Optimizing patient outcomes: the impact of multimodal preemptive analgesia in video-assisted thoracoscopic lobectomy.

OBJECTIVES: To evaluate the efficacy of a multimodal preemptive analgesia management approach, specifically incorporating ultrasound-guided thoracic paravertebral block (UG-TPVB) in conjunction with intravenous analgesia, after video-assisted thoracoscopic (VATS) lobectomy under the guidance of Enhanced Recovery After Surgery (ERAS). METHODS: A total of 690 patients who underwent VATS lobectomy between October 2021 and March 2022 were divided into the UG-TPVB group (group T, n = 345) and control group (group C, n = 345). Patients in group T received UG-TPVB prior to the induction of general anaesthesia, while group C did not undergo nerve block. A comparison was conducted between the two groups regarding various indicators, including postoperative sedation, static/dynamic numeric rating scale (NRS) scores, intraoperative fentanyl consumption, duration of mechanical ventilation/anaesthesia recovery/hospitalization, postoperative complications, and other relevant factors. RESULTS: The static/dynamic NRS scores of group T were lower than those of group C after surgery. Intraoperative fentanyl consumption in group T (0.384 ± 0.095 mg) was lower than that in group C (0.465 ± 0.053 mg). The duration of mechanical ventilation, anaesthesia recovery, and hospitalization were significantly shorter in group T compared to group C. Patient satisfaction rate in group T (70.1%) was higher than that in group C (53.6%). All differences were statistically significant (P < 0.05). CONCLUSIONS: The multimodal preemptive analgesia management strategy effectively reduces postoperative pain, decreases opioid consumption, and promotes faster recovery in patients undergoing VATS lobectomy.

Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy.

BACKGROUND: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies. METHODS: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms. RESULT: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM. CONCLUSION: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

Distinguishable Magnetic Reporter Coordination with Buoyancy-Magnetism Separation for Immobilization-Free Dual-Target Electrochemical Immunosensing.

Simultaneous sensitive and precise determination of multibiomarkers is of great significance for improving detection efficiency, reducing diagnosis and treatment expenses, and elevating survival rates. However, the development of simple and portable biosensors for simultaneous determination of multiplexed targets in biological fluids still faces challenges. Herein, a unique and versatile immobilization-free dual-target electrochemical biosensing platform, which combines distinguishable magnetic signal reporters with buoyancy-magnetism separation, was designed and constructed for simultaneous detection of carcinoembryonic (CEA) and α-fetoprotein (AFP) in intricate biological fluids. To construct such distinguishable magnetic signal reporters with signal transduction, amplification, and output, secondary antibodies of CEA and AFP were respectively functionalized on methylene blue (MB) and 6-(ferrocenyl)hexanethiol (FeC) modified Fe3O4@Au magnetic nanocomposites. Meanwhile, a multifunctional flotation probe with dual target recognition, capture, and isolation capability was prepared by conjugating primary antibodies (Ab1-CEA, Ab1-AFP) to hollow buoyant microspheres. The target antigens of CEA and AFP can trigger a flotation-mediated sandwich-type immunoreaction and capture a certain amount of the distinguishable magnetic signal reporter, which enables the conversion of the target CEA and AFP quantities to the signal of the potential-resolved MB and FeC. Thus, the MB and FeC currents of magnetically adsorbed distinguishable magnetic reporters can be used to determine the CEA and AFP targets simultaneously and precisely. Accordingly, the proposed strategy exhibited a delightful linear response for CEA and AFP in the range of 100 fg·mL-1-100 ng·mL-1 with detection limits of 33.34 and 17.02 fg·mL-1 (S/N = 3), respectively. Meanwhile, no significant nonspecific adsorption and cross-talk were observed. The biosensing platform has shown satisfactory performance in the determination of real clinical samples. More importantly, the proposed approach can be conveniently extended to universal detection just by simply substituting biorecognition events. Thus, this work opens up a new promising perspective for dual and even multiple targets and offers promising potential applications in clinical diagnosis.

Farnesol repurposing for prevention and treatment of Acinetobacter baumannii biofilms.

