Evaluation of Molecular Residual Disease by a Fixed Panel in Resectable Colorectal Cancer.

Purpose: Molecular residual disease (MRD) is a promising biomarker in colorectal cancer (CRC) for prognosis and guiding treatment, while the whole-exome sequencing (WES) based tumor-informed assay is standard for evaluating MRD based on circulating tumor DNA (ctDNA). In this study, we assessed the feasibility of a fixed-panel for evaluating MRD in CRC. Materials and Methods: 75 patients with resectable stage I-III CRC were enrolled. Tumor tissues obtained by surgery, and pre-operative and post-operative day 7 blood samples were collected. The ctDNA was evaluated using the tumor-agnostic and tumor-informed fixed assays, as well as the WES-based and panel-based personalized assays in randomly selected patients. Results: The tumor-informed fixed assay had a higher pre-operative positive rate than the tumor-agnostic assay (73.3% vs 57.3%). The pre-op ctDNA status failed to predict disease-free survival (DFS) in either of the fixed assays, while the tumor-informed fixed assay-determined post-op ctDNA positivity was significantly associated with worse DFS (HR, 20.74, 95%CI 7.19-59.83; p<0.001), which was an independent predictor by multivariable analysis (HR, 28.57, 95%CI 7.10-114.9; p<0.001). Sub-cohort analysis indicated the WES-based personalized assay had the highest pre-operative positive rate (95.1%). The two personalized assays and the tumor-informed fixed assay demonstrated same results in post-op landmark (HR, 26.34, 95%CI, 6.01-115.57; p<0.001), outperforming the tumor-agnostic fixed panel (HR, 3.04, 95%CI, 0.94-9.89; p=0.052). Conclusion: Our study confirmed the prognostic value of the ctDNA positivity at post-op day 7 by the tumor-informed fixed panel. The tumor-informed fixed panel may be a cost-effective method to evaluate MRD, which warrants further studies in future.

The individual difference of motor imagery ability evoked by visual stimulus and its personality manifestation.

Motor imagery has been commonly studied as a means of motor rehabilitation but, the individual differences limit its practical application. Visually evoked motor imagery has been widely highlighted by researchers because of its vivid stimulus. However, this modality is still not applicable to all persons. In this study, we studied the different performances of the visually evoked motor imagery between subjects and tried to explore the personality manifestation which can result in this performance. We found that conscientiousness and openness have negative connections with the performance of visually evoked motor imagery. To compare with spontaneous motor imagery, the visually evoked motor imagery reflects less personality difference between subjects with good and bad performances on motor imagery. This indicate that visually stimulus may increase the pervasive application of motor imagery. This study may provide benefits to predict the rehabilitation effect and to rapidly select the suitable motor rehabilitation methods.

Transport and transformations of cadmium in water-biofilm-sediment phases as affected by hydrodynamic conditions.

Hydrodynamic conditions play a crucial role in governing the fate, transport, and risks of metal elements. However, the contribution of hydrodynamic conditions to the fate and transport of heavy metals among water, sediment, and biofilm phases is poorly understood. In our study, we conducted experiments in controlled hydrodynamic conditions using a total of 6 two-phase and 9 three-phase mesocosms consisting of water, biofilm, and sediment. We also measured Cd (cadmium) specification in different phases to assess how hydrodynamic forces control Cd bioavailability. We found that turbulent flow destroyed the surface morphology of the biofilm and significantly decreased the content of extracellular polymeric substances (p < 0.05). This led to a decrease in the biofilm's adsorption capacity for Cd, with the maximum adsorption capacity (0.124 mg/g) being one-tenth of that under static conditions (1.256 mg/g). The Cd chemical forms in the biofilm and sediment were significantly different, with the highest amount of Cd in the biofilm being acid-exchangeable, accounting for up to 95.1% of the total Cd content. Cd was more easily released in the biofilm due to its weak binding state, while Cd in the sediment existed in more stable chemical forms. Hydrodynamic conditions altered the migration behavior and distribution characteristics of Cd in the system by changing the adsorption capacity of the biofilm and sediment for Cd. Cd mobility increased in laminar flow but decreased in turbulent flow. These results enhance our understanding of the underlying mechanisms that control the mobility and bioavailability of metals in aquatic environments with varying hydrodynamic conditions.

