Superconductivity from a melted insulator

Quantum phase transitions typically result in a broadened critical or crossover region at nonzero temperature. Josephson arrays are a model of this phenomenon, exhibiting a superconductor-insulator transition at a critical wave impedance, and a well-understood insulating phase. Yet high-impedance arrays used in quantum computing and metrology apparently evade this transition, displaying superconducting behavior deep into the nominally insulating regime. The absence of critical behavior in such devices is not well understood. Here we show that, unlike the typical quantum-critical broadening scenario, in Josephson arrays temperature dramatically shifts the critical region. This shift leads to a regime of superconductivity at high temperature, arising from the melted zero-temperature insulator. Our results quantitatively explain the low-temperature onset of superconductivity in nominally insulating regimes, and the transition to the strongly insulating phase. We further present, to our knowledge, the first understanding of the onset of anomalous-metallic resistance saturation. This work demonstrates a non-trivial interplay between thermal effects and quantum criticality. A practical consequence is that, counterintuitively, the coherence of high-impedance quantum circuits is expected to be stabilized by thermal fluctuations.Comment: 8+18 pages, 4+15 figure

Current state of biology and diagnosis of clonal mast cell diseases in adults

[EN] Mastocytosis comprises a heterogeneous group of disorders characterized by the presence of clonal mast cells (MC) in organs such as skin, bone marrow (BM), and gastrointestinal tract, among other tissues. The clonal nature of the disease can be established in most adult patients by the demonstration of activating KIT mutations in their BM MC. When highly sensitive techniques capable of identifying cells present at very low frequencies in a sample are applied, BM MC from virtually all systemic mastocytosis patients display unique immunophenotypical features, particularly the aberrant expression of CD25. By contrast, large, multifocal BM MC aggregates (the only World Health Organization major criterion for systemic mastocytosis) are absent in a significant proportion of patients fulfilling at least three minor criteria for systemic mastocytosis, particularly in subjects studied at early stages of the disease with very low MC burden. Moreover, recent molecular and immunophenotypical investigations of BM MC from patients with indolent systemic mastocytosis have revealed a close association of some biological features (e.g., multilineage involvement of hematopoiesis by the KIT mutation and an immature mast cell immunophenotype) with an increased risk for disease progression. These observations support the fact that, although the current consensus diagnostic criteria for systemic mastocytosis have been a major advance for the diagnosis and classification of the disease, rationale usage of the most sensitive diagnostic techniques available nowadays is needed to improve the diagnosis, refine the classification, and reach objective prognostic stratification of adult mastocytosis

CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis

[Aims]: CD30 expression by bone marrow (BM) mast cells (MC) has been reported recently in systemic mastocytosis (SM) patients. The aim of this study was to investigate the potential diagnostic and prognostic value of CD30 expression in SM as assessed by multiparameter flow cytometry. [Methods and results]: A total of 163 consecutive BM samples corresponding to 142 SM patients and 21 non-mastocytosis cases were studied. CD30 was positive in most SM patients (80%), but in only one non-mastocytosis case (4.8%). When combined with CD25, CD30 contributed to an improved accuracy over that of CD25 alone (98% versus 93%) mainly because most (eight of nine) of the well-differentiated SM (WDSM), who lacked CD25, were CD30+. Similar levels of expression of CD30 were observed among all different subgroups of SM except mast cell leukaemia; among indolent SM (ISM) patients, no significant association was observed between the levels of CD30 expression and other clinical and biological features of the disease. [Conclusions]: The increased expression of CD30 associated with absence of CD25 contributes to the diagnosis of WDSM and its distinction from other subtypes of SM. By contrast, CD30 expression did not contribute either to prognostic stratification of ISM or to the differential diagnosis between ISM and aggressive SM cases.This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS) PI11/02399, PS09/00032 and RETICs RD09/0076/00133, RD09/0076/00074 and RD12/0036/0048 (FEDER) from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain; Fundacion Sociosanitaria de Castilla-La Mancha (2010/008 y G-2010/C-002); Fundación Espanola de Mastocitosis (FEM 2010); and by a grant from Fundaçao para a Ciência e Tecnologia (FCT) of Portugal (SFRH/BD/22972/2005).Peer Reviewe

Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis

[Background]: Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined. [Objective]: We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM. Methods Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied. [Results]: Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM. [Conclusions]: WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria.Supported by grants from Asociación Española de Mastocitosis, Madrid, Spain (grant AEDM 2014); Instituto de Salud Carlos III, FEDER, Ministry of Economy and Competitivity, Madrid, Spain (grant PI11/02399); Fundación Ramón Areces, Madrid, Spain (grant CIVP16A1806); and Novartis Farmacéutica, S.A., Spain. I. Alvarez-Twose has received research support from Novartis Farmacéutica, S.A., Spain. A. García-Montero has received research support from Fundacion Ramon Areces (grant no. CIVP16A1806) and ISCIII Ministerio de Economia y Competitividad (grant no. PI11/02399). A. Orfao has received research support from Fundacion Ramon Areces (grant no. CIVP16A1806).Peer Reviewe

Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM

Spanish Network on Mastocytosis (REMA): et al.[Background]: Indolent systemic mastocytosis (ISM) without skin lesions (ISMs-) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs+). Interestingly, in almost one-half of ISMs- patients, MC-mediator release episodes are triggered exclusively by insects. [Objective]: We aimed to determine the clinical and laboratory features of ISMs- associated with insect-induced anaphylaxis (insectISMs-) versus other patients with ISM. [Methods]: A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs-, 72 ISMs- triggered by other factors (otherISMs-), 56 ISMs+, and 64 nonclonal MC activation syndrome, were studied. [Results]: Compared with otherISMs- and ISMs+ patients, insectISMs- cases showed marked male predominance (78% vs 53% and 46%; P <.001), a distinct pattern of MC-related symptoms, and significantly lower median serum baseline tryptase levels (22.4 vs 28.7 and 45.8 μg/L; P ≤.009). Moreover, insectISMs- less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤.001), and they systematically showed MC-restricted KIT mutation. [Conclusions]: ISMs- patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs- and ISMs+ patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.Supported by Fondo de Investigaciones Sanitarias –FIS– of the Instituto de Salud Carlos III, Ministery of Economy and Competitivity, Madrid, Spain grant PS09/00032; Fundación Sociosanitaria de Castilla-La Mancha grants 2010/008 and G-2010/ C-002; Fundacióon Española de Mastocitosis grant FEM 2011; BioB-HVS is supported by grant RETICS (Redes Temáticas de Investigación Cooperativa en Salud) RD09/ 00760074 (Toledo, Spain); RTICC (Red Temática de Investigación Cooperativa en Cáncer) grants RD09/0076/00133, RD12/0036/0048; FIS; FEDER, Ministery of Economy and Competitivity, Madrid, Spain grant PI11/02399; and Fundación Ramón Areces, Madrid, Spain grant CIVP16A1806; and by Associazione Italiana Leucemie e Linfomi of Verona (AIL-Verona) and ASIMAS (Associazione Italiana Mastocitosi). L. Escribano has been supported by one or more grants from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Fundacion Sociosanitaria de Castilla La Mancha, and from FEM. A. García-Montero has been supported by one or more grants from ISCIII. M. Mollejo and A. Orfao have been supported by one or more grants from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad. L. Sánchez-Muñoz has been supported by one or more grants from Fundacion Sociosanitaria de Castilla La Mancha.Peer Reviewe

TP53, ATRX alterations, and low tumor mutation load feature IDH-wildtype giant cell glioblastoma despite exceptional ultra-mutated tumors

