Macrophage heterogeneity in bone metastasis.

Previous studies illustrated that macrophage, a type of innate immune cell, plays critical roles in tumour progression and metastasis. Bone is the most frequent site of metastasis for several cancer types including breast, prostate, and lung. In bone metastasis, osteoclast, a macrophage subset specialized in bone resorption, was heavily investigated in the past. Recent studies illustrated that other macrophage subsets, e.g. monocyte-derived macrophages, and bone resident macrophages, promoted bone metastasis independent of osteoclast function. These novel mechanisms further improved our understanding of macrophage heterogeneity in the context of bone metastasis and illustrated new opportunities for future studies.

Influence of different baking temperatures of red kojic rice on the physicochemical properties, antioxidant capacity, and functional components of red starter wine.

BACKGROUND: To improve the quality of red starter wine, this study explored the effects of baking red kojic rice at varying temperatures on the physicochemical characteristics of red starter wine. Baking was predicated on understanding crucial enzyme activities and starch granule structure of red kojic rice at 75, 95, and 105 °C, leading to the production of three red starter wine variants (BHQW1, BHQW2, and BHQW3). RESULTS: The results revealed an increased alcohol (increase 0.50%), total sugar (increase 0.14 g L-1 ), and total acid (increase 0.54 g L-1 ) content in red starter wine fermented using baked red kojic rice compared with the control group (wine fermented with unbaked rice, HQW). Furthermore, both the 105 °C baked red kojic rice and its resulting BHQW3 demonstrated significantly higher red color values than HQW (increase 2.03 U g-1 and 0.15 U mL-1 respectively). The highest lovastatin content was presented in red kojic rice baked at 105 °C and its corresponding fermented wine (1420.63 ± 507.9 µg g-1 and 3368.87 ± 228.16 µg L-1 respectively). Additionally, BHQW groups displayed higher total flavonoids and phenols content than HQW. Regarding antioxidant capacity, all BHQW groups showed stronger overall antioxidant capacity than HQW. The determination of volatile components revealed the highest content of volatile compounds in BHQW2 (2621.19 ± 548.24 µg L-1 ) and significantly higher volatile esters in BHQW1 (254.46 ± 16.63 µg L-1 ). Moreover, 16 volatile compounds were identified only in BHQW groups, including isoamyl caprylate, 2-ethylhexyl alcohol, and benzaldehyde. CONCLUSION: Our findings suggested that the baking technique of red kojic rice could enhance the quality of red starter wine through enhancing antioxidant properties, increasing functional components, and enriching volatile flavor compounds, thus providing a foundation for new techniques in red starter wine production. © 2023 Society of Chemical Industry.

Comparison on the Effect and Complications of VATS and Radical Thoracotomy for Lung Cancer in the Treatment of Stages IIB-IIIA Non-Small Cell Lung Cancer.

Objective: Lung adenocarcinoma (NSCLC) is a common subtype of lung cancer, and its prevalence has gradually increased in recent years. There are various treatment methods for NSCLC, and surgical resection, as one of the important treatments, is crucial to improving the survival rate and quality of life of patients. To explore the effect and complications of video-assisted thoracic surgery (VATS) and radical thoracotomy for lung cancer (RTLC) in the treatment of stages IIB-IIIA non-small cell lung cancer (NSCLC). Methods: A total of 80 patients with NSCLC admitted to the hospital were enrolled between June 2019 and January 2021. According to the random number table method, they were divided into the VATS group (40 cases, VATS) and RTLC group (40 cases, RTLC). The operation time, intraoperative blood loss, postoperative drainage time, number of lymph node dissections, score of visual analogue scale (VAS) at 24 h after surgery, and hospitalization time were compared between the two groups. We chose specific inclusion criteria, including patients diagnosed with non-small cell lung cancer (NSCLC) who did not receive radiation therapy or chemotherapy before surgery, to ensure consistency and comparability across studies. We focused on indicators related to lung function and immune system, such as CD3+, CD4+ and CD8+ levels, as well as FEV1, FVC and MVV, to evaluate the impact of surgery on lung function and immune status. The levels of CD3+, CD4+, and CD8+ in both groups were detected by flow cytometry at 1 d before surgery and 3 d after surgery. The forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and maximal voluntary ventilation (MVV) in both groups were detected by spirometry before and at 1 month after surgery. The occurrence of postoperative complications in both groups was recorded. After 12 months of follow-up, survival rates in both groups were statistically analyzed. The progression-free survival (PFS) and 12-month overall survival (OS) in both groups were analyzed by the Kaplan-Meier method. Results: The incision length, operation time, intraoperative blood loss, postoperative drainage time, VAS score at 24 h after surgery, and hospitalization time in VATS group were significantly lower than those in RTLC group (P < .05). The two groups had no significant difference in the number of lymph node dissections (P > .05). At 3 d after surgery, levels of CD3+, CD4+ and CD8+ in VATS group were significantly higher than those in RTLC group (P < .05). At 1 month after surgery, FEV1, FVC, and MVV in VATS group operation were significantly higher than those in RTLC group (P < .05). The incidence of postoperative complications in VATS group was lower than that in RTLC group (5.00% vs. 20.00%) (P < .05). Kaplan-Meier survival analysis showed that there was no significant difference in 12-month OS or PFS between the two groups (P > .05). Conclusions: The long-term curative effect of VATS and RTLC is comparable on patients with stages IIB-IIIA NSCLC. The former has advantages such as less surgical injury, faster postoperative recovery, and higher safety, which can reduce the incidence of postoperative complications. This study provides clinicians with important information about the treatment of stage IIb ~ IIIa NSCLC and helps them choose surgical methods more wisely. These results also alert physicians to focus on operative time, blood loss, and complication risk to maximize patient outcomes.

