In Situ Atomic Reconstruction Engineering Modulating Graphene-Like MXene-Based Multifunctional Electromagnetic Devices Covering Multi-Spectrum.

With the diversified development of big data, detection and precision guidance technologies, electromagnetic (EM) functional materials and devices serving multiple spectrums have become a hot topic. Exploring the multispectral response of materials is a challenging and meaningful scientific question. In this study, MXene/TiO2 hybrids with tunable conduction loss and polarization relaxation are fabricated by in situ atomic reconstruction engineering. More importantly, MXene/TiO2 hybrids exhibit adjustable spectral responses in the GHz, infrared and visible spectrums, and several EM devices are constructed based on this. An antenna array provides excellent EM energy harvesting in multiple microwave bands, with |S11| up to - 63.2 dB, and can be tuned by the degree of bending. An ultra-wideband bandpass filter realizes a passband of about 5.4 GHz and effectively suppresses the transmission of EM signals in the stopband. An infrared stealth device has an emissivity of less than 0.2 in the infrared spectrum at wavelengths of 6-14 µm. This work can provide new inspiration for the design and development of multifunctional, multi-spectrum EM devices.

P2X7 receptor: a potential target for treating comorbid anxiety and depression.

In clinical practice, depression and anxiety frequently coexist, and they are both comorbid with somatic diseases. The P2X7R is an adenosine 5'-triphosphate (ATP)-gated non-selective cation channel that is widely expressed in immune-related cells. Under conditions of stress, chronic pain, and comorbid chronic physical illness, P2X7R activation in glial cells leads to neuroinflammation. This could contribute to the development of anxiety and depression-related emotional disturbances. Previous studies have shown that the P2X7 receptor (P2X7R) plays an important role in the pathogenesis of both anxiety and depression. Thus, the P2X7R may play a role in the comorbidity of anxiety and depression. Positron emission tomography can be used to assess the degree and location of neuroinflammation by monitoring functional and expression-related changes in P2X7R, which can facilitate clinical diagnoses and guide the treatment of patients with anxiety and depression. Moreover, single nucleotide polymorphisms (SNPs) in the P2X7R gene are associated with susceptibility to different types of psychiatric disorders. Thus, evaluating the SNPs of the P2X7R gene could enable personalized mood disorder diagnoses and treatments. If the P2X7R were set as a therapeutic target, selective P2X7R antagonists may modulate P2X7R function, thereby altering the balance of intra- and extra-cellular ATP. This could have therapeutic implications for treating anxiety and depression, as well as for pain management. According to in vitro and in vivo studies, the P2X7R plays an important role in anxiety and depression. In this review, we consider the potential of the P2X7R as a therapeutic target for comorbid anxiety and depression, and discuss the potential diagnostic and therapeutic value of this receptor.

Electronic and Nonlinear Optical Properties of B(III)-Submonoazaporphyrin-π-Diimide Compounds: A Density Functional Theory Study.

Three hypothetical complexes were designed using diimides (PMDI, NTCDI, and PTCDI) as the acceptor unit and B(III)-submonoazaporphyrin (1) as the donor unit. These complexes have smaller HOMO-LUMO energy gaps (3.39-3.96 eV) than pristine 1 (6.61 eV). Further, the energy gap can be tuned by changing the number of benzene rings of these diimides. Remarkably, these proposed complexes possess considerable first hyperpolarizabilities (ß0) (4865-6921 a.u.), and the regularity of the ß0 values remained the same in the gas phase and toluene solvent conditions. There is an inverse relationship between the energy gap and the polarizability/first hyperpolarizability. In addition, absorption spectra, frontier molecular orbitals, and hole electron distributions were obtained using time-dependent density functional theory calculations to emphasize the relationship between structure and properties. Ultraviolet-Visible absorption spectra reveals that all complexes show satisfying IR working regions. Further analysis of the first hyperpolarizability density reveals the nature of the excellent NLO properties of the studied systems. This study can provide valuable insights for the development of potential high-performance NLO molecules.

Discovery of a Meisoindigo-Derived PROTAC as the ATM Degrader: Revolutionizing Colorectal Cancer Therapy via Synthetic Lethality with ATR Inhibitors.

