Stellate ganglion block for visceral pain in elderly patients undergoing video-assisted thoracoscopic lung cancer surgery: a randomized, controlled trial.

BACKGROUND: Visceral pain occurs commonly following thoracic surgery, but an effective method to relieve visceral pain in thoracic surgery remains controversial. We test the effect of stellate ganglion blocks (SGB) on perioperative visceral pain following video-assisted thoracoscopic surgery (VATS). METHODS: A prospective, randomized, controlled trial enrolled 77 elderly patients undergoing VATS. Patients were randomized to SGB followed by modified intercostal nerve block (Group S, n=37); or modified intercostal nerve block only (Group C, n=40). Remifentanil 0.02-0.2 µg·kg-1·min-1 was titrated to keep pain threshold index values between 40-65 and maintain mean arterial pressure or heart rate values around 20% of baseline values. Patient-controlled intravenous analgesia with sufentanil was used in the postoperative period. The co-primary outcomes were the perioperative cumulative opioid consumption and pain scores on movement at 24 h after surgery. RESULTS: Compared with control group, SGB greatly reduced the intraoperative remifentanil consumption[300.00(235.00-450.00)µg versus 710.00(500.00-915.00)µg; P<0.01], with no difference in cumulative sufentanil consumption to 48h post-surgery. There was a statistically significant difference in pain scores on movement at 24h between groups [4.00(3.00-4.00) versus 4.00(3.25-5.00); P=0.01]. Further exploratory analyses showed significant difference for intra-chest pain on movement at 24h [3.00(2.00-3.00) versus 3.00(2.25-4.00); P=0.01]. No significant difference was observed in nausea/vomiting, time to pass flatus and postoperative length of stay. CONCLUSION: Preoperative stellate ganglion blocks for elderly patients could effectively blunt intraoperative visceral stress and reduce postoperative visceral pain extending 24 h after VATS. This initial finding deserve further investigation.

USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.

This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

IRF4-BLOC1S5: the first rearrangement gene identified in TEMPI syndrome.

Not available.

Ubiquitin-specific protease 14 targets PFKL-mediated glycolysis to promote the proliferation and migration of oral squamous cell carcinoma.

Aberrant upregulation of the ubiquitin-specific protease 14 (USP14) has been found in some malignant tumors, including oral squamous cell carcinoma (OSCC). In this study, we further demonstrated that aberrantly overexpressed USP14 was also closely related to adverse clinicopathological features and poor prognosis in patients with OSCC, so we hypothesized that USP14 might act as a tumor-promoting factor during the progression of OSCC. Notably, we originally proved that USP14 is a deubiquitinating enzyme for phosphofructokinase-1 liver type (PFKL), a key rate-limiting enzyme involved in the glycolytic pathway. USP14 interacts with PFKL and enhances its stability through deubiquitination in OSCC cells, which in turn enhances PFKL-mediated glycolytic metabolism and ultimately promote cellular proliferation, migration, and tumorigenesis. In this work, we have also demonstrated for the first time that USP14 is a critical regulator of glycolysis in OSCC and verified a novel mechanism whereby it is involved in tumor metastasis and growth. Collectively, our findings provide novel insights into the tumor-promoting role of USP14 and establish mechanistic foundations for USP14-targeting therapies.

Targeting iron-metabolism:a potential therapeutic strategy for pulmonary fibrosis.

Iron homeostasisis is integral to normal physiological and biochemical processes of lungs. The maintenance of iron homeostasis involves the process of intake, storage and output, dependening on iron-regulated protein/iron response element system to operate tightly metabolism-related genes, including TFR1, DMT1, Fth, and FPN. Dysregulation of iron can lead to iron overload, which increases the virulence of microbial colonisers and the occurrence of oxidative stress, causing alveolar epithelial cells to undergo necrosis and apoptosis, and form extracellular matrix. Accumulated iron drive iron-dependent ferroptosis to exacerbated pulmonary fibrosis. Notably, the iron chelator deferoxamine and the lipophilic antioxidant ferritin-1 have been shown to attenuate ferroptosis and inhibit lipid peroxidation in pulmonary fibrosis. The paper summarises the regulatory mechanisms of dysregulated iron metabolism and ferroptosis in the development of pulmonary fibrosis. Targeting iron metabolism may be a potential therapeutic strategy for the prevention and treatment of pulmonary fibrosis.

GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3­ITD acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation accounts for a large proportion of AML patients and diagnosed with poor prognosis. Although the prognosis of FLT3-ITD AML has been greatly improved, the drug resistance frequently occurred in the treatment of FLT3 targeting drugs. GNF-7, a multitargeted kinase inhibitor, which provided a novel therapeutic strategy for overriding leukemia. In this study, we explored the antitumor activity of GNF-7 against FLT3-ITD and clinically-relevant drug resistance in FLT3 mutant AML. METHODS: Growth inhibitory assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutants to evaluate the antitumor activity of GNF-7 in vitro. Western blotting was used to examine the inhibitory  effect of GNF-7 on FLT3 and its downstream pathways. Molecular docking and cellular thermal shift assay (CETSA) were performed to demonstrate the binding of FLT3 to GNF-7. The survival benefit of GNF-7 in vivo was assessed in mouse models of transformed Ba/F3 cells harboring FLT3-ITD and FLT3-ITD/F691L mutation. Primary patient samples and a patient-derived xenograft (PDX) model were also used to determine the efficacy of GNF-7. RESULTS: GNF-7 inhibited the cell proliferation of Ba/F3 cells expressing FLT3-ITD and exhibited potently anti-leukemia activity on primary FLT3-ITD AML samples. Moreover, GNF-7 could bind to FLT3 protein and inhibit the downstream signaling pathway activated by FLT3 including STAT5, PI3K/AKT and MAPK/ERK. In vitro and in vivo studies showed that GNF-7 exhibited potent inhibitory activity against FLT3-ITD/F691L that confers resistant to quizartinib (AC220) or gilteritinib. Importantly, GNF-7 showed potent cytotoxic effect on leukemic stem cells, significantly extend the survival of PDX model and exhibited similar therapy effect compared with gilteritinib. CONCLUSIONS: Our results show that GNF-7 is a potent FLT3-ITD inhibitor and may become a promising lead compound applied for treating some of the clinically drug resistant patients.

Anlotinib exerts an anti-T-cell acute lymphoblastic leukemia effect in vitro and in vivo.

BACKGROUND: Despite some progress having been made regarding the treatment of T-cell acute lymphoblastic leukemia (T-ALL), the prognosis of T-ALL, particularly adult T-ALL, is still poor. Identifying novel, effective anti-T-ALL drugs is of great significance. Anlotinib, an oral tyrosine kinase inhibitor currently utilized in the treatment of lung cancer, exhibited a promising anti-T-ALL effect. A comprehensive study should therefore be conducted to explore both the in vitro as well as in vivo mechanisms of the anti-T-ALL effects of anlotinib. METHODS: CCK8 assays and flow cytometry were employed to investigate the viability, cell cycle distribution, and apoptosis of T-ALL cell lines when treated with anlotinib. T-ALL xenograft mouse models were established to examine the in vivo antileukemic effects of anlotinib. Cellular and molecular analysis of T-ALL were conducted to define the underlying mechanisms. RESULTS: In vitro, anlotinib significantly inhibited the viability, induced G2/M phase arrest and apoptosis in T-ALL cell lines in a concentration-dependent pattern. In vivo, anlotinib also demonstrated a strong anti-tumor effect at doses that are well-tolerated. Interestingly, anlotinib could decrease the protein levels of the intracellular domains of NOTCH1 (ICN1) and c-Myc, two important targets for T-ALL. Mechanistically, anlotinib-induced c-Myc reduction was associated with proteasome-mediated degradation, while the ICN1 reduction was not due to protein degradation or transcriptional repression. CONCLUSIONS: The present study showed that anlotinib may be a promising anti-T-ALL candidate drug, and simultaneous reduction of the protein levels of both ICN1 and c-Myc may contribute to the anti-T-ALL efficacy of anlotinib.

Discovery of Novel SIRT1/2 Inhibitors with Effective Cytotoxicity against Human Leukemia Cells.

The sirtuin enzyme family members, SIRT1 and SIRT2, play both tumor-promoting and tumor-suppressing roles, depending on the context and experimental conditions. Compounds that inhibit either SIRT1 or SIRT2 show promising antitumor effects in several types of cancer models, both in vitro and in vivo. The simultaneous inhibition of SIRT1 and SIRT2 is helpful in treating cancer by completely blocking p53 deacetylation, leading to cell death. However, only a few SIRT1/2 dual inhibitors have been developed. Here, we report the discovery of a novel series of SIRT1/2 dual inhibitors via a rational drug design that involved virtual screening and a substructure search. Eleven of the derived compounds exhibited high inhibitory activities, with IC50 < 5 µM and high specificity for both SIRT1 and SIRT2. Compounds hsa55 and PS9 strongly induced apoptosis and showed antiproliferative effects against human leukemia cell lines, which could be due to their ability to increase of p53 and α-tubulin acetylation, as we observed in MOLM-13 cells. Therefore, the new scaffolds of these compounds and their efficacy in leukemia cell lines provide important clues for the further development of novel anti-leukemia drugs.

