel family: the prevalence of different HCN subtypes in organs and tissues, the possibility to target HCN gain- or loss-of-function associated with disease, the feasibility of novel isoform-selective drugs, as well as the discovery of HCN-mediated effects for old medicines. Key words: HCN channels, arrhythmias, cardiomyopathies, HCN blockers, [[beta].sub.3]-adrenoceptors. Resume : Les proteines activees par l'hyperpolarisation et modulees par les nucleotides cycliques (HCN) sont des canaux ioniques dependants du voltage conduisant les ions [Na.sup.+] comme les ions [K.sup.+], inhibes par des concentrations millimolaires de [Cs.sup.+] extracellulaire et modules par des nucleotides cycliques (principalement l'AMPc) qui participent de maniere cruciale a l'activite de pacemaker des cellules cardiaques nodales et de pacemakers accessoires. Au cours des dernieres decennies, beaucoup d'attention s'est centree sur le courant HCN dans les cellules sans activite de pacemaker et sur son role eventuel dans le declenchement d'arythmies. En fait, en plus des pacemakers, le courant HCN est present de maniere constitutive dans les oreillettes humaines et on propose depuis longtemps qu'il soutienne des arythmies auriculaires associees a differentes pathologies cardiaques, ou declenchees par divers signaux de modulation (catecholamines, serotonine, peptides natriuretiques). Les proprietes des courants [I.sub.f] auriculaires et ventriculaires, ainsi que leur modulation par des interventions pharmacologiques ont fait l'objet d'intenses etudes, portant notamment sur la synthese et la caracterisation de nouveaux composes permettant d'inhiber de maniere preferentielle les isoformes HCN1, HCN2 ou HCN4. Dans l'ensemble, des indices se manifestent quant a des occasions de strategies pharmacologiques futures exploitant les proprietes uniques de cette famille de canaux : la prevalence de differents sous-types de proteines HCN dans les organes et les tissus, la possibilite de cibler le gain ou la perte de fonction des proteines HCN associes aux maladies, la possibilite de developper de nouveaux medicaments selectifs pour des isoformes, ainsi que la decouverte d'effets medies par les proteines HCN avec des medicaments anciens. [Traduit par la Redaction] Mots-cles: canaux HCN, arythmies, cardiomyopathies, bloqueurs HCN, recepteurs [[beta].sub.3]-adrenergiques., Introduction The hyperpolarization-activated cyclic-nucleotide-gated (HCN) proteins are voltage-dependent ion channels, conducting both [Na.sup.+] and [K.sup.+] ions, blocked by millimolar concentrations of extracellular [Cs.sup.+] and modulated by cyclic nucleotides (mainly cAMP) [...]