Stiffness promotes cell migration, invasion, and invadopodia in nasopharyngeal carcinoma by regulating the WT-CTTN level.

Matrix stiffness potently promotes the malignant phenotype in various biological contexts. Therefore, identification of gene expression to participate in mechanical force signals transduced into downstream biochemical signaling will contribute substantially to the advances in nasopharyngeal carcinoma (NPC) treatment. In the present study, we detected that cortactin (CTTN) played an indispensable role in matrix stiffness-induced cell migration, invasion, and invadopodia formation. Advances in cancer research have highlighted that dysregulated alternative splicing contributes to cancer progression as an oncogenic driver. However, whether WT-CTTN or splice variants (SV1-CTTN or SV2-CTTN) regulate matrix stiffness-induced malignant phenotype is largely unknown. We proved that alteration of WT-CTTN expression modulated matrix stiffness-induced cell migration, invasion, and invadopodia formation. Considering that splicing factors might drive cancer progression through positive feedback loops, we analyzed and showed how the splicing factor PTBP2 and TIA1 modulated the production of WT-CTTN. Moreover, we determined that high stiffness activated PTBP2 expression. Taken together, our findings showed that the PTBP2-WT-CTTN level increases upon stiffening and then promotes cell migration, invasion, and invadopodia formation in NPC.

Aspertaichamide a, a novel cytotoxic prenylated indole alkaloid possessing a bicyclo[2.2.2]diazaoctane framework from a marine algal-derived endophytic fungus aspergillus taichungensis 299.

Filamentous fungi belonging to the genus Aspergillus are prodigious producers of alkaloids, particularly prenylated indole alkaloids, that often exhibit structurally diversified skeletons and potent biological activities. In this study, five prenylated indole alkaloids possessing a bicyclo[2.2.2]diazaoctane core ring system, including a novel derivative, namely aspertaichamide A (1), as well as four known compounds, (+)-stephacidin A (2), sclerotiamide (3), (-)-versicolamide B (4), and (+)-versicolamide B (5), were isolated and identified from A. taichungensis 299, an endophytic fungus obtained from the marine red alga Gelidium amansii. The chemical structures of the compounds were elucidated by comprehensive NMR and HRESIMS spectroscopic analyses. In addition to the previously reported prenylated indole alkaloids, aspertaichamide A (1) was characterized as having an unusual ring structure with the fusion of a 3-pyrrolidone dimethylbenzopyran to the bicyclo[2.2.2]diazaoctane moiety, which was rare in these kinds of compounds. The absolute configuration of 1 was determined by TDDFT-ECD calculations. In vitro cytotoxic assays revealed that the novel compound 1 possessed selective cytotoxic activity against five human tumor cell lines (A549, HeLa, HepG2, HCT-116, and AGS), with IC50 values of 1.7-48.5 µM. Most importantly, compound 1 decreased the viability of AGS cells in a concentration-dependent manner with an IC50 value of 1.7 µM. Further studies indicated that 1 may induce AGS cells programmed cell death via the apoptotic pathway.

Two novel teleost calreticulins PoCrt-1/2, with bacterial binding and agglutination activity, are involved in antibacterial immunity.

Calreticulin (Crt), a conserved lectin-like pleiotropic protein, plays crucial roles in mammalian immune response. In fish, the immunological function of Crt is limited investigated. Herein, we studied the antibacterial immunity of two type of Crt homologues (i.e. PoCrt-1 and PoCrt-2) in Japanese flounder (Paralichthys olivaceus). PoCrt-1 and PoCrt-2 are composed of 419 and 427 amino acid residues respectively, with 69.09% overall sequence identities with each other. Both PoCrt-1 and PoCrt-2 contain a signal peptide and three functional domains i.e. N-, P- and C-domains. Both PoCrt-1 and PoCrt-2 were constitutively expressed at various tissues with highest expression level in liver, and obviously regulated by Edwardsiella tarda and Vibrio harveyi. Furthermore, recombinant PoCrt-1 and PoCrt-2 (rPoCrt-1 and rPoCrt-2) could bind to different Gram-negative bacteria with highest binding index with E. tarda. At same time, in vitro rPoCrt-1 and rPoCrt-2 could agglutinate E. tarda, V. harveyi, and Vibrio anguillarum, and inhibit the bacterial growth. Similarly, in vivo rPoCrt-1 and rPoCrt-2 could significantly suppress the dissemination of E. tarda. Overall, these observations add new insights into the antibacterial immunity of Crt in P. olivaceus.