Background: Giant cell glioblastoma (gcGBM) is a rare morphological variant of IDH-wildtype (IDHwt) GBM that occurs in young adults and have a slightly better prognosis than "classic" IDHwt GBM. Methods: We studied 36 GBMs, 14 with a histopathological diagnosis of gcGBM and 22 with a giant cell component. We analyzed the genetic profile of the most frequently mutated genes in gliomas and assessed the tumor mutation load (TML) by gene-targeted next-generation sequencing. We validated our findings using The Cancer Genome Atlas (TCGA) data. Results: p53 was altered by gene mutation or protein overexpression in all cases, while driver IDH1, IDH2, BRAF, or H3F3A mutations were infrequent or absent. Compared to IDHwt GBMs, gcGBMs had a significant higher frequency of TP53, ATRX, RB1, and NF1 mutations, while lower frequency of EGFR amplification, CDKN2A deletion, and TERT promoter mutation. Almost all tumors had low TML values. The high TML observed in only 2 tumors was consistent with POLE and MSH2 mutations. In the histopathological review of TCGA IDHwt, TP53-mutant tumors identified giant cells in 37% of the cases. Considering our series and that of the TCGA, patients with TP53-mutant gcGBMs had better overall survival than those with TP53wt GBMs (log-rank test, P < .002). Conclusions: gcGBMs have molecular features that contrast to "classic" IDHwt GBMs: unusually frequent ATRX mutations and few EGFR amplifications and CDKN2A deletions, especially in tumors with a high number of giant cells. TML is frequently low, although exceptional high TML suggests a potential for immune checkpoint therapy in some cases, which may be relevant for personalized medicine

Complete response to gemtuzumab ozogamicin in a patient with refractory mast cell leukemia

Mast cell (MC) leukemia (MCL) is a subtype of systemic mastocytosis (SM) defined by the World Health Organization as ⩾ 20% of MCs in the bone marrow (BM) aspirate, with (leukemic variant) or without (aleukemic variant) ⩾ 10% of MCs in peripheral blood (PB). The European/American Consensus Group on Mastocytosis has recently proposed a new subclassification of MCL that distinguishes acute vs chronic MCL based on the presence vs absence of organ damage, respectively.Peer Reviewe

A singlet triplet hole spin qubit in planar Ge

Spin qubits are considered to be among the most promising candidates for building a quantum processor. GroupIV hole spin qubits have moved into the focus of interest due to the ease of operation and compatibility with Si technology. In addition, Ge offers the option for monolithic superconductor-semiconductor integration. Here we demonstrate a hole spin qubit operating at fields below 10 mT, the critical field of Al, by exploiting the large out-of-plane hole g-factors in planar Ge and by encoding the qubit into the singlet-triplet states of a double quantum dot. We observe electrically controlled g-factor-difference-driven and exchange-driven rotations with tunable frequencies exceeding 100 MHz and dephasing times of 1 $\mu$s which we extend beyond 150 $\mu$s with echo techniques. These results demonstrate that Ge hole singlet-triplet qubits are competing with state-of-the art GaAs and Si singlet-triplet qubits. In addition, their rotation frequencies and coherence are on par with Ge single spin qubits, but they can be operated at much lower fields underlining their potential for on chip integration with superconducting technologies

Chronic lymphocytic leukemia cells in lymph nodes show frequent NOTCH1 activation

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. Pathogenic mechanisms involve multiple external events (such as microenvironmental and antigenic stimuli) and internal events (genetic and epigenetic alterations) that are associated with the transformation, progression and evolution of CLL. CLL is characterized by an accumulation of mature B cells in peripheral blood, bone marrow and lymphoid tissues. Extracellular stimuli play an important role in the development and maintenance of neoplastic cells. B-CLL cells proliferate and activate pathogenic signaling pathways in anatomical structures known as proliferation centers, which are usually more conspicuous in involved lymph nodes.1 Its clinical course is quite heterogeneous, whereby some patients progress rapidly and have short survival, whereas others have a more stable clinical course that may not need treatment for years.This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO) (SAF2013-47416-R) Instituto de Salud Carlos III (ISCIII)- FEDER – MINECO- AES (CP11/00018, PI10/00621, RD012/0036/0060), and Asociación Española contra el Cancer (AECC). MS-B is supported by a Miguel Servet contract from ISCIII-FEDER (CP11/00018). Salary support to SG is provided by CP11/00018, from ISCIII-FEDER. JG-R is supported by a predoctoral grant from the Fundación Investigación Puerta de Hierro.S

Stratifying diffuse large B-cell lymphoma patients treated with chemoimmunotherapy: GCB/non-GCB by immunohistochemistry is still a robust and feasible marker

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches