Efficacy and safety of robotic versus laparoscopic liver resection for hepatocellular carcinoma: a propensity score-matched retrospective cohort study.

BACKGROUND: Evidence concerning long-term outcome of robotic liver resection (RLR) and laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) patients is scarce. METHODS: This study enrolled all patients who underwent RLR and LLR for resectable HCC between July 2016 and July 2021. Propensity score matching (PSM) was employed to create a 1:3 match between the RLR and LLR groups. A comprehensive collection and analysis of patient data regarding efficacy and safety have been conducted, along with the evaluation of the learning curve for RLR. RESULTS: Following PSM, a total of 341 patients were included, with 97 in the RLR group and 244 in the LLR group. RLR group demonstrated a significantly longer operative time (median [IQR], 210 [152.0-298.0] min vs. 183.5 [132.3-263.5] min; p = 0.04), with no significant differences in other perioperative and short-term postoperative outcomes. Overall survival (OS) was similar between the two groups (p = 0.43), but RLR group exhibited improved recurrence-free survival (RFS) (median of 65 months vs. 56 months, p = 0.006). The estimated 5-year OS for RLR and LLR were 74.8% (95% CI: 65.4-85.6%) and 80.7% (95% CI: 74.0-88.1%), respectively. The estimated 5-year RFS for RLR and LLR were 58.6% (95% CI: 48.6-70.6%) and 38.3% (95% CI: 26.4-55.9%), respectively. In the multivariate Cox regression analysis, RLR (HR: 0.586, 95% CI (0.393-0.874), p = 0.008) emerged as an independent predictor of reducing recurrence rates and enhanced RFS. The operative learning curve indicates that approximately after the 11th case, the learning curve of RLR stabilized and entered a proficient phase. CONCLUSIONS: OS was comparable between RLR and LLR, and while RFS was improved in the RLR group. RLR demonstrates oncological effectiveness and safety for resectable HCC.

YTHDC1 inhibits osteoclast differentiation to alleviate osteoporosis by enhancing PTPN6 messenger RNA stability in an m6A-hUR-dependent manner.

YTHDC1 has been confirmed to mediate osteoporosis (OP) progression by regulating osteogenic differentiation. However, whether YTHDC1 mediates osteoclast differentiation and its molecular mechanism remains unclear. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the levels of YTHDC1, PTPN6, NFATc1, TRAP, RUNX2, alkaline phosphatase, and HUR. YTHDC1 knockout mice was constructed by CRISPR/Cas9 system, and the OP mice model was established by ovariectomy. Hematoxylin and eosin staining and micro-computed tomography were used to evaluate bone formation and bone mass. Mouse primary bone marrow macrophage cells were isolated and induced into osteoclasts. TRAP-positive cells were detected using TRAP staining. MeRIP-qPCR, RIP-qPCR assay, RNA affinity isolation assay, and co-immunoprecipitation assay were used to confirm the interactions among YTHDC1, PTPN6, and HUR. YTHDC1 expression was reduced and positively correlated with lumbar bone mineral density in OP patients. In the ovariectomy model of YTHDC1 knockout mice, bone formation was reduced, bone histomorphology was changed, and osteoclastic-related factor (NFATc1 and TRAP) levels were enhanced. Overexpression YTHDC1 inhibited osteoclast differentiation. YTHDC1 increased PTPN6 messenger RNA stability in an m6A-dependent manner. Moreover, YTHDC1 interacted with HUR to positively regulate PTPN6 expression. PTPN6 knockdown promoted osteoclast differentiation, and this effect was reversed by overexpressing HUR or YTHDC1. YTHDC1 was involved in regulating OP progression through inhibiting osteoclast differentiation by enhancing PTPN6 messenger RNA stability in an m6A-HUR-dependent manner.

Acid/GSH Dual-Responsive Endosome Escape Dual Pro-drug Micelles Targeted Synergistic Treatment for A549/ADR.