Securing maize reproductive success under drought stress by harnessing CO2 fertilization for greater productivity.

Securing maize grain yield is crucial to meet food and energy needs for the future growing population, especially under frequent drought events and elevated CO2 (eCO2) due to climate change. To maximize the kernel setting rate under drought stress is a key strategy in battling against the negative impacts. Firstly, we summarize the major limitations to leaf source and kernel sink in maize under drought stress, and identified that loss in grain yield is mainly attributed to reduced kernel set. Reproductive drought tolerance can be realized by collective contribution with a greater assimilate import into ear, more available sugars for ovary and silk use, and higher capacity to remobilize assimilate reserve. As such, utilization of CO2 fertilization by improved photosynthesis and greater reserve remobilization is a key strategy for coping with drought stress under climate change condition. We propose that optimizing planting methods and mining natural genetic variation still need to be done continuously, meanwhile, by virtue of advanced genetic engineering and plant phenomics tools, the breeding program of higher photosynthetic efficiency maize varieties adapted to eCO2 can be accelerated. Consequently, stabilizing maize production under drought stress can be achieved by securing reproductive success by harnessing CO2 fertilization.

SCARB1 in extracellular vesicles promotes NPC metastasis by co-regulating M1 and M2 macrophage function.

Distant metastasis is currently the main factor affecting the prognosis of nasopharyngeal carcinoma (NPC), and understanding the mechanisms of metastasis and identifying reliable therapeutic targets are critical for improving prognosis and achieving clinical translation. Macrophages, as important immune cells in the tumor microenvironment (TME), have been shown to regulate metastasis. And extracellular vesicles (EVs) secreted by stromal cells and tumor cells play the important role in intercellular communication in the tumor microenvironment. However, the role of NPC-EVs on macrophages and their function in regulating macrophages to affect metastasis has not been fully clarified. In this study, we report that NPC-EVs can be uptake by macrophages and alter macrophage polarization, for the first time, we identified the genes implicated in these regulatory functions: SCARB1, HAAO, and CYP1B1. Moreover, we found that SCARB1 was positively associated with metastasis and poor prognosis of NPC. Interestingly, we found that SCARB1-rich EVs promoted M1 macrophages ferroptosis to decrease M1 macrophages infiltration by upregulating the HAAO level while decreasing phagocytosis of M2 macrophages by upregulating the CYP1B1 level. Finally, we identified the SCARB1-binding gene KLF9, which is involved in the transcription of HAAO and CYP1B1. Our findings showed that SCARB1-EVs promoted metastasis by co-regulating M1 and M2 macrophage function. The related mechanism will provide a new therapeutic strategy to help patients with NPC improve their prognosis.

SEMA5A-PLXNB3 Axis Promotes PDAC Liver Metastasis Outgrowth through Enhancing the Warburg Effect.

Patients bearing liver metastasis of pancreatic adeno carcinoma (PDAC) suffer from poor prognosis due to its short duration and high mortality. Complex tumor microenvironment (TME) exists in liver metastatic niches, and tumor-associated macrophages (TAMs) have play vital roles in metastasis generation and outgrowth. We have discovered that M2 type TAM-derived SEMA5A could bind to its tumor cell-expressed receptor PLXNB3 to promote tumor cell proliferation and outgrowth. We utilized liver metastasis samples of PDAC patients, intrasplenic injection mouse models, and Kras G12D/Trp53 R172H/Pdx1-Cre (KPC) mouse models for in vivo study. In mechanism investigation, we have discovered that SEMA5A-PLXNB3 axis could achieve tumor cell proliferation and survival via enhancing aerobic glycolysis termed as the Warburg effects. Targeting this axis may be a potential therapeutic approach for PDAC patients with unresectable liver metastasis.

Global profiling of protein lysine lactylation and potential target modified protein analysis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, often metastasizes to the lungs. The implications of lysine lactylation (Kla), a recently identified histone post-translational modification (PTM), in the pathology of HCC remain unclear. Here, we report the first proteomic survey of this specific modification in HCC (with no metastasis during 3 years of follow-up), normal liver tissues, and lung metastasis samples of HCC. Of the 2045 modification sites detected on 960 proteins, 1438 sites on 772 proteins contained quantitative information. Subsequently, we analyzed the differentially modified proteins among the different groups. Differentially lactylated proteins were found to be involved in several biological processes, including-but not limited to-amino acid metabolism, ribosomal protein synthesis, and fatty acid metabolism. In addition, we identified numerous highly valuable lactate-modified proteins from the literature. Among them, we verified the lactate modification levels of the following two tumor-related proteins and obtained similar results: USP14 and ABCF1. These two modified proteins will be further investigated in our future studies. This paper is the first report on the lactylome of HCC and it provides a reliable foundation for further research on Kla in HCC.

SEVs-mediated miR-6750 transfer inhibits pre-metastatic niche formation in nasopharyngeal carcinoma by targeting M6PR.

Reliable detection of circulating small extracellular vesicles (SEVs) and their miRNA cargo has been needed to develop potential specific non-invasive diagnostic and therapeutic marker for cancer metastasis. Here, we detected miR-6750, the precise molecular function of which was largely unknown, was significantly enriched in serum-SEVs from normal volunteers vs. patients with nasopharyngeal carcinoma (NPC). And we determined that miR-6750-SEVs attenuated NPC metastasis. Subsequently, miR-6750-SEVs was proven to inhibit angiogenesis and activate macrophage toward to M1 phenotype to inhibit pre-metastatic niche formation. After analyzing the expression level of miR-6750 in NPC cells, HUVECs and macrophage, we found that once miR-6750 level in NPC cells was close to or higher than normal nasopharyngeal epithelial cells (NP69), miR-6750-SEVs would be transferred from NPC cells to macrophage and then to HUVECs to modulate metastatic niche. Moreover, in vitro assays and BALB/c mouse tumor models revealed that miR-6750 directly targeted mannose 6-phosphate receptor (M6PR). Taken together, our findings revealed that miR-6750-M6PR axis can mediate NPC metastasis by remodeling tumor microenvironment (TME) via SEVs, which give novel sights to pathogenesis of NPC.

A vasculogenic mimicry prognostic signature associated with immune signature in human gastric cancer.

Background: Gastric cancer (GC) is one of the most lethal malignant tumors worldwide with poor outcomes. Vascular mimicry (VM) is an alternative blood supply to tumors that is independent of endothelial cells or angiogenesis. Previous studies have shown that VM was associated with poor prognosis in patients with GC, but the underlying mechanisms and the relationship between VM and immune infiltration of GC have not been well studied. Methods: In this study, expression profiles from VM-related genes were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Cox regression was performed to identify key VM-related genes for survival. Subsequently, a novel risk score model in GC named VM index and a nomogram was constructed. In addition, the expression of one key VM-related gene (serpin family F member 1, SERPINF1) was validated in 33 GC tissues and 23 paracancer tissues using immunohistochemistry staining. Results: Univariate and multivariate Cox regression suggested that SERPINF1 and tissue factor pathway inhibitor 2 (TFPI2) were independent risk factors for the prognosis of patients with GC. The AUC (> 0.7) indicated the satisfactory discriminative ability of the nomogram. SsGESA and ESTIMATE showed that higher expression of SERPINF1 and TFPI2 is associated with immune infiltration of GC. Immunohistochemistry staining confirmed that the expression of SERPINF1 protein was significantly higher in GC tissues than that in paracancer tissues. Conclusion: A VM index and a nomogram were constructed and showed satisfactory predictive performance. In addition, VM was confirmed to be widely involved in immune infiltration, suggesting that VM could be a promising target in guiding immunotherapy. Taken together, we identified SERPINF1 and TFPI2 as immunologic and prognostic biomarkers related to VM in GC.