Radiologic Identification of Pathologic Tumor Invasion in Patients With Lung Adenocarcinoma.

Importance: It is currently unclear whether high-resolution computed tomography can preoperatively identify pathologic tumor invasion for ground-glass opacity lung adenocarcinoma. Objectives: To evaluate the diagnostic value of high-resolution computed tomography for identifying pathologic tumor invasion for ground-glass opacity featured lung tumors. Design, Setting, and Participants: This prospective, multicenter diagnostic study enrolled patients with suspicious malignant ground-glass opacity nodules less than or equal to 30 mm from November 2019 to July 2021. Thoracic high-resolution computed tomography was performed, and pathologic tumor invasion (invasive adenocarcinoma vs adenocarcinoma in situ or minimally invasive adenocarcinoma) was estimated before surgery. Pathologic nonadenocarcinoma, benign diseases, or those without surgery were excluded from analyses; 673 patients were recruited, and 620 patients were included in the analysis. Statistical analysis was performed from October 2021 to January 2022. Exposure: Patients were grouped according to pathologic tumor invasion. Main Outcomes and Measures: Primary end point was diagnostic yield for pathologic tumor invasion. Secondary end point was diagnostic value of radiologic parameters. Results: Among 620 patients (442 [71.3%] female; mean [SD] age, 53.5 [12.0] years) with 622 nodules, 287 (46.1%) pure ground-glass opacity nodules and 335 (53.9%) part-solid nodules were analyzed. The median (range) size of nodules was 12.1 (3.8-30.0) mm; 47 adenocarcinomas in situ, 342 minimally invasive adenocarcinomas, and 233 invasive adenocarcinomas were confirmed. Overall, diagnostic accuracy was 83.0% (516 of 622; 95% CI, 79.8%-85.8%), diagnostic sensitivity was 82.4% (192 of 233; 95% CI, 76.9%-87.1%), and diagnostic specificity was 83.3% (324 of 389; 95% CI, 79.2%-86.9%). For tumors less than or equal to 10 mm, 3.6% (8 of 224) were diagnosed as invasive adenocarcinomas. The diagnostic accuracy was 96.0% (215 of 224; 95% CI, 92.5%-98.1%), diagnostic specificity was 97.2% (210 of 216; 95% CI, 94.1%-99.0%); for tumors greater than 20 mm, 6.9% (6 of 87) were diagnosed as adenocarcinomas in situ or minimally invasive adenocarcinomas. The diagnostic accuracy was 93.1% (81 of 87; 95% CI, 85.6%-97.4%) and diagnostic sensitivity was 97.5% (79 of 81; 95% CI, 91.4%-99.7%). For tumors between 10 to 20 mm, the diagnostic accuracy was 70.7% (220 of 311; 95% CI, 65.3%-75.7%), diagnostic sensitivity was 75.0% (108 of 144; 95% CI, 67.1%-81.8%), and diagnostic specificity was 67.1% (112 of 167; 95% CI, 59.4%-74.1%). Tumor size (odds ratio, 1.28; 95% CI, 1.18-1.39) and solid component size (odds ratio, 1.31; 95% CI, 1.22-1.42) could each independently serve as identifiers of pathologic invasive adenocarcinoma. When the cutoff value of solid component size was 6 mm, the diagnostic sensitivity was 84.6% (95% CI, 78.8%-89.4%) and specificity was 82.9% (95% CI, 75.6%-88.7%). Conclusions and relevance: In this diagnostic study, radiologic analysis showed good performance in identifying pathologic tumor invasion for ground-glass opacity-featured lung adenocarcinoma, especially for tumors less than or equal to 10 mm and greater than 20 mm; these results suggest that a solid component size of 6 mm could be clinically applied to distinguish pathologic tumor invasion.