Acinetobacter baumannii has emerged as a multidrug-resistant (MDR) superbug by causing severe infections, with high mortality rates. The ability of A. baumannii to form biofilms significantly contributes to its persistence in diverse environmental and hospital settings. Here we report that farnesol, an FDA-approved commercial cosmetic and flavoring agent, demonstrates efficacy for both inhibition of biofilm formation, and disruption of established A. baumannii biofilms. Moreover, no resistance to farnesol was observed even after prolonged culture in the presence of sub-inhibitory farnesol doses. Farnesol combats A. baumannii biofilms by direct killing, while also facilitating biofilm detachment. Furthermore, farnesol was safe, and effective, for both prevention and treatment of A. baumannii biofilms in an ex vivo burned human skin model. Since current treatment options for A. baumannii biofilm infections were mainly counted on the combination therapy of last-resort antibiotics, and clearly non-sustainable due to robust MDR phenotype of A. baumannii, we propose that farnesol alone can be repurposed as a highly effective agent for both preventing and treating life-threating biofilm-associated infections of A. baumannii due to its proven safety, convenient topical delivery, and excellent efficiency, plus its superiority of evading resistance development.

Remanufacturing and channel strategies in e-commerce closed-loop supply chain.

This paper studies the recycling and remanufacturing mode and sales channel issues in the closed-loop supply chain. Specifically, this study establishes an e-commerce closed-loop supply chain consisting of a manufacturer and an e-commerce platform, and divides the recycling model into recycling by the manufacturer or recycling by the platform. Considering two common sales models in e-commerce platforms: the resale model and agency model, combined with the recycling model, four different research scenarios are formed. We use backward induction to solve the Stackelberg game problem and explore the remanufacturing and channel strategies of the manufacturer and the e-commerce platform. The research results show that for the manufacturer, under the same recycling model, when consumers' preference for remanufactured products and the sensitivity of recycling volume to recycling prices are low, he will prefer the resale model. Under the same sales model, the manufacturer always prefers the recycling model in which he is responsible for recycling. However, the choice of platform is contrary to that of the manufacturer. In the resale model, both the manufacturer and the platform will choose to recycle by themselves, which cannot achieve a win-win situation. Under the agency model, when consumers' preference for remanufactured products is high and the sensitivity coefficient of recycling volume to recycling price is low, supply chain members can achieve a win-win situation, and the scope of the win-win situation decreases as the unit production cost of new products increases. In addition, rising consumer preference for remanufactured products will lead to lower consumer surplus.

Interventional therapy combined with tyrosine kinase inhibitors with or without immune checkpoint inhibitors as initial treatment for hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis.

BACKGROUND: Interventional therapy, in conjunction with tyrosine kinase inhibitors (TKIs), has shown promising outcomes for treating hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). With the advent of immunotherapy, the combined use of immune checkpoint inhibitors (ICIs) has attracted great attention due to their potential effectiveness in advanced HCC. This study aims to compare the efficacy and safety of a triple therapy regimen (Interventional therapy, TKIs and ICIs, IT-TKI-ICI) with a dual therapy regimen (Interventional therapy and TKIs, IT-TKI) in the treatment of HCC and PVTT (HCC-PVTT). METHODS: A comprehensive search was carried out in PubMed, Web of Science, Embase, Scopus, and the Cochrane Library databases. Primary outcome measures were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included tumor response rate, adverse event incidence as well as downstaging surgery rate. Statistical analysis was conducted using Revman 5.4 software. RESULTS: The meta-analysis finally included 6 cohort studies. The triple therapy group demonstrated significantly prolonged OS and PFS compared to the dual therapy group. Meanwhile, the former exhibited significantly higher rates of objective response rate (ORR), disease control rate (DCR) and better downstaging effects with a higher salvage surgery rate without significantly increasing adverse events. CONCLUSION: In comparison to dual therapy, the triple therapy with interventional therapy, TKIs, and ICIs demonstrates superior efficacy and equivalent safety for HCC-PVTT.

XTP8 Promotes Ovarian Cancer Progression by Activating AKT/AMPK/mTOR Pathway to Regulate EMT.

