Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer.

BACKGROUND: Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers suggests that early assessment of serum metabolites could serve as valuable biomarkers for predicting outcomes. This study aims to identify metabolites linked to treatment outcomes in patients with advanced NSCLC undergoing first-line or second-line therapy with programmed cell death 1 (PD-1) inhibitors plus chemotherapy. METHOD: 200 patients with advanced NSCLC receiving either first-line or second-line PD-1 inhibitor plus chemotherapy, and 50 patients undergoing first-line chemotherapy were enrolled in this study. The 200 patients receiving combination therapy were divided into a Discovery set (n=50) and a Validation set (n=150). These sets were further categorized into respond and non-respond groups based on progression-free survival PFS criteria (PFS≥12 and PFS<12 months). Serum samples were collected from all patients before treatment initiation for untargeted metabolomics analysis, with the goal of identifying and validating biomarkers that can predict the efficacy of immunotherapy plus chemotherapy. Additionally, the validated metabolites were grouped into high and low categories based on their medians, and their relationship with PFS was analyzed using Cox regression models in patients receiving combination therapy. RESULTS: After the impact of chemotherapy was accounted for, two significant differential metabolites were identified in both the Discovery and Validation sets: N-(3-Indolylacetyl)-L-alanine and methomyl (VIP>1 and p<0.05). Notably, upregulation of both metabolites was observed in the group with a poorer prognosis. In the univariate analysis of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were associated with longer PFS (HR=0.59, 95% CI, 0.41 to 0.84, p=0.003), and a prolonged PFS was also indicated by lower levels of methomyl (HR=0.67, 95% CI, 0.47 to 0.96, p=0.029). In multivariate analyses of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were significantly associated with a longer PFS (HR=0.60, 95% CI, 0.37 to 0.98, p=0.041). CONCLUSION: Improved outcomes were associated with lower levels of N-(3-Indolylacetyl)-L-alanine in patients with stage IIIB-IV NSCLC lacking driver gene mutations, who underwent first-line or second-line therapy with PD-1 inhibitors combined with chemotherapy. Further exploration of the potential predictive value of pretreatment detection of N-(3-Indolylacetyl)-L-alanine in peripheral blood for the efficacy of combination therapy is warranted. STATEMENT: The combination of ICIs and chemotherapy has established itself as the new standard of care for first-line or second-line treatment in patients with advanced NSCLC lacking oncogenic driver alterations. Therefore, identifying biomarkers that can predict the efficacy and prognosis of immunotherapy plus chemotherapy is of paramount importance. Currently, the only validated predictive biomarker is programmed cell death ligand-1 (PD-L1), but its predictive value is not absolute. Our study suggests that the detection of N-(3-Indolylacetyl)-L-alanine in patient serum with untargeted metabolomics prior to combined therapy may predict the efficacy of treatment. Compared with detecting PD-L1 expression, the advantage of our biomarker is that it is more convenient, more dynamic, and seems to work synergistically with PD-L1 expression.

Safety and efficacy of umbilical cord tissue-derived mesenchymal stem cells in the treatment of patients with aging frailty: a phase I/II randomized, double-blind, placebo-controlled study.

BACKGROUND: Mesenchymal stem cells (MSCs) hold a great promise for cell-based therapy in the field of regenerative medicine. In this study, we aimed to evaluate the safety and efficacy of intravenous infusion of human umbilical cord-derived MSCs (HUC-MSCs) in patients with aging frailty. METHODS: In this randomized, double-blind, placebo-controlled trial, participants diagnosed with aging frailty were randomly assigned to receive intravenous administrations of HUC-MSCs or placebo. All of serious adverse events and AEs were monitored to evaluate the safety of treatment during the 6-month follow-up. The primary efficacy endpoint was alteration of physical component scores (PCS) of SF-36 qualities of life at 6 months. The secondary outcomes including physical performance tests and pro-inflammatory cytokines, were also observed and compared at each follow-up visits. All evaluations were performed at 1 week, 1, 2, 3 and 6 months following the first intravenous infusion of HUC-MSCs. RESULTS: In the MSCs group, significant improvements in PCS of SF-36 were observed from first post-treatment visit and sustained throughout the follow-up period, with greater changes compared to the placebo group (p = 0.042). EQ-VAS scores of MSCs group improved significantly at 2 month (p = 0.023) and continued until the end of the 6-month visit (p = 0.002) in comparison to the placebo group. The timed up and go (TUG) physical performance test revealed significant group difference and showed continual enhancements over 6 months (p < 0.05). MSC transplantation improved the function of 4-m walking test (4MWT) compared with the placebo group with a decrease of 2.05 s at 6 months of follow-up (p = 0.21). The measurement of grip strength revealed group difference with MSCs group demonstrating better performance, particularly at 6 months (p = 0.002). Inflammatory cytokines (TNF-α, IL-17) exhibited declines in MSCs group at 6 months compared to the placebo group (p = 0.034 and 0.033, respectively). There was no difference of incidence of AEs between the two groups. CONCLUSION: Intravenous transplantation of HUC-MSCs is a safe and effective therapeutic approach on aging frailty. The positive outcomes observed in improving quality of life, physical performance, and reducing chronic inflammation, suggest that HUC-MSC therapy may be a promising potential treatment option for aging frailty. TRIAL REGISTRATION: Clinicaltrial.gov; NCT04314011; https://clinicaltrials.gov/ct2/show/NCT04314011 .