AR activates YAP/TAZ differentially in prostate cancer.

The Hippo signalling pathway is a master regulator of cell growth, proliferation, and cancer. The transcriptional coregulators of the Hippo pathway, YAP and TAZ, are central in various cancers. However, how YAP and TAZ get activated in most types of cancers is not well understood. Here, we show that androgens activate YAP/TAZ via the androgen receptor (AR) in prostate cancer (PCa), and that this activation is differential. AR regulates YAP translation while inducing transcription of the TAZ encoding gene, WWTR1 Furthermore, we show that AR-mediated YAP/TAZ activation is regulated by the RhoA GTPases transcriptional mediator, serum response factor (SRF). Importantly, in prostate cancer patients, SRF expression positively correlates with TAZ and the YAP/TAZ target genes CYR61 and CTGF We demonstrate that YAP/TAZ are not essential for sustaining AR activity, however, targeting YAP/TAZ or SRF sensitize PCa cells to AR inhibition in anchorage-independent growth conditions. Our findings dissect the cellular roles of YAP, TAZ, and SRF in prostate cancer cells. Our data emphasize the interplay between these transcriptional regulators and their roles in prostate tumorigenesis and highlight how these insights might be exploited therapeutically.

Design, synthesis, and biological activity of dual monoamine oxidase A and heat shock protein 90 inhibitors, N-Methylpropargylamine-conjugated 4-isopropylresorcinol for glioblastoma.

Monoamine oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and other cancers. In this study, a series of MAO A/HSP90 dual inhibitors were designed and synthesized in the hope to develop more effective treatment of GBM. Compounds 4-b and 4-c are conjugates of isopropylresorcinol (pharmacophore of HSP90 inhibitor) with the phenyl group of clorgyline (MAO A inhibitor) by a tertiary amide bond substituted with methyl (4-b) or ethyl (4-c) group, respectively. They inhibited MAO A activity, HSP90 binding, and the growth of both TMZ-sensitive and -resistant GBM cells. Western blots showed that they increased HSP70 expression indicating reduced function of HSP90, reduced HER2 and phospho-Akt expression similar to MAO A or HSP90 inhibitor itself. Both compounds decreased IFN-γ induced PD-L1 expression in GL26 cells, suggesting they can act as immune checkpoint inhibitor. Further, they reduced tumor growth in GL26 mouse model. NCI-60 analysis showed they also inhibited the growth of colon cancer, leukemia, non-small cell lung and other cancers. Taken together, this study demonstrates MAO A/HSP90 dual inhibitors 4-b and 4-c reduced the growth of GBM and other cancers, and they have potential to inhibit tumor immune escape.

Lentinan confers protection against type 1 diabetes by inducing regulatory T cell in spontaneous non-obese diabetic mice.

