[Oral dexketoprofen tromethamine for preemptive analgesia in extraction of impacted teeth: a randomized controlled double-blind trial].

PURPOSE: To study the preemptive analgesic effect of dexketoprofen tromethamine in extraction of impacted teeth. METHODS: Twenty patients with bilateral mandibular impacted teeth were selected, and were randomly divided into dexketoprofen tromethamine group(experimental group) and placebo group(control group). The pain scores of patients at 0.5, 2, 4, 8, 12, and 24 hours after tooth extraction were counted by numeric rating scale(NRS), and the total dosage of emergent analgesic drugs used in 24 hours was recorded. COX analysis method was used to compare the interval time and the number of cases of first application of emergent analgesic drugs after two operations, and the survival curve was drawn. SPSS 20.0 software package was used for data analysis. RESULTS: The NRS scores of postoperative pain in the experimental group were significantly lower than those in the control group at 2, 4, 8 and 12 hours after operation (P＜0.05). The dose of emergent analgesics used in the experimental group for 24 h was significantly lower than that in the control group (P＜0.05). Survival curve showed that the interval time between the first application of analgesics in the experimental group was significantly longer than that in the control group(P＜0.05). CONCLUSIONS: Dexketoprofen tromethamine can achieve obvious analgesic effect within 12 hours, but the analgesic effect is not obvious after 12 hours.

Ion channels in cancer-induced bone pain: from molecular mechanisms to clinical applications.

Cancer-induced bone pain (CIBP) caused by bone metastasis is one of the most prevalent diseases, and current treatments rely primarily on opioids, which have significant side effects. However, recent developments in pharmaceutical science have identified several new mechanisms for CIBP, including the targeted modification of certain ion channels and receptors. Ion channels are transmembrane proteins, which are situated on biological cell membranes, which facilitate passive transport of inorganic ions across membranes. They are involved in various physiological processes, including transmission of pain signals in the nervous system. In recent years, there has been an increasing interest in the role of ion channels in chronic pain, including CIBP. Therefore, in this review, we summarize the current literature on ion channels, related receptors, and drugs and explore the mechanism of CIBP. Targeting ion channels and regulating their activity might be key to treating pain associated with bone cancer and offer new treatment avenues.

Descending dopaminergic pathway facilitates itch signal processing via activating spinal GRPR+ neurons.

A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH ) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+ ) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+ ) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.

Phenotypic dimorphism between honeybee queen and worker is regulated by complicated epigenetic modifications.

Phenotypic dimorphism between queens and workers is an important biological characteristic of honeybees that has been the subject of intensive research. The enormous differences in morphology, lifespan, physiology, and behavior between queens and workers are caused by a complicated set of factors. Epigenetic modifications are considered to play an important role in this process. In this study, we analyzed the differences in chromosome interactions and H3K27ac and H3K4me1 modifications between the queens and workers using high-throughput chromosome conformation capture (Hi-C) and Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) technologies. We found that the queens contain more chromosome interactions and more unique H3K27ac modifications than workers; in contrast, workers have more H3K4me1 modifications than queens. Moreover, we identified Map3k15 as a potential caste gene in queen-worker differentiation. Our results suggest that chromosomal conformation and H3K27ac and H3K4me1 modifications are involved in regulating queen-worker differentiation, which reveals that the queen-worker phenotypic dimorphism is regulated by multiple epigenetic modifications.

The diverging epigenomic landscapes of honeybee queens and workers revealed by multiomic sequencing.

The role of the epigenome in phenotypic plasticity is unclear presently. Here we used a multiomics approach to explore the nature of the epigenome in developing honey bee (Apis mellifera) workers and queens. Our data clearly showed distinct queen and worker epigenomic landscapes during the developmental process. Differences in gene expression between workers and queens become more extensive and more layered during the process of development. Genes known to be important for caste differentiation were more likely to be regulated by multiple epigenomic systems than other differentially expressed genes. We confirmed the importance of two candidate genes for caste differentiation by using RNAi to manipulate the expression of two genes that differed in expression between workers and queens were regulated by multiple epigenomic systems. For both genes the RNAi manipulation resulted in a decrease in weight and fewer ovarioles of newly emerged queens compared to controls. Our data show that the distinct epigenomic landscapes of worker and queen bees differentiate during the course of larval development.