Ovarian cancer (OC) ranks as the fifth leading cause of cancer-related death in women. The main contributors to the poor prognosis of ovarian cancer are the high rates of recurrence and metastasis. Studies have indicated a crucial role for hepatitis B virus X Ag-Transactivated Protein 8 (XTP8), a protein containing the DEP domain, in various cellular processes, including cell growth, movement, and differentiation, across several types of cancers. However, the role of XTP8 in ovarian cancer remains unclear. We observed elevated expression of XTP8 in ovarian cancer. Silencing XTP8 inhibited cell proliferation, promoted apoptosis, and yielded contrasting results in cells overexpressing XTP8. Furthermore, XTP8 facilitated ovarian cancer invasion and migration, triggering epithelial-mesenchymal transition (EMT). Mechanistically, XTP8 silencing led to reduced phosphorylation levels of AKT, increased p-AMPK levels, and decreased p-mTOR levels, while XTP8 overexpression exerted the opposite effects. Additionally, the activation of p-AMPK rescued the promoting effect of XTP8 on EMT in ovarian cancer cell lines, indicating that XTP8 acts as an oncogene by modulating the AKT/AMPK/mTOR pathway. Through transcriptome sequencing to identify downstream targets of XTP8, we found that XTP8 influences the expression of Caldesmon (CALD1) at both transcriptional and translational levels. CALD1 can be considered a downstream target of XTP8. The collaborative action of XTP8 and CALD1 activates the AKT/AMPK/mTOR pathway, regulating EMT to promote ovarian cancer progression. Inhibiting this signaling axis might represent a potential therapeutic target for ovarian cancer.

Association between lactate dehydrogenase and the risk of diabetic kidney disease in patients with type 2 diabetes.

Objective: This study aims to investigate the association between lactate dehydrogenase (LDH) and the risk of diabetic kidney disease (DKD) in patients with type 2 diabetes (T2D). Methods: The study enrolled patients with diagnosis of T2D between 2009 and 2018 from the National Nutrition and Health Examination Survey (NHANES) database. Demographic information, laboratory test, and diagnostic data were collected. Restricted cubic spline (RCS) plots were used to assess the dose-effect relationship between LDH levels and the risk of DKD in patients with T2D. Based on LDH levels, individuals were divided into higher and lower groups using dichotomy, and multivariate logistic regression analysis was conducted to explore the relationship between different LDH levels and the risk of DKD in T2D patients. Stratified analysis was performed to assess the consistency of the result. Results: A total of 4888 patients were included in the study, with 2976 (60.9%) patients without DKD and 1912 (39.1%) patients with DKD. RCS plots showed that the risk of DKD increased with increasing LDH levels. Multifactorial logistic regression analysis revealed that T2D patients with higher LDH levels had a 45% increased risk of DKD compared to those with lower LDH levels (OR=1.45; 95% CI: 1.11-1.89). Furthermore, each standard deviation increase in LDH level was associated with a 24% increase in DKD incidence among T2D patients (OR=1.24; 95% CI: 1.07-1.44). Stratified analysis consistently supported these findings. Conclusions: LDH can serve as a valuable biomarker for screening DKD in patients with T2D.

ZNF146 regulates cell cycle progression via TFDP1 and DEPDC1B in ovarian cancer cells.

Ovarian cancer (OC) is the third most common kind of gynecological tumor, in addition to being the most lethal. Transcription factor Dp-1 (TFDP1) functions as a binding partner for E2F transcription factors, and its target genes include those involved in DNA synthesis, cell cycle, and apoptosis. However, the regulatory role of TFDP1 in OC remains incompletely understood. This study aimed to investigate the role and mechanism of TFDP1 in OC. TFDP1 was highly expressed in the ovarian epithelial tissues of OC patients, and the expression of TFDP1 in OC cells was higher than that in normal ovarian epithelial cells. Silencing of TFDP1 inhibited the biological activity of OC cells and hindered cell cycle entry. Zinc finger protein 146 (ZNF146) knockdown induced cell cycle arrest at the G0/G1 phase and tumor growth by blocking TFDP1 transcription, which was overturned by ectopic expression of TFDP1. TFDP1 stimulated DEP domain-containing protein 1B (DEPDC1B) expression through transcriptional activation. DEPDC1B increased the proportion of OC cells in the G2/M phase and potentiated tumor malignant progression in nude mice inhibited by sh-ZNF146. Taken together, these findings demonstrate that ZNF146 participates in TFDP1/DEPDC1B activation and plays a vital role in the cell cycle in OC.

SIRT3 suppression resulting from the enhanced ß-catenin signaling drives glycolysis and promotes hypoxia-induced cell growth in hepatocellular carcinoma cells.