BACKGROUND: Lentinan (LNT) is a complex fungal component that possesses effective antitumor and immunostimulating properties. However, there is a paucity of studies regarding the effects and mechanisms of LNT on type 1 diabetes. OBJECTIVE: In the current study, we investigated whether an intraperitoneal injection of LNT can diminish the risk of developing type 1 diabetes (T1D) in non-obese diabetic (NOD) mice and further examined possible mechanisms of LNT's effects. METHODS: Pre-diabetic female NOD mice 8 weeks of age, NOD mice with 140-160 mg/dL, 200-230 mg/dL or 350-450 mg/dL blood glucose levels were randomly divided into two groups and intraperitoneally injected with 5 mg/kg LNT or PBS every other day. Then, blood sugar levels, pancreas slices, spleen, PnLN and pancreas cells from treatment mice were examined. RESULTS: Our results demonstrated that low-dosage injections (5 mg/kg) of LNT significantly suppressed immunopathology in mice with autoimmune diabetes but increased the Foxp3+ regulatory T cells (Treg cells) proportion in mice. LNT treatment induced the production of Tregs in the spleen and PnLN cells of NOD mice in vitro. Furthermore, the adoptive transfer of Treg cells extracted from LNT-treated NOD mice confirmed that LNT induced Treg function in vivo and revealed an enhanced suppressive capacity as compared to the Tregs isolated from the control group. CONCLUSION: LNT was capable of stimulating the production of Treg cells from naive CD4 + T cells, which implies that LNT exhibits therapeutic values as a tolerogenic adjuvant and may be used to reverse hyperglycaemia in the early and late stages of T1D.

Macrophages promote anti-androgen resistance in prostate cancer bone disease.

Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing-like response of ECM-receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Selective Mediastinal Lymph Node Dissection Strategy for Clinical T1N0 Invasive Lung Cancer: A Prospective, Multicenter, Clinical Trial.

INTRODUCTION: We aimed to prospectively evaluate our previously proposed selective mediastinal lymph node (LN) dissection strategy for peripheral clinical T1N0 invasive NSCLC. METHODS: This is a multicenter, prospective clinical trial in China. We set six criteria for predicting negative LN stations and finally guiding selective LN dissection. Consolidation tumor ratio less than or equal to 0.5, segment location, lepidic-predominant adenocarcinoma (LPA), negative hilar nodes (stations 10-12), and negative visceral pleural invasion (VPI) were used separately or in combination as predictors of negative LN status in the whole, superior, or inferior mediastinal zone. LPA, hilar node involvement, and VPI were diagnosed intraoperatively. All patients actually underwent systematic mediastinal LN dissection. The primary end point was the accuracy of the strategy in predicting LN involvement. If LN metastasis occurred in certain mediastinal zone that was predicted to be negative, it was considered as an "inaccurate" case. RESULTS: A total of 720 patients were enrolled. The median number of LN dissected was 15 (interquartile range: 11-20). All negative node status in certain mediastinal zone was correctly predicted by the strategy. Compared with final pathologic findings, the accuracy of frozen section to diagnose LPA, VPI, and hilar node metastasis was 94.0%, 98.9%, and 99.6%, respectively. Inaccurate intraoperative diagnosis of LPA, VPI, or hilar node metastasis did not lead to inaccurate prediction of node-negative status. CONCLUSIONS: This is the first prospective trial validating the specific mediastinal LN metastasis pattern in cT1N0 invasive NSCLC, which provides important evidence for clinical applications of selective LN dissection strategy.

Microglial P2Y12 Signaling Contributes to Cisplatin-induced Pain Hypersensitivity via IL-18-mediated Central Sensitization in the Spinal Cord.

Administration of cisplatin and other chemotherapy drugs is crucial for treating tumors. However, cisplatin-induced pain hypersensitivity is still a critical clinical issue, and the underlying molecular mechanisms have remained unresolved to date. In this study, we found that repeated cisplatin treatments remarkedly upregulated the P2Y12 expression in the spinal cord. Expression of P2Y12 was predominant in the microglia. Pharmacological inhibition of P2Y12 expression markedly attenuated the cisplatin-induced pain hypersensitivity. Meanwhile, blocking the P2Y12 signal also suppressed cisplatin-induced microglia hyperactivity. Furthermore, the microglia Src family kinase/p38 pathway is required for P2Y12-mediated cisplatin-induced pain hypersensitivity via the proinflammatory cytokine IL-18 production in the spinal cord. Blocking the P2Y12/IL-18 signaling pathway reversed cisplatin-induced pain hypersensitivity, as well as activation of N-methyl-D-aspartate receptor and subsequent Ca2+-dependent signals. Collectively, our data suggest that microglia P2Y12-SFK-p38 signaling contributes to cisplatin-induced pain hypersensitivity via IL-18-mediated central sensitization in the spinal, and P2Y12 could be a potential target for intervention to prevent chemotherapy-induced pain hypersensitivity. PERSPECTIVE: Our work identified that P2Y12/IL-18 played a critical role in cisplatin-induced pain hypersensitivity. This work suggests that P2Y12/IL-18 signaling may be a useful strategy for the treatment of chemotherapy-induced pain hypersensitivity.

