Irreversible work and inner friction in quantum thermodynamic processes.

We discuss the thermodynamics of closed quantum systems driven out of equilibrium by a change in a control parameter and undergoing a unitary process. We compare the work actually done on the system with the one that would be performed along ideal adiabatic and isothermal transformations. The comparison with the latter leads to the introduction of irreversible work, while that with the former leads to the introduction of inner friction. We show that these two quantities can be treated on an equal footing, as both can be linked with the heat exchanged in thermalization processes and both can be expressed as relative entropies. Furthermore, we show that a specific fluctuation relation for the entropy production associated with the inner friction exists, which allows the inner friction to be written in terms of its cumulants.

Multidisciplinary working group: key role for percutaneous endovascular AV fistula program. Point of view.

Chronic kidney disease is a progressive condition that affects more than 10% of the general population worldwide. Hemodialysis is the most common therapeutic option for kidney failure, which develops in around one out of 1000 individuals in the general population. Hemodialysis needs a vascular access to connect to the extracorporeal machine. In the last few years percutaneous endovascular arterio-venous fistula technique has been increasingly employed with very promising results. Several advantages have been demonstrated in comparison to the standard surgical creation of an arteriovenous fistula. The percutaneous endovascular arterio-venous fistula technique requires multidisciplinary team work. In our practice, we have organized a multidisciplinary team that includes nephrologists, play a key role, interventional radiologists, vascular surgeons, anesthesiologists, and dialysis nurses. Procedural outcomes and feedback received from patients and family members are evaluated periodically in order to improve results. Nephrologists are involved in each step of the management of the percutaneous endovascular arterio-venous fistula: selection, mapping, creation, and follow up. Patient empowerment, education and involvement is required at each step. A dedicated training program, involving patients and the caregiver team is therefore needed. Additional research is required to confirm the benefit of the multidisciplinary team management in end-stage kidney disease patients.

Angiogenesis in hand chondroma: an immunohistochemical study.

Hand chondroma is a particular cartilagineous tumour, being clinically benign, but morphologically malignant. This study investigates the expression of VEGF together with other growth factors and proliferation markers such as TGFß2, Ki-67, TNF, FGF1, P53 in 8 cases of hand chondroma treated with courettage, in order to define the ethiopathogenesis of this tumour and the clinical significance of the resulting immunohistochemical profile, with particular respect to angiogenesis. VEGF was expressed in all cases; 5 cases were positive for TFGß2 and 3 for PDGF. None of the other factors was expressed. On the basis of histologic results a specific model of tumour progression based on the indicators of angiogenesis could be related to hand tumours, in which VEGF expression should be the first stadium of the tumour aggressiveness, and the following PDGF, TGF 2 expression should be accompanied with a morphological outline worsening. Nevertheless the non constant expression of these indicators and the absent expression of proliferated indicators can explain the scant tendency to the relapse in presence of accurate curettage. It is important to remember that the cellular polymorphism typical of the cartilaginous tumours does not allow the application of an only oncogenesis model.

Role of many body shake-up in core-valence-valence electron emission from single wall carbon nanotubes.

Auger core-valence-valence transitions from single wall Carbon nanotubes are studied using a tight-binding calculational scheme with nearest neighbor overlap, hopping interactions, and a double-zeta basis set. The resulting Hamiltonian approximates the unperturbed pi and sigma bands of the nanomaterials coupled with the free electron states outside the solid and the core-hole. As a first step, the Fermi's golden rule is applied to determine the so called one-electron spectrum of emitted electrons from different tubes, in which either the neutralizing or the ejected electrons, in the initial state, lie within nearest neighboring atomic sites to the core-hole. Many-body corrections are effectively modeled using a broadening function, which accounts for dynamic screening effects involving the initial and final states. Particular attention is paid to the asymmetric component of the broadening function, responsible for the shake-up of pi electrons. Finally, the Cini-Sawatzky distortion function is used to describe the final state effect of the hole-hole interaction. A quantitative estimation of the interplay of shake-up processes is proposed by adjusting the asymmetric parameters of the broadening function to reproduce measurements of Auger electrons ejected from bundles of single wall Carbon nanotubes.