[Preliminary application of indocyanine green fluorescence imaging technology in nasal endoscopic tumor surgery].

Objective:To preliminarily study the practical value of Indocyanine green（ICG） molecular fluorescence imaging technology in nasal endoscopic tumor surgery. Methods:Five patients with tumors related to nasal sinuses, orbital wall and skull base in the Department of Otolaryngology head and Neck Surgery, General Hospital of Xinjiang Military Command from December 2022 to April 2023 were enrolled. Among them, 3 were benign tumors and 2 were malignant tumors. All patients underwent surgery under the guidance of ICG molecular fluorescence imaging. ICG was administered intravenously through cubital vein at a dose of 0.5 mg/kg 12 to 24 h before surgery. Tumors were labeled by fluorescence imaging during the operation. surgeons cleared the tumor tissue strictly according to the labeled range and depth, malignant tumors were further expanded and cleaned according to pathology results. Results:All 5 patients achieved accurate tumor localization with the aid of fluorescence imaging technology. Resections were performed with reference to fluorescent labeling boundaries, all patients achieved complete tumor cleanup or negative margins. Conclusion:For tumor-related surgery under nasal endoscopy, ICG molecular fluorescence imaging technology can not only achieve accurate real-time positioning, but also provide evidence for surgeons to judge tumor boundaries. Therefore, we believe that the technology should have certain practical value in nasal endoscopic tumor surgery.

Porcine epidemic diarrhea virus E protein induces formation of stress granules and attenuates protein translation through activation of the PERK/eIF2α signaling pathway.

Porcine epidemic diarrhea virus (PEDV) envelope protein (E) has been characterized as an important structural protein that plays critical roles in the interplay with its host to affect the virus life cycle. Stress granules (SGs) are host translationally silent ribonucleoproteins, which are mainly induced by the phosphorylation of eIF2α in the PERK/eIF2α signaling pathway. Our previous study found that PEDV E protein caused endoplasmic reticulum stress response (ERS)-mediated suppression of antiviral proteins' translation. However, the link and the underlying mechanism by which PEDV induces SGs formation and suppresses host translation remain elusive. In this study, our results showed that PEDV E protein significantly elevated the expression of GRP78, CANX, and phosphorylation of PERK and eIF2α, indicating that the PERK/eIF2α branch of ERS was activated. PEDV E protein localized to the ER and aggregated into puncta to reconstruct ER structure, and further induced SGs formation, which has been caused through upregulating the G3BP1 expression level. In addition, a significant global translational stall and endogenous protein translation attenuation were detected in the presence of E protein overexpression, but the global mRNA transcriptional level remained unchanged, suggesting that the shutoff of protein translation was associated with the translation, not with the transcription process. Collectively, this study demonstrates that PERK/eIF2α activation is required for SGs formation and protein translation stall. This study is beneficial for us to better understand the mechanism by which PEDV E suppresses host protein synthesis, and provides us a new insight into the host translation regulation during virus infection.

Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

BACKGROUND: Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. PURPOSE: A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). METHODS: The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. RESULTS: In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96 h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. CONCLUSIONS: In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Long-term outcomes of definitive radiation with volumetric modulated arc therapy and concurrent chemotherapy for squamous cell carcinoma of the anus in a regional Australian cancer centre.