The Application of Nanotechnology for Quantification of Circulating Tumour DNA in Liquid Biopsies: A Systematic Review.

Technologies for quantifying circulating tumour DNA (ctDNA) in liquid biopsies could enable real-time measurements of cancer progression, profoundly impacting patient care. Sequencing methods can be too complex and time-consuming for regular point-of-care monitoring, but nanotechnology offers an alternative, harnessing the unique properties of objects tens to hundreds of nanometres in size. This systematic review was performed to identify all examples of nanotechnology-based ctDNA detection and assess their potential for clinical use. Google Scholar, PubMed, Web of Science, Google Patents, Espacenet and Embase/MEDLINE were searched up to 23rd March 2021. The review identified nanotechnology-based methods for ctDNA detection for which quantitative measures (e.g., limit of detection, LOD) were reported and biologically relevant samples were used. The pre-defined inclusion criteria were met by 66 records. LODs ranged from 10 zM to 50nM. 25 records presented an LOD of 10fM or below. Nanotechnology-based approaches could provide the basis for the next wave of advances in ctDNA diagnostics, enabling analysis at the point-of-care, but none are currently used clinically. Further work is needed in development and validation; trade-offs are expected between different performance measures e.g., number of sequences detected and time to result.

Interleukin 4 Controls the Pro-Tumoral Role of Macrophages in Mammary Cancer Pulmonary Metastasis in Mice.

Metastasis is the systemic manifestation of cancer and the main cause of death from breast cancer. In mouse models of lung metastases, recruitment of classical monocytes from blood to the lung and their differentiation to metastasis-associated macrophages (MAMs) facilitate cancer cell extravasation, survival and growth. Ablation of MAMs or their monocytic progenitors inhibits metastasis. We hypothesized that factors controlling macrophage polarization modulate tumor cell extravasation in the lung. We evaluated whether signaling by Th1 or Th2 cytokines in macrophages affected transendothelial migration of tumor cells in vitro. Interferon gamma and LPS inhibited macrophage-dependent tumor cell extravasation while the Th2 cytokine interleukin-4 (IL4) enhanced this process. We demonstrated that IL4 receptor (IL4rα)-null mice developed fewer and smaller lung metastasis in E0771-LG mammary cancer models of this disease. Adoptive transfer of wild-type monocytes to IL4rα-deficient mice partially rescued this phenotype. IL4 signaling in macrophages controlled the expression of the chemokine receptor CXCR2, necessary for IL4-mediated tumor cell extravasation in vitro. Furthermore, IL4 signaling in macrophages regulated the transcript abundance of several other genes already causally associated with mammary cancer lung metastasis including Ccl2, Csf1, Ccr1, Hgf and Flt1. The central role of IL4 signaling in MAMs was confirmed by high-resolution intravital imaging of the lung in mice at the time of metastatic seeding, which showed reduced physical interaction between tumor cells and IL4rα-deficient macrophages. This interaction with wild-type MAMs enhanced tumor cell survival and seeding, which was lost in the IL4rα mice. These data indicate that IL4 signaling in monocytes and macrophages is key during seeding and growth of breast metastasis in the lung, as it regulates pro-tumoral paracrine signaling between cancer cells and macrophages.

MYC sensitises cells to apoptosis by driving energetic demand.

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

Anticancer effects of zapotin flavone in human gastric carcinoma cells are mediated via targeting m-TOR/PI3K/AKT signalling pathway.

The current study aims to investigate the anticancer effects of zapotin flavone in human gastric carcinoma cells. MTT assay was performed to determine the cytotoxicity effects of zapotin against the gastric cancer cells (SNU-1) and normal gastric cells (GES-1). SNU-1 cell morphology was analyzed through phase-contrast microscopy. Apoptosis was identified through DAPI staining assay and quantified through annexin V/propidium iodide (PI) staining. The effects on cell migration and invasion were carried out through transwell assay. Apoptosis and m-TOR/PI3K/AKT signalling pathway related proteins were analysed through western blotting. Proliferation rate of gastric cancer SNU-1 cell line declined with enhanced zapotin concentrations in comparison to normal GES-1 cells. Substantial morphological changes after zapotin exposure, including nuclear condensation and membrane rupture was observed. Further, increasing number of apoptotic cells, suppression of both cell migration and invasion was observed with increased zapotin concentrations. Finally, western blotting indicated significant blocking of m-TOR/PI3K/AKT signalling pathway. We conclude that zapotin can act as a potential drug against the gastric cancer.