The precise mechanisms underlying the inhibitory effects of SIRT3, a mitochondrial sirtuin protein, on hepatocellular carcinoma (HCC) development, as well as its impact on mitochondrial respiration, remain poorly understood. We assessed sirtuins 3 (SIRT3) levels in HCC tissues and Huh7 cells cultured under hypoxic condition. We investigated the effects of SIRT3 on cell proliferation, glycolytic metabolism, mitochondrial respiration, mitophagy, and mitochondrial biogenesis in Huh7 cells. Besides, we explored the potential mechanisms regulating SIRT3 expression in hypoxically cultured Huh7 cells. Gradual reduction in SIRT3 expressions were observed in both adjacent tumor tissues and tumor tissues. Similarly, SIRT3 expressions were diminished in Huh7 cells cultured under hypoxic condition. Forced expression of SIRT3 attenuated the growth of hypoxically cultured Huh7 cells. SIRT3 overexpression led to a decrease in extracellular acidification rate while increasing oxygen consumption rate. SIRT3 downregulated the levels of hexokinase 2 and pyruvate kinase M2. Moreover, SIRT3 enhanced mitophagy signaling, as indicated by mtKeima, and upregulated key proteins involved in various mitophagic pathways while reducing intracellular reactive oxygen species levels. Furthermore, SIRT3 increased proxisome proliferator-activated receptor-gamma coactivator 1α levels and the amount of mitochondrial DNA in Huh7 cells. Notably, ß-catenin expressions were elevated in Huh7 cells cultured under hypoxic condition. Antagonists and agonists of ß-catenin respectively upregulated and downregulated SIRT3 expressions in hypoxically cultured Huh7 cells. The modulationsof glycolysis and mitochondrial respiration represent the primary mechanism through which SIRT3, suppressed by ß-catenin, inhibits HCC cell proliferation.

Clinical value of serum LINC02446 and S100B in early diagnosis and prognosis assessment of traumatic brain injury.

OBJECTIVE: To detect the expression levels of LINC02446 and S100B in serum of patients with traumatic brain injury (TBI) and explore their values as diagnostic and prognostic indicators for TBI. METHOD: Abnormal expressed RNAs in brain injury were screened from the dataset GSE1131475. Serums were collected from moderate to severe TBI patients at 1-3 and 4-12 h post injury. Quantitative polymerase chain reaction was used to detect the expression levels of LINC02446 and S100B in serum. The Glasgow Outcome Scale was used for prognostic evaluation. The diagnostic and prognostic efficacy of LINC02446 and S100B in TBI was evaluated using the receiver operating characteristic (ROC) curve. RESULT: The serum expression levels of LINC02446 and S100B in the TBI group were significantly increased. The expression levels of LINC02446 and S100B in the severe TBI group were significantly higher than those in the mild TBI group. ROC curve analysis showed that the combination of LINC02446 and S100B can distinguish TBI patients from healthy controls, as well as mild TBI from moderate to severe TBI. At the 6-month follow-up, the expression levels of LINC02446 and S100B in TBI patients with poor prognosis were significantly higher than those in patients with good prognosis, and ROC results showed their differentiation value. Moreover, the expression level of LINC02446 at 0-3 h can serve as an independent prognostic factor for poor prognosis. CONCLUSION: Serum LINC02446 and S100B hold clinical application value in the diagnosis and prognosis of TBI and are expected to become new potential biomarkers.

Dual-potential ratiometric electrochemiluminescence based on single emitter and single coreactant for the sensitive detection of carcinoembryonic antigen.

Dual-potential ratiometric electrochemiluminescence (ECL) is in favor of resistance to environmental interference. However, two kinds of emitters or coreactants, and a wide scan potential range (>2 V) are mandatory. This work developed a new dual-potential ratiometric ECL sensor for detection of carcinoembryonic antigen (CEA) using single emitter (luminol) and single coreactant (H2O2) with a mild potential range from -0.1 to 0.6 V. Luminol could produce a strong cathodic ECL (Ec) induced by hydroxyl radicals (HO‧) from the reduction of H2O2, and a relatively weak anodic ECL (Ea). After the ferrocene modified CEA aptamer (Apt-Fc) was attached, Fc could promote Ea by catalyzing the oxidation of H2O2, and reduce Ec by consuming HO‧. With the cycling amplification of the exonuclease I, CEA could substantially reduce the amount of Apt-Fc, resulting in the decrease of Ea and the rise of Ec. So, the ratio of Ec to Ea (Ec/Ea) was used as the detection signal, realizing the sensitive determination of CEA from 0.1 pg mL-1 to 10 ng mL-1 with a LOD of 41.85 fg mL-1 (S/N = 3). The developed sensor demonstrated excellent specificity, stability and reproducibility, with satisfactory results in practical detection.