A closer look to the new frontier of artificial intelligence in the percutaneous treatment of primary lesions of the liver.

The purpose of thermal ablation is induction of tumor death by means of localized hyperthermia resulting in irreversible cellular damage. Ablative therapies are well-recognized treatment modalities for HCC lesions and are considered standard of care for HCC nodules < 3 cm in diameter in patients not suitable for surgery. Effective lesion treatment rely on complete target volume ablation. Technical limitations are represented by large (> 3 cm) or multicentric nodules as well as complex nodule location and poor lesion conspicuity. Artificial Intelligence (AI) is a general term referred to computational algorithms that can analyze data and perform complex tasks otherwise prerogative of Human Intelligence. AI has a variety of application in percutaneous ablation procedures such as Navigational software, Fusion Imaging, and robot-assisted ablation tools. Those instruments represent relative innovations in the field of Interventional Oncology and promising strategies to overcome actual limitations of ablative therapy in order to increase feasibility and technical results. This work aims to review the principal application of Artificial Intelligence in the percutaneous ablation of primary lesions of the liver with special focus on how AI can impact in the treatment of HCC especially on potential advantages on the drawbacks of the conventional technique.

Maintenance of the differentiated state in skeletal muscle: activation of v-Src disrupts sarcomeres in quail myotubes.

We have used quail skeletal myotubes expressing a temperature-sensitive allele of the v-src oncogene to address the issue of the homeostasis of sarcomeric myofibrils in differentiated muscle cells. Reactivation of the v-Src tyrosine kinase by shifting the cultures to the permissive temperature leads within minutes to the formation of F-actin-containing bodies (ABs), that originate in the ventral region of the myotubes and increase in number concomitantly with the dismantling of the I-Z-I complex of the sarcomeres. This process is detailed by confocal and electron microscopy. Indirect immunofluorescence reveals that ABs contain muscle-specific protein isoforms associated with the I-Z-I complexes and vinculin, a component of the cytoskeletal network. Anti-phosphotyrosine antibodies label proteins in ABs and Z-discs. Evidence is presented indicating that this phenomenon specifically depends on the persistent activation of v-Src, rather than on a general increase in phosphotyrosine content such as that induced by vanadate. AB formation is prevented by activation of protein kinase C by phorbol ester or by treatment with the kinase inhibitor 2-aminopurine, without any detectable effect on tyrosine phosphorylation. Taken together these findings indicate that phosphorylation of specific target proteins by v-Src, although necessary, is not sufficient per se to induce AB formation. In addition, the signal transduction cascade that culminates in MAP kinase activation and its nuclear translocation is activated both by v-Src and phorbol ester, and is relatively unaffected by 2-aminopurine. These findings imply that both phorbol esters and 2-aminopurine operate, at least in part, at the level of alternative pathways that may diverge upstream of the MAP kinase and are presumably mediating the early effects of v-Src on the differentiated phenotype.

A systematic review and Meta-analysis on the association between Hand-Foot Syndrome (HFS) and Cancer Chemotherapy Efficacy.

Hand-foot syndrome (HFS) is a common skin toxicity of traditional chemotherapies. Some studies showed that HFS has an association with progression-free survival (PFS) and the overall survival (OS). So far, there is not available any systematic literature reviews or meta-analysis aimed to assess the associations between HFS, PFS and OS. For this reason, this study aims to quantitatively summarize, critically review, and interpret the recent literature related to the associations between HFS and efficacy of chemotherapy in terms of PFS and OS. Queries shaped by PICOM framework, a systematic search of three electronic databases (PubMed, Scopus, and Science Direct) was carried out for the period between January 2010 and December 2017. Quantitative data pooling was based on the calculation of Hazard Ratio (HR) with 95% Confidence Interval (95% CI) for the OS and PFS associated to the presence of HFS, through the data of original publications. Five papers were included in this systematic review for the quantitative data pooling. Patients with HFS showed improved PFS (HR = 0.532 [0.431-0.656]; p = 0.000) and improved OS (HR = 0.522 [0.427-0.638]; p = 0.000). HFS causes a reduction of compliance with oncology treatments. Healthcare providers should use this result as a trigger to foster patients' coping and the one of their family caregivers, enhancing their adherence to cancer treatments.