Macrophage diversity in cancer revisited in the era of single-cell omics.

Tumor-associated macrophages (TAMs) have multiple potent functions in cancer and, thus, represent important therapeutic targets. These diverse functions highlight the heterogenous nature of TAMs. Recent single cell omics technologies have significantly advanced our understanding of the molecular diversity of TAMs. However, a unifying nomenclature of TAM diversity and annotation of their molecular signatures is lacking. Here, we review recent major studies of single cell transcriptome, epigenome, metabolome, and spatial omics of cancer with a specific focus on TAMs. We also propose a consensus model of TAM diversity and present avenues for future research.

Efficacy of systemic lidocaine in postoperative delirium in elderly patients undergoing laparoscopic colorectal surgery: study protocol for a multicentre, prospective, double-blind, randomised, parallel-group, superiority, placebo-controlled trial.

INTRODUCTION: Systemic lidocaine may reduce pain intensity and accelerate postoperative recovery. However, the efficacy of systemic lidocaine in cognitive function has not been established. This study protocol is designed to clarify the effectiveness of lidocaine in postoperative delirium (POD) in elderly patients scheduled for elective laparoscopic colorectal surgery. METHODS AND ANALYSIS: This is a prospective, multicentre, randomised, double-blind, parallel-group, placebo-controlled trial. One thousand and twenty elderly patients will be randomly allocated in a ratio of 1:1 to receive either systemic lidocaine (a bolus of 1.5 mg/kg, followed by an infusion of 1.5 mg/kg/hour until the end of the surgery) or identical volumes and rates of 0.9% saline. The primary outcome measure is the prevalence of POD during the first 5 postoperative days. Secondary outcomes include emergence agitation, the area under the curve of the Numeric Rating Scale pain scores over 48 hours, postoperative 48-hour cumulative opioid consumption, postoperative nausea and vomiting (PONV), recovery of bowel function, quality of recovery, and patient satisfaction with postoperative analgesia. ETHICS AND DISSEMINATION: The Ethical Committee of the Fujian Provincial Hospital approved the study protocol (ref: K2021-06-018). Other participating subcentres must also obtain ethics committee approval before the start of the study. We will obtain written informed consent from each patient before they are randomised. This study will be presented at scientific conferences and submitted to international journals. TRIAL REGISTRATION NUMBER: ChiCTR2100050314.

Celastrol Induces Apoptosis and Autophagy via the AKT/mTOR Signaling Pathway in the Pituitary ACTH-secreting Adenoma Cells.

OBJECTIVE: Pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma is a relatively intractable endocrine adenoma that can cause a range of severe metabolic disorders and pathological changes involving multiple systems. Previous studies have shown that celastrol has antitumor effects on a variety of tumor cells via the AKT/mTOR signaling. However, whether celastrol has pronounced antitumor effects on pituitary ACTH-secreting adenoma is unclear. This study aimed to identify a new effective therapeutic drug for pituitary ACTH-secreting adenoma. METHODS: Mouse pituitary ACTH-secreting adenoma cells (AtT20 cells) were used as an experimental model in vitro and to establish a xenograft tumor model in mice. Cells and animals were administered doses of celastrol at various levels. The effects of celastrol on cell viability, migration, apoptosis and autophagy were then examined. Finally, the potential involvement of AKT/mTOR signaling in celastrol's mechanism was assessed. RESULTS: Celastrol inhibited the proliferation and migration of pituitary adenoma cells in a time- and concentration-dependent manner. It blocked AtT20 cells in the G0/G1 phase, and induced apoptosis and autophagy by downregulating the AKT/mTOR signaling pathway. Similar results were obtained in mice. CONCLUSION: Celastrol exerts potent antitumor effects on ACTH-secreting adenoma by downregulating the AKT/mTOR signaling in vitro and in vivo.

Preparation, Identification, Molecular Docking Study and Protective Function on HUVECs of Novel ACE Inhibitory Peptides from Protein Hydrolysate of Skipjack Tuna Muscle.