Meisoindigo (Mei) has long been recognized in chronic myeloid leukemia (CML) treatment. To elucidate its molecular target and mechanisms, we embarked on designing and synthesizing a series of Mei-derived PROTACs. Through this endeavor, VHL-type PROTAC 9b was identified to be highly cytotoxic against SW620, SW480, and K562 cells. Employing DiaPASEF-based quantitative proteomic analysis, in combination with extensive validation assays, we unveiled that 9b potently and selectively degraded ATM across SW620 and SW480 cells in a ubiquitin-proteasome-dependent manner. 9b-induced selective ATM degradation prompted DNA damage response cascades, thereby leading to the cell cycle arrest and cell apoptosis. This pioneering discovery renders the advent of ATM degradation for anti-cancer therapy. Notably, 9b-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both in vitro and in vivo. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.

Design of High-Performance Inorganic-Organic Hybrid Nonlinear Optical Materials Using Superhalogen Al13 and Dianhydrides.

Novel inorganic-organic hybrid complexes Al13-X (X represents the dianhydrides PMDA, NTCDA, and PTCDA) are theoretically designed and studied using density functional theory (DFT) and time-dependent DFT. These conjugated dianhydrides containing four acceptor carbonyl groups are commonly used as electron acceptor materials. These compounds possess large binding energies, reflecting the sufficient binding of Al13 to the dianhydride molecule. The binding nature of the complexes is of charge transfer type, i.e., electrons are transferred from the aluminum cluster to the dianhydride. All of the aimed complexes have large mean polarizability (α0) and first hyperpolarizability (ß0). The ß0 values are explained on the basis of electronic transitions in crucial excited states using the TD-DFT method. Additionally, the hole-electron distribution was analyzed, revealing the nature of electronic excitation. Absorption spectra analysis shows that these complexes have an excellent infrared (IR) transparent region (1000-5000 nm). Therefore, these inorganic-organic hybrid complexes with high stability can be considered as potential candidates for new IR nonlinear optical molecules.

Laser-Induced Preparation of Anderson-Type Polyoxometalate-Derived Sulfide/Oxide Electrocatalysts for Electrochemical Water Oxidation.

Developing cost-effective and high-active electrocatalysts is vital to enhance the electrocatalytic performance for oxygen evolution reaction (OER). However, traditional pyrolysis methods require complicated procedures, exact temperatures, and long reaction times, leading to high costs and low yields of electrocatalysts in potential industrial applications. Herein, a rapid and economic laser-induced preparation strategy is proposed to synthesize three bimetallic sulfide/oxide composites (MMoOS, M=Fe, Co, and Ni) on a nickel foam (NF) substrate. A focused CO2 laser with high energy is applied to decompose Anderson-type polyoxometalate (POM)-based precursors, enabling the creation of abundant heteropore and defective structures in the MMoOS composites that have multi-components of MS/Mo4O11/MoS2. Remarkably, owing to the structural interactions between the active species, FeMoOS shows superior electrocatalytic performance for OER in an alkaline medium, exhibiting a low overpotential of 240 mV at 50 mA cm-2, a small Tafel slope of 79 mV dec-1, and good durability for 80 h. Physical characterizations after OER imply that partially dissolved Mo-based species and new-formed NiO/NiOOH can effectively uncover abundant active sites, fasten charge transfer, and modify defective structures. This work provides a rapid laser-induced irradiation method for the synthesis of POM-derived nanocomposites as promoted electrocatalysts.

Sodium tanshinone IIA sulfonate suppresses microglia polarization and neuroinflammation possibly via regulating miR-125b-5p/STAT3 axis to ameliorate neuropathic pain.