Chemoproteomics and Phosphoproteomics Profiling Reveals Salvianolic Acid A as a Covalent Inhibitor of mTORC1.

Salvianolic acid A (SAA), a major active ingredient of Salvia miltiorrhiza Bunge (Danshen), displays strong antiproliferative activity against cancer cells. However, their protein targets remain unknown. Here, we deconvoluted the protein targets of SAA using chemoproteomics and phosphoproteomics. By using alkynylated SAA as a probe, we discovered that SAA is a covalent ligand that can modify cellular proteins via its electrophilic α,ß-unsaturated ester moiety. The subsequent chemoproteomics profiling revealed that 46 proteins were covalently modified by SAA, including Raptor, a subunit of mTORC1 for recruiting substrates for mTORC1. Although gene ontology enrichment analysis of these proteins suggested that SAA displays a promiscuous protein interaction, phosphoproteomics profiling revealed that the SAA modulated phosphoproteins were mainly enriched in the signaling pathways of PI3K-Akt-mTOR, which is closely related to cell growth and proliferation. This was confirmed by the biochemical assay with purified mTORC1, a Western blot assay with phospho-specific antibodies, and a cellular thermal shift assay. Our work discovered that SAA is a covalent ligand for protein modification and mTORC1 is one of its targets. Moreover, our work demonstrated that the integrative profiling of chemoproteomics and phosphoproteomics can be a powerful tool for target deconvolution for bioactive natural products.

Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression.

Increased expression of branched-chain amino acid transaminase 1 or 2 (BCAT1 and BCAT2) has been associated with aggressive phenotypes of different cancers. Here we identify a gain of function of BCAT1 glutamic acid to alanine mutation at codon 61 (BCAT1E61A) enriched around 2.8% in clinical gastric cancer samples. We found that BCAT1E61A confers higher enzymatic activity to boost branched-chain amino acid (BCAA) catabolism, accelerate cell growth and motility and contribute to tumor development. BCAT1 directly interacts with RhoC, leading to elevation of RhoC activity. Notably, the BCAA-derived metabolite, branched-chain α-keto acid directly binds to the small GTPase protein RhoC and promotes its activity. BCAT1 knockout-suppressed cell motility could be rescued by expressing BCAT1E61A or adding branched-chain α-keto acid. We also identified that candesartan acts as an inhibitor of BCAT1E61A, thus repressing RhoC activity and cancer cell motility in vitro and preventing peritoneal metastasis in vivo. Our study reveals a link between BCAA metabolism and cell motility and proliferation through regulating RhoC activation, with potential therapeutic implications for cancers.

Nanoparticle-Based Combination Therapy for Ovarian Cancer.

Ovarian cancer is one of the most common malignant tumors in gynecology with a high incidence. Combination therapy, eg, administration of paclitaxel followed by a platinum anticancer drug is recommended to treat ovarian cancer due to its advantages in, eg, reducing side effects and reversing (multi)drug-resistance compared to single treatment. However, the benefits of combination therapy are often compromised. In chemo and chemo/gene combinations, co-deposition of the combined therapeutics in the tumor cells is required, which is difficult to achieve due to dramatic pharmacokinetic differences between combinational agents in free forms. Moreover, some undesired properties such as the low-water solubility of chemodrugs and the difficulty of cellular internalization of gene therapeutics also hinder the therapeutic potential. Delivery of dual or multiple agents by nanoparticles provides opportunities to tackle these limits. Nanoparticles encapsulate hydrophobic drug(s) to yield aqueous dispersions facilitating its administration and/or to accommodate hydrophilic genes facilitating its access to cells. Moreover, nanoparticle-based therapeutics can not only improve drug properties (eg, in vivo stability) and ensure the same drug disposition behavior with controlled drug ratios but also can minimize drug exposure of the normal tissues and increase drug co-accumulation at targeted tissues via passive and/or active targeting strategies. Herein, this work summarizes nanoparticle-based combination therapies, mainly including anticancer drug-based combinations and chemo/gene combinations, and emphasizes the advantageous outcomes of nanocarriers in the combination treatment of ovarian cancer. In addition, we also review mechanisms of synergetic effects resulting from different combinations.

A Study of Strength Parameter Evolution and a Statistical Damage Constitutive Model of Cemented Sand and Gravel.