To prepare bioactive peptides with high angiotensin-I-converting enzyme (ACE)-inhibitory (ACEi) activity, Alcalase was selected from five kinds of protease for hydrolyzing Skipjack tuna (Katsuwonus pelamis) muscle, and its best hydrolysis conditions were optimized using single factor and response surface experiments. Then, the high ACEi protein hydrolysate (TMPH) of skipjack tuna muscle was prepared using Alcalase under the optimum conditions of enzyme dose 2.3%, enzymolysis temperature 56.2 °C, and pH 9.4, and its ACEi activity reached 72.71% at 1.0 mg/mL. Subsequently, six novel ACEi peptides were prepared from TMPH using ultrafiltration and chromatography methods and were identified as Ser-Pro (SP), Val-Asp-Arg-Tyr-Phe (VDRYF), Val-His-Gly-Val-Val (VHGVV), Tyr-Glu (YE), Phe-Glu-Met (FEM), and Phe-Trp-Arg-Val (FWRV), with molecular weights of 202.3, 698.9, 509.7, 310.4, 425.6, and 606.8 Da, respectively. SP and VDRYF displayed noticeable ACEi activity, with IC50 values of 0.06 ± 0.01 and 0.28 ± 0.03 mg/mL, respectively. Molecular docking analysis illustrated that the high ACEi activity of SP and VDRYF was attributed to effective interaction with the active sites/pockets of ACE by hydrogen bonding, electrostatic force, and hydrophobic interaction. Furthermore, SP and VDRYF could significantly up-regulate nitric oxide (NO) production and down-regulate endothelin-1 (ET-1) secretion in HUVECs after 24 h treatment, but also abolish the negative effect of 0.5 µM norepinephrine (NE) on the generation of NO and ET-1. Therefore, ACEi peptides derived from skipjack tuna (K. pelamis) muscle, especially SP and VDRYF, are beneficial components for functional food against hypertension and cardiovascular diseases.

N-Methylpropargylamine-Conjugated Hydroxamic Acids as Dual Inhibitors of Monoamine Oxidase A and Histone Deacetylase for Glioma Treatment.

Glioma treatment remains a challenge with a low survival rate due to the lack of effective therapeutics. Monoamine oxidase A (MAO A) plays a role in glioma development, and MAO A inhibitors reduce glioma growth. Histone deacetylase (HDAC) inhibition has emerged as a promising therapy for various malignancies including gliomas. We have synthesized and evaluated N-methylpropargylamine-conjugated hydroxamic acids as dual inhibitors of MAO A and HDAC. Compounds display potent MAO A inhibition with IC50 from 0.03 to <0.0001 µM and inhibit HDAC isoforms and cell growth in the micromolar to nanomolar IC50 range. These selective MAO A inhibitors increase histone H3 and α-tubulin acetylation and induce cell death via nonapoptotic mechanisms. Treatment with 15 reduced tumor size, reduced MAO A activity in brain and tumor tissues, and prolonged the survival. This first report on dual inhibitors of MAO A and HDAC establishes the basis of translational research for an improved treatment of glioma.

Transcriptome and single-cell analysis reveal the contribution of immunosuppressive microenvironment for promoting glioblastoma progression.

Background and objectives: GBM patients frequently exhibit severe local and systemic immunosuppression, limiting the possible efficacy of immunotherapy strategies. The mechanism through which immunosuppression is established in GBM tumors is the key to successful personalized immunotherapies. Methods: We divided GBM patients into subtypes according to the expression characteristics of the TME typing-related signature matrix. WGCNA analysis was used to get co-expressed gene modules. The expression activity of hub genes retrieved from co-expressed modules was validated in two single-cell datasets. Then, cell-cell interaction was calculated. Results: Four subtypes were identified in the TCGA and CGGA RNA-seq datasets simultaneously, one of which was an immunosuppressive subtype rich in immunosuppressive factors with low lymphocyte infiltration and an IDH1 mutation. Three co-expressed gene modules related to the immunosuppressive subtype were identified. These three modules are associated with the inflammatory response, angiogenesis, hypoxia, and carbon metabolism, respectively. The genes of the inflammatory response were mainly related to myeloid cells, especially TAM, angiogenesis was related to blood vessels; hypoxia and glucose metabolism were related to tumors, TAM, and blood vessels. Moreover, there was enhanced interaction between tumor cells and TAM. Discussion: This research successfully found the immunosuppressive subtype and the major cell types, signal pathways, and molecules involved in the formation of the immunosuppressive subtype and will provide new clues for the improvement of GBM personalized immunotherapy in the future.