The resistance of cancer cells to anticancer drugs has been recognized as one of the main reasons for chemotherapy failure. Multidrug combination therapy is one of the most effective ways to solve this problem. Therefore, in this article, we designed and synthesized a pH/GSH dual-responsive camptothecin/doxorubicin (CPT/DOX) dual pro-drug synergistic treatment system with the aim of overcoming the resistance of non-small cell lung cancer A549/ADR cells to DOX. The pro-drug cRGD-PEOz-S-S-CPT (cPzT) was obtained by linking CPT to poly(2-ethyl-2-oxazoline) (PEOz) with endosomal escape properties through a GSH-responsive disulfide bond and modifying it with the targeted peptide cRGD. The pro-drug mPEG-NH-N=C-DOX (mPX) was synthesized by attaching DOX to polyethylene glycol (PEG) through acid-sensitive hydrazone bonds. The dual pro-drug micelles cPzT/mPX configured according to the CPT/DOX mass ratio of 3:1 showed a strong synergistic therapeutic effect at IC50 with a combined therapy index CI = 0.49, far less than 1. Moreover, with the further improvement of the inhibition rate, the 3:1 ratio showed a stronger synergistic therapeutic effect than other ratios. The cPzT/mPX micelles not only had better targeted uptake ability but also showed a better therapeutic effect in both 2D and 3D tumor suppression assays relative to free CPT/DOX and significantly enhanced the penetration ability into solid tumors. In addition, the results of confocal laser scanning microscopy (CLSM) showed that cPzT/mPX could effectively overcome the resistance of A549/ADR cells to DOX by delivering DOX into the nucleus to exert its effect. Thus, this dual pro-drug synergistic therapy system combining targeting and endosomal escape ability provides a possible strategy to overcome tumor drug resistance.

An ATP-binding cassette transporter G2 (CgABCG2) regulates the haemocyte proliferation by modulating the G1/S phase transition of cell cycle in oyster Crassostrea gigas.

ATP-binding cassette transporter G2 (ABCG2) is a half-transporter of the G subfamily in ATP-binding cassette transporters (ABC transporter), which is involved in the regulation of multidrug-resistant, cell cycle, and cell proliferation. In the present study, a homologue of ABCG2 (named as CgABCG2) with the conserved AAA domain and ABC2 membrane domain was identified from the Pacific oyster Crassostrea gigas. The open reading frame (ORF) of CgABCG2 was of 1956 bp encoding a predicted polypeptide of 652 amino acids, which shared 56.7%-65.7% sequence similarities with previously identified ABCG2s from other animals. The mRNA transcripts of CgABCG2 were detected in all the tested tissues with higher expression levels in gonad and haemocytes (19.31-fold and 11.23-fold of that in adductor muscle respectively, p < 0.05). CgABCG2 was mainly distributed on the cell membrane of the haemocytes with a partial distribution in the cytoplasm and nucleus. After Vibrio splendidus stimulation, the mRNA expression level of CgABCG2 in haemocytes was significantly up-regulated at 3 h and 6 h, which was 5.22-fold and 8.60-fold (p < 0.05) of that in control, respectively. After the expression of CgABCG2 was interfered by RNAi, the number of cells with EdU positive signals was reduced in both haemocytes and the potential hematopoietic sites. And the mRNA expression level of CgPCNA, CgGATA3, CgRunx, CgSCL and CgC-kit decreased significantly (p < 0.05), which were about 0.66-, 0.37-, 0.32-, 0.50-, and 0.50-fold of that in the negative control group, respectively. While the mRNA expression level of CgCDK2 increased significantly (1.84-fold to that in control, p < 0.05) and that of stem cell-related factor CgSOX2 did not change significantly in the si-CgABCG2 oysters. Moreover, the cell cycle of haemocytes was detected by flow cytometry, which was arrested at G0/G1 phase in the si-CgABCG2 oysters. All the results collectively suggested that CgABCG2 might involve the proliferation of haemocytes by regulating the expression of haematopoiesis related transcription factors and the G1/S phase transition of the cell cycle in oyster C. gigas.

The expression profile of a multi-stress inducible transient receptor potential vanilloid 4 (TRPV4) in Pacific oyster Crassostrea gigas.