Excitatory Projections from the Prefrontal Cortex to Nucleus Accumbens Core D1-MSNs and κ Opioid Receptor Modulate Itch-Related Scratching Behaviors.

Itch is an uncomfortable and complex sensation that elicits the desire to scratch. The nucleus accumbens (NAc) activity is important in driving sensation, motivation, and emotion. Excitatory afferents from the medial prefrontal cortex (mPFC), amygdala, and hippocampus are crucial in tuning the activity of dopamine receptor D1-expressing and D2-expressing medium spiny neurons (Drd1-MSN and Drd2-MSN) in the NAc. However, a cell-type and neural circuity-based mechanism of the NAc underlying acute itch remains unclear. We found that acute itch induced by compound 48/80 (C48/80) decreased the intrinsic membrane excitability in Drd1-MSNs, but not in Drd2-MSNs, in the NAc core of male mice. Chemogenetic activation of Drd1-MSNs alleviated C48/80-induced scratching behaviors but not itch-related anxiety-like behaviors. In addition, C48/80 enhanced the frequency of spontaneous EPSCs (sEPSCs) and reduced the paired-pulse ratio (PPR) of electrical stimulation-evoked EPSCs in Drd1-MSNs. Furthermore, C48/80 increased excitatory synaptic afferents to Drd1-MSNs from the mPFC, not from the basolateral amygdala (BLA) or ventral hippocampus (vHipp). Consistently, the intrinsic excitability of mPFC-NAc projecting pyramidal neurons was increased after C48/80 treatment. Chemogenetic inhibition of mPFC-NAc excitatory synaptic afferents relieved the scratching behaviors. Moreover, pharmacological activation of κ opioid receptor (KOR) in the NAc core suppressed C48/80-induced scratching behaviors, and the modulation of KOR activity in the NAc resulted in the changes of presynaptic excitatory inputs to Drd1-MSNs in C48/80-treated mice. Together, these results reveal the neural plasticity in synapses of NAc Drd1-MSNs from the mPFC underlying acute itch and indicate the modulatory role of the KOR in itch-related scratching behaviors.SIGNIFICANCE STATEMENT Itch stimuli cause strongly scratching desire and anxiety in patients. However, the related neural mechanisms remain largely unclear. In the present study, we demonstrated that the pruritogen compound 48/80 (C48/80) shapes the excitability of dopamine receptor D1-expressing medium spiny neurons (Drd1-MSNs) in the nucleus accumbens (NAc) core and the glutamatergic synaptic afferents from medial prefrontal cortex (mPFC) to these neurons. Chemogenetic activation of Drd1-MSNs or inhibition of mPFC-NAc excitatory synaptic afferents relieves the scratching behaviors. In addition, pharmacological activation of κ opioid receptor (KOR) in the NAc core alleviates C48/80-induced itch. Thus, targeting mPFC-NAc Drd1-MSNs or KOR may provide effective treatments for itch.

[Study on the thickness and morphology of lingual bone of impacted mandibular third molar based on CBCT and Simplant 3D reconstruction].