The spinal cord microglia play a pivotal role in neuroinflammation and neuropathic pain (NP). Sodium tanshinone IIA sulfonate (STS), a derivative of tanshinone IIA, has anti-inflammatory and anti-hyperalgesic effects. However, its underlying mechanism in NP remains unclear. This study aimed to investigate the effect of STS and elucidate possible mechanisms in a rat model of spared nerve injury. In vivo experiments, STS and AG490 were administered intraperitoneally once daily for 14 consecutive days after surgery. The results showed that the expression of miR-125b-5p in the spinal dorsal horn was substantially reduced, whereas signal transducer and activator of transcription 3 (STAT3) signaling was increased. After treatment with STS, the mechanical thresholds, expression of miR-125b-5p, and microglial M2 marker such as Arg-1 in the spinal cord horn increased significantly, whereas multiple pro-inflammatory cytokines and apoptosis were significantly reduced. Moreover, STAT3 pathway-related proteins and expression of the microglial M1 marker, CD68, were appreciably inhibited. In vitro, lipopolysaccharide (LPS) was used to induce an inflammatory response in BV-2 microglial cells. STS pretreatment inhibited LPS-stimulated pro-inflammatory cytokine secretion, reduced STAT3 pathway related-proteins and apoptosis, increased miR-125b-5p and proopiomelanocortin expression, and enhanced microglia transformation from M1 to M2 phenotype in BV-2 cells. These effects were reversed after the inhibition of miR-125b-5p expression in BV-2 cells. A dual-luciferase reporter assay confirmed that STAT3 binds to miR-125b-5p. In summary, these results suggest that STS exerts anti-hyperalgesic and anti-neuroinflammatory effects in rats with NP possibly via the miR-125b-5p/STAT3 axis.

Icariin ameliorates glycolytic dysfunction in Alzheimer's disease models by activating the Wnt/ß-catenin signaling pathway.

It was reported that the Wnt/ß-catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/ß-catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg-AD mice were treated with ICA. HT22 cells, the Aß25-35 peptide and Dickkopf-1 (DKK1) agent (a specific inhibitor of the Wnt/ß-catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti-AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg-AD mice back to wild-type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aß25-35 . However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg-AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/ß-catenin pathway.

Systematic Characterization of the Clinical and Pathological Features of Schwannomas Harboring SH3PXD2A::HTRA1 Fusion.

The understanding of schwannoma tumorigenesis has been reshaped by the recent identification of SH3PXD2A::HTRA1 fusion in 10% of intracranial/spinal schwannomas. Nonetheless, pathologic features of schwannomas harboring this fusion, as well as its prevalence outside intracranial/spinal locations, have not been characterized. We screened 215 consecutive schwannomas for their clinicopathologic characteristics and fusion status using reverse-transcriptase polymerase chain reaction (RT-PCR). Among 29 (13.5%) fusion-positive schwannomas, the most prevalent location was peripheral somatic tissue (30.7%, 19/62), followed by spinal/paraspinal (18.4%, 7/38), body cavity/deep structures (10%, 2/20), intracranial (1.3%, 1/75), and viscera (0/13). All 8 cellular, 4 microcystic/reticular, and 3 epithelioid schwannomas were fusion-negative, as were 41/42 nonschwannomatous peripheral nerve sheath tumors. Remarkably, a distinct 'serpentine' palisading pattern, comprising ovoid/plump cells shorter than usual schwannian cells in a hyalinized stroma, was identified in most fusion-positive cases and the schwannomatous component of the only fusion-positive malignant peripheral nerve sheath tumor. To validate this finding, 60 additional cases were collected, including 36 with (≥10% arbitrarily) and 24 without appreciable serpentine histology, of which 29 (80.6%) and 2 (8.3%) harbored the fusion, respectively. With percentages of 'serpentine' areas scored, 10% was determined as the optimal practical cut-off to predict the fusion status (sensitivity, 0.950; specificity, 0.943). Fusion positivity was significantly associated with serpentine histology, smaller tumors, younger patients, and peripheral somatic tissue, while multivariate logistic linear regression analysis only identified serpentine histology and location as independent fusion-predicting factors. RNA in situ hybridization successfully detected the fusion junction, highly concordant with RT-PCR results. Gene expression profiling on 18 schwannomas demonstrated segregation largely consistent with fusion status. Fusion-positive cases expressed significantly higher HTRA1 mRNA abundance, perhaps exploitable as a biomarker. In summary, we systematically characterize a series of 60 SH3PXD2A::HTRA1 fusion-positive schwannomas, showing their distinctive morphology and location-specific prevalence for the first time.