Vitamin K and D association stimulates in vitro osteoblast differentiation of fracture site derived human mesenchymal stem cells.

There is growing interest in osteoinductive agents for fracture healing especially in patients with non-union or delayed-union fractures. The aim of the present study is the assessment of the association of Vitamins D3 and K1 on proliferation and differentiation of human mesenchymal stem cells (hMSCs) derived from fracture sites in view of a possible clinical use. The synergic effect of Vitamin D3 and Vitamin K2 in preventing osteoporosis has been documented in clinical practice; however no reports investigating this association for fracture healing are present. Our data show a different outcome on cell proliferation linked to the different timing of drug administration as well as a synergic effect of the two vitamins on cell differentiation. The high level of osteocalcin and carboxylated osteocalcin detected in hMSCs treated with the association of the two vitamins in comparison with controls and with single vitamin administration underline the differentiation of these cells into osteoblastic phenotype. Our results indicate for the first time that vitamin D3 and K1 association is able to modulate in vitro the differentiation towards osteoblastic phenotype of hMSCs derived from fracture sites, thus offering clinicians a promising and low-cost strategy for reparative osteogenesis.

Transcription of muscle-specific genes is repressed by reactivation of pp60v-src in postmitotic quail myotubes.

Quail myogenic cells infected with temperature sensitive (ts) mutants of Rous sarcoma virus (RSV) exhibit a temperature-dependent transformation and block of differentiation. When the cells are allowed to differentiate at the restrictive temperature (41 degrees C) and then shifted back to the permissive temperature (35 degrees C), a sharp reduction in the accumulation of muscle-specific mRNAs is observed, following reactivation of the transforming protein pp60v-src. A kinetic analysis of this down-regulation reveals that the reduction in the accumulation of muscle-specific transcripts occurs fairly rapidly within 6 to 20 h after the shift back, depending on the mRNA analyzed. Studies on transcription of endogenous muscle-specific genes and a transfected chloramphenicol acetyltransferase reporter gene under the control of muscle-specific promoters, at the different temperatures, suggest that the oncogene exerts its control mainly at the transcriptional level. On the contrary, transcription of the CMD1 gene, the avian homolog of the mouse muscle regulatory MyoD gene, is not significantly affected by the oncogene both in proliferating myoblasts and in myotubes shifted back to 35 degrees C. These findings are consistent with the conclusion that v-src blocks myogenesis by controlling transcription of muscle-specific genes independently of cell proliferation. Furthermore, they suggest the existence of an alternative pathway, not requiring the silencing of CMD1 transcription, through which the oncogene exerts its effect.

Distinct effects of Rac1 on differentiation of primary avian myoblasts.

Rho family GTPases have been implicated in the regulation of the actin cytoskeleton in response to extracellular cues and in the transduction of signals from the membrane to the nucleus. Their role in development and cell differentiation, however, is little understood. Here we show that the transient expression of constitutively active Rac1 and Cdc42 in unestablished avian myoblasts is sufficient to cause inhibition of myogenin expression and block of the transition to the myocyte compartment, whereas activated RhoA affects myogenic differentiation only marginally. Activation of c-Jun N-terminal kinase (JNK) appears not to be essential for block of differentiation because, although Rac1 and Cdc42 GTPases modestly activate JNK in quail myoblasts, a Rac1 mutant defective for JNK activation can still inhibit myogenic differentiation. Stable expression of active Rac1, attained by infection with a recombinant retrovirus, is permissive for terminal differentiation, but the resulting myotubes accumulate severely reduced levels of muscle-specific proteins. This inhibition is the consequence of posttranscriptional events and suggests the presence of a novel level of regulation of myogenesis. We also show that myotubes expressing constitutively active Rac1 fail to assemble ordered sarcomeres. Conversely, a dominant-negative Rac1 variant accelerates sarcomere maturation and inhibits v-Src-induced selective disassembly of I-Z-I complexes. Collectively, our findings provide a role for Rac1 during skeletal muscle differentiation and strongly suggest that Rac1 is required downstream of v-Src in the signaling pathways responsible for the dismantling of tissue-specific supramolecular structures.

