Disease Recurrence during Adjuvant Immune Checkpoint Inhibitor Treatment in Metastatic Melanoma: Clinical,Laboratory, and Radiological Characteristics in Patients from a Single Tertiary Referral Center

Despite the dramatic improvements in recurrence-free survival in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICI), a number of patients develop metastases during adjuvant therapy. It is not currently possible to predict which patients are most likely to develop disease recurrence due to a lack of reliable biomarkers. Thus, we retrospectively analyzed the case records of all patients who commenced adjuvant ICI therapy between January 2018 and December 2021 in a single university skin cancer center (n = 46) (i) to determine the rates of disease recurrence, (ii) to examine the utility of established markers, and (iii) to examine whether re-challenge with immunotherapy resulted in clinical response. Twelve out of forty-six (26%) patients developed a relapse on adjuvant immunotherapy in our cohort, and the median time to relapse was 139 days. Adjuvant immunotherapy was continued in three patients. Of the twelve patients who developed recurrence during adjuvant immunotherapy, seven had further disease recurrence within the observation period, with a median time of 112 days after the first progress. There was no significant difference comparing early recurrence (<180 days after initiation) on adjuvant immunotherapy to late recurrence (>180 days after initiation) on adjuvant immunotherapy. Classical tumor markers, including serum lactate dehydrogenase (LDH) and S-100, were unreliable for the detection of disease recurrence. Baseline lymphocyte and eosinophil counts and those during immunotherapy were not associated with disease recurrence. Interestingly, patients with NRAS mutations were disproportionately represented (60%) in the patients who developed disease recurrence, suggesting that these patients should be closely monitored during adjuvant therapy.     

Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization

Tropomyosin receptor kinase A (TrkA/NTRK1) is a high-affinity receptor for nerve growth factor (NGF), a potent pain mediator. NGF/TrkA signaling elevates synovial sensory neuronal distributions in the joints and causes osteoarthritis (OA) pain. We investigated the mechanisms of pain transmission as to whether peripheral sensory neurons are linked to the cellular plasticity in the dorsal root ganglia (DRG) and are critical for OA hyperalgesia. Sensory neuron-specific deletion of TrkA was achieved by tamoxifen injection in 4-week-old TrkA^fl/fl;Na_V1.8^CreERT2 (Ntrk1 ^fl/fl;Scn10a^CreERT2) mice. OA was induced by partial medial meniscectomy (PMM) in 12-week-old mice, and OA-pain-related behavior was analyzed for 12 weeks followed by comprehensive histopathological examinations. OA-associated joint pain was markedly improved without cartilage protection in sensory-neuron-specific conditional TrkA knock-out (cKO) mice. Alleviated hyperalgesia was associated with suppression of the NGF/TrkA pathway and reduced angiogenesis in fibroblast-like synovial cells. Elevated pain transmitters in the DRG of OA-induced mice were significantly diminished in sensory-neuron-specific TrkA cKO and global TrkA cKO mice. Spinal glial activity and brain-derived neurotropic factor (BDNF) were significantly increased in OA-induced mice but were substantially eliminated by sensory-neuron-specific deletion. Our results suggest that augmentation of NGF/TrkA signaling in the joint synovium and the peripheral sensory neurons facilitate pro-nociception and centralized pain sensitization.     

A Spin Resonance Investigation of Magnetism and Dynamics in the Charge-transfer Salts β"-(BEDT-TTF)4[(H3O)M(C2O4)3]S

We report a spin resonance study of the family of quasi-two-dimensional organic (super)conductors β”-(BEDT-TTF)₄[(H₃O)M(C₂O₄)₃]S, where M is a 3d transition metal ion and S is a host solvent molecule. The spin systems for M = Cr³⁺ (S = 3/2) and M = Fe³⁺ (S = 5/2) are investigated by means of both resonant and field modulation techniques in the frequency range between 50 and 313 GHz. The role of the different solvent molecules in determining the degree of spin-orbit coupling and the local symmetry at the metal ion site is established. The low temperature behaviour of intensities, positions and widths of the resonant lines shows significant modifications of the spin-orbit coupling, and of the inter-and intra-ionic spin-spin inter actions. Despite the onset of a weak antiferromagnetic internal field at low temperature, the ultimate narrowing of the lines suggests spin-lattice interactions may still be the dominant relaxation process. Diamagnetic screening in the mixed state of the superconducting samples for fields parallel to the quasi-two-dimensional layers induces additional lineshifts only below B = 2.5T and T = 4K, determining the threshold of full field penetration within the anion layers.     

