LncRNA HOXA11-AS drives cisplatin resistance of human LUAD cells via modulating miR-454-3p/Stat3.

Over the past several years, long non-coding RNAs (lncRNAs) have attracted more and more attention due to their special functions. They are vital biomarkers in multiple diseases. LncRNA HOMEOBOX A11 (HOXA11) has been found to be aberrantly expressed in some kinds of malignant tumors. In this study, we mainly discuss the oncogenic role of it in promoting malignant progression and chemoresistance in lung adenocarcinoma (LUAD) cells. The expression of HOXA11-AS was much stronger in cisplatin-resistant LUAD cells. Based on The Cancer Genome Atlas database, patients with high expression of HOXA11-AS had shorter survival time. Additionally, knockdown of HOXA11-AS caused positive changes in cell activities of LUAD. For example, cell proliferation and migration were weakened, the epithelial mesenchymal transition process was reversed, and apoptosis was induced. These changes were more obvious in cells treated with cisplatin. Next, the HOXA11-AS/miR-454-3p/Stat3 (signal transducer and activator of transcription 3) pathway was found to influence the cisplatin resistance of LUAD cells. HOXA11-AS specifically acted as a competing endogenous RNA (ceRNA) in LUAD cells. The combinations among these three genes were demonstrated. Finally, rescue assays were applied to demonstrate the ceRNA pattern consisting of HOXA11-AS, miR-454-3p and Stat3. In conclusion, lncRNA HOXA11-AS acted as a ceRNA to promote cisplatin resistance of human LUAD cells via the miR-454-3p/Stat3 axis.

From metabolic to epigenetic: Insight into trained macrophages in atherosclerosis (Review).

Atherosclerosis (AS) is a chronic inflammatory disease caused by the deposition of lipoproteins and sequent immune responses. Within the atherosclerotic plaque, macrophages are the most abundant immune cells and play a great part as protagonists and promoters of AS. In the past decade, the concept of 'trained immunity' has emerged, which highlights the memory characteristics of innate immunity, thus opening up a new avenue of research. Evidence suggests that trained immunity may regulate the onset and progression of AS with trained macrophages playing an important and dynamic role in atherogenesis. The present review provided a summary of concepts related to trained immunity and its relationship with AS. Furthermore, different phenotypes of macrophages responding to various stimuli within the atherosclerotic plaque were presented, along with the complex mechanisms of metabolic and epigenetic reprogramming in the cells. Finally, several promising therapeutic approaches for AS cardiovascular disease were discussed, which may shed light on new clinical strategies.

Deciphering Vanadium Speciation in Smelting Ash and Adaptive Responses of Soil Microorganisms.

Abundant smelting ash is discharged during pyrometallurgical vanadium (V) production. However, its associated V speciation and resultant ecological impact have remained elusive. In this study, V speciation in smelting ash and its influence on the metabolism of soil microorganisms were investigated. Smelting ashes from V smelters contained abundant V (19.6-115.9 mg/g). V(V) was the dominant species for soluble V, while solid V primarily existed in bioavailable forms. Previously unrevealed V nanoparticles (V-NPs) were prevalently detected, with a peak concentration of 1.3 × 1013 particles/g, a minimal size of 136.0 ± 0.6 nm, and primary constituents comprising FeVO4, VO2, and V2O5. Incubation experiments implied that smelting ash reshaped the soil microbial community. Metagenomic binning, gene transcription, and component quantification revealed that Microbacterium sp. and Tabrizicola sp. secreted extracellular polymeric substances through epsB and yhxB gene regulation for V-NPs aggregation to alleviate toxicity under aerobic operations. The V K-edge X-ray absorption near-edge structure (XANES) spectra suggested that VO2 NPs were oxidized to V2O5 NPs. In the anaerobic case, Comamonas sp. and Achromobacter sp. reduced V(V) to V(IV) for detoxification regulated by the napA gene. This study provides a deep understanding of the V speciation in smelting ash and microbial responses, inspiring promising bioremediation strategies to reduce its negative environmental impacts.

The Efficacy and Safety of Apatinib and Anlotinib in Advanced Non-Small Cell Lung Cancer.