MicroRNA-222 regulates muscle alternative splicing through Rbm24 during differentiation of skeletal muscle cells.

A number of microRNAs have been shown to regulate skeletal muscle development and differentiation. MicroRNA-222 is downregulated during myogenic differentiation and its overexpression leads to alteration of muscle differentiation process and specialized structures. By using RNA-induced silencing complex (RISC) pulldown followed by RNA sequencing, combined with in silico microRNA target prediction, we have identified two new targets of microRNA-222 involved in the regulation of myogenic differentiation, Ahnak and Rbm24. Specifically, the RNA-binding protein Rbm24 is a major regulator of muscle-specific alternative splicing and its downregulation by microRNA-222 results in defective exon inclusion impairing the production of muscle-specific isoforms of Coro6, Fxr1 and NACA transcripts. Reconstitution of normal levels of Rbm24 in cells overexpressing microRNA-222 rescues muscle-specific splicing. In conclusion, we have identified a new function of microRNA-222 leading to alteration of myogenic differentiation at the level of alternative splicing, and we provide evidence that this effect is mediated by Rbm24 protein.

Transformation of NIH3T3 cells by Rous sarcoma virus occurs with high efficiency in the absence of proviral rearrangements or amplification.

NIH3T3 cells could be transformed by a mammaltropic strain of Rous sarcoma virus (RSV) with an efficiency 10(3) times greater than that observed in Balb/c 3T3 cells or other mammalian cell lines and almost identical to that of chick embryo fibroblasts. In infected NIH3T3 cells a single, properly integrated, provirus was sufficient to induce focus formation; moreover, kinase activity of pp60v-src and tyrosine phosphorylation of cellular proteins could be detected very soon after infection in the majority of cells. On the other hand, in transformed foci from RSV-infected Balb/c 3T3 cells both rearrangements and amplification of proviral sequences were frequently detected. Accordingly, expression of pp60v-src and ensuing tyrosine phosphorylation of cellular proteins occurred, at high levels, only in a minority of the infected cells. Furthermore, by using a murine retrovirus carrying the v-src oncogene and an independent selectable marker, we found that Balb/c 3T3 cells were transformed with a 100-fold lower efficiency than NIH3T3 cells, yet the majority of infected untransformed Balb/c 3T3 cells expressed active pp60v-src. These findings are consistent with the existence in most mammalian cell lines of a major restriction to v-src-induced transformation, operating at the level of proviral expression, that is apparently absent in NIH3T3 cells.

Differential influence of adjacent normal cells on the proliferation of mammalian cells transformed by the viral oncogenes myc, ras and src.

We investigated the role of adjacent normal cells in the modulation of focal outgrowth of mammalian fibroblasts transformed by different viral oncogenes (myc, src and ras). NIH3T3 cells transformed by these three oncogenes were derived by transfection or infection and showed comparable cloning efficiencies in semi-solid medium. However, upon replating in liquid medium a small number of transformed cells together with a vast excess of normal mouse embryo fibroblasts C3H10T1/2, ras- and src-transformed cells were able to overgrow the monolayer and formed distinct foci, whereas myc-transformed cells lacked this ability. Conditioned medium from normal cells did not affect the proliferation of myc-transformed cells at clonal density. Addition of phorbol ester tumour promoters, either at the time of plating or as late as after one week, efficiently rescued focus formation by myc-transformed cells. In contrast, when myc-transformed cells were cultivated alone, their clone size and cloning efficiency were slightly reduced by the addition of tumour promoters. These results indicate that cell-cell contacts between transformed cells and adjacent normal cells specifically inhibit the growth of myc- but not of ras- or src-transformed cells. The ability of tumour promoters and phospholipase-C to rescue the focus forming ability of myc-transformed cells is consistent with the possibility that activation of protein-kinase C is involved in the clonal expansion of 'suppressed' myc-bearing cells.

