Litoamentenes A-K, eleven undescribed cembranoids with cytotoxicity from the South China Sea soft coral Litophyton amentaceum.

Eleven undescribed cembrane-type diterpenoids, named litoamentenes A-K (1-11), were isolated from the soft coral Litophyton amentaceum collected from the South China Sea. Their structures were elucidated by extensive analysis of spectroscopic data, comparison with the literature data, single crystal X-ray diffraction, quantum chemical calculations and TDDFT-ECD calculations. This is the first systematic investigation of L. amentaceum. In particular, compounds 1-3 are cembrane-type norditerpenoids that lack isopropyl side chains. Compound 6 is a cembrane-type norditerpenoid without a methyl group at C-4, the first natural product identified with this carbon skeleton. Compounds 6, 9 and 10 showed modest cytotoxicity against several human cancer cell lines with IC50 values ranging from 3.99 to 14.56 µM.

Clinical evidence for the prognostic impact of metformin in cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Preclinical studies suggest that metformin might enhance the efficacy of immune checkpoint inhibitors (ICIs) and potentially influence the prognoses of cancer patients undergoing ICIs treatment. This study endeavors to assess the prognostic significance of metformin in cancer patients undergoing ICIs therapy, aiming to furnish evidence-based insights for clinical practice. METHODS: A thorough literature search was conducted across electronic databases to encompass all potential records published before November 20th, 2023. A meta-analysis was executed utilizing Stata 17.0 to derive pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 22 studies encompassing 9,011 patients met the inclusion criteria. Meta-analyses revealed a significant correlation between metformin use and poorer OS (HR, 1.13; 95 %CI, 1.04-1.23; P = 0.004) rather than PFS (HR, 1.04; 95 %CI, 0.96-1.14; P = 0.345) among cancer patients undergoing ICIs treatment. Subgroup analysis delineated that the concurrent administration of metformin and ICIs significantly associated with adverse prognoses in the European population (OS: HR, 1.23; 95 %CI, 1.10-1.39; P = 0.001; PFS: HR, 1.14; 95 %CI, 1.02-1.28; P = 0.024). CONCLUSION: Based on current clinical evidence, concomitant metformin use does not appear to improve the prognostic outcomes for cancer patients undergoing ICIs therapy and may potentially correlate with inferior prognoses. Further studies are imperative to comprehensively elucidate the impact of metformin within the realm of ICIs therapy.

Fibroblast activation protein promotes progression of hepatocellular carcinoma via regulating the immunity.

Fibroblast activation protein (FAP) has been indicated to express in cancer-associated fibroblasts (CAFs) in most cancers. This work was dedicated to exploring FAP's effects on hepatocellular carcinoma (HCC). The data were extracted from The Cancer Genome Atlas, Gene Expression Omnibus, ImmPort, and Reactome databases. The correlation between FAP and HCC patients' prognosis was explored via survival analysis. The qRT-PCR and western blot analysis were used to analyze the FAP mRNA and protein expression levels, respectively. The cell proliferation and apoptosis were determined using the cell counting kit-8 assay kit and Annexin V-FITC/PI apoptosis kit, respectively. The HCC patients with FAP overexpression displayed a worse prognosis. The FAP expression was positively associated with the infiltration levels of tumor purity, B cell, CD8 + T cell, CD4 + T cell, macrophage, neutrophil, and dendritic cell. The optimal nine immune related genes were screened between two groups (FAP high vs. low). Moreover, we identified 24 energy metabolism related genes (FAP high vs. low) and these 24 genes were highly expressed in the high FAP expression group. The FAP expression had a significant positive correlation with the expression of PD-1, CTLA4, PDL-1, and PDL-2. The FAP overexpression promoted proliferation and migration while inhibiting the apoptosis of HCC cells. The FAP overexpression promoted the progression of HCC by regulating the immunity to affect the prognosis of HCC patients, thereby serving as a poor prognostic marker for HCC patients.