Accidental ingestion of multiple magnetic beads by children and their impact on the gastrointestinal tract: a single-center study.

OBJECTIVE: In this study, we aimed to enhance the treatment protocols and help understand the harm caused by the accidental ingestion of magnetic beads by children. METHODS: Data were collected from 72 children with multiple gastrointestinal perforations or gastrointestinal obstructions. The 72 pediatric patients were divided into a perforation and a non-perforation group. The data collected for the analysis included the gender, age, medical history, place of residence (rural or urban), and symptoms along with the educational background of the caregiver, the location and quantity of any foreign bodies discovered during the procedure, whether perforation was confirmed during the procedure, and the number of times magnetic beads had been accidentally ingested. RESULTS: The accuracy rate of preoperative gastrointestinal perforation diagnosis via ultrasound was 71%, while that of the upright abdominal X-ray method was only 46%. In terms of symptoms, the risk of perforation was 13.844 and 12.703 times greater in pediatric patients who experienced vomiting and abdominal pain with vomiting and abdominal distension, respectively, compared to patients in an asymptomatic state. There were no statistical differences between the perforation and the non-perforation groups in terms of age, gender, medical history, and the number of magnetic beads ingested (P > 0.05); however, there were statistical differences in terms of white blood cell count (P = 0.048) and c-reactive protein levels (P = 0.033). A total of 56% of cases underwent a laparotomy along with perforation repair and 19% underwent gastroscopy along with laparotomy. All pediatric patients recovered without complications following surgery. CONCLUSION: Abdominal ultrasonography and/or upright abdominal X-ray analyses should be carried out as soon as possible in case of suspicion of accidental ingestion of magnetic beads by children. In most cases, immediate surgical intervention is required. Given the serious consequences of ingesting this type of foreign body, it is essential to inform parents and/or caregivers about the importance of preventing young children from using such products.

RNA Interference-Screening of Potentially Lethal Gene Targets in the White-Backed Planthopper Sogatella furcifera via a Spray-Induced and Nanocarrier-Delivered Gene Silencing System.

RNA interference (RNAi) is a widespread post-transcriptional silencing mechanism that targets homologous mRNA sequences for specific degradation. An RNAi-based pest management strategy is target-specific and considered a sustainable biopesticide. However, the specific genes targeted and the efficiency of the delivery methods can vary widely across species. In this study, a spray-induced and nanocarrier-delivered gene silencing (SI-NDGS) system that incorporated gene-specific dsRNAs targeting conserved genes was used to evaluate phenotypic effects in white-backed planthopper (WBPH). At 2 days postspraying, transcript levels for all target genes were significantly reduced and knockdown of two gene orthologs, hsc70-3 and PP-α, resulted in an elevated mortality (>60%) and impaired ecdysis. These results highlight the utility of the SI-NDGS system for identifying genes involved in WBPH growth and development that could be potentially exploitable as high mortality target genes to develop an alternative method for WBPH control.

Activation of the alternative complement pathway modulates inflammation in thoracic aortic aneurysm/dissection.

Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.

Diagnostic value of 18F-PSMA-1007 PET/CT for predicting the pathological grade of prostate cancer.