INTRODUCTION: Concurrent chemoradiotherapy is the standard of care in the curative intent treatment of squamous cell carcinoma (SCC) of the anus. Volumetric arc therapy (VMAT) is a highly conformal radiation therapy technique that has been implemented to reduce toxicity for these patients. However, there are few reports evaluating the long-term outcomes of VMAT. Thus, we evaluated the survival and toxicity outcomes of anal cancer patients treated in our regional cancer centre undergoing curative intent chemoradiotherapy using VMAT and following the Australian EviQ guidelines. METHODS: All consecutive patients treated with the VMAT technique for curative-intent definitive chemoradiotherapy for anal SCC at our institution from 2013 until 2022 were retrospectively reviewed for survival and toxicity outcomes. Kaplan-Meier estimates of locoregional control, distant metastasis-free survival, disease-free survival, anal cancer-specific survival and overall survival were obtained. RESULTS: In total, 44 patients were analysed. The median follow-up was 48.9 months (Range 7.8-107). 97.7% of patients completed the prescribed radiation therapy and 88.6% chemotherapy. Five patients (11.4%) recurred. Four (9.1%) had isolated local failures, and one (2.3%) had an isolated distant failure. There were no regional nodal failures. The Kaplan-Meier estimates for locoregional control, distant metastasis-free survival, disease-free survival, anal cancer-specific survival and overall survival were 90.3%, 97.7%, 88.1%, 97.1% and 87% at 3 years, and 90.3%, 97.7%, 88.1%, 93.0% and 72.3% at 5 years, respectively. Acute grade 3 genitourinary (GU), gastrointestinal (GI) and skin toxicities occurred in 2.2%, 6.8% and 13.6% of patients, respectively. There were no acute grade 4 toxicities. Late grade 2 GU and GI toxicities occurred in 6.8% and 11.3% of patients, respectively. There were no late grade 3 or 4 toxicities or treatment-related deaths. The 5 -year colostomy-free survival rate was 86.4%. CONCLUSION: Outcomes for anal SCC after definitive chemoradiotherapy using VMAT in our regional cancer centre results in low rates of grade 3/4 toxicity, high rates of organ preservation and excellent survival outcomes.

Multi-functional ratiometric detection based on dual-emitting N-doped carbon dots.

Ratiometric fluorescence probes based on multi-emission carbon dots improve accuracy and sensitivity on detecting various environment issues. Herein, a novel dual-emitting N-doped carbon dots (N-CDs) was synthesized from citric acid and urea via a solvothermal method in N,N-dimethylformamide (DMF). The blue and orange emissions of N-CDs in water were modulated, and pure white light-emitting with Commission Internationale de L'Eclairage (CIE) coordinates of (0.33, 0.33) was achieved. The two PL centers behaved differently for Fe3+, Cu2+ and Ag+ ions, with the limit of detection (LOD) of ppm as fluorescence probes. Additionally, N-CDs displayed unique solvatochromism phenomenon. A new green emission appeared in organic solvents and gradually quenched with the increase of solvent polarity. The ratiometric PL displayed an excellent linear response for detecting water, and the LOD was between 0.003 % and 0.3 % in DMF, ethanol, isopropanol and N-methylpyrrolidone. Furthermore, N-CDs exhibited pH-sensitive response in the range of 4.0-7.0 and temperature-dependent response during heating-cooling cycles between 15 and 70 °C. A simple, efficient and reliable multi-functional ratiometric probe for detecting metal ions, water content, pH and temperature simultaneously was realized. However, there is a need for future application research to overcome the limitation imposed by the excitation wavelength of 330 nm.

The effects of robot-assisted laparoscopic surgery with Trendelenburg position on short-term postoperative respiratory diaphragmatic function.