Evaluating How Different Drying Techniques Change the Structure and Physicochemical and Flavor Properties of Gastrodia elata.

We evaluated the drying characteristics and structure, as well as the physicochemical and flavor properties, of G. elata treated by hot-air drying (HAD), vacuum drying (VD), freeze drying (FD), microwave drying (MD), and microwave vacuum drying (MVD). We found that MD and MVD showed the shortest drying times, while FD and MVD were able to better retain the active ingredients and color of the samples. However, the different drying methods did not change the internal structure of G. elata, and its main components did not fundamentally change. In addition, E-nose and HS-SPME-GC-MS effectively differentiated the volatile components, and 36 compounds were detected by HS-SPME-GC-MS. Of these samples, alcohols and aldehydes were the main substances identified. In particular, MVD samples possessed the most species of organic volatiles, but the FD method effectively eliminated pungent odors from the G. elata. Overall, MVD shows the most obvious advantages, improving drying rate while maintaining the original shape, color, and active components in G. elata. Ultimately, MVD is the preferred method to obtain high-quality dried G. elata, and our drying-method characterizations can be used to investigate similar structural and chemical changes to similar herbs in the future.

Repurposing Farnesol for Combating Drug-Resistant and Persistent Single and Polymicrobial Biofilms.

Biofilm-associated infections caused by drug-resistant and persistent bacteria remain a significant clinical challenge. Here we report that farnesol, commercially available as a cosmetic and flavoring agent, shows significant anti-biofilm properties when dissolved in ethanol using a proprietary formulation emulsion technique. Farnesol in the new formulation inhibits biofilm formation and disrupts established biofilms for Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, including their polymicrobial biofilms, and, moreover, kills S. aureus persister cells that have developed tolerance to antibiotics. No resistance to farnesol was observed for S. aureus after twenty continuous passages. Farnesol combats biofilms by direct killing, while also facilitating biofilm detachment. Furthermore, farnesol was safe and effective for preventing and treating biofilm-associated infections of both types of bacteria in an ex vivo burned human skin model. These data suggest that farnesol in the new formulation is an effective broad-spectrum anti-biofilm agent with promising clinical potential. Due to its established safety, low-cost, versatility, and excellent efficacy-including ability to reduce persistent and resistant microbial populations-farnesol in the proprietary formulation represents a compelling transformative, translational, and commercial platform for addressing many unsolved clinical challenges.

Melatonin's effect on hair follicles in a goat (Capra hircus) animal model.

Introduction: Melatonin can treat androgenetic alopecia in males. Goats can be used as animal models to study melatonin treatment for human alopecia. In this study, a meta-analysis of melatonin's effects on goat hair follicles was pursued. Methods: Literature from the last 20 years was searched in Scopus, Science Direct, Web of Science and PubMed. Melatonin's effect on goat hair follicles and litter size were performed through a traditional meta-analysis and trial sequential analysis. A network meta-analysis used data from oocyte development to blastocyst. The hair follicle genes regulated by melatonin performed KEGG and PPI. We hypothesized that there are differences in melatonin receptors between different goats, and therefore completed melatonin receptor 1A homology modelling and molecular docking. Results: The results showed that melatonin did not affect goat primary follicle or litter size. However, there was a positive correlation with secondary follicle growth. The goat melatonin receptor 1A SNPs influence melatonin's functioning. The wild type gene defect MR1 is a very valuable animal model. Discussion: Future studies should focus on the relationship between goat SNPs and the effect of embedded melatonin. This study will provide theoretical guidance for the cashmere industry and will be informative for human alopecia research.

Boosting the electrochromic performance of P-doped WO3 films via electrodeposition for smart window applications.