This study was designed to evaluate the diagnostic efficacy of relevant parameters of 18F-prostate-specific membrane antigen (PSMA)-1007 PET/CT in predicting the pathological grade of primary prostate cancer. Briefly, a prospective analysis was performed on 53 patients diagnosed with prostate cancer by systematic puncture biopsy, followed by 18F-PSMA-1007 PET/CT examination prior to treatment within 10 d. The patients were grouped in accordance with the Gleason grading system revised by the International Association of Urology Pathology (ISUP). They were divided into high-grade group (ISUP 4-5 group) and low-grade group (ISUP 1-3 group). The differences in maximum standardized uptake value (SUVmax), tumor-to-background ratio (TBR), intraprostatic PSMA-derived tumor volume (iPSMA-TV), and intraprostatic total lesion PSMA (iTL-PSMA) between the high- and low-grade group were statistically significant (p < .001). No significant difference was found for mean standardized uptake value (SUVmean) between the high- and low-grade groups (Z = -1.131, p = .258). Besides, binary multivariate logistic regression analysis showed that only iPSMA-TV and iTL-PSMA were independent predictors of the pathological grading, for which the odds ratios were 18.821 [95% confidence interval (CI): 2.040-173.614, p = .010] and 0.758 (95% CI: 0.613-0.938, p = .011), respectively. The area under the ROC of this regression model was 0.983 (95% CI: 0.958-1.00, p < .001). Only iTL-PSMA was a significant parameter for distinguishing ISUP-4 and ISUP-5 groups (Z = -2.043, p = .041). In a nutshell, 18F-PSMA-1007 PET/CT has good application value in predicting the histopathological grade of primary prostate cancer. Three-dimensional volume metabolism parameters iPSMA-TV and iTL-PSMA were found to be independent predictors for pathological grade.

Lipid mediator resolvin D2 inhibits ATP currents in rat primary sensory neurons.

Resolvin D2 (RvD2), an endogenous lipid mediator derived from docosahexaenoic acid, has been demonstrated to have analgesic effects. However, little is known about the mechanism underlying RvD2 in pain relief. Herein, we demonstrate that RvD2 targeted the P2X3 receptor as an analgesic. The electrophysiological activity of P2X3 receptors was suppressed by RvD2 in rat dorsal root ganglia (DRG) neurons. RvD2 pre-application dose-dependently decreased α,ß-methylene-ATP (α,ß-meATP)-induced inward currents. RvD2 remarkably decreased the maximum response to α,ß-meATP, without influencing the affinity of P2X3 receptors. RvD2 also voltage-independently suppressed ATP currents. An antagonist of the G protein receptor 18 (GPR18), O-1918, prevented the RvD2-induced suppression of ATP currents. Additionally, intracellular dialysis of the Gαi/o -protein antagonist pertussis toxin (PTX), the PKA antagonist H89, or the cAMP analog 8-Br-cAMP also blocked the RvD2-induced suppression. Furthermore, α,ß-meATP-triggered depolarization of membrane potential along with the action potential bursts in DRG neurons were inhibited by RvD2. Lastly, RvD2 attenuated spontaneous nociceptive behaviors as well as mechanical allodynia produced by α,ß-meATP in rats via the activation of the peripheral GPR18. These findings indicated that RvD2 inhibited P2X3 receptors in rat primary sensory neurons through GPR18, PTX-sensitive Gαi/o -proteins, and intracellular cAMP/PKA signaling, revealing a novel mechanism that underlies its analgesic effects by targeting P2X3 receptors.

C-C chemokine receptor 5 is essential for conventional NK cell trafficking and liver injury in a murine hepatitis virus-induced fulminant hepatic failure model.

BACKGROUND: Previous studies have demonstrated that natural killer (NK) cells migrated into the liver from peripheral organs and exerted cytotoxic effects on hepatocytes in virus-induced liver failure. AIM: This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis  virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism. RESULTS: By gene array analysis, chemokine (C-C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1ß and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1ß or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model. CONCLUSION: The CCR5-MIP-1ß/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.

Corrigendum: Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes.

[This corrects the article DOI: 10.3389/fphar.2022.972397.].

CCK-8 enhances acid-sensing ion channel currents in rat primary sensory neurons.

Cholecystokinin (CCK) is a peptide that has been implicated in pain modulation. Acid sensitive ion channels (ASICs) also play an important role in pain associated with tissue acidification. However, it is still unclear whether there is an interaction between CCK signaling and ASICs during pain process. Herein, we report that a functional link between them in rat dorsal root ganglion (DRG) neurons. Pretreatment with CCK-8 concentration-dependently increased acid-evoked ASIC currents. CCK-8 increased the maximum response of ASICs to acid, but did not changed their acid sensitivity. Enhancement of ASIC currents by CCK-8 was mediated by the stimulation of CCK2 receptor (CCK2R), rather than CCK1R. The enhancement of ASIC currents by CCK-8 was prevented by application of either G-protein inhibitor GDP-ß-S or protein kinase C (PKC) inhibitor GF109203×, but not by protein kinase A (PKA) inhibitor H-89 or JNK inhibitor SP600125. Moreover, CCK-8 increased the number of action potentials triggered by acid stimuli by activating CCK2R. Finally, CCK-8 dose-dependently exacerbated acid-induced nociceptive behavior in rats through local CCK2R. Together, these results indicated that CCK-8/CCK2R activation enhanced ASIC-mediated electrophysiological activity in DRG neurons and nociception in rats. The enhancement effect depended on G-proteins and intracellular PKC signaling rather than PKA and JNK signaling pathway. These findings provided that CCK-8/CCK2R is an important therapeutic target for ASIC-mediated pain.