OBJECTIVE: To study how Pneumoperitoneum under Trendelenburg position for robot-assisted laparoscopic surgery impact the perioperative respiratory parameters, diagrammatic function, etc. METHODS: Patients undergoing robot-assisted laparoscopic surgery in the Trendelenburg position and patients undergoing general surgery in the supine position were selected. The subjects were divided into two groups according to the type of surgery: robot-assisted surgery group and general surgery group. ① Respiratory parameters such as lung compliance, oxygenation index, and airway pressure were recorded at 5 min after intubation, 1 and 2 h after pneumoperitoneum. ② Diaphragm excursion (DE) and diaphragm thickening fraction (DTF) were recorded before entering the operating room (T1), immediately after extubation (T2), 10 min after extubation (T3), and upon leaving the postanesthesia care unit (T4). ③ Peripheral venous blood (5 ml) was collected before surgery and 30 min after extubation and was analyzed by enzyme-linked immunosorbent assay to determine the serum concentration of Clara cell secretory protein 16 (CC16) and surfactant protein D (SP-D). RESULT: ① Compared with the general surgery group (N = 42), the robot-assisted surgery group (N = 46) presented a significantly higher airway pressure and lower lung compliance during the surgery(P < 0.001). ② In the robot-assisted surgery group, the DE significantly decreased after surgery (P < 0.001), which persisted until patients were discharged from the PACU (P < 0.001), whereas the DTF only showed a transient decrease postoperatively (P < 0.001) and returned to its preoperative levels at discharge (P = 0.115). In the general surgery group, the DE showed a transient decrease after surgery(P = 0.011) which recovered to the preoperative levels at discharge (P = 1). No significant difference in the DTF was observed among T1, T2, T3, and T4. ③ Both the general and robot-assisted surgery reduced the postoperative serum levels of SP-D (P < 0.05), while the robot-assisted surgery increased the postoperative levels of CC16 (P < 0.001). CONCLUSION: Robot-assisted laparoscopic surgery significantly impairs postoperative diaphragm function, which does not recover to preoperative levels at PACU discharge. Elevated levels of serum CC16 after surgery suggest potential lung injury. The adverse effects may be attributed to the prolonged Trendelenburg position and pneumoperitoneum during laparoscopic surgery.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Real-world impact of chemotherapy on overall survival in craniomaxillofacial osteosarcoma.

OBJECTIVES: The goal of this study was to identify the survival benefit of chemotherapy in craniomaxillofacial osteosarcoma (CMFO) patients based on a US population. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to select patients with CMFO from 1988 to 2016. Age and tumor size were grouped by X-tail. Cox analysis were used to estimate hazards ratios (HR) among patients. All of patients were divided into two cohorts by using Propensity Score Matching (PSM) method to evaluate the effect of chemotherapy. All prognostic factors were included in the nomograms which predict the median survival time. RESULTS: 410 patients were included in our study. The results of survival rate, Kaplan-Meier and Cox regression were showed no significant difference between the group of chemotherapy performed and the group without chemotherapy. PSM analysis also demonstrated the limited survival advantage of chemotherapy. Moreover, all factors were further incorporated to construct the novel nomograms and its concordance indices (C-index) for internal validation of OS prediction were 0.749 (95 %CI:0.731-0.767). CONCLUSIONS: Our study did not show the advantage of chemotherapy on the overall survival outcome of CMFO. Although neoadjuvant chemotherapy was currently recommended in clinical treatment, more rigorous randomized controlled trials are still needed. Nomograms would assist clinicians in making more accurate survival evaluation and choosing the optimal medical treatment.

Targeting Neutrophil Extracellular Trap under Flow in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura.

Neutrophil NETosis is a unique form of cell death, characterized by release of decondensed chromatin and anti-microbial contents to the extracellular space, involved in infection, inflammation, and thrombosis. However, the role of NETosis in pathogenesis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) and how a targeted therapy affects the accumulation of neutrophil extracellular traps (NETs) under flow remain to be determined. Flow cytometry demonstrated that the percentage of neutrophils undergoing NETosis in whole blood from iTTP patients on admission is significantly increased with a concurrent decrease in the capacity of inducible NETosis by shigatoxin. Following therapy, the percentage of H3Cit+MPO+ neutrophils was significantly reduced with an improvement of inducible NETosis in these patients. Additionally, little to no NET and thrombus formation was detected under flow in whole blood from iTTP patients when platelet counts were very low, but the NET and thrombus formation were dramatically increased following therapy when platelet count rose to 50x109/L or was restored to normal with donor platelets. Similarly, there was no thrombus and NET accumulation under flow in whole blood from vwf-/- mice, but NET accumulation was significantly higher in Adamts13-/- than wild-type mice. Finally, recombinant ADAMTS13 or caplacizumab (or anfibatide) prevents the NET and thrombus formation under flow in whole blood from iTTP patients (or Adamts13-/- mice). These results indicate that neutrophil NETosis and NET formation depend on platelets and VWF in iTTP, and a targeted therapy such as recombinant ADAMTS13 or caplacizumab may prevent the NET and thrombus formation under flow in iTTP.