Interactive model for predicting the oncological outcome of patients with early-stage huge hepatocellular carcinoma after hepatectomy: a multicenter population-based study.

An interactive model for predicting the oncological outcome of patients with early-stage huge hepatocellular carcinoma (ES-HHCC) after hepatectomy is still lacking. This study was aimed at exploring the independent risk parameters and developing an interactive model for predicting the cancer-specific survival (CSS) of ES-HHCC. Data from patients with ES-HHCC who underwent hepatectomy were collected. The dimensionality of the clinical features was reduced by least absolute shrinkage and selection operator regression and further screened as predictors of CSS by Cox regression. Then, an interactive prediction model was developed and validated. Among the 514 screened patients, 311 and 203 of them were assigned into the training and validation cohort, respectively. Six independent variables, including alpha-fetoprotein, cirrhosis, microvascular invasion, satellite, tumor morphology, and tumor diameter, were identified and incorporated into the prediction model for CSS. The model achieved C-indices of 0.724 and 0.711 in the training and validation cohorts, respectively. Calibration curves showed general consistency in both cohorts. Compared with single predictor, the model had a better performance and greater benefit according to the time-independent receiver operating characteristic curve and decision curve analysis (P < 0.05). The calculator owned satisfactory accuracy and flexible operability for predicting the CSS of ES-HHCC, which could serve as a practical tool to stratify patients with different risks, and guide decision-making.

Biocontrol activity and potential mechanism of volatile organic compounds from Aspergillus niger strain La2 against pear Valsa canker.

BACKGROUND: Valsa canker caused by Valsa pyri is one of the most destructive diseases of pear, leading to severe yield and economic losses. Volatile organic compounds (VOCs) from endophytes have important roles in the regulation of plant disease. In this study, we investigated the biocontrol activity of the endophytic fungus Aspergillus niger strain La2 and its antagonistic VOCs against pear Valsa canker. RESULTS: Strain La2 exhibited an obvious inhibitory effect against V. pyri. A colonization assay suggested that strain La2 could complete its life cycle on pear twigs. The symptoms of pear Valsa canker were weakened on detached pear twigs after treatment with strain La2. In addition, VOCs from strain La2 also significantly suppressed mycelial growth in V. pyri. Based on the results of headspace solid-phase microextraction/gas chromatography-mass spectrometry analysis, six possible VOCs produced by strain La2 were detected, of which 2,4-di-tert-butylphenol and 4-methyl-1-pentanol were the main antagonistic VOCs in terms of their effect on pear Valsa canker in vitro and in vivo. Further results showed that 4-methyl-1-pentanol could destroy the V. pyri hyphal structure and cell membrane integrity. Importantly, the activities of pear defense-related enzymes (polyphenol oxidase, phenylalanine ammonia lyase and superoxide dismutase) were enhanced after 4-methyl-1-pentanol treatment in pear twigs, suggesting that 4-methyl-1-pentanol might induce a plant disease resistance response. CONCLUSION: Aspergillus niger strain La2 and its VOCs 2,4-di-tert-butylphenol and 4-methyl-1-pentanol have potential as novel biocontrol agents of pear Valsa canker. © 2024 Society of Chemical Industry.

Total laparoscopic partial hepatectomy versus open partial hepatectomy for primary left-sided hepatolithiasis: study protocol for a randomized controlled trial.