Impact of Genomic Alterations on the Clinical Outcome of Patients With Hepatitis B-related Hepatocellular Carcinoma Receiving Curative Surgery: A Retrospective Cohort Study.

BACKGROUND/AIM: The aim of the current study was to obtain comprehensive genomic information on viral hepatitis B (HBV)-related hepatocellular carcinoma (HCC) and identify potential biomarkers of early recurrence in patients receiving curative surgery. PATIENTS AND METHODS: A total of 104 patients with HBV-related HCC receiving curative surgery at Kaohsiung Chang Gung Memorial Hospital between January 2017 and December 2020 were identified, including 52 patients each with and without recurrence. Next-generation sequencing was performed to investigate genomic alterations caused by surgical resection of specimens. The Kaplan-Meier method was used to estimate disease-free survival and overall survival. RESULTS: The landscape of gene mutations in HCC patients of our cohort showed a median number of single nucleotide variants of 250, a median number of insertions and deletions of 22, and a median number of protein-coding mutations of 185. The 10 most frequently mutated genes were TP53 (43%), TTN (39%), MUC16 (28%), PCLO (25%), OBSCN (22%), ADGRV1 (19%), ALB (18%), SYNE1 (18%), DNAH17 (17%), and RYR1 (17%). The tumour mutation burden was 4.8 mutations per megabase, and high microsatellite instability was reported in only three patients. In addition, the mutational signatures showed that aristolochic acid exposure was highly implicated in our HCC cohort. Five mutant genes, TBC1D4, ITGA4, RPS6KA3, VWA8, and FMN2, were more frequent in the recurrence group than that in the non-recurrence group. CONCLUSION: Our results present an in-depth genomic analysis of HBV-related HCC. The study findings provide an improved understanding of the related molecular mechanisms and identify potential biomarkers associated with early tumour recurrence after curative resection.

The prognostic significance of histologic variant on survival outcomes in patients with metastatic urothelial carcinoma receiving immune checkpoint inhibitor therapy.

BACKGROUND: While the treatment guidelines have been established for pure urothelial carcinoma (pUC), patients with variant type urothelial carcinoma (vUC) face limited effective treatment options. The effectiveness of immune checkpoint inhibitors (ICI) in patients with vUC remains uncertain and necessitates additional research. METHOD: We conducted a retrospective, multicenter study to explore the effectiveness of ICI in patients with pUC or vUC in Taiwan. We evaluated the overall response rate (ORR) through univariate logistic regression analysis and examined the overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier analysis. Additionally, we employed univariate and multivariate Cox proportional hazards models to analyze the data. RESULT: A total of 142 patients (116 pUC, 26 vUC) were included in our final analysis. The ORR was marginally higher in patients with pUC compared to those with vUC (34.5% vs. 23.1%, p = 0.26). Among all patients, 12.9% with pUC achieved a complete response (CR) after ICI treatment, while no vUC cases achieved CR (p = 0.05). There were no significant differences in PFS (median 3.6 months vs. 4.1 months, p = 0.34) or OS (median 16.3 months vs. 11.0 months, p = 0.24) when comparing patients with pUC or vUC. In the subgroup analysis, patients with pUC who underwent first-line ICI treatment exhibited significantly improved OS compared to those with vUC (24.6 months vs. 9.1 months, p = 0.004). CONCLUSION: The use of ICI as monotherapy is a feasible and effective treatment approach for patients with metastatic vUC.