Background: Anlotinib and apatinib, both vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), are clinically established in the treatment of advanced non-small cell lung cancer (NSCLC) in China, with anlotinib emerging as a standard treatment strategy. This study was conducted to evaluate the efficacy and safety of apatinib and anlotinib, and to compare their differences in treating patients with advanced NSCLC. Patients and Methods: We retrospectively analyzed the data of patients with advanced NSCLC treated with apatinib or anlotinib at a hospital in Eastern China from January 2017 to December 2021. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profile. Results: A total of 145 patients were included in this study. Median PFS (mPFS) was 3.53 months for the apatinib group and 5.3 months for the anlotinib group (HR = 0.59, 95% CI: 0.41-0.84; P = 0.004), and median OS (mOS) was 7.6 months versus 15.6 months (HR = 0.68, 95% CI: 0.46-1.00; P = 0.048), which all showed significant differences after adjusting for confounders (P < 0.05). Subgroup analysis revealed that the presence or absence of bone metastases significantly influenced PFS in both treatment groups. The ORR was 3.03% in the anlotinib group versus 10.13% in the apatinib group (P = 0.12), the DCR was 72.73% versus 51.90% (P = 0.21). No unanticipated adverse events (AEs) were observed. The incidence of grade 3-4 AEs was significantly higher in the apatinib group (31.65% vs 13.64%, P < 0.05). Conclusion: Anlotinib demonstrated greater efficacy and safety compared to apatinib in the treatment of advanced NSCLC, particularly in patients with bone metastases and EGFR(-).

Coupling of selenate reduction and pyrrhotite oxidation by indigenous microbial consortium in natural aquifer.

Pyrrhotite is ubiquitously found in natural environment and involved in diverse (bio)processes. However, the pyrrhotite-driven bioreduction of toxic selenate [Se(VI)] remains largely unknown. This study demonstrates that Se(VI) is successfully bioreduced under anaerobic condition with the participation of pyrrhotite for the first time. Completely removal of Se(VI) was achieved at initial concentration of 10 mg/L Se(VI) and 0.56 mL/min flow rate in continuous column experiment with indigenous microbial consortium and pyrrhotite. Variation in hydrochemistry and hydrodynamics affected Se(VI) removal performance. Se(VI) was reduced to insoluble Se(0) while elements in pyrrhotite were oxidized to Fe(III) and SO42-. Breakthrough study indicated that biotic activity contributed 81.4 ± 1.07% to Se(VI) transformation. Microbial community analysis suggested that chemoautotrophic genera (e.g., Thiobacillus) could realize pyrrhotite oxidation and Se(VI) reduction independently, while heterotrophic genera (e.g., Bacillus, Pseudomonas) contributed to Se(VI) detoxification by utilizing metabolic intermediates generated through Fe(II) and S(-II) oxidation, which were further verified by pure culture tests. Metagenomic and qPCR analyses indicated genes encoding enzymes for Se(VI) reduction (e.g., serA, napA and srdBAC), S oxidation (e.g., soxB) and Fe oxidation (e.g., mtrA) were upregulated. The elevated electron transporters (e.g., nicotinamide adenine dinucleotide, cytochrome c) promoted electron transfer from pyrrhotite to Se(VI). This study gains insights into Se biogeochemistry under the effect of Fe(II)-bearing minerals and provides a sustainable strategy for Se(VI) bioremediation in natural aquifer.

Card9 protects fungal peritonitis through regulating Malt1-mediated activation of autophagy in macrophage.

Fungal peritonitis is an inflammatory condition of the peritoneum which occurs secondary to peritoneal dialysis. Most cases of peritonitis are caused by microbial invasion into the peritoneal cavity, resulting in high morbidity and mortality. Unlike bacterial peritonitis, little is known on fungal peritonitis. Card9, an adapter protein, plays a critical role in anti-fungal immunity. In this study, by using zymosan-induced peritonitis and C. albicans-induced peritonitis mouse model, we demonstrated that fungal peritonitis was exacerbated in Card9-/- mice, compared with WT mice. Next, we found the autophagy activation of peritonealmacrophages was impaired in Card9-/- peritonitis mice. The autophagy agonist, MG132, ameliorated peritonitis in Card9-/- mice. The result of microarray analysis indicates Malt1 was significantly decreased in Card9-/- peritonitis mice. Furthermore, we demonstrated that Malt1 interacts with P62 and mediates the function of P62 to clear ubiquitinated proteins. After overexpression of Malt1, impaired autophagy activation caused by Card9 deficient was significantly rescued. Together, our results indicate that Card9 protects fungal peritonitis by regulating Malt1-mediated autophagy in macrophages. Our research provides a new idea for the pathogenesis of fungal peritonitis, which is of great significance for the clinical treatment of fungal peritonitis.

Long noncoding RNA VPS9D1-AS1 promotes esophageal squamous cell carcinoma progression via the Wnt/ß-catenin signaling pathway.