Development and validation of a tissue-based DNA methylation risk-score model to predict the prognosis of surgically resected pancreatic cancer patients.

Background: Pancreatic cancer (PC) is a highly malignant tumor associated with low survival rates. It is challenging to predict the survival of surgically resected patients with PC. A prognostic staging tool could be beneficial to guide treatments and also aid post-treatment surveillance. This study aimed to identify tissue-based DNA methylation risk-score model to predict the prognosis of surgically resected pancreatic cancer patients. Methods: We performed a monocentric, retrospective study that included 50 patients with stage I-II PC from The First Affiliated Hospital of Soochow University (SU cohort). Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted methylation profiling. Results: In total, 1,162 DNA methylation blocks (DMBs) were differentially methylated in tumor tissues compared with adjacent long-distance tissues (P<0.05). Least Absolute Shrinkage and Selection Operator (LASSO) and stepwise regression analyses revealed a significant correlation between the methylation signature (risk score) and overall survival (OS). Patients in the high-risk group showed significantly poorer OS than those in the low-risk group in the survival analysis [P≤0.001; area under curve (AUC) at 1 year, 0.789; AUC at 2 years, 0.852]. The risk score was also validated using clinical and methylation data of 166 PC patients from The Cancer Genome Atlas pancreatic ductal adenocarcinoma (TCGA-PDAC) dataset. Patients in the high-risk group showed significantly poorer OS than those in the low-risk group (P=0.004; AUC at 1 years, 0.677; AUC at 3 years, 0.611). When clinical parameters were considered, the risk score was the only independent prognostic parameter (P<0.001) in the Cox regression analysis. Furthermore, low-risk patients had higher levels of immune infiltration, anti-tumor immune activation, and increased sensitivity to gemcitabine and paclitaxel. In contrast, high-risk patients had lower KRAS mutation rates and benefited more from cisplatin. Conclusions: In our study, we constructed and validated a tissue-based DNA methylation risk-score model to predict prognosis and identify PC patients with a high mortality risk at the time of surgery. This model might provide a tissue-based prognostic assessment tool for clinicians to aid their treatment decision-making.

Halometabolites isolated from the marine-derived fungi with potent pharmacological activities.

Halometabolites, usually produced in marine environment, are an important group of natural halogenated compounds with rich biological functionality and drugability and thus play a crucial role in pharmaceutical and/or agricultural applications. In the exploration of novel halometabolites from marine microorganisms, the growing number of halogenated compounds makes it necessary to fully present these metabolites with diverse structures and considerable bioactivities. This review particularly focuses on the chemodiversity and bioactivities of halometabolites from marine-derived fungi. As a result, a total of 145 naturally halogenated compounds, including 118 chlorinated, 23 brominated, and four iodinated compounds, were isolated from 17 genera of marine-derived fungi. Interestingly, many of halometabolites, especially for the brominated and iodinated compounds, are generated by the substitution of bromide and iodide ions for the chloride ion in cultivation process. In addition, these compounds possess diverse structural types, which are classified into polyketides (62.7%), phenols (16.6%), alkaloids (14.5%), and terpenoids (6.2%). Their cytotoxic, antibacterial, and anti-inflammatory activities indicate the high potential of these halogenated compounds as lead compounds for drug discovery.

Suppression of long intergenic non-protein coding RNA 1123 constrains lower extremity deep vein thrombosis via microRNA-125a-3p to target interleukin 1 receptor type 1.