Cemented sand and gravel (CSG) has a wide range of applications in dam construction, and its properties are between rockfill and roller compacted concrete (RCC). A difference in gel content will result in a variance in CSG's structure and mechanical properties. To investigate the intricate structural mechanical properties of CSG, this study conducted a series of laboratory tests and associated discrete element analyses. Accordingly, the evolution law of the strength parameters of CSG is explored and a statistical damage constitutive model suitable for CSG is established. The main contributions of this study are as follows: (1) The failure mechanism of the CSG was described from the microscopic level, and the evolution law of the strength parameter cohesion and friction angle of the CSG was analyzed and summarized. (2) Based on the particle flow model, the energy development law and the spatiotemporal distribution law of acoustic emission (AE) provide illustrations of the strain hardening-softening transition features and the interaction between cohesion and friction of CSG. (3) The evolution function between the strength parameter and the strain softening parameter was built, and the critical strain softening parameter was determined by the microcrack evolution law of the particle flow model. (4) The accuracy of the evolution curve was confirmed by comparing it to experimental results. (5) Based on the relationship between cohesion loss and material damage, a statistical damage constitutive model was developed using the improved Mohr-Coulomb strength criterion as the micro strength function. The constitutive model can accurately describe the stress-strain curves of CSG with different gel content. Furthermore, the model reflects the strain hardening-softening properties of CSG and reveals the relationship between the weakening of cohesion and material damage at the microscopic level. These findings provide valuable guidelines for investigating the damage laws and microcosmic failure features of CSG and other relevant materials.

Corrigendum: In Living Color: Pigment-Based Microbial Ecology At the Mineral-Air Interface.

[This corrects the article DOI: 10.1093/biosci/biac091.].

Multi-SUMOylation of NAC1 is essential for the growth of prostate cancer cells.

Nucleus accumbens-associated 1 (NAC1) is a member of pox virus and zinc finger/bric-a-brac tramtrack broad complex (BTB/POZ) gene family. Overexpression of NAC1 is implicated in cancer development, recurrence and chemotherapy resistance. In our previous study, we found NAC1 was a potential small ubiquitin-like modifier (SUMO) substrate in prostate cancer cells. However, there was still lack of evidences to further support and validate the result. In this work, we found that NAC1 is a multi-SUMO-sites acceptor. The SUMO acceptor lysines were K167, K318, K368, K483 and K498. SUMOylation didn't alter the localization of NAC1, but facilitated the formation of NAC1 nuclear bodies. Compared with NAC1 wild type (NAC1 WT), the SUMO-sites mutant of NAC1 (NAC1 SM) suppressed cell proliferation and tumor growth in cellular and animal levels. This work uncovered the function of SUMOylation of NAC1 in prostate cancer cells.

In Living Color: Pigment-Based Microbial Ecology At the Mineral-Air Interface.

Pigment-based color is one of the most important phenotypic traits of biofilms at the mineral-air interface (subaerial biofilms, SABs), because it reflects the physiology of the microbial community. Because color is the hallmark of all SABs, we argue that pigment-based color could convey the mechanisms that drive microbial adaptation and coexistence across different terrestrial environments and link phenotypic traits to community fitness and ecological dynamics. Within this framework, we present the most relevant microbial pigments at the mineral-air interface and discuss some of the evolutionary landscapes that necessitate pigments as adaptive strategies for resource allocation and survivability. We report several pigment features that reflect SAB communities' structure and function, as well as pigment ecology in the context of microbial life-history strategies and coexistence theory. Finally, we conclude the study of pigment-based ecology by presenting its potential application and some of the key challenges in the research.

JOSD2 regulates PKM2 nuclear translocation and reduces acute myeloid leukemia progression.

Pyruvate kinase M2 (PKM2) plays an important role in the metabolism and proliferation of leukemia cells. Here, we show that deubiquitinase JOSD2, a novel tumor suppressor, blocks PKM2 nuclear localization by reducing its K433 acetylation in acute myeloid leukemia (AML). Firstly, we show that JOSD2 is significantly down-regulated in primary AML cells. Reconstitute of JOSD2 in AML cells significantly inhibit cell viability and induce cell apoptosis. Next, PKM2 is identified as a novel interaction protein of JOSD2 by mass spectrometry, co- immunoprecipitation and co-immunofluorescence in HL60 cells. However, JOSD2 does not affect PKM2 protein stability. We then found out that JOSD2 inhibits nuclear localization of PKM2 by reducing its K433 acetylation modification, accompanied by decreased downstream gene expression through non-glycolytic functions. Finally, JOSD2 decreases AML progression in vivo. Taken together, we propose that JOSD2 blocks PKM2 nuclear localization and reduces AML progression.

Parthenolide reveals an allosteric mode to inhibit the deISGylation activity of SARS-CoV­2 papain-like protease.

