Molecular Insights into the Breast and Prostate Cancer Cells in Response to the Change of Extracellular Zinc.

Zinc dyshomeostasis is manifested in breast and prostate cancer cells. This study attempted to uncover the molecular details prodded by the change of extracellular zinc by employing a panel of normal and cancerous breast and prostate cell lines coupled with the top-down proteomics with two-dimensional gel electrophoresis followed by liquid chromatography-tandem mass spectrometry. The protein samples were generated from MCF-7 breast cancer cells, MCF10A normal breast cells, PC3 prostate cancer cells, and RWPE-1 normal prostate cells with or without exogenous zinc exposure in a time course (T0 and T120). By comparing the cancer cells vs respective normal epithelial cells without zinc treatment (T0), differentially expressed proteins (23 upregulated and 18 downregulated in MCF-7 cells; 14 upregulated and 30 downregulated in PC3 cells) were identified, which provides insights into the intrinsic differences of breast and prostate cancer cells. The dynamic protein landscapes in the cancer cells prodded by the extracellular zinc treatment reveal the potential roles of the identified zinc-responsive proteins (e.g., triosephosphate isomerase, S100A13, tumour proteins hD53 and hD54, and tumour suppressor prohibitin) in breast and prostate cancers. This study, for the first time, simultaneously investigated the two kinds of cancer cells related to zinc dyshomeostasis, and the findings shed light on the molecular understanding of the breast and prostate cancer cells in response to extracellular zinc variation.

Investigation of the mechanisms for wireless nerve stimulation without active electrodes.

Electric-field stimulation of neuronal activity can be used to improve the speed of regeneration for severed and damaged nerves. Most techniques, however, require invasive electronic circuitry which can be uncomfortable for the patient and can damage surrounding tissue. A recently suggested technique uses a graft-antenna-a metal ring wrapped around the damaged nerve-powered by an external magnetic stimulation device. This technique requires no electrodes and internal circuitry with leads across the skin boundary or internal power, since all power is provided wirelessly. This paper examines the microscopic basic mechanisms that allow the magnetic stimulation device to cause neural activation via the graft-antenna. A computational model of the system was created and used to find that under magnetic stimulation, diverging electric fields appear at the metal ring's edges. If the magnetic stimulation is sufficient, the gradients of these fields can trigger neural activation in the nerve. In-vivo measurements were also performed on rat sciatic nerves to support the modeling finding that direct contact between the antenna and the nerve ensures neural activation given sufficient magnetic stimulation. Simulations also showed that the presence of a thin gap between the graft-antenna and the nerve does not preclude neural activation but does reduce its efficacy.

Validity of serum neurofilament light chain as a prognostic biomarker of disease activity in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating and neuroinflammatory disease of the human central nervous system with complex pathoetiology, heterogeneous presentations and an unpredictable course of disease progression. There remains an urgent need to identify and validate a biomarker that can reliably predict the initiation and progression of MS as well as identify patient responses to disease-modifying treatments/therapies (DMTs). Studies exploring biomarkers in MS and other neurodegenerative diseases currently focus mainly on cerebrospinal fluid (CSF) analyses, which are invasive and impractical to perform on a repeated basis. Recent studies, replacing CSF with peripheral blood samples, have revealed that the elevation of serum neurofilament light chain (sNfL) in the clinical stages of MS is, potentially, an ideal prognostic biomarker for predicting disease progression and for possibly guiding treatment decisions. However, there are unresolved factors (the definition of abnormal values of sNfL concentration, the standardisation of measurement and the amount of change in sNfL concentration that is significant) that are preventing its use as a biomarker in routine clinical practice for MS. This updated review critiques these recent findings and highlights areas for focussed work to facilitate the use of sNfL as a prognostic biomarker in MS management.

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare Aß deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on Aß input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

Histological and Top-Down Proteomic Analyses of the Visual Pathway in the Cuprizone Demyelination Model.