Regulation of the tyrosine kinase substrate Eps8 expression by growth factors, v-Src and terminal differentiation.

SH3-containing proteins are involved in signal transduction by a number of growth factor receptors and in the organization of the cytoskeleton. The recently identified Eps8 protein, which contains an SH3 domain, is coupled functionally and physically to the EGFR and is tyrosine phosphorylated by this receptor and other receptors as well. Here, we examined the regulation of eps8 expression in response to mitogenic or differentiative signals. We show that Eps8 is expressed at low levels in resting fibroblasts, but its expression is strongly induced during activation by serum, phorbol esters and the v-src oncogene. Conversely, expression of Eps8, but not of other EGFR substrates such as Shc or Eps15, is virtually extinguished in non-proliferating, terminally differentiated murine myogenic cells. The putative role of Eps8 protein as a v-Src substrate was analysed in murine fibroblasts and in quail myogenic cells expressing a temperature-sensitive variant of the tyrosine kinase. Tyrosine phosphorylation of Eps8 was detected only at the permissive temperature. A non-myristylated, transformation-defective mutant of v-Src did not phosphorylate Eps8, whereas it phosphorylated Shc. Together, these findings indicate that Eps8 may be a critical substrate of v-Src. They further establish Eps8 as an example of a signal transducer whose expression senses the balance between growth and differentiation and might, therefore, be involved in the determination of the phenotype.

Induction of telomerase activity in v-myc-transformed avian cells.

Telomerase activity is detectable in the majority of tumors or immortalized cell lines, but is repressed in most normal human somatic cells. It is generally assumed that reactivation of telomerase prevents the erosion of chromosome ends which occurs in cycling cells and, hence, hinders cellular replicative senescence. Here, we show that the expression of v-Myc oncoprotein by retroviral infection of telomerase-negative embryonal quail myoblasts and chicken neuroretina cells is sufficient for reactivating telomerase activity, earlier than telomere shortening could occur. Furthermore, the use of a conditional v-Myc-estrogen receptor protein (v-MycER) causes estrogen-dependent expression of detectable levels of telomerase activity in recently infected chick embryo fibroblasts and neuroretina cells. We conclude that the high levels of telomerase activity in v-Myc-expressing avian cells are not the mere consequence of transformation or of a differentiative block, since v-Src tyrosine kinase, which prevents terminal differentiation and promotes cell transformation, fails to induce telomerase activity.

Epidemiology of multiple sclerosis: results from a large observational study in the UK.

Multiple sclerosis (MS) progression to mortality may not be solely determined by the underlying autoimmune process. We conducted a study in a large cohort of MS patients with the aim of describing characteristics of MS patients and identification of predictors for all-cause mortality in this patient group. We performed a retrospective analysis of primary care data from the UK Clinical Practice Research Datalink. Incident MS cases diagnosed between 1993 and 2006 were identified and validated using electronic and original medical records. Patients were followed to identify deaths; hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional regression with age as time-scale. In total, 1713 incident MS cases were identified. Following MS diagnosis, frequent comorbidities were infections (80%), and depression (46%). Adjusted HRs (95% CIs) for all-cause mortality were: 2.0 (1.2-3.4) for current smoking; 7.6 (3.2-17.7) for alcohol abuse; 2.7 (1.6-4.5) for pneumonia and influenza; 4.1 (2.7-6.3) for urinary tract infections; 2.2 (1.2-4.2) for heart disease and 4.9 (2.9-8.0) for cancer. Our results suggest that MS survival is influenced not only by the underlying autoimmune process, but also by patient comorbidities and lifestyle factors.