Lower extremity deep vein thrombosis (LEDVT) is a disorder of venous return caused by abnormal blood clotting. LEDVT can obstruct the lumen and is the third most common vascular disease after cerebrovascular disease and coronary artery disease. LncRNAs are associated with thrombosis and potentially affect the pathogenesis of DVT. However, no studies have reported the effect of LINC01123 on LEDVT. The aim of this study was to investigate the effect of LINC01123 on LEDVT in rats via the miR-125a-3p/interleukin 1 receptor type 1 (IL1R1) axis. Lentiviral vectors that altering LINC01123, miR-125a-3p and IL1R1 expression were pre-injected into the tail vein of rats, and an LEDVT model was established 1 day later. Detection of LINC01123, miR-125a-3p and IL1R1 expression was performed. Inflammatory factors in femoral venous blood, the length and weight of the thrombus, the histomorphological changes were determined in the rat model. The targeting relation of miR-125a-3p with LINC01123 or IL1R1 was verified. The results presented that LEDVT rats expressed high LINC01123 and IL1R1 and low miR-125a-3p expression levels. After silencing LINC01123 or elevating miR-125a-3p, the rate of thrombosis, length and weight of thrombus, and levels of inflammatory factors were reduced. The targeting relation was presented between miR-125a-3p with LINC01123 or IL1R1. Elevating IL1R1 was available to turn around the action of silence of LINC01123 on LEDVT rats. All in all, suppression of LINC01123 restrains LEDVT via miR-125a-3p to target IL1R1.

Lactoferrin improves hepatic insulin resistance and pancreatic dysfunction in high-fat diet and streptozotocin-induced diabetic mice.

Lactoferrin (Lf) is an iron-binding glycoprotein with potentially beneficial biological functions. However, the interaction between Lf and type 2 diabetes mellitus (T2DM) remains unclear. We hypothesized that Lf would improve hepatic insulin resistance and pancreatic dysfunction in diabetic mice. Male C57BL/6J mice were fed a high-fat diet for 15 weeks and injected with streptozotocin (STZ) for 5 consecutive days to establish a T2DM model. One week after STZ injection, mice with ≥11.1 mmol/L fasting blood glucose concentration were considered T2DM mice. These mice received 0.5% or 2% Lf solution for another 12 weeks. Biochemical parameters were measured, and histopathological examination of the pancreas and liver was performed. Hepatic protein expression related to the insulin signalling pathway was also assessed. Diabetic mice showed insulin resistance and abnormal glucolipid metabolism. Lf decreased serum concentrations of glycated serum protein, fasting insulin, cholesterol, and triglyceride and increased liver insulin sensitivity. Hematoxylin-eosin staining showed that Lf reversed the abnormal pancreatic islets of diabetic mice. Lf improved pancreatic dysfunction by reducing oxidative stress and inflammation responses. Furthermore, Lf upregulated the protein expression of insulin receptor, insulin receptor substrate-1, glucose transporter 4, phosphor phosphatidylinositol 3-kinase/phosphatidylinositol 3-kinase (PI3K), and phosphor protein kinase B/protein kinase B (AKT) in the liver. This study indicated that Lf supplementation improved hepatic insulin resistance and pancreatic dysfunction, possibly by regulating the PI3K/AKT signaling pathway in T2DM mice.

Treatment Response to Immunotherapy After Crizotinib Resistance in a Patient With Pulmonary Sarcomatoid Carcinoma Harboring MET Exon 14 Skipping Mutation: A Case Report.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with poor prognosis. The skipping mutation in exon 14 of MET, an oncogenic driver of NSCLC, occurs more frequently in PSC than other subtypes. Treatment options for patients with PSC include targeted therapies and immunotherapies, while the best treatment regimen has not been established due to limited number of patients. In this report, we presented a case with metastatic PSC harboring MET 14 exon skipping mutation. The patient received crizotinib but soon acquired drug resistance. Then, the patient turned to immunotherapy in combination with chemotherapy and has achieved a progression-free survival for 15 months as of the data cutoff date. The comprehensive genomic sequencing after crizotinib resistance revealed additional genetic alterations such as CD274 (also known as programmed cell death ligand 1) amplification which might be associated with treatment response of the patient.

RhoGDI2 induced malignant phenotypes of pancreatic cancer cells via regulating Snail expression.