Transient receptor potential vanilloid 4 (TRPV4) is one of the major non-selective cation channel proteins, which plays a crucial role in sensing biotic and abiotic stresses, such as pathogen infection, temperature, mechanical pressure and osmotic pressure changes by regulating Ca2+ homeostasis. In the present study, a TRPV4 homologue was identified in Pacific oyster Crassostrea gigas, designated as CgTRPV4. The open reading frame (ORF) of CgTRPV4 was of 2298 bp encoding a putative polypeptide of 765 amino acid residues with three typical ankyrin domains and six conserved transmembrane domains of TRPV4 subfamily proteins, as well as multiple N-glycosylation sites, cAMP- and cGMP-dependent protein kinase phosphorylation sites, protein kinase C phosphorylation sites, casein kinase II phosphorylation sites, and prokaryotic membrane lipoprotein lipid attachment site. The deduced amino acid sequence of CgTRPV4 shared 20.5%-26.2% similarity with TRPV4s from other species. During the early ontogenesis stages of oyster, the mRNA transcripts of CgTRPV4 were detectable in all the stages with the highest expression level in fertilized eggs and the lowest in D-hinged larvae. In adult oyster, the CgTRPV4 mRNA could be detected in all the examined tissues, including gill, hepatopancreas, adductor muscle, labial palp, mantle and haemocyte, with the highest expression level in gill (45.08-fold of that in hepatopancreas, p < 0.05). In immunocytochemical assay, the CgTRPV4 positive signals were distributed in both endoplasmic reticulum and cytoplasmic membrane of oyster haemocytes. The mRNA expression of CgTRPV4 in gill was significantly up-regulated after high temperature stress at 30°C (p < 0.05) and after Vibrio splendidus stimulation (p < 0.05). These results indicated that CgTRPV4 was a classical member of TRPV4 family in oyster, which was induced by either biotic or abiotic stimulations and involved in mediating the stress response of oysters.

Pathogenesis from Inflammation to Cancer in NASH-Derived HCC.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. As opposed to the majority of patients with HCC, approximately 20-30% of cases of non-alcoholic steatohepatitis (NASH)-derived HCC develop malignant tumours in the absence of liver cirrhosis. NASH is characterized by metabolic dysregulation, chronic inflammation and cell death in the liver, which provide a favorable setting for the transformation of inflammation into cancer. This review aims to describe the pathogenesis and the underlying mechanism of the transition from inflammation to cancer in NASH.

Risk factors for falls in hospitalized patients with cancer: A systematic review and meta-analysis.

A primary cancer diagnosis has been confirmed as an important risk factor for falls, and the incidence of falls has been shown to be higher in patients who have undergone cancer treatment than in those who have not undergone cancer treatment. Falls during hospitalization increase the medical costs of additional treatment and falls-related mortality. Many falls are preventable and a good understanding of the predictors of falls in this population is needed. However, the risk factors for falls have not yet been identified. The purpose of this review was to identify the risk factors for falls in hospitalized patients with cancer. Eleven English and Chinese electronic databases were searched from their inception to April 2022 and the methodological quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Five studies involving 1237 patients with cancer were included. The meta-analysis identifies eleven risk factors for falls in hospitalized patients with cancer, including age, history of falls, opiates, benzodiazepines, steroids, antipsychotics, sedatives, radiation therapy, chemotherapy, the use of an assistive device and length of hospitalization. Based on the evidence presented in this article, healthcare workers have the capacity to help reduce fall risk through the development of preventive support strategies in this population. Multicenter, prospective studies of patients with cancer should be conducted to further identify and validate their risk factors for falls.

ROS function as an inducer of autophagy to promote granulocyte proliferation in Pacific oyster Crassostrea gigas.

Hematopoiesis is the biological process to generate new blood cells in the living body and reactive oxygen species (ROS) contribute significantly to the regulation of haematopoietic cell homeostasis. In the present study, the involvement of ROS in the proliferation of haemocytes was examined in Pacific oyster Crassostrea gigas. The ROS content in haemocytes increased significantly after lipopolysaccharide (LPS) treatment, but decreased after the treatment with antioxidant N-Acetyl-L-cysteine (NAC, a scavenger of ROS). The percentage of 5-ethynyl-2'-deoxyuridine labeled (EdU+) granulocytes in total haemocytes significantly increased at 12 h (4.12-fold, p < 0.001) and 24 h (2.36-fold, p < 0.001) after LPS treatment, while decreased at 12 h (0.26-fold, p < 0.001) and 24 h (0.61-fold, p < 0.05) after NAC treatment, respectively. Meanwhile, the percentage of haemocytes with autophagosome positive signals significantly increased at 12 h (1.17-fold, p < 0.01) and 24 h (1.19-fold, p < 0.05) after LPS treatment, but significantly reduced at 12 h (0.41-fold, p < 0.001) and 24 h (0.28-fold, p < 0.001) after the NAC treatment, respectively. After ammonium chloride (NH4Cl) treatment, the percentage of haemocytes with autophagosome and EdU+ granulocytes significantly increased at 12 h, which was 1.27-fold (p < 0.01) and 1.70-fold (p < 0.01) of control group, respectively. These results collectively suggested that ROS produced after LPS treatment could act as an inducer for autophagy and involved in regulating the proliferation of some granulocytes in C. gigas.