PURPOSE: The potential relationship between impacted mandibular third molar and lingual bone thickness was investigated by quantitative measurement of lingual bone thickness, and a three-dimensional visualization model of lingual bone was established. METHODS: Image data of 200 cases of mandibular impacted third molar were collected from the database of Hefei Stomatological Hospital. Thickness measurement and three-dimensional reconstruction of lingual bone at different measurement sites were performed by Simplant Pro software. Statistical analysis was performed using SPSS 22.0 software package, and the comparison of lingual thickness at different measurement sites was performed using rank sum test. Whether the thickness of bone plate was "high-risk type" was taken as the result variable, different related factors were analyzed by logistic regression. RESULTS: The lingual bone at the middle point of the root of the third molar was the thinnest. Multiple teeth, mesio-inclined and dial-inclined teeth, and Class Ⅱ and Ⅲ impacted teeth had thin lingual bone(P＜0.05). The mesial and distal inclines were observed, and the lingual bone was thin in the root apical region of the teeth in Class Ⅱ and Class Ⅲ(P＜0.05). In the lower impacted teeth, the thin lingual bone at the central crown site was more likely to be found in Class Ⅲ teeth(P＜0.05). CONCLUSIONS: The thickness of lingual bone was related to the number of impacted tooth roots, tilt direction and impacted type. In the extraction of impacted teeth, the above factors should be considered, and the injury of lingual nerve, lingual bone and surrounding soft tissue should be vigilant.

NFAT1 Orchestrates Spinal Microglial Transcription and Promotes Microglial Proliferation via c-MYC Contributing to Nerve Injury-Induced Neuropathic Pain.

Peripheral nerve injury-induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T-cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2-mediated DNA demethylation. Global or microglia-specific deletion of Nfat1 attenuates SNL-induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia-related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il-1b, and c-Myc in the spinal cord. Microglia-specific overexpression of c-MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c-MYC by intrathecal injection of inhibitor or siRNA alleviates SNL-induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c-MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

Plasticity of neuronal excitability and synaptic balance in the anterior nucleus of paraventricular thalamus after nerve injury.

The anterior nucleus of the paraventricular thalamus (aPVT) integrates various synaptic inputs and conveys information to the downstream brain regions for arousal and pain regulation. Recent studies have indicated that the PVT plays a crucial role in the regulation of chronic pain, but the plasticity mechanism of neuronal excitability and synaptic inputs for aPVT neurons in neuropathic pain remains unclear. Here, we report that spinal nerve ligation (SNL) significantly increased the neuronal excitability and reset the excitatory/inhibitory (E/I) synaptic inputs ratio of aPVT neurons in mice. SNL significantly increased the membrane input resistance, firing frequency, and the half-width of action potential. Additionally, SNL enlarged the area of afterdepolarization and prolonged the rebound low-threshold spike following a hyperpolarized current injection. Further results indicate that an inwardly rectifying current density was decreased in SNL animals. SNL also decreased the amplitude, but not the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), nor the amplitude or frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) of aPVT neurons. Moreover, SNL disrupted the E/I synaptic ratio, caused a decrease in weighted tau and half-width of averaged sIPSCs, but did not change these physiological properties of averaged sEPSCs. Finally, pharmacological activation of the GABAA receptor at aPVT could effective relieve SNL-induced mechanical allodynia in mice. These results reveal the plasticity of intrinsic neuronal excitability and E/I synaptic balance in the aPVT neurons after nerve injury and it may play an important role in the development of pain sensitization.

Circulating Tumor DNA Characteristics Based on Next Generation Sequencing and Its Correlation With Clinical Parameters in Patients With Lymphoma.

Background: Lymphoma is a heterogeneous group of tumors in terms of morphological subtypes, molecular alterations, and management. However, data on circulating tumor DNA (ctDNA) mutated genes are limited. The purpose of this study was to investigate the features of the ctDNA mutated genes, the prognosis, and the association between the ctDNA mutated genes and the clinical parameters in lymphoma. Methods: Differences in the ctDNA between the mutated genes and the prognosis of 59 patients with Hodgkin's lymphoma (HL) (10.2%), germinal center B-cell-like lymphoma (GCB) (28.8%), nongerminal center B-cell-like lymphoma (non-GCB) (50.8%), and marginal zone lymphoma (MZL) (10.2%) were analyzed by next generation sequencing (NGS) targeting 121 lymphoma-relevant genes. Results: Genetic alterations were identified in the ctDNA samples with a median of 6 variants per sample. The genetic variation of the ctDNA in the plasma was found to be significantly correlated with the clinical indices in lymphoma. The genetic heterogeneity of different lymphoma subtypes was clearly observed in the ctDNAs from HL, GCB, non-GCB, and MZL, confirming that distinct molecular mechanisms are involved in the pathogenesis of different lymphomas. Conclusion: Our findings suggest that NGS-based ctDNA mutation analysis reveals genetic heterogeneity across lymphoma subtypes, with potential implications for discovering therapeutic targets, exploring genomic evolution, and developing risk-adaptive therapies.