BACKGROUND: Rho GDP dissociation inhibitor 2 (RhoGDI2) has been shown to contribute to the aggressive phenotypes of human cancers, such as tumor metastasis and chemoresistance. OBJECTIVE: This study aimed to assess the effects of RhoGDI2 on tumor progression and chemoresistance in pancreatic cancer cells. METHODS: The expression of RhoGDI2 in pancreatic cancer cells was detected by Western blot analysis. Gain-of-function and loss-of-function approaches were done to examine the malignant phenotypes of the RhoGDI2-expressing or RhoGDI2-depleting cells. The correlation between RhoGDI2 and Snail was also analyzed. RESULTS: Differential expression of RhoGDI2 protein in pancreatic cancer cell lines was identified. Gain-of-function and loss-of-function experiments showed that RhoGDI2 induced the malignant phenotypes of pancreatic cancer cells, including proliferation, migration, invasion, and gemcitabine (GEM) chemoresistance. The upregulation of RhoGDI2 stimulated the expression of Snail, resulting in the altered expression of epithelial marker E-cadherin and mesenchymal marker Vimentin, which were characteristics of the tumorigenic activity of epithelial-mesenchymal transition. The expression of RhoGDI2 and Snail was upregulated in clinical tumor samples, and higher expression of RhoGDI2 or Snail was significantly associated with poor patient survival in pancreatic ductal adenocarcinoma (PDAC). CONCLUSION: The findings indicated that RhoGDI2 promoted GEM resistance and tumor progression in pancreatic cancer and that RhoGDI2 might be a potential therapeutic target in patients with PDAC.

Preventive effect of sanguinarine on intestinal injury in mice exposed to whole abdominal irradiation.

Intestinal injury is one of the major side effects that are induced by medical radiation exposure, and has limited effective therapies. In this study, we investigated the beneficial effects of sanguinarine (SAN) on intestinal injury induced by ionizing radiation (IR) both in vitro and in vivo. Mice were exposed to whole abdominal irradiation (WAI) to mimic clinical scenarios. SAN was injected intraperitoneally to mitigate IR-induced injury. Histological examination was performed to assess the tissue injuries of the spleen and small intestine. A small intestinal epithelial cell line-6 (IEC-6) was analyzed for its viability and apoptosis in vitro under different treatments. Inflammation-related pathways and serum inflammatory cytokines were detected via Western blot analysis and ELISA, respectively. High-throughput sequencing was used to characterize the gut microbiota profile. High-performance liquid chromatography was performed to assess short-chain fatty acid contents in the colon. In vitro, SAN pretreatment protected cell viability and reduced apoptosis in IEC-6 cells. In vivo, SAN pretreatment protected immune organs, alleviated intestinal injury, and promoted intestinal recovery. SAN also reduced the levels of inflammatory cytokines, suppressed high mobility group box 1 (HMGB1)/ Toll-like receptor 4 (TLR4) pathway activation, and modulated gut microbiota composition. Our findings demonstrate that the beneficial properties of SAN alleviated intestinal radiation injury. Thus, SAN represents a therapeutic option for protecting against IR-induced intestinal injury in preclinical settings.

Antimicrobial and cytotoxic phenolic bisabolane sesquiterpenoids from the fungus Aspergillus flavipes 297.

Phenolic bisabolane-type sesquiterpenoids (PBS) represent a rare class of natural products with diverse biological activities. In this study, chemical investigations of the fungus Aspergillus flavipes 297 resulted in the isolation and identification of seven PBS, including a pair of new enantiomers (+)-1a and (-)-1b, a new derivative 2, and five previously reported ones 3-7. The chemical structures of the isolated PBS were determined by extensive NMR and HRESIMS spectroscopic analysis. The absolute configurations of the separated enantiomers (+)-1a and (-)-1b were solved by comparison of the experimental ECD spectra with those of the TDDFT-ECD calculated spectra. The new compounds 1 and 2 represent rare cases of PBS bearing a methylsulfinyl group, which was distinct from the commonly-observed PBS structurally. All the isolated compounds 1-7 were evaluated their antimicrobial and cytotoxic activities. As a result, the tested compounds showed selective antimicrobial activity against several pathogenic bacteria and fungi with the MIC (minimum inhibiting concentrations) values ranging from 2 to 64 µg/mL. Moreover, enantiomers (+)-1a and (-)-1b, together with compound 2, exhibited promising cytotoxicity against MKN-45 and HepG2 cell lines, respectively, indicating that the methylsulfinyl substituent enhanced cytotoxicity to a certain degree.