A change in visual perception is a frequent early symptom of multiple sclerosis (MS), the pathoaetiology of which remains unclear. Following a slow demyelination process caused by 12 weeks of low-dose (0.1%) cuprizone (CPZ) consumption, histology and proteomics were used to investigate components of the visual pathway in young adult mice. Histological investigation did not identify demyelination or gliosis in the optic tracts, pretectal nuclei, superior colliculi, lateral geniculate nuclei or visual cortices. However, top-down proteomic assessment of the optic nerve/tract revealed a significant change in the abundance of 34 spots in high-resolution two-dimensional (2D) gels. Subsequent liquid chromatography-tandem mass spectrometry (LC-TMS) analysis identified alterations in 75 proteoforms. Literature mining revealed the relevance of these proteoforms in terms of proteins previously implicated in animal models, eye diseases and human MS. Importantly, 24 proteoforms were not previously described in any animal models of MS, eye diseases or MS itself. Bioinformatic analysis indicated involvement of these proteoforms in cytoskeleton organization, metabolic dysregulation, protein aggregation and axonal support. Collectively, these results indicate that continuous CPZ-feeding, which evokes a slow demyelination, results in proteomic changes that precede any clear histological changes in the visual pathway and that these proteoforms may be potential early markers of degenerative demyelinating conditions.

Expression profiles of the genes associated with zinc homeostasis in normal and cancerous breast and prostate cells.

Zn2+ dyshomeostasis is an intriguing phenomenon in breast and prostate cancers, with breast cancer cells exhibiting higher intracellular Zn2+ level compared to their corresponding normal epithelial cells, in contrast to the low Zn2+ level in prostate cancer cells. In order to gain molecular insights into the zinc homeostasis of breast and prostate cancer cells, this study profiled the expression of 28 genes, including 14 zinc importer genes (SLC39A1-14) that encode Zrt/Irt-like proteins 1-14 to transport Zn2+ into the cytoplasm, 10 zinc exporter genes (SLC30A1-10) which encode Zn2+ transporters 1-10 to transport Zn2+ out of the cytoplasm, and 4 metallothionein genes (MT1B, MT1F, MT1X, MT2A) in breast (MCF10A, MCF-7, MDA-MB-231) and prostate (RWPE-1, PC3, DU145) cell lines in response to extracellular zinc exposures at a mild cytotoxic dosage and a benign dosage. The RNA samples were prepared at 0 min (T0), 30 min (T30), and 120 min (T120) in a time course with or without zinc exposure, which were used for profiling the baseline and dynamic gene expression. The up-regulation of MT genes was observed across the breast and prostate cancer cell lines. The expression landscape of SLC39A and SLC30A was revealed by the quantitative reverse transcription polymerase chain reaction data of this study, which sheds light on the divergence of intracellular Zn2+ levels for breast and prostate cancer cells. Taken together, the findings are valuable in unraveling the molecular intricacy of zinc homeostasis in breast and prostate cancer cells.

The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis.

In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site of demyelination by microglia is critically important to achieve adequate remyelination and to slow the progression of the disease. However, how microglia phagocytose the myelin debris, and why clearance is impaired in MS, is not fully known; likewise, the role of the microglia in remyelination remains unclear. Recent studies using cuprizone (CPZ) as an animal model of central nervous system demyelination revealed that the up-regulation of signaling proteins in microglia facilitates effective phagocytosis of myelin debris. Moreover, during demyelination, protective mediators are released from activated microglia, resulting in the acceleration of remyelination in the CPZ model. In contrast, inadequate microglial activation or recruitment to the site of demyelination, and the production of toxic mediators, impairs remyelination resulting in progressive demyelination. In addition to the microglia-mediated phagocytosis, astrocytes play an important role in the phagocytic process by recruiting microglia to the site of demyelination and producing regenerative mediators. The current review is an update of these emerging findings from the CPZ animal model, discussing the roles of microglia and astrocytes in phagocytosis and myelination.

Characterisation of the Mouse Cerebellar Proteome in the GFAP-IL6 Model of Chronic Neuroinflammation.

GFAP-IL6 transgenic mice are characterised by astroglial and microglial activation predominantly in the cerebellum, hallmarks of many neuroinflammatory conditions. However, information available regarding the proteome profile associated with IL-6 overexpression in the mouse brain is limited. This study investigated the cerebellum proteome using a top-down proteomics approach using 2-dimensional gel electrophoresis followed by liquid chromatography-coupled tandem mass spectrometry and correlated these data with motor deficits using the elevated beam walking and accelerod tests. In a detailed proteomic analysis, a total of 67 differentially expressed proteoforms including 47 cytosolic and 20 membrane-bound proteoforms were identified. Bioinformatics and literature mining analyses revealed that these proteins were associated with three distinct classes: metabolic and neurodegenerative processes as well as protein aggregation. The GFAP-IL6 mice exhibited impaired motor skills in the elevated beam walking test measured by their average scores of 'number of footslips' and 'time to traverse' values. Correlation of the proteoforms' expression levels with the motor test scores showed a significant positive correlation to peroxiredoxin-6 and negative correlation to alpha-internexin and mitochondrial cristae subunit Mic19. These findings suggest that the observed changes in the proteoform levels caused by IL-6 overexpression might contribute to the motor function deficits.