BACKGROUND: The advantages of laparoscopic left-sided hepatectomy (LLH) for treating hepatolithiasis in terms of the time to postoperative length of hospital stay (LOS), morbidity, long-term abdominal wall hernias, hospital costs, residual stone rate, and recurrence of calculus have not been confirmed by a randomized controlled trial. The aim of this trial is to compare the safety and effectiveness of LLH with open left-sided hepatectomy (OLH) for the treatment of hepatolithiasis. METHODS: Patients with hepatolithiasis eligible for left-sided hepatectomy will be recruited. The experimental design will produce two randomized arms (laparoscopic and open hepatectomy) at a 1:1 ratio and a prospective registry. All patients will undergo surgery in the setting of an enhanced recovery after surgery (ERAS) programme. The prospective registry will be based on patients who cannot be randomized because of the explicit treatment preference of the patient or surgeon or because of ineligibility (not meeting the inclusion and exclusion criteria) for randomization in this trial. The primary outcome is the LOS. The secondary outcomes are percentage readmission, morbidity, mortality, hospital costs, long-term incidence of incisional hernias, residual stone rate, and recurrence of calculus. It will be assumed that, in patients undergoing LLH, the length of hospital stay will be reduced by 1 day. A sample size of 86 patients in each randomization arm has been calculated as sufficient to detect a 1-day reduction in LOS [90% power and α = 0.05 (two-tailed)]. The trial is a randomized controlled trial that will provide evidence for the merits of laparoscopic surgery in patients undergoing liver resection within an ERAS programme. CONCLUSIONS: Although the outcomes of LLH have been proven to be comparable to those of OLH in retrospective studies, the use of LLH remains restricted, partly due to the lack of short- and long-term informative RCTs pertaining to patients with hepatolithiasis in ERAS programmes. To evaluate the surgical and long-term outcomes of LLH, we will perform a prospective RCT to compare LLH with OLH for hepatolithiasis within an ERAS programme. TRIAL REGISTRATION: ClinicalTrials.gov NCT03958825. Registered on 21 May 2019.

Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity.

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.

Synthesis and Biological Evaluation of ß-Lactam Derivatives Targeting Speckle-Type POZ Protein (SPOP).

Speckle-type POZ protein (SPOP) acts as a cullin3-RING ubiquitin ligase adaptor, which facilitates the recognition and ubiquitination of substrate proteins. Previous research suggests that targeting SPOP holds promise in the treatment of clear cell renal cell carcinoma (ccRCC). On the basis of the reported SPOP inhibitor 230D7, a series of ß-lactam derivatives were synthesized in this study. The biological activity assessment of these compounds revealed E1 as the most potent inhibitor, which can disrupt the SPOP-substrate interactions in vitro and suppress the colony formation of ccRCC cells. Taken together, this study provided compound E1 as a potent inhibitor against ccRCC and offered insight into the development of the ß-lactam SPOP inhibitor.

DNA-PK-Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance.

Detection of cytoplasmic DNA is an essential biological mechanism that elicits IFN-dependent and immune-related responses. A better understanding of the mechanisms regulating cytoplasmic DNA sensing in tumor cells could help identify immunotherapeutic strategies to improve cancer treatment. Here we identified abundant cytoplasmic DNA accumulated in lung squamous cell carcinoma (LUSC) cells. DNA-PK, but not cGAS, functioned as a specific cytoplasmic DNA sensor to activate downstream ZAK/AKT/mTOR signaling, thereby enhancing the viability, motility, and chemoresistance of LUSC cells. DNA-PK-mediated cytoplasmic DNA sensing boosted glycolysis in LUSC cells, and blocking glycolysis abolished the tumor-promoting activity of cytoplasmic DNA. Elevated DNA-PK-mediated cytoplasmic DNA sensing was positively correlated with poor prognosis of human patients with LUSC. Targeting signaling activated by cytoplasmic DNA sensing with the ZAK inhibitor iZAK2 alone or in combination with STING agonist or anti-PD-1 antibody suppressed the tumor growth and improved the survival of mouse lung cancer models and human LUSC patient-derived xenografts model. Overall, these findings established DNA-PK-mediated cytoplasmic DNA sensing as a mechanism that supports LUSC malignancy and highlight the potential of targeting this pathway for treating LUSC. SIGNIFICANCE: DNA-PK is a cytoplasmic DNA sensor that activates ZAK/AKT/mTOR signaling and boosts glycolysis to enhance malignancy and chemoresistance of lung squamous cell carcinoma.