Extent and complexity of RNA processing in honey bee queen and worker caste development.

The distinct honeybee (Apis mellifera) worker and queen castes have become a model for the study of genomic mechanisms of phenotypic plasticity. Here we performed a nanopore-based direct RNA sequencing with exceptionally long reads to compare the mRNA transcripts between queen and workers at three points during their larval development. We found thousands of significantly differentially expressed transcript isoforms (DEIs) between queen and worker larvae. These DEIs were formatted by a flexible splicing system. We showed that poly(A) tails participated in this caste differentiation by negatively regulating the expression of DEIs. Hundreds of isoforms uniquely expressed in either queens or workers during their larval development, and isoforms were expressed at different points in queen and worker larval development demonstrating a dynamic relationship between isoform expression and developmental mechanisms. These findings show the full complexity of RNA processing and transcript expression in honey bee phenotypic plasticity.

Enhanced function of NR2C/2D-containing NMDA receptor in the nucleus accumbens contributes to peripheral nerve injury-induced neuropathic pain and depression in mice.

N-methyl-d-aspartate receptors (NMDARs) dysfunction in the nucleus accumbens (NAc) participates in regulating many neurological and psychiatric disorders such as drug addiction, chronic pain, and depression. NMDARs are heterotetrameric complexes generally composed of two NR1 and two NR2 subunits (NR2A, NR2B, NR2C and NR2D). Much attention has been focused on the role of NR2A and NR2B-containing NMDARs in a variety of neurological disorders; however, the function of NR2C/2D subunits at NAc in chronic pain remains unknown. In this study, spinal nerve ligation (SNL) induced a persistent sensory abnormity and depressive-like behavior. The whole-cell patch clamp recording on medium spiny neurons (MSNs) in the NAc showed that the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) was significantly increased when membrane potential held at -40 to 0 mV in mice after 14 days of SNL operation. In addition, selective inhibition of NR2C/2D-containing NMDARs with PPDA caused a larger decrease on peak amplitude of NMDAR-EPSCs in SNL than that in sham-operated mice. Appling of selective potentiator of NR2C/2D, CIQ, markedly enhanced the evoked NMDAR-EPSCs in SNL-operated mice, but no change in sham-operated mice. Finally, intra-NAc injection of PPDA significantly attenuated SNL-induced mechanical allodynia and depressive-like behavior. These results for the first time showed that the functional change of NR2C/2D subunits-containing NMDARs in the NAc might contribute to the sensory and affective components in neuropathic pain.

Systemic immune inflammation index, ratio of lymphocytes to monocytes, lactate dehydrogenase and prognosis of diffuse large B-cell lymphoma patients.