Electrochromic smart windows have attracted more attention from researchers due to their potential applications for energy conservation in buildings. As the most key component, the electrochromic layer is still limited by the complexity of the preparation process and poor performance, such as lower stability, slow response time, and low coloration efficiency. In this study, as a simple and expedient method, electrodeposition is successfully used to prepare amorphous WO3 films doped with P. By optimizing the amount of P in the PW-2 film, a large optical modulation of 80.8% at 550 nm is achieved, and the P-doped amorphous WO3 film also shows a fast response time, a high CE, and good cycling stability. The mechanism of the P-doped amorphous WO3 films to improve the electrochromic properties is as follows. Firstly, by appropriate phosphorus doping, the stress of the film is released, and the binding force is improved. Secondly, the films possess proper cracks, which accelerate the diffusion of ions. Thirdly, the films make the nanoparticles more uniform, and provide more active sites. Furthermore, the electrochromic smart windows based on the P-doped amorphous WO3 film display a large temperature difference of 11 °C, which indicates good solar thermal regulation ability, and promises practical applications for building energy conservation.

Ablation for malignant liver tumor using high-intensity focused ultrasound and radio-frequency: A meta-analysis.

BACKGROUND: Primary liver cancer is a major health issue, so finding the most effective treatment is vital. OBJECTIVE: The present meta-analysis compares high-intensity focused ultrasound (HIFU) to radiofrequency (RF) ablation for primary liver cancer treatment. METHODS: PubMed, MEDLINE, CNKI, VIP, and Wanfang were used to search for English and Chinese papers. After carefully confirming data completeness and applying inclusion and exclusion criteria, RevMan 5.3 was used to evaluate the included literature. Data analysis utilized a fixed-effects model for heterogeneity between 0.1 and 0.5. RESULTS: The meta-analysis included 304 patients: 119 had HIFU and 185 RF ablation. For primary liver cancer, HIFU and RF ablation were equally efficacious (odds ratio 1.02, 95% confidence interval [0.54, 1.92]). Overall survival, disease-free survival, and complications at 1, 2, and 3 years were not significantly different (odds ratio 0.72, 95% confidence range [0.04, 12.79], P= 0.82). CONCLUSION: The meta-analysis shows no significant difference in efficacy, long-term survival rates, or complication rates between HIFU and RF ablation for primary liver cancer, but more large-scale, high-quality randomized clinical trials are needed to prove their equivalence. Both therapy strategies seem promising, but additional information is needed to determine their respective merits.

Rolapitant treats lung cancer by targeting deubiquitinase OTUD3.

BACKGROUND: Lung cancer is cancer with the highest morbidity and mortality in the world and poses a serious threat to human health. Therefore, discovering new treatments is urgently needed to improve lung cancer prognosis. Small molecule inhibitors targeting the ubiquitin-proteasome system have achieved great success, in which deubiquitinase inhibitors have broad clinical applications. The deubiquitylase OTUD3 was reported to promote lung tumorigenesis by stabilizing oncoprotein GRP78, implying that inhibition of OTUD3 may be a therapeutic strategy for lung cancer. RESULTS: In this study, we identified a small molecule inhibitor of OTUD3, Rolapitant, by computer-aided virtual screening and biological experimental verification from FDA-approved drugs library. Rolapitant inhibited the proliferation of lung cancer cells by inhibiting deubiquitinating activity of OTUD3. Quantitative proteomic profiling indicated that Rolapitant significantly upregulated the expression of death receptor 5 (DR5). Rolapitant also promoted lung cancer cell apoptosis through upregulating cell surface expression of DR5 and enhanced TRAIL-induced apoptosis. Mechanistically, Rolapitant directly targeted the OTUD3-GRP78 axis to trigger endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-DR5 signaling, sensitizing lung cancer cells to TRAIL-induced apoptosis. In the vivo assays, Rolapitant suppressed the growth of lung cancer xenografts in immunocompromised mice at suitable dosages without apparent toxicity. CONCLUSION: In summary, the present study identifies Rolapitant as a novel inhibitor of deubiquitinase OTUD3 and establishes that the OTUD3-GRP78 axis is a potential therapeutic target for lung cancer.

Evaluating the efficacy of balloon pulmonary angioplasty using quantitative analysis of SPECT pulmonary ventilation/perfusion scintigraphy in patients with chronic thromboembolic pulmonary hypertension.