Artificial intelligence-based diagnosis of standard endoscopic ultrasonography scanning sites in the biliopancreatic system: a multicenter retrospective study.

BACKGROUND: There are challenges for beginners to identify standard biliopancreatic system anatomical sites on endoscopic ultrasonography (EUS) images. Therefore, the authors aimed to develop a convolutional neural network (CNN)-based model to identify standard biliopancreatic system anatomical sites on EUS images. METHODS: The standard anatomical structures of the gastric and duodenal regions observed by EUS was divided into 14 sites. The authors used 6230 EUS images with standard anatomical sites selected from 1812 patients to train the CNN model, and then tested its diagnostic performance both in internal and external validations. Internal validation set tests were performed on 1569 EUS images of 47 patients from two centers. Externally validated datasets were retrospectively collected from 16 centers, and finally 131 patients with 85 322 EUS images were included. In the external validation, all EUS images were read by CNN model, beginners, and experts, respectively. The final decision made by the experts was considered as the gold standard, and the diagnostic performance between CNN model and beginners were compared. RESULTS: In the internal test cohort, the accuracy of CNN model was 92.1-100.0% for 14 standard anatomical sites. In the external test cohort, the sensitivity and specificity of CNN model were 89.45-99.92% and 93.35-99.79%, respectively. Compared with beginners, CNN model had higher sensitivity and specificity for 11 sites, and was in good agreement with the experts (Kappa values 0.84-0.98). CONCLUSIONS: The authors developed a CNN-based model to automatically identify standard anatomical sites on EUS images with excellent diagnostic performance, which may serve as a potentially powerful auxiliary tool in future clinical practice.

Dendrocandin U from Dendrobium officinale Kimura et Migo Inhibits M1 Polarization in Alveolar Macrophage by Suppressing NF-κB Signaling Pathway.

Dendrobium officinale Kimura et Migo is a valuable and homologous medicine and food traditional Chinese medicine. Currently there are few studies on the anti-inflammatory activity of lipophilic components. The aim of this study was to explore the anti-inflammatory effect and mechanism of the lipophilic compounds in Dendrobium officinale. Six compounds were isolated and identified, including three bibenzyl compounds, dendrocandin U, dendronbibisline B, erianin, and three lignans, (-)-syringaresinol, (+)-syringaresinol-O-ß-D-glucopyranoside, 5-methoxy-(+)-isolariciresinol. Among them, dendronbibisline B and 5-methoxy-(+)-isolariciresinol were isolated from Dendrobium officinale for the first time. Besides, we found dendrocandin U, dendronbibisline B and (-)-syringaresinol exhibited the anti-inflammation to inhibit nitric oxide secretion induced by lipopolysaccharide (LPS)/interferon (IFN-γ) in MH-S cells. Furthermore, dendrocandin U could inhibit the expression of tumor necrosis factor-α (TNF-α), Cluster of Differentiation 86 (CD86), and reduce inflammatory morphological changes of macrophages. Meanwhile, we confirmed that the anti-inflammation mechanism of dendrocandin U was to inhibit M1 polarization by suppressing toll-like receptor 4 (TLR4)/recombinant myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. In this paper, dendrocandin U with significant anti-inflammatory activity was found from Dendrobium officinale, which could provide a basis for the study of its anti-inflammatory drugs.

Oncological prognosis and morbidity of hepatectomy in elderly patients with hepatocellular carcinoma: a propensity score matching and multicentre study.