The VPS9D1 antisense RNA1 (VPS9D1-AS1, lncRNA MYU) can act as an oncogene or an antioncogene in different malignancies. In the present study, we demonstrated that VPS9D1-AS1 is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and assessed its biological function and clinical prognosis. RNA-sequencing was conducted in four pairs of ESCC tissues and normal adjacent tissues (NATs). Compared with controls, lncRNA VPS9D1-AS1 was highly expressed in ESCC tissues, cell lines and plasma. VPS9D1-AS1 upregulation significantly correlated with the histopathological grade and clinical stage of ESCC. Analyses revealed poor prognosis in ESCC patients with high VPS9D1-AS1 expression. VPS9D1-AS1 knockdown led to the inhibition of tumor proliferation, migration, and invasion in vivo and vitro. VPS9D1-AS1 silencing downregulated the Wnt/ß-catenin signaling pathways by acting on key proteins such as ß-catenin and c-Myc. However, the expressions of these proteins increased after the addition of pathway agonist CT99021. Therefore, taken together VPS9D1-AS1 is highly expressed in ESCC and its expression can lead to poor prognosis. In conclusion, this study suggested that VPS9D1-AS1 acts as a vital part in facilitating ESCC progression and can be a potential biomarker for the diagnosis of patients with ESCC.

Bornlisy Attenuates Colitis-Associated Colorectal Cancer via Inhibiting GPR43-Mediated Glycolysis.

There is evidence that probiotics have a broad antitumor effect in colorectal cancer (CRC). However, the mechanism remains obscure. Here, we investigated the effect of Bornlisy (BO)-cocktails of three probiotics on colitis-associated colon cancer (CAC) and the underlying mechanism. The treatment of CAC mice with BO resulted in decreased tumor loads as compared with their counterparts. BO also inhibited the proliferation and metastasis of CRC cells in vitro. Furthermore, BO inhibited cell proliferation through downregulating glycolysis. Activating glycolysis reversed the protective role of BO in the CAC mice. Mechanically, BO administration promoted the activation of GPR43, followed by its downstream PLC-PKC-ERK pathway, which led to decreased glucose metabolism. These results suggest that BO may provide an intervention strategy for CRC therapy, while GPR43 is a potential targeting receptor during the BO treatment.

C. tropicalis promotes chemotherapy resistance in colon cancer through increasing lactate production to regulate the mismatch repair system.

Due to chemotherapeutic drug resistance, tumor recurrence is common in patients with colorectal cancer (CRC) and chemo-resistant patients are often accompanied by defects in the mismatch repair system (MMR). Our previous study has shown that Candida tropicalis (C. tropicalis) is closely related to the occurrence and development of colorectal cancer, but whether this conditional pathogenic fungus is involved in chemotherapy needs further investigation. Here we found that C. tropicalis promoted chemotherapy resistance of colon cancer to oxaliplatin. Compared with oxaliplatin-treated group, the expression of functional MMR proteins in tumors were decreased in C.tropicalis/oxaliplatin -treated group, while the glycolysis level of tumors was up-regulated and the production of lactate was significantly increased in C.tropicalis/oxaliplatin -treated group. Inhibiting lactate production significantly alleviated the chemoresistance and rescued the decreased expression of MMR caused by C. tropicalis. Furthermore, we found that lactate down-regulated the expression of MLH1 through the GPR81-cAMP-PKA-CREB axis. This study clarified that C. tropicalis promoted chemoresistance of colon cancer via producing lactate and inhibiting the expression of MLH1, which may provide novel ideas for improving CRC chemotherapy effect.

Enhanced Microbial Chromate Reduction Using Hydrogen and Methane as Joint Electron Donors.

Hydrogen and methane commonly co-exist in aquifer. Either hydrogen or methane has been individually utilized as electron donor for bio-reducing chromate. However, little is known whether microbial chromate reduction would be suppressed or promoted when both hydrogen and methane are simultaneously supplied as joint electron donors. This study for the first time demonstrated microbial chromate reduction rate could be accelerated by both hydrogen and methane donating electrons. The maximum chromate reduction rate (4.70 ±â€¯0.03 mg/L·d) with a volume ratio of hydrogen to methane at 1:1 was significantly higher than that with pure hydrogen (2.53 ±â€¯0.02 mg/L·d) or pure methane (2.01 ±â€¯0.02 mg/L·d) as the sole electron donor (p < 0.01). High-throughput 16S rRNA gene amplicon sequencing detected potential chromate reducers (e.g., Spirochaetaceae, Delftia and Azonexus) and hydrogenotrophic bacteria (e.g., Acetoanaerobium) and methane-metabolizing microorganisms (e.g., Methanobacterium), indicating that these microorganisms might play important roles on microbial chromate reduction using both hydrogen and methane as electron donors. Abundant hupL and mcrA genes responsible for hydrogen oxidation and methane conversion were harbored, together with chrA gene for chromate reduction. More abundant extracellular cytochrome c and intracellular NADH were detected with joint electron donors, suggesting more active electron transfers.

