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Purpose. Tumor metastasis remains the leading cause of cancer-related mortality in biliary tract cancer. The etiology and mechanism of bile tract carcinoma metastasis are unclear. Methods. The primary tumor and blood samples of 14 patients with biliary tract cancer were collected, followed by nucleic acid extraction and library construction. Target sequencing with 556 panel genes and WES were performed to detect the hot spot genes variations. Bioinformatics was used to comprehensively analyze the sequencing data of these samples, including the differences of tumor mutation burden and signaling pathways. Results. The results showed that the mutation frequency of TP53 gene was the highest and the mutations of CTNNB1, EPHA7, ARID2, and PIK3CA were only found in metastatic samples. The TMB mean values of metastatic and non-metastatic groups were 12.97 and 10.38 mutations per Mb, respectively. There were significant differences in the enrichment pathways of cellular components between the tumor metastasis and non-metastatic samples. Conclusions. We identified multiple pathway differences, which helps us better understand metastatic biliary tumors and design clinical therapy for personalized medicine. [ABSTRACT FROM AUTHOR]

Purpose: The sensitivity of advanced hepatocellular carcinoma (HCC) to Sorafenib is low. The purpose of this study was to investigate the effects of cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on the prognosis of HCC and the sensitivity of HCC cells to Sorafenib. Patients and methods: Streptavidin-perosidase (SP) staining was performed to determine the expression of CDKN2B in HCC tissues and adjacent tissues. The cell counting kit-8 (CCK-8) assay was carried out to determine cell viability. CDKN2B mRNA and protein were tested by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. CDKN2B gene was silenced or over-expressed in the cells by plasmid transfection technique. Flow cytometry was carried out to detect cell cycle and apoptosis. Results: SP staining results showed that CDKN2B was positive in adjacent tissues and in HCC tissues from partial response (PR) patients, CDKN2B was slightly positive in stable disease (SD) patients, but negative in progression disease (PD) patients. The survival rate of patients with low expression of CDKN2B was low. Up-regulation of CDKN2B expression could promote the pro-apoptotic effect of Sorafenib and cell arrest in G1 phase. When the CDKN2B gene expression was down-regulated, the cell apoptosis rate and the proportion of cells treated with Sorafenib in G1 phase decreased. Silencing CDKN2B reversed CDKN2B overexpression caused by Sorafenib. Conclusion: CDKN2B genes were lowly expressed in tumor tissues from HCC patients who were treated with Sorafenib and had a poor prognosis. Up-regulation of CDKN2B promoted sensitivity of HCC to Sorafenib, and similarly down-regulation of CDKN2B reduced the sensitivity. [ABSTRACT FROM AUTHOR]

Purpose: Ventral tegmental area (VTA) dopamine system plays an important role in depression and is also involved in pain experience. In this study, we investigated the VTA dopaminergic (DA) neuron firing and local field potential (LFP) in pain-related depression, and we try to explore the underlying relationship between pain and depression.Materials and methods: We used neuropathic pain model [spare nerve injury (SNI)] to induce pain-related depression. The Dixon up–down method was used to test mechanical hypersensitivity. Behavioral changes like open field test, sucrose preference test, and forced swim test were used to test depression-like behaviors. Gabapentin (GBP) was used to explore the chronic analgesic treatment that could reverse pain-related depression. To investigate the in vivo variations of VTA DA neuron firing and LFP, multichannel acquisition processor system was used.Results: We used SNI to induce depression-like behaviors. Repeated GBP treatment reversed these behaviors after 14 days of injection. An in vivo electrophysiological analysis of the firing characteristics of VTA DA neurons and LFP revealed that SNI increased the firing rate of DA neurons, but not the burst firing activity. Surprisingly, chronic GBP reversed the firing rate of DA neurons and reduced the burst firing activity. Moreover, SNI increased the LFP power in delta and theta oscillation and decreased it in beta oscillation. Repeated administration of GBP significantly suppressed theta oscillation. Above all, chronic GBP altered these characteristics to reverse depression-like behaviors.Conclusion: The present study confirmed that the tonic firing activity of VTA DA neurons, but not the burst firing activity, was the key factor in peripheral neuropathy–induced depression. Chronic GBP regulated the firing pattern of DA neurons and decreased theta oscillation in VTA to treat pain-related depression. This variation tendency of electrophysiological characteristics of VTA DA neurons and theta oscillation in VTA might represent an attempt to cope with pain-related negative mood disorder. [ABSTRACT FROM AUTHOR]

