Molecular pathway of pancreatic cancer‐associated neuropathic pain Giri, Shweta Subhash; Tripathi, Alok Shiomurti; Erkekoğlu, Pınar ...
Journal of biochemical and molecular toxicology,
April 2024, 2024-Apr, 2024-04-00, 20240401, Letnik:
38, Številka:
4
Journal Article
Recenzirano
The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal ...adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer‐associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene‐related peptide which is also involved in pain. Matrix metalloproteases are the zinc‐associated proteases enzymes which activates proinflammatory interleukin‐1β into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.
Background
A distal‐predominant demyelinating symmetric pattern is most frequent in patients with neuropathy associated with anti‐myelin‐associated glycoprotein (MAG) antibodies. The literature ...however lacks longitudinal data to describe whether this is consistent over time.
Methods
From the Ottawa Neuromuscular Center database, we identified 23 patients with both immunoglobulin M gammopathy and anti‐MAG antibodies. For median, ulnar and fibular motor conduction studies, we analyzed distal latency and amplitude, negative peak duration, terminal latency index (TLI), and conduction velocity. For median, ulnar, sural, and superficial fibular sensory conduction studies, we analyzed distal latency and amplitude. Results were compared for the earliest and the latest data sets.
Results
The mean time interval between the two assessment points was 6.5 years. Median and ulnar motor nerve conduction studies did not show a significant change for any of the parameters tested. There was disproportionate prolongation of median distal motor latency and reduction in TLI, compared to the ulnar nerve. Deep fibular motor conduction studies showed a marked reduction in amplitudes over time. Sensory potentials were recordable in the upper limb in less than 50% at the first study and less than 25% on the most recent study. There was an even larger attrition of recordable sural and superficial fibular sensory potentials.
Conclusions
Our results highlight the stability of median and ulnar motor conduction study results over a mean observation period of 6.5 years. In contrast, lower limb motor and all sensory potentials show a marked trend toward becoming unrecordable.
In the context of the double carbon target, this study aims to reduce the metal resource consumption caused by the replacement of the failed disc cutter rings of tunnel boring machine (hereafter ...referred to as cutter rings). For this purpose, for the first time, a cutter-ring remanufacturing method is introduced considering key heat-treatment processes of preheating and post-weld tempering through metal active gas arc welding. First, a finite element model was developed to simulate this remanufacturing process route, establishing the optimal parameter ranges for the preheating and tempering temperatures. Subsequently, a self-developed integrated experimental platform was designed combining heat treatment and surfacing remanufacturing. A three-factor and three-level orthogonal experiment was conducted within the optimized parameter ranges. Further, a weighted comparative and range analysis method is proposed, and the impacts of the critical heat-treatment processes on the remanufacturing performance of the cutter rings exhibiting a uniform wear are investigated, resulting in the identification of the optimal heat-treatment combination. Results revealed that these pivotal heat treatments are instrumental in curbing defects (e.g., cracks) and substantially decreasing the residual stress in remanufactured cutter rings. Furthermore, the post-weld tempering temperature is the primary factor influencing the comprehensive performance and an array of physical and mechanical properties, including indent depth, hardness, shear strength, and impact toughness. The comprehensive performance of the best-produced sample impressively surged by 10.5 % compared to a standard engineering cutter ring.
Anti‐myelin‐associated glycoprotein (MAG) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the human natural ...killer‐1 (HNK‐1) epitope. This carbohydrate epitope is highly expressed on adhesion molecules such as MAG, a glycoprotein present in myelinated nerves. We previously showed the therapeutic potential of the glycopolymer poly(phenyl disodium 3‐O‐sulfo‐β‐d‐glucopyranuronate)‐(1→3)‐β‐d‐galactopyranoside (PPSGG) in selectively neutralizing anti‐MAG IgM antibodies in an immunological mouse model and ex vivo with sera from anti‐MAG neuropathy patients. PPSGG is composed of a biodegradable backbone that multivalently presents a mimetic of the HNK‐1 epitope. In this study, we further explored the pharmacodynamic properties of the glycopolymer and its ability to inhibit the binding of anti‐MAG IgM to peripheral nerves. The polymer selectively bound anti‐MAG IgM autoantibodies and prevented the binding of patients’ anti‐MAG IgM antibodies to myelin of non‐human primate sciatic nerves. Upon PPSGG treatment, neither activation nor inhibition of human and murine peripheral blood mononuclear cells nor alteration of systemic inflammatory markers was observed in mice or ex vivo in human peripheral blood mononuclear cells. Intravenous injections of PPSGG to mice immunized against the HNK‐1 epitope removed anti‐MAG IgM antibodies within less than 1 hr, indicating a fast and efficient mechanism of action as compared to a B‐cell depletion with anti‐CD20. In conclusion, these observations corroborate the therapeutic potential of PPSGG for an antigen‐specific treatment of anti‐MAG neuropathy.
Read the Editorial Highlight for this article on page 465.
Anti‐MAG (myelin‐associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the HNK‐1 (human natural killer‐1) epitope. This glycoepitope is highly expressed on adhesion molecules such as MAG and is localized mainly in paranodal loops and Schmidt–Lantermann incisures of the peripheral nervous system. The glycopolymer PPSGG selectively bound anti‐MAG IgM autoantibodies and prevented the binding of patients’ autoantibodies to myelin of primate sciatic nerves in the IFA (indirect fluorescents assay) anti‐MAG IgM assay (right panel). These findings corroborate the therapeutic potential of PPSGG for an antigen‐specific treatment of anti‐MAG neuropathy.
Read the Editorial Highlight for this article on page 465.