Highly efficient heterostructured stannic disulfide/stannic anhydride hybrids: Synthesis, morphology, and photocatalytic reduction of chromium (VI) under visible light.

Highly efficient heterostructured stannic disulfide/stannic anhydride (SnS2/SnO2) hybrids with different morphologies were fabricated via a two-step hydrothermal method. The composition and morphology of the obtained products were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and UV-vis diffuse reflectance spectroscopy (DRS). The SEM images showed that core-shell structured SnS2/SnO2 nanotubes and hierarchical SnS2 flowers decorated with SnO2 particles were fabricated under different synthetic conditions. The DRS results of the hybrids showed that the absorption edges were gradually redshifted with increasing SnS2 content. In the photocatalytic reduction of chromium (VI) under visible light, the SnS2/SnO2 hybrid prepared with thioacetamide addition of 0.60 g exhibited the best photocatalytic activity, which was approximately 6.8 times higher than that of pure SnS2. This increase in the reduction performance might be ascribed to the strengthened absorption of visible light, the rapid interfacial charge transfer and the promoted charge separation efficiency. Photocurrent- response measurements, electrochemical impedance spectroscopy, and photoluminescence emission tests confirmed the faster charge transfer and efficient charge separation over the heterostructured SnS2/SnO2 hybrids. Lastly, a photocatalytic reduction mechanism for chromium (VI) over SnS2/SnO2 hybrids was proposed.

Coexistence of MSI with KRAS mutation is associated with worse prognosis in colorectal cancer.

Kristen rat sarcoma viral oncogene homolog (KRAS) and microsatellite instability (MSI) are prognostic markers of colorectal cancer (CRC). However, the clinical value is still not fully understood, when giving the consideration to both the molecular makers. Five hundred fifty-one patients with CRC were retrospectively assessed by determining their clinicopathological features. KRAS mutations were detected by polymerase chain reaction. MSI, a defect in the mismatch repair (MMR) system, was detected by immunohistochemistry. The prognostic value of KRAS in combination with MSI was studied. Among 551 CRC patients, mutations in KRAS codon 12 and KRAS codon 13 were detected in 34.5% and 10.5% of patients, respectively. Four hundred one tumors were randomly selected to detect for MMR proteins expression. In this analysis, 30 (7.5%) tumors that had at least 1 MMR protein loss were defined as MMR protein-deficient (MMR-D), and the remaining tumors were classed as MMR protein-intact (MMR-I). According to KRAS mutation and MSI status, CRC was classified into 4 groups: Group 1, KRAS-mutated and MMR-I; Group 2, KRAS-mutated and MMR-D; Group 3, KRAS wild and MMR-I; and Group 4, KRAS wild and MMR-D. We found that patients in Group4 had the best prognosis. In conclusion, combination status of KRAS and MSI status may be used as a prognostic biomarker for CRC patient, if validated by larger studies.

Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population.

Colorectal cancers (CRCs) exhibiting microsatellite instability (MSI) have special biological behavior. The clinical predictors for MSI and its survival relevance for the Chinese population were still unclear. Seven hundred ninety-five CRC patients were retrospectively assessed. Mismatch repair (MMR) proteins (MSH2, MSH6, PMS1, and MLH1) expression was detected by immunohistochemistry using tumor tissues of all patients. DNA MSI status was analyzed by polymerase chain reaction in 182 samples randomly selected from the 795 cases. Among all CRC tumor tissues, 97 cases (12.2%) were with an MMR protein-deficient (MMR-D) phenotype, whereas 698 cases (87.8%) were with an MMR proteins intact (MMR-I) phenotype. A total of 21 (11.5%) CRCs were identified as having high microsatellite instability, 156 (85.7%) tumors were having microsatellite stability (MSS), and five (2.7%) were having low microsatellite instability. Importantly, MMR status was demonstrated to be moderately consistent with MSI status (κ=0.845, 95% confidence interval [CI] 0.721, 0.969). Unconditional logistic regression analysis revealed age, number of lymph node, tumor diameter, and tumor site as predictors for MSI with a substantial ability to discriminate different MSI status by area under curve of 80.62% using receiver operation curve. Compared with MMR-I, MMR-D was an independent prognostic factor for longer overall survival (hazard ratio =0.340, 95% CI 0.126, 0.919; P=0.034). MMR-D is an independent prognostic factor for better outcome. Our results may provide evidence for individualized diagnosis and treatment of CRC, but this will require further validation in larger sample studies.