A human monoclonal autoantibody isolated from a patient with infectious mononucleosis reactive with both self antigens and Epstein-Barr virus nuclear antigen (EBNA).

In order to investigate the mechanism(s) by which Epstein-Barr virus (EBV) induces the outcome of autoantibodies during infectious mononucleosis (IM), a human IgM (k) monoclonal antibody to cytoskeletal filaments of epithelial cells has been prepared by EBV transformation of peripheral blood B lymphocytes obtained from a patient with IM. The antibody was also found to react with smooth muscle of frozen sections of human stomach tissue by immunofluorescence, and with the Epstein-Barr nuclear antigen (EBNA) by an enzyme-linked immunosorbent assay. These findings demonstrate at the clonal level the epitope homology between host's cell antigens and EBV-encoded nuclear antigen, which might have relevance in EBV-induced autoimmunity.

Antibodies to histones in infectious mononucleosis.

A polyspecific human monoclonal (auto)antibody, isolated from a patient in the acute phase of infectious mononucleosis, was found to react with all subfractions (H1, H2A, H2B, H3 and H4) of histones. This finding prompted us to study the occurrence of antibodies to histones in sera of patients with infectious mononucleosis. It was found that IgM binding to histones was detectable both in control and patient sera; however, sera from patients showed binding values of IgM antibodies to histones significantly higher than those of healthy controls; moreover, both in control and patient groups anti-histone IgM activity was found to correlate with serum IgM concentration. These findings suggest that anti-histone IgM antibodies belong to the class of antibodies defined as "natural antibodies" and that their increase during infectious mononucleosis is due to Epstein-Barr virus-induced polyclonal B cell activation.

Epstein-Barr virus-transformed human B lymphocytes produce natural antibodies to histones.

To study the mechanism(s) responsible for the appearance of Epstein-Barr virus (EBV)-induced anti-histone autoantibodies, peripheral blood B lymphocytes from healthy donors were infected with EBV and the resulting lymphoblastoid cell lines were tested for secretion of antibodies reacting with histones. It was found that EBV-transformed cells produce IgM antibody reactive with histones and that the frequency of EBV-inducible circulating B lymphocytes that produce antibodies to histones is at least 10(-5). Moreover, in cultures of tonsillar lymphoid cells, the enrichment in CD5+ B lymphocytes increases the percentage of EBV-transformed cultures making anti-histone IgM antibodies. EBV may therefore, also in vivo, induce natural anti-histone antibody by polyclonal B-cell activation without any requirement of antigen to trigger antibody response.

Detection of an idiotope on a human monoclonal autoantibody by monoclonal anti-idiotypic antibody and its relationship to Epstein-Barr virus-induced autoimmunity.

We have recently described a human IgM monoclonal antibody (mAb), reactive with both self antigens, i.e., cytoskeleton filaments and smooth muscle, and Epstein-Barr virus (EBV)-induced nuclear antigen (EBNA), produced by EBV-transformed B lymphocytes isolated from a patient with infectious mononucleosis (IM). In order to achieve higher antibody secretion in culture supernatant, the mAb-producer cells were fused with ouabain-resistant mouse myeloma cells and a stable human-mouse heterohybrid, coded HY 5488, producing up to 80 micrograms/ml IgM mAb, was isolated after 4 cloning procedures. Purified HY 5844 mAb was used to immunize mice for the production of a murine anti-idiotypic mAb, which was used to probe the expression of the idiotope of HY 5488 mAb (Id 5488) in sera of IM patients and normal controls by ELISA. It was found that Id 5488 is expressed both in IM patients and normal controls, and that Id 5488 expression is significantly higher in IM patients' sera; furthermore, in IM sera a statistically significant correlation between Id 5488 expression and anti-cytoskeleton and anti-smooth muscle autoantibodies was found. It is suggested that at least part of EBV-induced IgM autoantibodies appearing during IM are secreted by B lymphocytes programmed to the production of "natural antibodies" bearing Id 5488-like idiotopes.