Structural Properties of the Disordered Spherical and other Mean Field Spin Models

We extend the approach of Aizenman, Sims and Starr for the SK-type models to their spherical versions. Such an extension has already been performed for diluted spin glasses. The factorization property of the optimal structures found by Guerra for the SK model, which holds for diluted models as well, is verified also in the case of spherical systems, with the due modifications. Hence we show that there are some common structural features in various mean field spin models. These similarities seem to be quite paradigmatic, and we summarize the various techniques typically used to prove the structural analogies and to tackle the computation of the free energy per spin in the thermodynamic limit.Comment: 24 page

Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered

Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration

Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC box). HDACi, on the other hand, modulate the activity of class I and II histone deacetylases. They mediate their protective function, in part, by regulating the acetylation status of histones or transcription factors, including Sp1, and in turn chromatin accessibility to the transcriptional machinery. Because these two classes of structurally and functionally diverse compounds mediate similar therapeutic functions, we investigated whether they act on redundant or synergistic pathways to protect neurons from oxidative death. Non-protective doses of each of the drugs do not synergize to create resistance to oxidative death suggesting that these distinct agents act via a similar pathway. Accordingly, we found that protection by MTM and HDACi is associated with diminished expression of the oncogene, Myc and enhanced expression of a tumor suppressor, p21waf1/cip1. We also find that neuroprotection by MTM or Myc knockdown is associated with downregulation of class I HDAC levels. Our results support a model in which the established antitumor drug MTM or canonical HDACi act via distinct mechanisms to converge on the downregulation of HDAC levels or activity respectively. These findings support the conclusion that an imbalance in histone acetylase and HDAC activity in favor of HDACs is key not only for oncogenic transformation, but also neurodegeneration

Dimensional Crossover in the Large N Limit

We consider dimensional crossover for an $O(N)$ Landau-Ginzburg-Wilson model on a $d$-dimensional film geometry of thickness $L$ in the large $N$-limit. We calculate the full universal crossover scaling forms for the free energy and the equation of state. We compare the results obtained using ``environmentally friendly'' renormalization with those found using a direct, non-renormalization group approach. A set of effective critical exponents are calculated and scaling laws for these exponents are shown to hold exactly, thereby yielding non-trivial relations between the various thermodynamic scaling functions.Comment: 25 pages of PlainTe

A new perturbative expansion of the time evolution operator associated with a quantum system

A novel expansion of the evolution operator associated with a -- in general, time-dependent -- perturbed quantum Hamiltonian is presented. It is shown that it has a wide range of possible realizations that can be fitted according to computational convenience or to satisfy specific requirements. As a remarkable example, the quantum Hamiltonian describing a laser-driven trapped ion is studied in detail.Comment: 32 pages; modified version with examples of my previous paper quant-ph/0404056; to appear on the J. of Optics B: Quantum and Semiclassical Optics, Special Issue on 'Optics and Squeeze Transformations after Einstein

Relaxation and overlap probability function in the spherical and mean spherical model

The problem of the equivalence of the spherical and mean spherical models, which has been thoroughly studied and understood in equilibrium, is considered anew from the dynamical point of view during the time evolution following a quench from above to below the critical temperature. It is found that there exists a crossover time $t^* \sim V^{2/d}$ such that for $t < t^*$ the two models are equivalent, while for $t > t^*$ macroscopic discrepancies arise. The relation between the off equilibrium response function and the structure of the equilibrium state, which usually holds for phase ordering systems, is found to hold for the spherical model but not for the mean spherical one. The latter model offers an explicit example of a system which is not stochastically stable.Comment: 11 pages, 1 figure, references corrected, to appear in Phys.Rev.

Condensation vs. phase-ordering in the dynamics of first order transitions

The origin of the non commutativity of the limits $t \to \infty$ and $N \to \infty$ in the dynamics of first order transitions is investigated. In the large-N model, i.e. $N \to \infty$ taken first, the low temperature phase is characterized by condensation of the large wave length fluctuations rather than by genuine phase-ordering as when $t \to \infty$ is taken first. A detailed study of the scaling properties of the structure factor in the large-N model is carried out for quenches above, at and below T_c. Preasymptotic scaling is found and crossover phenomena are related to the existence of components in the order parameter with different scaling properties. Implications for phase-ordering in realistic systems are discussed.Comment: 15 pages, 13 figures. To be published in Phys. Rev.

Polarised target for Drell-Yan experiment in COMPASS at CERN, part I

In the polarised Drell-Yan experiment at the COMPASS facility in CERN pion beam with momentum of 190 GeV/c and intensity about $10^8$ pions/s interacted with transversely polarised NH$_3$ target. Muon pairs produced in Drel-Yan process were detected. The measurement was done in 2015 as the 1st ever polarised Drell-Yan fixed target experiment. The hydrogen nuclei in the solid-state NH$_3$ were polarised by dynamic nuclear polarisation in 2.5 T field of large-acceptance superconducting magnet. Large helium dilution cryostat was used to cool the target down below 100 mK. Polarisation of hydrogen nuclei reached during the data taking was about 80 %. Two oppositely polarised target cells, each 55 cm long and 4 cm in diameter were used. Overview of COMPASS facility and the polarised target with emphasis on the dilution cryostat and magnet is given. Results of the polarisation measurement in the Drell-Yan run and overviews of the target material, cell and dynamic nuclear polarisation system are given in the part II.Comment: 4 pages, 2 figures, Proceedings of the 22nd International Spin Symposium, Urbana-Champaign, Illinois, USA, 25-30 September 201

The NMDA receptor activation by D-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle

Astrocytes express the 3-phosphoglycerate dehydrogenase (Phgdh) enzyme required for the synthesis of L-serine from glucose. Astrocytic L-serine was proposed to regulate NMDAR activity by shuttling to neurons to sustain D-serine production, but this hypothesis remains untested. We now report that inhibition of astrocytic Phgdh suppressed the de novo synthesis of L-and D-serine and reduced the NMDAR synaptic potentials and long-term potentiation (LTP) at the Schaffer collaterals-CA1 synapse. Likewise, enzymatic removal of extracellular L-serine impaired LTP, supporting an L-serine shuttle mechanism between glia and neurons in generating the NMDAR coagonist D-serine. Moreover, deletion of serine racemase (SR) in glutamatergic neurons abrogated D-serine synthesis to the same extent as Phgdh inhibition, suggesting that neurons are the predominant source of the newly synthesized D-serine. We also found that the synaptic NMDAR activation in adult SR-knockout (KO) mice requires Phgdh-derived glycine, despite the sharp decline in the postnatal glycine levels as a result of the emergence of the glycine cleavage system. Unexpectedly, we also discovered that glycine regulates D-serine metabolism by a dual mechanism. The first consists of tonic inhibition of SR by intracellular glycine observed in vitro, primary cultures, and in vivo microdialysis. The second involves a transient glycine-induce D-serine release through the Asc-1 transporter, an effect abolished in Asc-1 KO mice and diminished by deleting SR in glutamatergic neurons. Our observations suggest that glycine is a multifaceted regulator of D-serine metabolism and implicate both D-serine and glycine in mediating NMDAR synaptic activation at the mature hippocampus through a Phgdh-dependent shuttle mechanism