PURPOSE: With increasing life expectancy, the number of elderly patients (≥ 65 years) with hepatocellular carcinoma (HCC) has steadily increased. Hepatectomy remains the first-line treatment for HCC patients. However, the prognosis of hepatectomy for elderly patients with HCC remains unclear. METHODS: Clinical and follow-up data from 1331 HCC patients who underwent surgery between 2008 and 2020 were retrospectively retrieved from a multicentre database. Patients were divided into elderly (≥ 65 years) and non-elderly (< 65 years) groups, and PSM was used to balance differences in the baseline characteristics. The postoperative major morbidity and cancer-specific survival (CSS) of the two groups were compared and the independent factors that were associated with the two study endpoints were identified by multivariable regression analysis. RESULTS: Of the 1331 HCC patients enrolled in this study, 363 (27.27%) were elderly, while 968 (72.73%) were not. After PSM, 334 matched samples were obtained. In the propensity score matching (PSM) cohort, a higher rate of major morbidity was found in elderly patients (P = 0.040) but the CSS was similar in the two groups (P = 0.087). Multivariate analysis revealed that elderly age was not an independent risk factor associated with high rates of major morbidity (P = 0.117) or poor CSS (P = 0.873). The 1-, 3- and 5-year CSS rates in the elderly and non-elderly groups were 91.0% versus 86.2%, 71.3% versus 68.8% and 55.9% versus 58.0%, respectively. Preoperative alpha fetoprotein (AFP) level, Child‒Pugh grade, intraoperative blood transfusion, extended hemi hepatectomy, and tumour diameter could affect the postoperative major morbidity and preoperative AFP level, cirrhosis, Child‒Pugh grade, macrovascular invasion, microvascular invasion (MVI), satellite nodules, and tumor diameter were independently and significantly associated with CSS. CONCLUSION: Age itself had no significant effect on the prognosis of elderly patients with HCC after hepatectomy. Hepatectomy can be safely performed in elderly patients after cautious perioperative management.

Structure-Activity Relationship Study of 1H-Pyrrole-3-carbonitrile Derivatives as STING Receptor Agonists.

The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1H-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure-activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system. Representative compounds 7F, 7P, and 7R all displayed comparable activities to the reported STING agonist SR-717 in binding various hSTING alleles and induced reporter signal in human THP1 cell lines. Model compound 7F induced phosphorylation of TBK1, IRF3, p65, and STAT3 in a STING-dependent fashion and stimulated the expression of target genes IFNB1, CXCL10, and IL6 in a time-dependent manner in human THP1 cells. Our findings afforded a series of novel STING agonists with promising potential.

Surgical Treatment of Osteosarcoma Induced Distant Pre-Metastatic Niche in Lung to Facilitate the Colonization of Circulating Tumor Cells.

Recently, the major challenge in treating osteosarcoma patients is the metastatic disease, most commonly in the lungs. However, the underlying mechanism of recurrence and metastasis of osteosarcoma after surgical resection of primary tumor remains unclear. This study aims to investigate whether the pulmonary metastases characteristic of osteosarcoma is associated with surgical treatment and whether surgery contributes to the formation of pre-metastatic niche in the distant lung tissue. In the current study, the authors observe the presence of circulating tumor cells in patients undergoing surgical resection of osteosarcoma which is correlated to tumor recurrence. The pulmonary infiltrations of neutrophils and Gr-1+ myeloid cells are characterized to form a pre-metastatic niche upon the exposure of circulating tumor cells after surgical resection. It is found that mitochondrial damage-associated molecular patterns released from surgical resection contribute to the formation of pre-metastatic niche in lung through IL-1ß secretion. This study reveals that surgical management for osteosarcoma, irrespective of the primary tumor, might promote the formation of postoperative pre-metastatic niche in lung which is with important implications for developing rational therapies during peri-operative period.