The coronavirus papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for viral polypeptide cleavage and the deISGylation of interferon-stimulated gene 15 (ISG15), which enable it to participate in virus replication and host innate immune pathways. Therefore, PLpro is considered an attractive antiviral drug target. Here, we show that parthenolide, a germacrane sesquiterpene lactone, has SARS-CoV-2 PLpro inhibitory activity. Parthenolide covalently binds to Cys-191 or Cys-194 of the PLpro protein, but not the Cys-111 at the PLpro catalytic site. Mutation of Cys-191 or Cys-194 reduces the activity of PLpro. Molecular docking studies show that parthenolide may also form hydrogen bonds with Lys-192, Thr-193, and Gln-231. Furthermore, parthenolide inhibits the deISGylation but not the deubiquitinating activity of PLpro in vitro. These results reveal that parthenolide inhibits PLpro activity by allosteric regulation.

Golgi scaffold protein PAQR3 as a candidate suppressor of gastric cardia adenocarcinoma via regulating TGF-ß/Smad pathway.

OBJECTIVES: To investigate the function of PAQR3 in gastric cardia adenocarcinoma (GCA) and understand the possible mechanism of PAQR3 in regulating epithelial-mesenchymal transition (EMT). METHODS: We detected PAQR3 protein in 146 GCA tissues and paired normal adjacent tissues (PNTs) specimens using immunohistochemical analysis, and explored its clinical significance. The expression levels of PAQR3 protein in 20 GCA tissues, their paired PNTs, HGC27, SGC7901, and GES-1 cells were analyzed by Western blot. Wild-type PAQR3 was overexpressed in HGC27 cells. The effects of PAQR3 overexpression on the function of HGC27 cells and its underlying mechanisms were then analyzed through a series of cell and molecular biology experiments. RESULTS: PAQR3 was significantly down-regulated in GCA tissues when compared with paired PNTs (p < 0.0001). The expression level of PAQR3 in GCA tissues was significantly negatively correlated with Helicobacter pylori infection (p = 0.000), venous invasion (p = 0.000), invasion depth (p = 0.000), lymph node metastasis (p = 0.022), tumor stage (p = 0.000), and patient survival (p = 0.009). Downregulation of PAQR3 was highly correlated with increased EMT signature and activated TGF-ß/Smad pathway in GCA tissues. Overexpression of PAQR3 in HGC27 cells negatively regulates its cellular functions, such as cell proliferation and migration, and suppresses EMT. Mechanistically, overexpression of PAQR3 significantly down-regulates the protein expression levels of TGF-1, p-Smad2, and p-Smad3 in HGC27 cells. CONCLUSION: PAQR3 was significantly down-regulated in GCA tissues, HGC27, and SGC7901 cells. PAQR3 significantly inhibits the proliferation, migration, and invasion of HGC27 cells. Mechanistically, PAQR3 can inhibit the EMT process in HGC27 cells by regulating TGF-ß/Smad signaling pathway.

Rural Workplace Sustainable Development of Smart Rural Governance Workplace Platform for Efficient Enterprise Performances.

In the long developmental process, China's agriculture has transformed from organic agriculture to inorganic agriculture. New technologies have made the modernization of agriculture possible. However, most older people who are engaged in agriculture may not completely understand the modernization of agriculture. Based on the limitations of traditional image target detection methods, a deep learning-based pest target detection and recognition method is proposed from a blockchain perspective, to analyze and research agricultural data supervision and governance and explore the effectiveness of deep learning methods in crop pest detection and recognition. The comparative analysis demonstrates that the average precision (AP) of GA-CPN-LAR (global activation-characteristic pyramid network-local activation region) increases by 4.2% compared with other methods. Whether under the Inception or ResNet-50 backbone networks, the AP of GA-CPN-LAR is significantly better than other methods. Compared with the ResNet-50 backbone network, GA-CPN-LAR has higher accuracy and recall rates under Inception. Precision-recall curve measurement shows that the proposed method can significantly reduce the false detection rate and missed detection rate. The GA-CPN-LAR model proposed here has a higher AP value on the MPD dataset than the other target detection methods, which can be increased by 4.2%. Besides, the accuracy and recall of the GA-CPN-LAR method corresponding to two representative pests under the initial feature extractor are higher than the MPD dataset baseline. In addition, the research results of the MPD dataset and AgriPest dataset also show that the pest target detection method based on convolutional neural networks (CNNs) has a good presentation effect and can significantly reduce false detection and missed detection. Moreover, the pest regulation based on blockchain and deep learning comprehensively considers global and local feature extraction and pattern recognition, which positively impacts the conscientization of agricultural data processing and promotes the sustainable development of rural areas.