Precise delivery of multi-stimulus-responsive nanocarriers based on interchangeable visual guidance.

Cancer treatment is imminent, and controlled drug carriers are an important development direction for future clinical chemotherapy. Visual guidance is a feasible means to achieve precise treatment, reduce toxicity and increase drug efficacy. However, the existing visual control methods are limited by imaging time-consuming, sensitivity and side effects. In addition, the ability of the carrier to respond to environmental stimuli in vivo is another difficulty that limits its application. Here, we propose a highly stimulus-responsive GC liposome with precise tracing and sensitive feedback capabilities. It combines magnetic resonance imaging and fluorescence imaging, and addresses the need for precise visualization by alternating imaging modalities. More importantly, GC liposomes are a carrier that can accumulate stimuli. In this paper, by tracking the fragmentation process of empty GC and drug-loaded D-GC liposomes, we confirm the synergistic effect between multiple stimuli, which can result in a more efficient drug release performance. Finally, in mice models we examined the GC liposome imaging approach and the D-GC + UV group guided by this visualization exhibited the highest tumor inhibition efficiency (6.85-fold). This study highlights the advantages of alternate visualization-guided and co-stimulation treatment strategies, and provides design ideas and potential materials for efficient and less toxic cancer treatments.

Series of High Magnetic Resonance-Guided Photoinduced Nanodelivery Systems for Precisely Improving the Efficiency of Cancer Therapy.

Nanochemotherapy is recognized as one of the most promising cancer treatment options, and the design of the carrier has a crucial impact on the final efficacy. To precisely improve the efficacy and reduce the toxicity, we combined the clinical contrast agent (Gd-DTPA) with a stimulus-sensitive o-nitrobenzyl ester and then prepared a series of nNBGD lipids by varying the carbon chain length of the hydrophobic group. The self-assembled nNBGD liposomes can be tracked by MRI to localize the aggregation of drug carriers in vivo, so as to prompt the application of light stimulation at the optimal time to facilitate the precise release of carriers at the lesion site. And the application potential of this strategy was verified with 88% tumor suppression effect in the 12NBGD-DOX+UV group. In addition, this paper emphasizes that small differences in structure can affect the overall performance of the carriers. By exploration of the differences in stability, drug loading, stimulus responsiveness, MRI imaging effect, and toxicity of the series of nNBGD carriers, the relationship between the length of the hydrophobic group of nNBGD lipids and the overall performance of the carriers is given, which provides experimental support and design reference for other carriers.

Sensitive and precise visually guided drug delivery nanoplatform with dual activation of pH and light.

Controlled-release drug carriers in cancer therapy are the most ideal way to reduce toxicity and improve drug efficacy. Since light stimulation is precise and operable, most multi-stimulation response carriers utilize phototherapy to enhance release efficiency. However, phototoxicity severely limits the application of phototherapy. Herein, we designed and synthesized a Cou-ONB lipid with sensitive fluorescence feedback and multi-stimulus response. COBL liposomes prepared from Cou-ONB lipids will passively aggregate at the tumor and guide phototherapy by fluorescence. More importantly, it can reflect the drug release effect in vivo through its own sensitive fluorescence changes, further enabling precise phototherapy and reducing phototoxicity. In this paper, the multi-stimulus superimposed response and precise fluorescence-guided performance of COBL liposomes were investigated at the molecular, liposome, cellular, and animal levels. Finally, tumor treatment experiments showed that the d-COBL-UV group had the best tumor suppression effect (5.3-fold). This paper highlights a real-time fluorescence-guided multi-stimulus superposition strategy and provides a design idea to precisely implement exogenous stimuli by displaying the degree of drug release, aiming to achieve less toxic and more efficient cancer therapy through timely and precise multi-stimulation. STATEMENT OF SIGNIFICANCE: Multi-stimulus responsive drug carriers have been extensively developed in the last decade. Visual guidance is an important tool to achieve precision medicine and precise control of drug release. However, the available visualization materials are more aimed at directing stimulation at the optimal moment. There is little discussion on when to stop exogenous stimulation and how to minimize the damage of stimulation to the patient. Here, we provide a Cou-ONB lipid that not only responds to multiple stimuli, but also provides sensitive feedback on its own dissociation with a fluorescent signal so that physicians can adjust exogenous stimuli in a timely manner. This paper provides insights to facilitate precision drug delivery systems, providing viable design ideas for precise, efficient, and less toxic cancer therapies.