Investigations into an overlooked early component of painful nociceptive withdrawal reflex responses in humans.

Introduction: The role of pain as a warning system necessitates a rapid transmission of information from the periphery for the execution of appropriate motor responses. The nociceptive withdrawal reflex (NWR) is a physiological response to protect the limb from a painful stimulus and is often considered an objective measure of spinal nociceptive excitability. The NWR is commonly defined by its latency in the presumed Aδ-fiber range consistent with the canonical view that "fast pain" is signaled by Aδ nociceptors. We recently demonstrated that human skin is equipped with ultrafast (Aß range) nociceptors. Here, we investigated the short-latency component of the reflex and explored the relationship between reflex latency and pain perception. Methods: We revisited our earlier work on NWR measurements in which, following convention, only reflex responses in the presumed Aδ range were considered. In our current analysis, we expanded the time window to search for shorter latency responses and compared those with pain ratings. Results: In both cohorts, we found an abundance of recordings with short-latency reflex responses. In nearly 90% of successful recordings, only single reflex responses (not dual) were seen which allowed us to compare pain ratings based on reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range. Conclusion: We found a preponderance of short-latency painful reflex responses. Based on this finding, we suggest that short-latency responses must be considered in future studies. Whether these are signaled by the ultrafast nociceptors remains to be determined.

Minocycline Treatment Reduces Mass and Force Output From Fast-Twitch Mouse Muscles and Inhibits Myosin Production in C2C12 Myotubes.

Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis. Mice were injected with minocycline (40 mg/kg i.p.) daily for 5 days and sacrificed at day six. Fast-twitch EDL, TA muscles and slow-twitch soleus muscles were dissected out, the TA muscle was snap-frozen and the remaining muscles were attached to force transducer whilst maintained in an organ bath. In C2C12 myotubes, minocycline was applied to the media at a final concentration of 10 µg/mL for 48 h. In minocycline treated mice absolute maximal force was lower in fast-twitch EDL while in slow-twitch soleus there was an increase in the time to peak and relaxation of the twitch. There was no effect of minocycline treatment on the other contractile parameters measured in isolated fast- and slow-twitch muscles. In C2C12 cultured cells, minocycline treatment significantly reduced both myosin heavy chain content and protein synthesis without visible changes to myotube morphology. In the TA muscle there was no significant changes in myosin heavy chain content. These results indicate that high dose minocycline treatment can cause a reduction in maximal isometric force production and mass in fast-twitch EDL and impair protein synthesis during myogenesis in C2C12 cultured cells. These findings have important implications for future studies investigating the efficacy of minocycline treatment in neuromuscular or other muscle-atrophy inducing conditions.

Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers.

Multiple Sclerosis (MS) is a demyelinating disease of the human central nervous system having an unconfirmed pathoetiology. Although animal models are used to mimic the pathology and clinical symptoms, no single model successfully replicates the full complexity of MS from its initial clinical identification through disease progression. Most importantly, a lack of preclinical biomarkers is hampering the earliest possible diagnosis and treatment. Notably, the development of rationally targeted therapeutics enabling pre-emptive treatment to halt the disease is also delayed without such biomarkers. Using literature mining and bioinformatic analyses, this review assessed the available proteomic studies of MS patients and animal models to discern (1) whether the models effectively mimic MS; and (2) whether reasonable biomarker candidates have been identified. The implication and necessity of assessing proteoforms and the critical importance of this to identifying rational biomarkers are discussed. Moreover, the challenges of using different proteomic analytical approaches and biological samples are also addressed.

Revisiting the Pathoetiology of Multiple Sclerosis: Has the Tail Been Wagging the Mouse?

Multiple Sclerosis (MS) is traditionally considered an autoimmune-mediated demyelinating disease, the pathoetiology of which is unknown. However, the key question remains whether autoimmunity is the initiator of the disease (outside-in) or the consequence of a slow and as yet uncharacterized cytodegeneration (oligodendrocytosis), which leads to a subsequent immune response (inside-out). Experimental autoimmune encephalomyelitis has been used to model the later stages of MS during which the autoimmune involvement predominates. In contrast, the cuprizone (CPZ) model is used to model early stages of the disease during which oligodendrocytosis and demyelination predominate and are hypothesized to precede subsequent immune involvement in MS. Recent studies combining a boost, or protection, to the immune system with disruption of the blood brain barrier have shown CPZ-induced oligodendrocytosis with a subsequent immune response. In this Perspective, we review these recent advances and discuss the likelihood of an inside-out vs. an outside-in pathoetiology of MS.