The potassic alkaline igneous rocks along the Ailao Shan-Red River (ASRR) shear zone range in composition from ultramafic to felsic and are characterized by similar trace element patterns and radiogenic isotope ratios. Their distribution, and in some cases their structure and outcrop outline, suggest a genetic relationship to the ASRR shear zone. Zircons separated from 12 potassic alkaline bodies along the ASRR zone have been dated by an in situ U-Pb method to temporally constrain the left-lateral movements along the shear zone. The ages of the alkaline bodies range from 34.0 to 36.3 Ma. These new zircon ages, together with previous data, suggest that the onset age of the left-lateral movements along the ASRR shear zone began at or slightly before 36 Ma and that the movements lasted from ≥36 to 17 Ma. When uncertainties are taken into account, the duration of motion on the ASRR shear zone coincides with the opening of the South China Sea, implying a genetic relationship between these two events. [ABSTRACT FROM AUTHOR]

Abstract: Two types of acid-sensing ion channel (ASIC)-like currents in cultured rat hippocampal neurons were recorded and their characteristics were studied by using a whole-cell recording technique. The results revealed that the ASIC-like currents, induced by a quick drop of the extracellular pH, decayed with different time constants (τ) of 229 ± 16 (Type I) and 1209 ± 56ms (Type II). The ASIC-like currents displayed different sensitivities to extracellular proton (pH0.5 was 6.17 ± 0.04 for Type I and 5.70 ± 0.07 for Type II) and amiloride, a specific ASIC channel blocker (IC50 was 1.19 ± 0.37μM for Type I and 0.14 ± 0.02μM for Type II). Among all the 360 recorded neurons, ASIC-like currents were induced in 314 neurons (87.2%). In the neurons expressing ASICs, Type I currents were evoked from 269 neurons (85.7%) and Type II currents were induced only from 45 neurons (14.3%). As these ASIC-like currents presented various electrophysiological and pharmacological properties, further experiments should be conducted to decipher the complex subunit composition of ASICs in the hippocampus. [Copyright &y& Elsevier]

A response by Hua-Ying Liang, Ian H. Campbell, Charlotte A. Allen, Wei-Dong Sun, Ying-Weng Xie and Yuan-Qian Zhang to the letter to the editor about their article "The Age of the Potassic Alkaline Igneous Rocks Along the Ailao Shan-Red River Shear Zone: Implications for the Onset Age of Left-Lateral Shearing" in the 2007 issue is presented.