Histone lysine-specific demethylase 1 regulates the proliferation of hemocytes in the oyster Crassostrea gigas.

Background: Lysine-specific demethylase 1 (LSD1) is an essential epigenetic regulator of hematopoietic differentiation, which can specifically mono-methylate H3K4 (H3K4me1) and di-methylate H3K4 (H3K4me2) as a transcriptional corepressor. Previous reports have been suggested that it participated in hematopoiesis and embryonic development process. Here, a conserved LSD1 (CgLSD1) with a SWIRM domain and an amino oxidase (AO) domain was identified from the Pacific oyster Crassostrea gigas. Methods: We conducted a comprehensive analysis by various means to verify the function of CgLSD1 in hematopoietic process, including quantitative real-time PCR (qRT-PCR) analysis, western blot analysis, immunofluorescence assay, RNA interference (RNAi) and flow cytometry. Results: The qRT-PCR analysis revealed that the transcripts of CgLSD1 were widely expressed in oyster tissues with the highest level in the mantle. And the transcripts of CgLSD1 were ubiquitously expressed during larval development with the highest expression level at the early D-veliger larvae stage. In hemocytes after Vibrio splendidus stimulation, the transcripts of CgLSD1 were significantly downregulated at 3, 6, 24, and 48 h with the lowest level at 3 h compared to that in the Seawater group (SW group). Immunocytochemical analysis showed that CgLSD1 was mainly distributed in the nucleus of hemocytes. After the CgLSD1 was knocked down by RNAi, the H3K4me1 and H3K4me2 methylation level significantly increased in hemocyte protein. Besides, the percentage of hemocytes with EdU-positive signals in the total circulating hemocytes significantly increased after V. splendidus stimulation. After RNAi of CgLSD1, the expression of potential granulocyte markers CgSOX11 and CgAATase as well as oyster cytokine-like factor CgAstakine were increased significantly in mRNA level, while the transcripts of potential agranulocyte marker CgCD9 was decreased significantly after V. splendidus stimulation. Conclusion: The above results demonstrated that CgLSD1 was a conserved member of lysine demethylate enzymes that regulate hemocyte proliferation during the hematopoietic process.

Magnetic Resonance Imaging-Guided Multi-Stimulus-Responsive Drug Delivery Strategy for Personalized and Precise Cancer Treatment.

The emergence of nano-targeted controlled release liposomal drug carriers has provided a breakthrough in cancer therapy. However, their clinical efficacy is unsatisfactory, which is related to individualized differences in targeted drugs and poor in vivo release efficiency. In this paper, we prepared a class of personalized targeted and precisely controlled-release therapeutic drug carriers (GF liposomes) by co-assembling targeting and traceable o-nitrobenzyl ester lipids to propose a magnetic resonance imaging (MRI)-guided personalized in vivo targeted drug screening strategy and a multi-stimulus superimposed controlled-release strategy. Furthermore, by following the drug release process of drug-loaded liposomes (GF-D), it was found that these liposomes could rely on energy superposition to achieve more sensitive and efficient controlled drug release. In addition, the indispensable adjustment of liposome formulation for personalized MRI-based targeted therapy was verified by differential cellular uptake and in vivo magnetic resonance imaging. In the end, the 10.22-fold tumor suppression effect in the stimulus superposition group (GF-D-UV) indicates that the multi-stimulus cumulative response strategy and MRI-guided in vivo screening strategy can more effectively treat cancer. This contribution provides a concise and clever design idea for the future development of personalized precise and efficient clinical cancer therapies.

Endogenous reactive oxygen species burst induced and spatiotemporally controlled multiple drug release by traceable nanoparticles for enhancing antitumor efficacy.