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis.

Cuprizone (CPZ)-feeding in mice induces atrophy of peripheral immune organs (thymus and spleen) and suppresses T-cell levels, thereby limiting its use as a model for studying the effects of the immune system in demyelinating diseases such as Multiple Sclerosis (MS). To investigate whether castration (Cx) can protect the peripheral immune organs from CPZ-induced atrophy and enable T-cell recruitment into the central nervous system (CNS) following a breach of the blood-brain barrier (BBB), three related studies were carried out. In Study 1, Cx prevented the dose-dependent reductions (0.1% < 0.2% CPZ) in thymic and splenic weight, size of the thymic medulla and splenic white pulp, and CD4 and CD8 (CD4/8) levels remained comparable to gonadally intact (Gi) control males. Importantly, 0.1% and 0.2% CPZ were equipotent at inducing central demyelination and glial activation. In Study 2, combining Cx with 0.1% CPZ-feeding and BBB disruption with pertussis toxin (PT) enhanced CD8+ T-cell recruitment into the CNS. The increased CD8+ T-cell level observed in the parenchyma of the cerebrum, cerebellum, brainstem and spinal cord were confirmed by flow cytometry and western blot analyses of CNS tissue. In Study 3, PT+0.1% CPZ-feeding to Gi female mice resulted in similar effects on the peripheral immune organs, CNS demyelination, and gliosis comparable to Gi males, indicating that testosterone levels alone were not responsible for the immune response seen in Study 2. The combination of Cx+0.1% CPZ-feeding+PT indicates that CPZ-induced demyelination can trigger an "inside-out" immune response when the peripheral immune system is spared and may provide a better model to study the initiating events in demyelinating conditions such as MS.

Minocycline reduces experimental muscle hyperalgesia induced by repeated nerve growth factor injections in humans: A placebo-controlled double-blind drug-crossover study.

BACKGROUND: Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial, the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested. METHODS: An initial cohort (n = 10) received repeated injections (5 µg: days 0, 2 and 4) of nerve growth factor (NGF) in the flexor carpi ulnaris muscle of the forearm and pressure pain thresholds were collected at day 0 (control), day 7 (peak) and day 14 (recovery). A second cohort (n = 18) underwent an identical procedure, however, half received a placebo between days 0 and 7 before switching to minocycline from days 7 to 14 (P1/M2), while the remaining subjects received minocycline (day 0: 200mg then 100mg b.i.d. for 7 days) before switching to placebo (M1/P2). RESULTS: The initial cohort exhibited a diffuse muscular pain hypersensitivity with a decrease in pressure pain thresholds at day 7 before a partial return to normalcy at day 14. The P1/M2 treatment group exhibited an identical peak in hypersensitivity at day 7, however, after switching to minocycline in week 2 showed a significant reduction in muscle hyperalgesia compared with the initial cohort at day 14. The M1/P2 treatment group had significantly less (~43%) hyperalgesia at day 7 compared with the other groups. CONCLUSIONS: The study indicates that the administration of minocycline can reduce experimentally induced muscle pain regardless of the time of administration. SIGNIFICANCE: In a double-blind placebo-controlled drug-crossover study, the common antibiotic minocycline was found to reduce the muscle hyperalgesia induced by intramuscular injection of nerve growth factor. The results of the study showed that both concomitant (pre-emptive) and delayed administration of minocycline can ameliorate the onset and facilitate the resolution of experimentally induced muscle hyperalgesia.

Behavioural and histological changes in cuprizone-fed mice.