Application of Biologic Graft in Nasal Septal Perforation Repair.

Objective: To explore the clinical outcome when biomaterials are used to repair nasal septal perforations. Methods: A total of 12 patients were treated. The nasal septum was dissected via endoscopic approach. A 4 cm × 7 cm biologic graft (Biodesign® Tissue Graft) was folded to form a double layer, was placed over the perforation, and was affixed into place using suture. Results: Follow-up ranged from 2 to 8 months after the operation. One patient was not completely healed and presented with a remaining defect of about 2 mm × 8 mm in the upper part of the nasal septum. The remaining 11 patients healed completely. Conclusion: Using a biologic graft to repair nasal septal perforations is an easy operation as it prevents the need to take autologous tissue from the patient, allows for a repair to be performed without creating septal flaps, and has good histocompatibility. It is a safe and effective method that can be used clinically.

Terahertz radiation induced by shift currents in liquids.

Considerable progress has been made in the experimental studies on laser-induced terahertz (THz) radiation in liquids. Liquid THz demonstrates many unique features different from the gas and plasma THz. For example, the liquid THz can be efficiently produced by a monochromatic laser. Its yield is maximized with a longer driving-pulse duration. It is also linearly dependent on the excitation pulse energy. In two-color laser fields, an unexpected unmodulated THz field was measured, and its energy dependence of the driving laser is completely different from that of the modulated THz waves. However, the underlying microscopic mechanism is still unclear due to the difficulties in the description of ultrafast dynamics in complex disordered liquids. Here we propose a shift-current model. The experimental observations could be reproduced by our theory successfully. In addition, our theory could be further utilized to investigate the nuclear quantum effect in the THz radiation in H2O and D2O. This work provides fundamental insights into the origin of the THz radiation in bulk liquids.

ABHD7-mediated depalmitoylation of lamin A promotes myoblast differentiation.

LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/ß hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.

Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

Comprehensive analysis of pain genes in prognosis of kidney renal clear cell carcinoma and tumor immunotherapy: A comprehensive bioinformatic study.

Background: The effect of pain genes (NAV1, EHMT2, SP1, SLC6A4, COMT, OPRM1, OPRD1, CYP2D6, and CYP3A4) have not been reported previously in kidney renal clear cell carcinoma (KIRC) patients and thus we made a comprehensive analysis of pain genes in the prognosis of KIRC and tumor immunotherapy. Methods: In this study, TCGA, Kaplan-Meier plotter, Metascape, STRING, Human Protein Atlas, Single Cell Expression Atlas database, LinkedOmics, cBioPortal, MethSurv, CancerSEA, COSMIC database and R package (ggplot2, version 3.3.3) were used for comprehensive analysis of pain genes in KIRC. Pearson and Spearman correlation coefficients were for co-expression analysis. Immunotherapy and TISIDB database were used for tumor Immunotherapy. Results: Representative pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4) were statistically significant (p < 0.0001) in the prognosis of KIRC. Immunotherapy (anti-PD-1 therapy, anti-PD-L1 therapy, and anti-CTLA4 therapy) and immunomodulator (immunoinhibitor, immunostimulator, and MHC molecule) in KIRC were significant associated with pain genes (SP1, SLC6A4, COMT, OPRD1, CYP2D6, and CYP3A4), which were the important addition to clinical decision making for patients. Conclusions: Our study uncovered a mechanism for the effect of pain genes on KIRC outcome via the modulation of associated co-expression gene networks, gene variation, and tumor Immunotherapy.