• Sleep deprivation leads to disrupted small-world networks. • Sleep loss induces enhanced clustering coefficient while reduced global efficiency. • Disrupted small-world networks link to attention decline after sleep deprivation. Sleep deprivation critically affects vigilant attention. Previous neuroimaging studies have revealed altered inter-regional functional connectivity after sleep deprivation, which may disrupt topological properties of brain functional networks. However, little is known about alterations in the topology of intrinsic connectivity and its involvement in attention performance after sleep deprivation. In the current study, we investigated the topological properties of brain networks derived from resting-state functional magnetic resonance imaging of 26 healthy men in rested wakefulness (RW) state and after 36 h of total sleep deprivation (TSD). In the predefined sparsity threshold range, both global and nodal network properties were evaluated based on graph theory analysis. Vigilant attention was assessed using the psychomotor vigilance test (PVT) before and after TSD. Furthermore, Pearson's correlation analyses were conducted to explore the association between altered network properties and changed PVT performance after TSD. At the global level, the brain functional networks in the TSD state showed a significantly lower small-world coefficient than RW, with decreased global efficiency. At the nodal level, the altered regions were selectively distributed in frontoparietal networks, sensorimotor networks, temporal regions, and salience networks. More specifically, the altered clustering coefficient in the posterior superior temporal sulcus (pSTS) and insula, and altered local efficiency in pSTS were further associated with PVT performance after TSD. Our results suggest that the topological properties of brain functional networks are disrupted, and aberrant topology of temporal networks and salience networks may act as neural signatures underlying the vigilant attention impairments after TSD. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a familiar malignant tumor, and cepharanthine (CEP) was proven to prevent the malignant activity of multiple cancer cells, including HCC. However, there are few reports on the regulatory role of CEP in HCC. After treatment with CEP or/and JAK2/Stat3 inhibitor (AG490), the associative functions were assessed by MTT, wound healing, Trans well, and Hochest33342-PI double staining in HCC cells. Then the levels of CDK4, MMP-9, Bcl-2, p-JAK2/JAK2, and p-Stat3/Stat3 were monitored via western blot. Besides, the HCC xenograft model was constructed to verify the effects of CEP on tumor growth and the JAK/Stat3 pathway. CEP could restrain proliferation and metastasis and facilitate apoptosis in HCC cells. CEP also reduced Bcl-2 (anti-apoptosis), CDK4 (proliferation), and MMP-9 (invasion) expressions, and inhibited JAK2 and Stat3 phosphorylation. Besides, CEP suppressed HCC progression by JAK2/Stat3 pathway. Moreover, CEP inhibited the growth of subcutaneous HCC xenografts and reduced p-JAK2 and p-Stat3 in tumor tissues. CEP could suppress HCC progression by attenuating the JAK2/Stat3 pathway, indicating that CEP might be a therapeutic drug for HCC patients.

Background: Trace elements such as copper are essential for human health. Recently the journal Nat Rev Cancer has put forward the concept of Cuproplasia, a way of promoting tumor growth through reliance on copper. We attempted to conduct a comprehensive analysis of Cuproplasia-related genes in lung adenocarcinoma (LUAD) to explore the mechanism of action of Cuproplasia-related genes in LUAD. Method: Transcriptome data and clinical information of LUAD were obtained from TCGA-LUAD and GSE31210, and prognostic models of Cuproplasia-related genes were constructed and verified by regression analysis of GSVA, WGCNA, univariate COX and lasso. The signal pathways affected by Cuproplasia-related genes were analyzed by GO, KEGG and hallmarK pathway enrichment methods. Five immunocell infiltration algorithms and IMVIGOR210 data were used to analyze immune cell content and immunotherapy outcomes in the high-low risk group. Results: In the results of WGCNA, BROWN and TURQUOISE were identified as modules closely related to Cuproplasia score. In the end, lasso regression analysis established a Cuproplasia-related signature (CRS) based on 24 genes, and the prognosis of high-risk populations was worse in TCGA-LUAD and GSE31210 datasets. The enrichment analysis showed that copper proliferation was mainly through chromosome, cell cycle, dna replication, g2m checkpoint and other pathways. Immunoinfiltration analysis showed that there were differences in the content of macrophages among the four algorithms. And IMVIGOR210 found that the lower the score, the more effective the immunotherapy was. Conclusion: The Cuproplasia related gene can be used to predict the prognosis and immunotherapy outcome of LUAD patients, and may exert its effect by affecting chromosome-related pathways and macrophages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kuang, Zheng, Ma, Zeng, Wu, Weng and Chen.)

It is commonly believed that alertness and attention decrease after sleep deprivation (SD). However, there are not enough studies on the changes in psychomotor vigilance testing (PVT) during SD and the corresponding changes in brain function and brain structure after SD. Therefore, we recruited 30 healthy adult men to perform a 36 h acute SD experiment, including the measurement of five indicators of PVT every 2 h, and analysis of cerebral blood flow (CBF) and grey matter volume (GMV) changes, before and after SD by magnetic resonance imaging (MRI). The PVT measurement found that the mean reaction time (RT), fastest 10% RT, minor lapses, and false starts all increased progressively within 20 h of SD, except for major lapses. Subsequently, all indexes showed a significant lengthening or increasing trend, and the peak value was in the range of 24 h-32 h and decreased at 36 h, in which the number of major lapses returned to normal. MRI showed that CBF decreased in the left orbital part of the superior frontal gyrus, the left of the rolandic operculum, the left triangular part, and the right opercular part of the inferior frontal gyrus, and CBF increased in the left lingual gyrus and the right superior gyrus after 36 h SD. The left lingual gyrus was negatively correlated with the major lapses, and both the inferior frontal gyrus and the superior frontal gyrus were positively correlated with the false starts. Still, there was no significant change in GMV. Therefore, we believe that 36 h of acute SD causes alterations in brain function and reduces alert attention, whereas short-term acute SD does not cause changes in brain structure.