Effect of renin-angiotensin-aldosterone system inhibitors on survival outcomes in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: Effect of renin-angiotensin-aldosterone system inhibitors (RAASIs) in combination with immune checkpoint inhibitors (ICIs) on prognoses in cancer patients remains controversial. This study systematically evaluated the effect of RAASIs on survival outcomes in cancer patients receiving ICIs treatment and provided an evidence-based reference for the rational use of RAASIs and ICIs combination therapy in clinical practice. Methods: Studies evaluating the prognosis of RAASIs-used versus RAASIs-free in cancer patients receiving ICIs treatment from inception to 1 November 2022 were retrieved by searching PubMed, Cochrane Library, Web of Science, Embase, and major conference proceedings. Studies in English reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and/or progression-free survival (PFS) were included. Statistical analyses were conducted using the software Stata 17.0. Results: A total of 12 studies containing 11739 patients were included, comprising ~4861 patients in the RAASIs-used and ICIs-treated group and ~6878 patients in RAASIs-free and ICIs-treated group. The pooled HR was 0.85 (95%CI, 0.75-0.96; P = 0.009) for OS and 0.91 (95%CI, 0.76-1.09; P = 0.296) for PFS, indicating a positive effect of RAASIs concomitant with ICIs on cancer patients. This effect was observed especially in patients with urothelial carcinoma (HR, 0.53; 95%CI, 0.31-0.89; P = 0.018) and renal cell carcinoma (HR, 0.56; 95%CI, 0.37-0.84; P = 0.005) on OS. Conclusion: Concomitant use of RAASIs and ICIs enhanced the efficacy of ICIs and this combination regimen was associated with significantly improved OS and a trend towards better PFS. RAASIs can be considered as adjuvant drugs when hypertensive patients receive ICIs treatment. Our results provide an evidence-based reference for the rational use of the RAASIs and ICIs combination therapy to improve the efficacy of ICIs in clinical practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022372636; https://inplasy.com/, identifier INPLASY2022110136.

Online calculators for predicting the risk of anastomotic stricture after hepaticojejunostomy for bile duct injury after cholecystectomy: a multicenter retrospective study.

BACKGROUND: Anastomotic stricture is a common underlying cause of long-term morbidity after hepaticojejunostomy (HJ) for bile duct injury (BDI) following cholecystectomy. However, there are no methods for predicting stricture risk. This study was aimed at establishing two online calculators for predicting anastomotic stricture occurrence (ASO) and stricture-free survival (SFS) in this patient population. METHODS: The clinicopathological characteristics and follow-up information of patients who underwent HJ for BDI after cholecystectomy from a multi-institutional database were reviewed. Univariate and multivariate analyses of the risk factors of ASO and SFS were performed in the training cohort. Two nomogram-based online calculators were developed and validated by internal bootstrapping resamples ( n =1000) and an external cohort. RESULTS: Among 220 screened patients, 41 (18.64%) experienced anastomotic strictures after a median follow-up of 110.7 months. Using multivariate analysis, four variables, including previous repair, sepsis, HJ phase, and bile duct fistula, were identified as independent risk factors associated with both ASO and SFS. Two nomogram models and their corresponding online calculators were subsequently developed. In the training cohort, the novel calculators achieved concordance indices ( C -indices) of 0.841 and 0.763 in predicting ASO and SFS, respectively, much higher than those of the above variables. The predictive accuracy of the resulting models was also good in the internal ( C -indices: 0.867 and 0.821) and external ( C -indices: 0.852 and 0.823) validation cohorts. CONCLUSIONS: The two easy-to-use online calculators demonstrated optimal predictive performance for identifying patients at high risk for ASO and with dismal SFS. The estimation of individual risks will help guide decision-making and long-term personalized surveillance.

Blocking the CXCL1-CXCR2 axis enhances the effects of doxorubicin in HCC by remodelling the tumour microenvironment via the NF-κB/IL-1ß/CXCL1 signalling pathway.