Focused ion beam-shaped microtools for ultra-precision machining of cylindrical components

Focused ion beam (FIB) sputtering is used to shape a variety of cutting tools with dimensions in the 15–100 μm range and cutting edge radii of curvature of 40 nm. The shape of each microtool is controlled to a pre-specified geometry that includes rake and relief features. We demonstrate tools having rectangular, triangular, and other complex-shaped face designs. A double-triangle tip on one tool is unique and demonstrates the versatility of the fabrication process. The FIB technique allows observation of the tool during fabrication, and, thus, reproducible features are generated with sub-micron precision. Tools are made from tungsten carbide, high-speed tool steel, and single crystal diamond. Application of FIB-shaped tools in ultra-precision microgrooving tests shows that the cross-section of a machined groove is an excellent replication of the microtool face. Microgrooves on 40–150 μm pitch are cut into 3 mm diameter polymer rods, for groove arc lengths greater than 12 cm. The surface finish of machined features is also reported; groove roughness (R_a) is typically less than 0.2 μm. Ultra-precision machining of cylindrical substrates is extended to make bound metal microcoils having feature sizes of 20–40 μm.     

Improved Speech Synthesis Using Fuzzy Methods

The paper presents theoretical support for and describes the use of a fuzzy paradigm in implementing a TTS system for the Romanian language, employing a rule-based formant synthesizer. In the framework of classic TTS systems, we propose a new approach in order to improve formant trace computation, aiming at increasing synthetic speech perceptual quality. A fuzzy system is proposed for solving the problem of the phonemes that are prone to multi-definitions in rule-based speech synthesis. In the introductory section, we briefly present the background of the problem and our previous results in speech synthesis. In the second section, we deal with the problem of the context-dependent phonemes at the letter-to-sound module level of our TTS system. Then, we discuss the case of the phoneme /l/ and the solution adopted to define it for different contexts. A fuzzy system is associated with each parameter (denoted F1 and F2) to implement the results of the complete analysis of the phoneme /l/ behavior. The knowledge used in implementing the fuzzy module is acquired by natural speech analysis. In the third section, we exemplify the computation of the synthesis parameters F1 and F2 of the phoneme /l/ in the context of the two syllable sequences. The parameter values are contrasted with those obtained from the spectrogram analysis of the natural speech sequences. The last section presents the main conclusions and further research objectives.     

Output‐based H2 optimal controllers for a class of discrete‐time stochastic linear systems with periodic coefficients

The aim of the paper is to present a design procedure of the optimal controller minimizing the H₂‐type norm of discrete‐time stochastic linear systems with periodic coefficients simultaneously affected by a nonhomogeneous but periodic Markov chain and state and control multiplicative white noise perturbations. Firstly, two H₂‐type norms for the linear stochastic systems under consideration were introduced. These H₂‐type norms may be viewed as measures of the effect of the additive white noise perturbations on the regulated output of the considered system. Before deriving of the state space representation of the optimal controller, some useful formulae of the two H₂‐type norms were obtained. These formulae are expressed in terms of periodic solutions of some suitable linear equations and are derived in the absence of some additional assumptions regarding the Markov chain other than the periodicity of the sequence of the transition probability matrices. Further, it is shown that the optimal H₂ controller depends on the stabilizing solutions of some specific systems of coupled Riccati equations, which generalize the well‐known control and filtering equations from linear time invariant case. For the readers convenience, the paper presents iterative numerical algorithms for the computations of the stabilizing solutions of these Riccati type systems. The theoretical developments are illustrated by numerical examples. Copyright © 2014 John Wiley & Sons, Ltd.