BACKGROUND: In malignant tumors, inflammation plays a vital role in the development, invasion, and metastasis of cancer cells. Diffuse large B-cell lymphoma (DLBCL), the most common malignant proliferative disease of the lymphatic system, is commonly associated with inflammation. The international prognostic index (IPI), which includes age, lactate dehydrogenase (LDH), number of extranodal lesions, Ann Arbor score, and Eastern Cooperative Oncology Group (ECOG) score, can evaluate the prognosis of DLBCL. However, its use in accurately identifying high-risk patients and guiding treatment is poor. Therefore, it is important to find novel immune markers in predicting the prognosis of DLBCL patients. AIM: To determine the association between the systemic immune inflammation index (SII), ratio of lymphocytes to monocytes (LMR), ratio of LMR to LDH (LMR/LDH), and prognosis of patients with DLBCL. METHODS: A total of 68 patients diagnosed with DLBCL, treated in our hospital between January 2016 and January 2020, were included. χ 2 test, Pearson's R correlation, Kaplan Meier curves, and Cox proportional risk regression analysis were used. The differences in the SII, LMR, and LMR/LDH among patients with different clinicopathological features were analyzed. The differences in progression-free survival time among patients with different SII, LMR, and LMR/LDH expressions and influencing factors affecting the prognosis of DLBCL patients, were also analyzed. RESULTS: The LMR and LMR/LDH in patients with Ann Arbor stage III-IV, ECOG score ≥ 2, and SII, IPI score 2-5 were significantly higher than those of patients with Ann Arbor stage I-II and ECOG score < 2 (P < 0.05). Patients with high SII, LMR, and LMR/LDH had progression-free survival times of 34 mo (95%CI: 32.52-38.50), 35 mo (95%CI: 33.42-36.58) and 35 mo (95%CI: 33.49-36.51), respectively, which were significantly lower than those with low SII, LMR, and LMR/LDH (P < 0.05); the SII, LMR, and LMR/LDH were positively correlated (P < 0.05). Cox proportional risk regression analysis showed that the SII, LMR, and LMR/LDH were influencing factors for the prognosis of DLBCL patients (hazard ratio = 1.143, 1.665, and 1.704, respectively; P < 0.05). CONCLUSION: The SII, LMR, and LMR/LDH are related to the clinicopathological features of DLCBL, and they also influence the prognosis of patients with the disease.

Epigallocatechin-3-gallate attenuates acute pancreatitis induced lung injury by targeting mitochondrial reactive oxygen species triggered NLRP3 inflammasome activation.

Green tea has been considered as a health-promoting beverage and is widely consumed worldwide. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol derived from green tea leaves with potent antioxidative and chemopreventive activities, has been reported to offer protection against inflammation-driven tissue damage. Here, we evaluated the protective effects of EGCG against lung injury during acute pancreatitis (AP) and further revealed the detailed mechanism. The results showed that EGCG significantly attenuated l-arginine-induced AP and the consequent pulmonary damage in mice. Moreover, EGCG substantially attenuated oxidative stress and concurrently suppressed NOD-like receptor protein 3 (NLRP3) inflammasome activation in the lung. In vitro, EGCG considerably reduced the production of mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (ox-mtDNA) in alveolar macrophages (AMs) challenged with AP-conditioned plasma. Meanwhile, the amount of ox-mtDNA bound to NLRP3 decreased significantly by the treatment with EGCG, resulting in impaired NLRP3 inflammasome activation. In addition, the antagonism of NLRP3 signaling by EGCG was affected in the presence of the mtROS stimulant rotenone or scavenger Mito-TEMPO. Altogether, EGCG possesses potent activity to attenuate lung injury during AP progression by inhibiting NLRP3 inflammasome activation. As for the mechanism, the EGCG-conferred restriction of NLRP3 inflammasome activation probably arises from the elimination of mtROS as well as its oxidative product ox-mtDNA, which consequently enables the protection against AP-associated lung injury.

CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain.

The medium spiny neurons (MSNs) in the nucleus accumbens (NAc) integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output. Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation (SNL). SNL increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the MSNs. SNL also decreased the paired-pulse ratio (PPR) of evoked IPSCs but increased the PPR of evoked EPSCs. Moreover, acute bath application of C-C motif chemokine ligand 2 (CCL2) increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs, and especially strengthened the amplitude of N-methyl-D-aspartate receptor (NMDAR)-mediated miniature EPSCs. Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio. Finally, Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression (LTD) in the NAc after SNL. These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.

Thoracoscopic total laryngo-pharyngo-oesophagectomy for the pharyngoesophageal junction cancer: a single-center experience of multidisciplinary team.

