Observation of mesoscopic conductance fluctuations in YBaCuO grain boundary Josephson Junctions

Magneto-fluctuations of the normal resistance R_N have been reproducibly observed in high critical temp erature superconductor (HTS) grain boundary junctions, at low temperatures. We attribute them to mesoscopic transport in narrow channels across the grain boundary line. The Thouless energy appears to be the relevant energy scale. Our findings have significant implications on quasiparticle relaxation and coherent transport in HTS grain boundaries.Comment: Revised version, minor changes. 4 pages, 4 figure

Mesoscopic conductance fluctuations in YBa2_2Cu3_3O7−δ_{7-\delta} grain boundary Junction at low temperature

The magneto-conductance in YBCO grain boundary Josephson junctions, displays fluctuations at low temperatures of mesoscopic origin. The morphology of the junction suggests that transport occurs in narrow channels across the grain boundary line, with a large Thouless energy. Nevertheless the measured fluctuation amplitude decreases quite slowly when increasing the voltage up to values about twenty times the Thouless energy, of the order of the nominal superconducting gap. Our findings show the coexistence of supercurrent and quasiparticle current in the junction conduction even at high nonequilibrium conditions. Model calculations confirm the reduced role of quasiparticle relaxation at temperatures up to 3 Kelvin.Comment: 11 pages, 5 figures, accepted with minor changes in Phys.Rev.

Immunotherapy of brain metastases: breaking a "dogma"

Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases. Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events. Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting

Identification of subgroups of early breast cancer patients at high risk of nonadherence to adjuvant hormone therapy: results of an italian survey.

The aim of this study was the identification of subgroups of patients at higher risk of nonadherence to adjuvant hormone therapy for breast cancer. Using recursive partitioning and amalgamation (RECPAM) analysis, the highest risk was observed in the group of unmarried, employed women, or housewives. This result might be functional in designing tailored intervention studies aimed at improvement of adherence. Background: Adherence to adjuvant endocrine therapy (HT) is suboptimal among breast cancer patients. A high rate of nonadherence might explain differences in survival between clinical trial and clinical practice. Tailored interventions aimed at improving adherence can only be implemented if subgroups of patients at higher risk of poor adherence are identified. Because no data are available for Italy, we undertook a large survey on adherence among women taking adjuvant HT for breast cancer. Patients and Methods: Patients were recruited from 10 cancer clinics in central Italy. All patients taking HT for at least 1 year were invited, during one of their follow-up visit, to fill a confidential questionnaire. The association of sociodemographic and clinical characteristics of participants with adherence was assessed using logistic regression. The RECPAM method was used to evaluate interactions among variables and to identify subgroups of patients at different risk of nonadherence. Results: A total of 939 patients joined the study and 18.6% of them were classified as nonadherers. Among possible predictors, only age, working status, and switching from tamoxifen to an aromatase inhibitor were predictive of nonadherence in multivariate analysis. RECPAM analysis led to the identification of 4 classes of patients with a different likelihood of nonadherence to therapy, the lowest being observed in retired women with a low level of education, the highest in the group of unmarried, employed women, or housewives. Conclusion: The identification of these subgroups of “real life” patients with a high prevalence of nonadherers might be functional in designing intervention studies aimed at improving adherenc

Coherent quasiparticle transport in grain boundary junctions employing high-Tc superconductors

Magneto-fluctuations of the normal resistance RN have been reproducibly observed in YBa2Cu3O7-d biepitaxial grain boundary junctions at low temperatures. We attribute them to mesoscopic transport in narrow channels across the grain boundary line, occurring in an unusual energy regime. The Thouless energy appears to be the relevant energy scale. Possible implications on the understanding of coherent transport of quasiparticles in HTS and of the dissipation mechanisms are discussed.Comment: Submitted on behalf of TIMA Editions (http://irevues.inist.fr/tima-editions

Coherent quasiparticle transport in grain boundary junctions employing high-Tc superconductors

mesoscopic physics, nanodevices, high critical temperature superconductorsMagneto-fluctuations of the normal resistance RN have been reproducibly observed in YBa2Cu3O7-ä biepitaxial grain boundary junctions at low temperatures. We attribute them to mesoscopic transport in narrow channels across the grain boundary line, occurring in an unusual energy regime. The Thouless energy appears to be the relevant energy scale. Possible implications on the understanding of coherent transport of quasiparticles in HTS and of the dissipation mechanisms are discussed