Inflammation is a core mechanism for oncogenesis. Chemokines act as important mediators of chronic inflammation and the tumour inflammatory response. However, there is limited information on chemokines in hepatocellular carcinoma (HCC), a disease for which almost all cases are derived from chronic liver inflammation. Here, we explored the protumor effects of CXCL1, a commonly elevated inflammatory chemokine in cirrhosis, in HCC. The protumor role was confirmed in clinical samples from HCC patients. CXCL1 enhanced tumorigenesis in the hepatic inflammatory microenvironment directly by acting on tumour cells and indirectly through promoting the recruitment of macrophages. The increase in the number of macrophages in the tumour microenvironment (TME) promoted tumour cell epithelial-mesenchymal transition (EMT) and significantly increased CXCL1 levels in the TME partly through NF-κB/IL-1ß activation. To investigate the potential therapeutic value of CXCL1 in HCC with an inflammatory background, an antibody blocking CXCL1 was used alone or combined with the chemotherapy agent doxorubicin (DOX), with the goal of reshaping the TME. It has been shown that blocking CXCL1-CXCR2 inhibits tumour progression and reduces macrophage recruitment in the TME. The combination regimen has been shown to synergistically reduce the number of pro-tumour macrophages in the TME and suppress tumour progression. This provides insight into therapeutic strategies for treating HCC patients with high CXCL1 expression.

The prognostic signature based on glycolysis-immune related genes for acute myeloid leukemia patients.

Acute myeloid leukemia (AML) is widely considered an immunoresponsive malignancy. However, potential association between glycolysis-immune related genes and AML patients' prognosis has been seldom studied. AML-related data was downloaded from TCGA and GEO databases. We grouped patients according to Glycolysis status, Immune Score and combination analysis, basing on which overlapped differentially expressed genes (DEGs) were identified. The Risk Score model was then established. The results showed that totally 142 overlapped genes were probably correlated with glycolysis-immunity in AML patients, among which 6 optimal genes were screened to construct Risk Score. High Risk Score was an independent poor prognostic factor for AML. In conclusion, we established a relatively reliable prognostic signature of AML based on glycolysis-immunity related genes, including METTL7B, HTR7, ITGAX, TNNI2, SIX3 and PURG.

Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists.

The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC50 = 0.38 ± 0.03 µM) and mouse RAW 264.7 cells (EC50 = 12.94 ± 1.78 µM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent.

Bicarbonated Ringer's solution improves L-arg-induced acute pancreatitis in rats via the NF-κB and Nrf2 pathways.

OBJECTIVE: Bicarbonated Ringer's solution (BRS), as a new generation of crystalline fluid, has been widely used for intravenous fluid resuscitation in patients with shock diseases. The purpose of our study is to investigate the intervention effects and potential mechanisms of BRS on L-arg-induced AP in rats. METHODS: The AP model was induced by intraperitoneal injection of 20% L-arg. BRS was infused immediately following the previous L-arg injection. The pancreatic tissue was harvested for histological examination. The serum levels of amylase and lipase activity, lactic acid, proinflammatory and anti-inflammatory cytokines were determined. The peroxide and antioxidant activities in the pancreatic tissue were measured. The protein and mRNA levels of nuclear factor-κB, TNF-α, nuclear factor erythroid 2-related Factor 2 and heme oxygenase-1 were determined by Western blot and quantitative reverse transcription PCR analysis. RESULTS: Pancreatic tissue injuries were obviously alleviated, with a significant increase in normal acinar cells after BRS treatment. The serum levels of amylase, lipase, lactic acid, IL-1ß and TNF-α were significantly decreased, while IL-10 was obviously increased by inhibiting the NF-κB pathway and TNF-α. Moreover, Nrf2 pathway and HO-1 were promoted by BRS treatment, which resulted in significantly reduced malondialdehyde and reactive oxygen species levels. In contrast, antioxidant activities, including glutathione peroxidase and so on, were markedly increased after BRS treatment. CONCLUSIONS: Bicarbonated Ringer's solution improves L-arg-induced acute pancreatitis in rats through the NF-κB and Nrf2 pathways, indicating that BRS holds promise as a priority in fluid resuscitation to treat acute pancreatitis.