Accepted

Paclitaxel is a chemotherapeutic agent widely used for many types of malignancies. However, when paclitaxel is used to treat tumors, patients commonly experience severe neuropathic pain that is difficult to manage. The mechanism underlying paclitaxel-induced neuropathic pain remains unclear. Evidence demonstrates correlations between mechanisms of paclitaxel-mediated pain and associated actions of ion channels, neuroinflammation, mitochondrial damage, and other factors. This review provides a comprehensive analysis of paclitaxel-induced neuropathic pain mechanisms and suggestions for effective interventions.

Transient receptor potential melastatin-7 (TRPM7) is a selective cation permeable channel which plays important roles in cellular and developmental biology such as cell proliferation, survival, differentiation and migration. This channel is also known to be necessary for transmitter release in the peripheral nervous system. In this study, immunohistochemistry for TRPM7 was conducted in the rat lumbar dorsal root ganglion (DRG).

Bone cancer pain (BCP), which seriously affects the quality of life of patients, remains a clinically challenging problem. Hence, there is an urgent need to investigate new mechanisms and develop new therapeutics to relieve BCP. In the present study, we investigated the analgesic effect of melatonin on BCP and the underlying mechanisms. Male C57BL/6 mice were used to establish BCP models. We found that the levels of sirtuin 1 (SIRT1) and nucleus-high mobility group box-1 (HMGB1) were decreased, whilst the levels of HMGB1, cytoplasm-HMGB1 and inflammatory cytokines (TNF-α, IL-6, IL-1β) were increased in the spinal cord of BCP mice on days 7, 14 and 21 after implantation compared with the levels in sham mice. Intrathecal administration of melatonin dose-dependently increased values of PWMT and TWL compared with the BCP group. However, intrathecal administration of EX527 (a selective SIRT1 antagonist) reversed the analgesic effect of melatonin. Moreover, mice in the melatonin group exhibited an increase in SIRT1 and nucleus-HMGB1, whilst there was a decrease in HMGB1, cytoplasm-HMGB1, rage, acetyl-HMGB1 and inflammatory cytokines compared with those in BCP mice. EX527 also reversed these changes. Furthermore, SIRT1 physically interacted with HMGB1 in the BCP mice. In conclusion, intrathecal administration of melatonin attenuates BCP through SIRT1-dependent inhibition of HMGB1 translocation and inflammatory cytokines. Melatonin may be a promising drug for the clinical treatment of BCP.

The purpose of this study was to determine the effects of an open-labeled placebo (OLP) compared to a waitlist control (WL) in reducing cancer-related fatigue (CRF) in patients with advanced cancer using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events (AEs) of treatment for pain in cancer and palliative care, resulting in increased morbidity and reduced quality of life. This review is a partial update of a 2008 review, and critiques as previous update (2018) trials only for people with cancer and people receiving palliative care.

Secukinumab, the first IL-17A inhibitor, is widely used to treat immune diseases, including plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, many studies have reported adverse events associated with secukinumab, including gastrointestinal disorders, infection and infestations, and hypersensitive and nervous system disorders.

Treatment of neuropathic pain (NP) is challenging. Interest in real-world evidence (RWE) for benefit-risk assessments of NP treatments increases given the paucity of drugs showing efficacy in randomized controlled trials and restricted labels of available medicines. To provide further context, a literature review regarding regulatory use of RWE and a clinical trial registry search for randomized controlled trials over the last 10 years was carried out. Taken together, and especially for available NP treatments, there is increasing support to consider RWE when evaluating their benefit-risk profile. Examples are provided in which RWE could be used effectively for updating the product label and informing treatment recommendations. Collected and analyzed according to state-of-the-art standards, RWE can inform treatment recommendations and product label decisions.

We present a case of a 53-year-old male who presented with functionally limiting bilateral lower extremity neuropathic pain secondary to multiple subtypes of small fiber neuropathy. He had failed management with multiple conservative measures including oral medications, physical therapy and desensitization techniques. He ultimately underwent placement of a spinal cord stimulator and continued to experience 80% improvement of his pain, as well as improved function and quality of life at 5 month follow-up. To our knowledge, this is the first reported case of successful treatment of multiple subtypes of small fiber neuropathy with spinal cord stimulator.

Previous investigations indicate that vessel wall elasticity may contribute to the occurrence of an ischemic stroke-associated headache. In this prospective study, the association between radiologic parameters of intracranial hemodynamic changes and concomitant headaches during the early phase of ischemic stroke was examined. Consecutive patients with acute ischemic stroke (AIS) from the First Affiliated Hospital of Soochow University were recruited and divided into two groups according to their questionnaire results and the International Headache criteria 3 criteria. Baseline data including stroke sub-types and neurological function at admission and discharge were collected. non-contrast CT, CT angiography, and CT perfusion were performed to assess intracranial hemodynamic changes. Multiple adjusted logistic models were used and possible confounding factors were included in sequential models. A total of 190 patients with AIS (93 headaches and 97 non-headache) were recruited. There were significant differences between the two groups in gender, hypertension, Alberta stroke program early CT score, relative cerebral blood flow (rCBF); and relative cerebral blood volume (rCBV). Furthermore, rCBV (adjusted OR, 0.160; 95%CI, 0.055-0.461; p < 0.001) and rCBF (adjusted OR, 0.309; 95%CI, 0.113-0.844; p < 0.05) were significantly associated with concomitant headache during the early phase of AIS in fully adjusted models. After adjusting for sociodemographic characteristics and other confounding factors, P-values for the ORs were robust and intensified. Patients with lower rCBV and rCBF tended to experience the concomitant headache during the early phase of AIS. Regional hypoperfusion and microcirculation might play an important role in this separate clinical entity.

Lysophosphatidic acid receptor 1 (LPA) is one of the six G protein-coupled receptors activated by the bioactive lipid, lysophosphatidic acid (LPA). LPA is a drug target for various diseases, including cancer, inflammation, and neuropathic pain. Notably, LPA agonists have potential therapeutic value for obesity and urinary incontinence. Here, we report a cryo-electron microscopy structure of the active human LPA-G complex bound to ONO-0740556, an LPA analog with more potent activity against LPA. Our structure elucidated the details of the agonist binding mode and receptor activation mechanism mediated by rearrangements of transmembrane segment 7 and the central hydrophobic core. A structural comparison of LPA and other phylogenetically-related lipid-sensing GPCRs identified the structural determinants for lipid preference of LPA. Moreover, we characterized the structural polymorphisms at the receptor-G-protein interface, which potentially reflect the G-protein dissociation process. Our study provides insights into the detailed mechanism of LPA binding to agonists and paves the way toward the design of drug-like agonists targeting LPA.