Objective: To compare the effects of medical ozone oil and urea ointment for prevention and treatment of hand-foot skin reaction (HFSR) caused by sorafenib in patients with hepatocellular carcinoma (HCC)., Methods: A total of 99 patients diagnosed with advanced HCC according to National Comprehensive Cancer Network (NCCN) who were scheduled to receive sorafenib treatment for the first time were enrolled in this study between April, 2018 and January, 2020. The patients were randomized into medical ozone oil group ( n =49) and urea ointment group (control group, n =49) for treatment with local application of 1 mL medical ozone oil (experimental group) and 10% urea ointment (2 g) on the palm and plantar skin (including the fingers and joints) for 12 weeks (3 times per day) starting at the beginning of sorafenib treatment, respectively. The patients were observed for occurrence of HFSR every 2 weeks for 14 weeks., Results: Eight patients were excluded for poor compliance or protocol violations, leaving a total of 91 patients for analysis, including 44 in medical ozone oil group and 47 in urea ointment group. Sixteen (36.4%) of patients in ozone oil group developed HFSR, a rate significantly lower than that in urea ointment group (57.4%; P < 0.05). The incidence of grade 2/3 HFSR was also lower in ozone oil group than in urea ointment group (15.9% [7/44] vs 27.7 [13/47])., Conclusions: Medical ozone oil can significantly reduce the incidence and severity of HFSR to improve the quality of life of HCC patients receiving sorafenib treatment.

Objective: To explore the effects of hyperpolarization-activated cyclic nucleotide-gated channels 2(HCN2) in the formation of peripheral neuropathic pain in rats., Methods: Twenty-four healthy adult rats were divided into two groups randomly( n =12):the sham group rats were only isolated the left L4, L5 spinal nerve, the spinal nerve ligation(SNL) group was separated the spinal nerve and performed the corresponding ligation. The behavioral experiments were tested 7 days after operation; The model rats were randomly divided into 3 groups( n =6):① negative group(Saline), intra-plantar injection of saline in left hindpaws; ② positive group(gabapentin, GBPT), intraperitoneal injection of gabapentin; ③ experimental group(ZD7288), intra-plantar injection of ZD7288 in left hindpaws. The behavioral experiments were tested before injection and 1 h, 4 h, 24 h and 48 h after injection; Obtaining the dorsal root ganglion(DRG) of the control group (before operation), sham group and the SNL group( n =6), using qPCR and Western blot to analyze the mRNA and protein of HCN2 in rats' DRG., Results: The rat model of neuropathic pain was successfully established. Compared with saline group, GBPT group and ZD7288 group could significantly reduce the symptoms of neuropathic pain in rats after injection 1 h ( P <0.01), and there was no difference between GBPT group and ZD7288 group. Compared with control group and sham group, the expression of HCN2 mRNA in SNL group's DRG was significantly increased ( P <0.01), and the expression of HCN2 channel protein was also increased significantly ( P <0.05)., Conclusions: HCN2 is involved in the development of peripheral neuropathic pain and is likely to be a potential new target for the treatment of neuropathic pain.