Reactive oxygen species (ROS) are not only used as a therapeutic reagent in chemodynamic therapy (CDT), to stimulate the release of antineoplastic drugs, they can also be used to achieve a combined effect of CDT and chemotherapy to enhance anticancer effects. Herein, we synthesized a pH-responsive prodrug (PEG2k-NH-N-DOX), ROS-responsive prodrug (PEG2k-S-S-CPT-ROS), organic CDT agents (TPP-PEG2k-LND, TPP-PEG2k-TOS), and T1-enhanced magnetic resonance imaging contrast agents (Gd-DTPA-N16-16), and used them to encapsulate combrestatinA4 (CA4) to prepare traceable pH/ROS dual-responsive multifunctional nanoparticles (TLDCAG NPs) with endogenous ROS burst and spatiotemporally controlled multiple drug release ability. Firstly, TLDCAG NPs were accumulated in the tumor cell microenvironment via an enhanced permeability and retention (EPR) effect. Secondly, CA4 was released and specifically destroyed angiogenesis to facilitate the interaction between the tumor and the remaining TLDCG NPs. After accumulating in tumor cells, the TLDCG NPs could be destroyed under acidic conditions to quickly release doxorubicin (DOX), TPP-PEG2k-LND, and TPP-PEG2k-TOS. Thirdly, TPP-PEG2k-LND and TPP-PEG2k-TOS quickly targeted mitochondria, induced endogenous ROS bursts, reduced the mitochondrial membrane potential, and induced tumor cell apoptosis. Endogenous ROS can not only be used as a therapeutic reagent for CDT, but also can cut off the thioketal bond in PEG2k-S-S-CPT-ROS and release camptothecin (CPT). Finally, TLDCAG NPs were traced by magnetic resonance imaging (MRI). Furthermore, in vitro and vivo results indicate that the TLDCAG NPs have vigorous antitumor activity and negligible systemic toxicity. Therefore, the TLDCAG NPs provide an efficient strategy for enhancing antitumor efficacy.

A traceable, GSH/pH dual-responsive nanoparticles with spatiotemporally controlled multiple drugs release ability to enhance antitumor efficacy.

Constructing highly efficient and multifunctional nanoparticles to overcome the multiple challenges of targeted drug delivery is a new strategy urgently needed in tumor therapy. Here, we synthesized pH-responsive prodrug (PEG2K-NH-N-DOX), GSH-responsive prodrug (PEG2K-S-S-CPT), folate-receptor targeting polymers (FA-PEG2K-L8, FA-PEG2K-TOS) and T1-enhanced magnetic resonance imaging contrast agents (Gd-DTPA-N16-16), used to encapsulate combrestatinA4 (CA4) to prepare multifunctional nanoparticles (FTDCAG NPs). Unlike other nanoparticles, FTDCAG NPs contains three drugs with the ability to control the release in time and space, which can maximize the effectiveness of precise cancer chemotherapy. We first confirmed that specific binding between FTDCAG NPs and overexpressed folate-receptor cells by flow cytometry and confocal laser scanning microscopy. We then investigated the spatiotemporally controlled release ability of FTDCAG NPs loaded with doxorubicin (DOX), CA4 and camptothecin (CPT). Relative to pH = 7.4, the release efficiency of CA4 in the pH = 6.5 increased by 63.4 %. The first released CA4 is able to destroy the angiogenesis and help tumor cells to be exposed to the remaining FTDCG NPs. After being internalized into the tumor cells, FTDCG NPs is disassembled and the CPT and DOX were released due to the increase of intracellular GSH concentration and the decrease of pH value. Besides, the relaxation time of FTDCAG NPs is 3.86 times that of clinical Gd-DTPA, and the in vitro and vivo T1-weighted imaging is brighter, which can be used to trace the nanoparticles by MRI. Therefore, FTDCAG NPs provide an efficient strategy for the design of multifunctional drug delivery systems for enhancing antitumor efficacy.

Silencing LncRNA-DANCR attenuates inflammation and DSS-induced endothelial injury through miR-125b-5p.