Feeding cuprizone (CPZ) to mice causes demyelination and reactive gliosis in the central nervous system (CNS), hallmarks of some neurodegenerative diseases like multiple sclerosis. However, relatively little is known regarding the behavioural deficits associated with CPZ-feeding and much of what is known is contradictory. This study investigated whether 37 days oral feeding of 0.2% CPZ to young adult mice evoked sensorimotor behavioural changes. Behavioural tests included measurements of nociceptive withdrawal reflex responses and locomotor tests. Additionally, these were compared to histological analysis of the relevant CNS regions by analysis of neuronal and glial cell components. CPZ-fed mice exhibited more foot slips in walking ladder and beam tests compared to controls. In contrast, no changes in nociceptive thresholds to thermal or mechanical stimuli occurred between groups. Histological analysis showed demyelination throughout the CNS, which was most prominent in white matter tracts in the cerebrum but was also elevated in areas such as the hippocampus, basal ganglia and diencephalon. Profound demyelination and gliosis was seen in the deep cerebellar nuclei and brain stem regions associated with the vestibular system. However, in the spinal cord changes were minimal. No loss of oligodendrocytes, neurons or motoneurons occurred but a significant increase in astrocyte staining ensued throughout the white matter of the spinal cord. The results suggest that CPZ differentially affects oligodendrocytes throughout the CNS and induces subtle motor changes such as ataxia. This is associated with deficits in CNS regions associated with motor and balance functions such as the cerebellum and brain stem.

Modulation of Muscle Pain Is Not Somatotopically Restricted: An Experimental Model Using Concurrent Hypertonic-Normal Saline Infusions in Humans.

We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)-ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)-50 µl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.

Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis.

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the 'inside-out' theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the 'inside-out' role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.

Variability of Oxaliplatin-Induced Neuropathic Pain Symptoms in Each Cycle and Its Implications on the Management of Colorectal Cancer Patients: A Retrospective Study in South Western Sydney Local Health District Hospitals, Sydney, Australia.

Oxaliplatin-induced neuropathic pain limits treatment compliance. However, the variability of neuropathic pain symptoms in each cycle for individual patients and the impacts on treatment compliance remain untested. Data from 322 adult patients who received oxaliplatin-based chemotherapy were extracted based on pattern of chemotherapy, adverse events, and patient survival. Cox regression and survival analyses were employed. Seventy-eight percent of patients developed neuropathic pain that oscillated between a complete absence and presence on a cycle-by-cycle basis. Consequently, the presence of neuropathy in one cycle did not predict the incidence of neuropathy in subsequent cycles. This implies that neuropathic pain need not be a sufficient criterion to reduce, delay, or cease chemotherapy. In the case of multiple system adverse events during combined drug treatment, the responsible cause for dose reduction was not identified. Cox regression analysis revealed that middle age (61-78 years old, P=0.003) and oxaliplatin cumulative dose <850 mg/m2 (P=0.002) were associated with patient mortality. Completion of chemotherapy (8 cycles) and cumulative dose >850 mg/m2 of oxaliplatin prolonged the median survival time by 8 and 5 months, respectively. As oxaliplatin-induced neuropathic pain fluctuates across cycles in a manner that varies from patient-to-patient, current assumptions on the predictive nature of the emergence of neuropathy (and its impact on treatment compliance) need to be reconsidered. Detailed patient-by-patient analysis of adverse events should be applied to future studies in order to determine the efficacy of current treatments (and future interventions) and whether neuropathic pain should be retained as a criterion to vary the treatment. Additionally, when two or more system toxicities occurred in cases of combined drug treatment, the causes for drug reduction should be separately recorded.

Behavioural phenotypes in the cuprizone model of central nervous system demyelination.

The feeding of cuprizone (CPZ) to animals has been extensively used to model the processes of demyelination and remyelination, with many papers adopting a narrative linked to demyelinating conditions like multiple sclerosis (MS), the aetiology of which is unknown. However, no current animal model faithfully replicates the myriad of symptoms seen in the clinical condition of MS. CPZ ingestion causes mitochondrial and endoplasmic reticulum stress and subsequent apoptosis of oligodendrocytes leads to central nervous system demyelination and glial cell activation. Although there are a wide variety of behavioural tests available for characterizing the functional deficits in animal models of disease, including that of CPZ-induced deficits, they have focused on a narrow subset of outcomes such as motor performance, cognition, and anxiety. The literature has not been systematically reviewed in relation to these or other symptoms associated with clinical MS. This paper reviews these tests and makes recommendations as to which are the most important in order to better understand the role of this model in examining aspects of demyelinating diseases like MS.

Tactile sensory channels over-ruled by frequency decoding system that utilizes spike pattern regardless of receptor type.

The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies < 60 Hz) and vibratory hum (frequencies > 60 Hz), subserved by two distinct receptor types (Meissner's and Pacinian corpuscle, respectively), which may engage different neural processing pathways or channels and fulfil quite different biological roles. In psychological and physiological literature, those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency, thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.