Objective: To explore the underlying electrophysiological mechanism of depression induced by chronic pain in dopaminergic neurons in midbrain ventral tegmental area (VTA) of rats., Methods: Twenty-four healthy adult rats were divided into two groups randomly( n =12):12 rats formed the sham group by exposing the spared nerve, and another 12 rats were served as the spared nerve injury (SNI)group by branchedness sciatic nerve injury surgery. The mechanical allodynia test were detected on the day of 3, 7, 14, 28, 42 and 56 after surgery, and the depressive-like behaviors such as open-field test, sucrose preference and forcedswim test were detected at the same time. Then we used the Multichannel Acquisition Processor (MAP) system to record the firing activity of neurons in VTA in both Sham rats and SNI rats., Results: ①Comparing to sham rats, the paw withdrawalmechanical threshold of SNI rats was decreased significantly ( P < 0.01);② According to depression-related behavioral test, SNI rats showed significant difference in open field text, sucrose preference, focus swim text comparing with Sham rats ( P < 0.01);③ The firing rate and burst activity of dopaminergic neuronsin midbrain VTA are increased in depression rats compare to sham rats( P <0.05)., Conclusions: Chronic pain could induce depression, and the increase of spontaneous firing rate of dopaminergic neurons in midbrain VTA might be contribute to the depression induced by the chronic neuropathic pain.

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, distributing in a variety of tissues, especially in excitable cells such as heart cells and many kinds of neurons, have an important role in the modulation of heart rate and neuronal excitability. Different from typical voltage-gated sodium channels and potassium channels, HCN channels were evoked inward currents when the cell was hyperpolarized. More and more recent studies have disclosed that HCN channels play important roles in the nervous system, which were linked with its special electrophysiological features as well as its regulatory effect on the cellular membrane excitability. HCN channels could be modulated by many factors including both extracellular molecules and intracellular signaling cascades, which made its functions complicated in the different condition. Based on its role, HCN channels are presumed to be a promising target for chronic pain and brain disorders. In this paper, we will focus on the advancement of roles of HCN channels in the neural system as well as its complex modulator factors.

Aim: To investigate whether agmatine could selectively block a given type of the voltage-gated calcium channels (VGCC) and whether related receptors are involved in the blocking effect of agmatine on VGCC., Methods: The whole-cell patch recording technique was performed to record VGCC currents in the cultured neonatal rat hippocampal neurons., Results: Verapamil (100 micromol/L), a selective blocker of L-type calcium channel, significantly inhibited VGCC current by 80 %+/- 7 %. Agmatine (100 micromol/L) could further depress the remained currents by 25 %+/-6 %. The alpha 2-adrenoceptor antagonist yohimbine (10 micromol/L) and the I2 imidazoline receptor antagonist idazoxon (10 and 40 micromol/L) had no significant effect on VGCC currents when used respectively. When the mixture of yohimbine and agmatine was applied, VGCC currents were still depressed remarkably. However, the blocking effect of agmatine was decreased by 29 %+/- 8 % in the presence of idazoxon (10 micromol/L). The effect of idazoxon did not increase at a higher concentration (40 micromol/L)., Conclusion: Agmatine could block the L- and other types of VGCC currents in the cultured rat hippocampal neurons. Blocking effect of agmatine on VGCC was partially related to I2 imidazoline receptor and had no relationship with alpha 2-adrenoceptors.

Aim: To investigate the mechanism of agmatine by observing the effect of agmatine on the voltage-gated channels in rat hippocampal neurons., Methods: The whole-cell patch recording technique was performed to record the voltage-gated potassium, sodium, and calcium currents in cultured rat hippocampus. Agmatine was applied directly to the single neuron using a pressure injector with microtubules., Results: Agmatine (500 micromol/L) had no significant effect on the voltage-gated potassium and sodium channels. Agmatine reversibly blocked the voltage-gated calcium channel and the blockade was enhanced with the increasing concentration of agmatine. The inhibitory rates were 21%+/-4%, 35%+/-6%, 49%+/-6%, 67%+/-4%, 69%+/-6%, 86%+/-8%, and 87%+/- 9%, at the concentration of 0.1, 0.5, 1.0, 5.0, 10.0, 50.0, and 100 micromol/L, respectively. IC50 was (1.2+/-0.4) micromol/L. Two-way ANOVA revealed that change of membrane potential displayed a significant interaction with the blockade by agmatine., Conclusion: Agmatine reversibly blocked the voltage-gated calcium channel in rat hippocampal neurons in a concentration- and voltage-dependent way. Agmatine might perform its physiological and pharmacological effects partially by blocking the calcium channel.