Current Methods to Unravel the Functional Properties of Lysosomal Ion Channels and Transporters

open18siA distinct set of channels and transporters regulates the ion fluxes across the lysosomal membrane. Malfunctioning of these transport proteins and the resulting ionic imbalance is involved in various human diseases, such as lysosomal storage disorders, cancer, as well as metabolic and neurodegenerative diseases. As a consequence, these proteins have stimulated strong interest for their suitability as possible drug targets. A detailed functional characterization of many lysosomal channels and transporters is lacking, mainly due to technical difficulties in applying the standard patch-clamp technique to these small intracellular compartments. In this review, we focus on current methods used to unravel the functional properties of lysosomal ion channels and transporters, stressing their advantages and disadvantages and evaluating their fields of applicability.openFesta M.; Minicozzi V.; Boccaccio A.; Lagostena L.; Gradogna A.; Qi T.; Costa A.; Larisch N.; Hamamoto S.; Pedrazzini E.; Milenkovic S.; Scholz-Starke J.; Ceccarelli M.; Vitale A.; Dietrich P.; Uozumi N.; Gambale F.; Carpaneto A.Festa, M.; Minicozzi, V.; Boccaccio, A.; Lagostena, L.; Gradogna, A.; Qi, T.; Costa, A.; Larisch, N.; Hamamoto, S.; Pedrazzini, E.; Milenkovic, S.; Scholz-Starke, J.; Ceccarelli, M.; Vitale, A.; Dietrich, P.; Uozumi, N.; Gambale, F.; Carpaneto, A

No impact of NRAS mutation on features of primary and metastatic melanoma or on outcomes of checkpoint inhibitor immunotherapy: An italian melanoma intergroup (IMI) study

Neuroblastoma RAS Viral Oncogen Homolog (NRAS) mutant melanoma is usually considered more aggressive and more responsive to checkpoint inhibitor immunotherapy (CII) than NRAS wildtype. We retrospectively recruited 331 metastatic melanoma patients treated with CII as first line: 162 NRAS-mutant/BRAF wild-type and 169 wt/wt. No substantial differences were observed among the two cohorts regarding the melanoma onset and disease-free interval. Also, overall response to CII, progression-free survival and overall survival were similar in the two groups. Therefore, our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant melanoma. The controversy in the published data could be due to different patient characteristics and treatment heterogeneity. We believe our data adds evidence to clear up these controversial issues. Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7-18) versus 9 months (95% CI, 6-16) and 32 (95% CI, 23-49) versus 27 months (95% CI, 16-35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM

PIEZO1-R1864H rare variant accounts for a genetic phenotype-modifier role in dehydrated hereditary stomatocytosis.

phenotype-modifier role in dehydrated hereditary stomatocytosis Dehydrated hereditary stomatocytosis (DHS) is an autosomal dominant hereditary hemolytic anemia characterized by erythrocyte dehydration due to loss of the cation content. Affected subjects exhibit highly variable clinical presentation, ranging from absence of clinical symptoms to lethal perinatal edema. They may present severe iron overload leading to hepatic transplantation, or life-threatening thromboembolic disease after splenectomy, thus making the diagnosis of this condition problematic.1 DHS results in two different forms: i) DHS1, the most frequent, is caused by mutations in PIEZO1, encoding a cation selective channel activated by mechanical force; ii) DHS2 due to an altered KCNN4 gene, encoding a Ca2+-sensitive (Gardos) channel.2-4 In particular, PIEZO1 is a large and highly polymorphic gene. Several electrophysiology studies demonstrated that the mutations cause a gain-of-function phenotype with delayed inactivation of the channel.5-10 We studied 7 DHS patients from two unrelated families (A-B) showing highly variable clinical expressivity and carrying the same new PIEZO1 mutation. We demonstrated that the presence of an additional de novo PIEZO1 rare missense variant in one of the 2 probands accounts for a more severe phenotype