Safety and Pharmacokinetics of HRS-2261, a P2X3 Receptor Antagonist, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

BACKGROUND: P2X3 receptor antagonists hold promising potential as a therapeutic option for patients with refractory or unexplained chronic cough, a condition lacking approved therapies. This study assessed the safety, tolerability, and pharmacokinetics (PK) of HRS-2261, a novel selective P2X3 receptor antagonist, in healthy subjects. METHODS: This randomized, double-blinded, placebo-controlled phase 1 trial of HRS-2261 consisted of three phases: the single ascending dose (SAD) study phase, the food-effect study phase, and the multiple ascending dose (MAD) study phase. In the SAD phase, healthy subjects were randomly assigned to receive a single oral dose of HRS-2261 (25, 100, 200, 400, 800, and 1200 mg) or placebo. Subjects in the 200 mg group of the SAD phase progressed directly to the food-effect phase following safety evaluation. In the MAD phase, healthy subjects were randomized to receive HRS-2261 (50, 200, and 400 mg) or placebo twice daily for 14 consecutive days. The primary endpoints were safety and tolerability. RESULTS: A total of 62 and 30 subjects were enrolled in the SAD and MAD phases, respectively, with 12 subjects from the SAD phase transitioning to the food-effect phase. The incidence and severity of adverse events (AEs) were not dose dependent, and most AEs were mild except for one moderate AE (epididymitis, which was not related to treatment) in the 400 mg group. Dysgeusia was reported in nine subjects, including two from the SAD phase, one from the food-effect phase, and six from the MAD phase. The median Tmax and geometric mean t1/2 were 0.9-2.0 h and 4.1-8.5 h in the SAD, and 2.0-2.7 h and 4.6-5.0 h on day 14 in the MAD, respectively. Drug exposures in the SAD and MAD phases were both less than dose proportional. The accumulation of the drug was slight with repeated twice-daily dosing. Food-effect study results showed that food intake did not affect the plasma exposure of HRS-2261. CONCLUSIONS: HRS-2261 demonstrated good tolerability, with a low incidence of dysgeusia. The PK profile was favorable. This study supports further development of HRS-2261 as a potential P2X3 receptor antagonist for chronic cough. TRIAL REGISTRATION NUMBER: Clinical trials.gov, identifier: NCT05274516. Trial registration date: March 10, 2022.

Physiologically based pharmacokinetic modeling of ritonavir-oxycodone drug interactions and its implication for dosing strategy.

The concomitant administration of ritonavir and oxycodone may significantly increase the plasma concentrations of oxycodone. This study was aimed to simulate DDI between ritonavir and oxycodone, a widely used opioid, and to formulate dosing protocols for oxycodone by using physiologically based pharmacokinetic (PBPK) modeling. We developed a ritonavir PBPK model incorporating induction and competitive and time-dependent inhibition of CYP3A4 and competitive inhibition of CYP2D6. The ritonavir model was evaluated with observed clinical pharmacokinetic data and validated for its CYP3A4 inhibition potency. We then used the model to simulate drug interactions between oxycodone and ritonavir under various dosing scenarios. The developed model captured the pharmacokinetic characteristics of ritonavir from clinical studies. The model also accurately predicts exposure changes of midazolam, triazolam, and oxycodone in the presence of ritonavir. According to model simulations, the steady-state maximum, minimum and average concentrations of oxycodone increased by up to 166% after co-administration with ritonavir, and the total exposure increased by approximately 120%. To achieve similar steady-state concentrations, halving the dose with an unchanged dosing interval or doubling the dosing interval with an unaltered single dose should be practical for oxycodone, whether formulated in uncoated or controlled-release tablets during long-term co-medication with ritonavir. The results revealed exposure-related risks of oxycodone-ritonavir interactions that have not been studied clinically and emphasized PBPK as a workable method to direct judicious dosage.

Breaking the Mutual Constraint between Polarization and Voltage Resistance with Nanograined High-Entropy Ceramic.

Dielectric ceramics with a high energy storage capacity are key to advanced pulsed power capacitors. However, conventional materials face a mutual constraint between polarization strength and the breakdown strength bottleneck. To address this limitation, the concept of nanograined high-entropy ceramics is introduced in this work. By introducing a large number of constituent elements into the A-site of perovskite material lattice, high-entropy (Bi0.2K0.2Ba0.2Sr0.2Ca0.2)TiO3-0.2 'CuO relaxor ceramic with nanoscale grains have been successfully prepared, which breaks the mutual constraint between polarization strength and breakdown strength bottleneck and results a recoverable energy density (Wrec ∼ 6.86 J/cm3) and an efficiency (η ∼ 87.7%) at 670 kV/cm. Moreover, its excellent stability makes it potentially useful under a variety of extreme conditions, including at high temperatures and high/low frequencies. These obtained results demonstrate that this nanograined high-entropy lead-free perovskite ceramic has great potential for energy storage applications.