Background: Single-photon emission computed tomography (SPECT) ventilation perfusion imaging is the main imaging method for the diagnosis of pulmonary embolism, and its application in the diagnosis and efficacy evaluation of chronic thromboembolic pulmonary hypertension (CTEPH) has been paid more and more attention. In recent years, with the development of computer software technology, ventilation/perfusion (V/Q) imaging quantitative analysis technology has become more and more mature. The objective of this study was to investigate the utility of quantitative analysis of pulmonary V/Q scintigraphy in evaluating the efficacy of balloon pulmonary angioplasty (BPA) in patients with CTEPH. Methods: In this retrospective analysis, we collected data of patients diagnosed with CTEPH who underwent BPA at the China-Japan Friendship Hospital from April 2018 to September 2020. The sample consisted of 23 males and 28 females, with an average age of 55.1±12.7 years. All patients underwent V/Q scintigraphy within one week before surgery, and we reviewed the pulmonary angiography within 1-3 months following the last BPA procedure. We repeated V/Q scintigraphy within 1 week before or after the pulmonary angiography, at the time of collecting clinical and hemodynamic parameters of these patients. We divided the patients into two groups based on the presence of residual pulmonary hypertension post-surgery and compared the pre- and post-operative quantitative pulmonary perfusion defect percentage scores (PPDs%) using the t-test. Results: In all, 102 V/Q scintigraphy scans were performed in 51 patients. The quantitative PPDs% were positively correlated with the hemodynamic indexes mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and mean right ventricular pressure (RVP) (r=0.605, 0.391, and 0.464, respectively, all P<0.001) and negatively correlated with the 6-minute walking distance (6MWD) (r=-0.254, P=0.010). The average preoperative quantitative PPDs% were (49.0±15.6)% which significantly decreased to (33.5±13.9)% after surgery (t=11.249, P<0.001). The preoperative quantitative PPDs% were (54.7±15.7)% and (44.0±13.8)% in the residual pulmonary hypertension group and the non-residual pulmonary hypertension group, respectively (t=2.599, P=0.012). The postoperative quantitative PPDs% were (41.5±12.5)% and (26.3±11.0)%, in the residual pulmonary hypertension group and the non-residual pulmonary hypertension group, respectively (t=4.647, P<0.001). Conclusions: In this study, we found that quantitative analysis of SPECT pulmonary V/Q scintigraphy adequately reflected the pulmonary artery pressure and clinical status in patients with CTEPH. Our results demonstrate its definite utility in predicting residual pulmonary hypertension and in evaluating the postoperative efficacy of BPA in patients with CTEPH.

Force-Induced Site-Specific Enzymatic Cleavage Probes Reveal That Serial Mechanical Engagement Boosts T Cell Activation.

The T cell membrane is studded with >104 T cell receptors (TCRs) that are used to scan target cells to identify short peptide fragments associated with viral infection or cancerous mutation. These peptides are presented as peptide-major-histocompatibility complexes (pMHCs) on the surface of virtually all nucleated cells. The TCR-pMHC complex forms at cell-cell junctions, is highly transient, and experiences mechanical forces. An important question in this area pertains to the role of the force duration in immune activation. Herein, we report the development of force probes that autonomously terminate tension within a time window following mechanical triggering. Force-induced site-specific enzymatic cleavage (FUSE) probes tune the tension duration by controlling the rate of a force-triggered endonuclease hydrolysis reaction. This new capability provides a method to study how the accumulated force duration contributes to T cell activation. We screened DNA sequences and identified FUSE probes that disrupt mechanical interactions with F > 7.1 piconewtons (pN) between TCRs and pMHCs. This rate of disruption, or force lifetime (τF), is tunable from tens of minutes down to 1.9 min. T cells challenged with FUSE probes with F > 7.1 pN presenting cognate antigens showed up to a 23% decrease in markers of early activation. FUSE probes with F > 17.0 pN showed weaker influence on T cell triggering further showing that TCR-pMHC with F > 17.0 pN are less frequent compared to F > 7.1 pN. Taken together, FUSE probes allow a new strategy to investigate the role of force dynamics in mechanotransduction broadly and specifically suggest a model of serial mechanical engagement boosting TCR activation.