PURPOSE: The aims of this study were to review the surgical experience and evaluate the feasibility of thoracoscopic total laryngo-pharyngo-oesophagectomy by multidisciplinary team in the patients with pharyngoesophageal junction cancer. METHODS: A total of 31 patients with pharyngoesophageal junction cancer who underwent thoracoscopic total laryngo-pharyngo-oesophagectomy with gastric pull-up reconstruction performed by a collaborative thoracic surgery and otolaryngology surgery team in our department from January 2009 to January 2019 were retrospectively analysed. Surgical experience, Postoperative morbidity, overall survival were evaluated. RESULTS: The median age was 62 years old. Among these patients, 20 had hypopharyngeal cancer, 11 had cervical oesophageal cancer. No patients died during the perioperative period, and the median operation time was 4 h 30 min. The mean hospital stay was 13 days. The rate of complications was 32.3%. There were two cases of anastomotic leakage, four cases of moderate pulmonary infection. The median follow-up period was 31 months. Four patients were lost to follow-up in the second and fourth years and were considered to have died at that time. The 3- and 5-year overall survival rates were 52.6% and 31.6%, respectively. CONCLUSION: As a salvage surgery, thoracoscopic total laryngo-pharyngo-oesophagectomy by multidisciplinary team can be performed with an acceptable level of perioperative morbidity and mortality, relatively good recovery, and acceptable survival outcome for patients with pharyngoesophageal junction cancer.

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice.

Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca2+ concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.

CXCL10/CXCR3 Signaling in the DRG Exacerbates Neuropathic Pain in Mice.

Chemokines and receptors have been implicated in the pathogenesis of chronic pain. Here, we report that spinal nerve ligation (SNL) increased CXCR3 expression in dorsal root ganglion (DRG) neurons, and intra-DRG injection of Cxcr3 shRNA attenuated the SNL-induced mechanical allodynia and heat hyperalgesia. SNL also increased the mRNA levels of CXCL9, CXCL10, and CXCL11, whereas only CXCL10 increased the number of action potentials (APs) in DRG neurons. Furthermore, in Cxcr3-/- mice, CXCL10 did not increase the number of APs, and the SNL-induced increase of the numbers of APs in DRG neurons was reduced. Finally, CXCL10 induced the activation of p38 and ERK in ND7-23 neuronal cells and DRG neurons. Pretreatment of DRG neurons with the P38 inhibitor SB203580 decreased the number of APs induced by CXCL10. Our data indicate that CXCR3, activated by CXCL10, mediates p38 and ERK activation in DRG neurons and enhances neuronal excitability, which contributes to the maintenance of neuropathic pain.

[Clinical Value of Serum Amyloid A and Misfolded Transthyretin for Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients].

OBJECTIVE: To evaluate the clinical value of serum amyloid A (SAA1/2) and misfolded transthyretin (TTR) for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients. METHODS: 30 R/R DLBCL patients were enrolled as observation group, 20 remission/stabilization DLBCL and 10 chronic lymphadenitis patients were enrolled as control group. SELDI technique, Tris-Tricine sodium dodecyl sulfate-polyacrylamide gel electro-phoresis, the shotgun-LTQ-MS method, and bioinformatics technique were used to detected and analyzed SAA and TTR in R/R DLBCL patients. SPSS 21.0 software was used to analyze the relationship between the high expression of SAA, misfolded TTR in serum and the clinicopathological features, survival time of R/R DLBCL. patients Chi-square test was used to analyze clinical count data, Kaplan-Meier curve was used for survival analysis, and Log-Rank test was used to compare single-factor survival differences. RESULTS: The high expression of SAA and TTR (SAA+TTR+) was significantly associated with extranodal lesion, high level of LDH, and NCCN-IPI scores, and also correlated with non-GCB type. TTR+ was correlated with C-MYC in pathological tissue, while SAA+ was also associated with B-symptoms. The survival time of patients in SAA+, TTR+, and SAA+TTR+ group were shorter than that in control group. CONCLUSION: Both SAA and misfolded TTR are poor prognosis factors of R/R DLBCL patients.