Chickens are a highly important source of protein for a large proportion of the human population. The caecal microbiota plays a crucial role in chicken nutrition through the production of short-chain ...fatty acids, nitrogen recycling, and amino acid production. In this study, we sequence DNA from caecal content samples taken from 24 chickens belonging to either a fast or a slower growing breed consuming either a vegetable-only diet or a diet containing fish meal.
We utilise 1.6 T of Illumina data to construct 469 draft metagenome-assembled bacterial genomes, including 460 novel strains, 283 novel species, and 42 novel genera. We compare our genomes to data from 9 European Union countries and show that these genomes are abundant within European chicken flocks. We also compare the abundance of our genomes, and the carbohydrate active enzymes they produce, between our chicken groups and demonstrate that there are both breed- and diet-specific microbiomes, as well as an overlapping core microbiome.
This data will form the basis for future studies examining the composition and function of the chicken caecal microbiota.
ABSTRACT
Introduction: Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM‐PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated ...glycoprotein (MAG) and gangliosides. Methods: To test whether B‐cell‐stimulating cytokines are increased in IgM‐PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM‐PNP and 113 controls. Results: Median interleukin (IL)‐6 concentrations were higher in patients with IgM‐PNP, and median IL‐10 concentrations were higher in the subgroup with anti‐MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. Discussion: Median IL‐6 and IL‐10 serum concentrations differ between patients with anti‐MAG neuropathy and other patients with IgM‐PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune‐mediated disease mechanisms. Muscle Nerve 59:694–698, 2019
Abstract
We propose a functional measure over the torsion tensor. We discuss two completely equivalent choices for the Wheeler–DeWitt supermetric for this field, the first one is based on its ...algebraic decomposition and the other is inspired by teleparallel theories of gravity. The measure is formally defined by requiring the normalization of the Gaußian integral. To achieve such a result we split the torsion tensor into its spin-parity eigenstates by constructing a new, York-like, decomposition. Of course, such a decomposition has a wider range of applicability to any kind of tensor sharing the symmetries of the torsion. As a result of this procedure a functional Jacobian naturally arises, whose formal expression is given exactly in the phenomenologically interesting limit of maximally symmetric spaces. We also discuss the explicit computation of this Jacobian in the case of a four-dimensional sphere
S
4
with particular emphasis on its logarithmic divergences.
Background and purpose
Rituximab, a chimeric anti‐CD20 monoclonal antibody, has been used in polyneuropathy associated with anti‐myelin‐associated glycoprotein (anti‐MAG) antibody polyneuropathy with ...controversial results. Herein, two patients with anti‐MAG antibody neuropathy and concurrent chronic lymphocytic leukemia (CLL) are reported, who dramatically responded to obinutuzumab, a novel glycoengineered humanized anti‐CD20 monoclonal antibody.
Methods
Patient 1 was an 82‐year‐old man with severe demyelinating sensory‐motor neuropathy. He was wheelchair‐bound, with loss of sensation up to the knees. He had a CLL, immunoglobulin M (IgM) lambda monoclonal gammopathy, with anti‐MAG antibodies >70 000 Bühlmann titer units (BTU). Patient 2 was an 84‐year‐old woman with demyelinating neuropathy, paresthesias and gait instability. She had CLL and IgM kappa paraprotein with anti‐MAG antibodies >70 000 BTU. Both patients were treated with obinutuzumab intravenously at 100 mg on day +1, 900 mg +2, then at 1000 mg on days 8 and 15 of cycle 1 and day 1 of cycles 2–6; chlorambucil was given orally at 0.5 mg/kg on days 1 and 15 of cycles 1–6.
Results
Patient 1 at cycle 6 was able to stand, gait was possible with monolateral support, hypoesthesia and strength improved. M‐protein and IgM level decreased. In patient 2, already after three cycles, the monoclonal component disappeared and there was dramatic improvement of symptoms and gait normalization. At the end of therapy anti‐MAG antibody titer decreased to 5462 BTU. Neurophysiology also improved.
Conclusions
In our patients, obinutuzumab was effective as a first‐line treatment of anti‐MAG antibody polyneuropathy. CLL might have had a role in the response to therapy, but the associations might be considered in future trials.
Most of the previously published results of the zenith sky twilight brightness, obtained by different investigators, are given in different units. These results have been converted to (mag/arcsec
2
) ...to make a comparison between them. The variation of the colour indices (B-V) and (B-R) of the zenith sky twilight with the sun's depression will be studied. The present photometric results of the zenith sky twilight brightness expressed in mag/arcsec
2
, have been obtained for the first time for blue, yellow and red colours.
Introduction
We assessed the specific sonographic pattern of structural nerve abnormalities in immunoglobulin M (IgM) neuropathy and disease controls.
Methods
We enrolled 106 incident patients—32 ...patients with IgM neuropathy, 42 treatment‐naive patients with chronic inflammatory demyelinating polyneuropathy, and 32 patients with axonal neuropathies. All patients underwent standardized ancillary testing in addition to standardized sonography of the brachial plexus and the large arm and leg nerves bilaterally.
Results
We found widespread nerve enlargement in IgM neuropathy and chronic inflammatory demyelinating polyneuropathy (CIDP), with specific enlargement of brachial plexus and proximal segments of median nerve but not in axonal disease controls (P < .001). Sonographic nerve hypertrophy in IgM neuropathy was not associated with nerve conduction, clinical, or laboratory characteristics.
Discussion
Immunoglobulin M neuropathy is characterized by widespread nerve enlargement indistinguishable from CIDP. Our data provide evidence to confirm that the disease process is not confined to the more distal parts of nerves in either classical demyelinating or axonal variants of neuropathy with associated IgM.
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