BACKGROUND: LncRNA-DANCR is involved in inflammation and acts as a major contributor to colon cancer. The effects and mechanism of LncRNA-DANCR were first investigated in a DSS-induced colitis model in vivo and vitro. MATERIAL AND METHODS: Sprague-Dawley rats were given DSS to induce the colitis model. TNF-α, IL-1ß, IL-6 levels and expression of intestinal adhesion proteins ZO-1 and MUC2 in colon tissues and DSS-induced NCM460 cells were measured using corresponding kits. A hematoxylin and eosin (H&E) staining assay was performed to evaluate colon tissue pathology conditions. Protein expression levels in DSS-induced NCM460 cells were evaluated by Western blotting, and cell apoptosis was detected using a TUNEL assay. Gene levels in DSS-induced NCM460 cells were evaluated by PCR. The StarBase online tool was used to predict the LncRNA-DANCR target. The LncRNA-DANCR target was verified using a luciferase reporter assay. RESULTS: LncRNA-DANCR was up-regulated in DSS-induced groups of rats. TNF-α, IL-1ß and IL-6 expression was significantly increased in DSS-induced groups of rats and cells. Zo-1 and MUC2 expression levels were decreased in DSS-induced groups of rats. Silencing LncRNA-DANCR reduced inflammation, cell apoptosis and up-regulated ZO-1, MUC2 and Claudin-1 in DSS-induced cells. MiR-125b-5p was the downstream LncRNA-DANCR target. All LncRNA-DANCR effects in the colitis model were reversed by the miR-125b-5p inhibitor. CONCLUSION: LncRNA-DANCR/miR-125b-5p, which may act as a regulatory axis in inflammation, apoptosis and barrier function dysregulation, can provide an essential reference for the development of new drugs in colitis treatment.

A five lncRNA signature for prognosis prediction in hepatocellular carcinoma.

This study was conducted to screen prognosis­â€‹associated long­noncoding RNAs (lncRNAs) and a prognosis assessment model in hepatocellular carcinoma (HCC). lncRNA­ and mRNA­sequencing data of early­stage HCC samples were downloaded from The Cancer Genome Atlas database. The samples were divided into training set and validation set. Differentially expressed lncRNAs (DELs) between poor prognosis and good prognosis samples were screened with DEseq and edgeR. Cox regression analysis was conducted to identify prognosis­associated lncRNAs in the training set. A prognosis risk assessment model was established to calculate the risk score for each patient in the training set, and the prognosis prediction function was tested and validated in the validation dataset. The connection between the risk assessment model and clinical features was analyzed. A co­expression network between lncRNAs and corresponding genes was constructed, and functional enrichment was performed for these genes. A total of 81 DELs were screened between poor and good prognosis samples in the training set, and 43 prognosis­associated lncRNAs were observed. Of these DELs, five were used to construct the risk assessment model (RP11­325L7.2, DKFZP434L187, RP11­100L22.4, DLX2­AS1 and RP11­104L21.3). Low­risk samples exhibited longer survival time compared with the high­risk samples. The five lncRNAs exhibited significant differences in expression levels between different prognosis groups. Risk score was an independent prognostic factor for HCC. In the entire set, the low­risk group demonstrated significantly better prognosis compared with the high­risk group, even across all age, sex and alcohol consumption subgroups. 'Nucleoside­triphosphatase regulator activity', 'GTPase regulator activity', 'enzyme binding', 'peroxisome proliferator­activated receptor signaling pathway' and 'fatty acid metabolism' were the most significantly enriched functional terms. The signature lncRNAs screened in this study may have constitute novel strategies and biomarkers that predict the prognosis of HCC, and these may also contribute to a deeper understanding of the mechanisms underlying HCC development.

Protective humoral and CD4+ T cellular immune responses of Staphylococcus aureus vaccine MntC in a murine peritonitis model.

Staphylococcus aureus can cause different types of diseases from mild skin infections to life-threatening sepsis worldwide. Owing to the emergence and transmission of multidrug-resistant strains, developing an impactful immunotherapy especially vaccine control approach against S. aureus infections is increasingly encouraged and supported. S. aureus manganese transport protein C (MntC), which is a highly-conserved cell surface protein, can elicit protective immunity against S. aureus and Staphylococcus epidermidis. In this study, we evaluated the humoral immune response and CD4+ T cell-mediated immune responses in a mouse peritonitis model. The results showed that MntC-specific antibodies conferred an essential protection for mice to reduce invasion of S. aureus, which was corroborated via the opsonophagocytic killing assay and passive immunization experiment in mice, and moreover MntC-induced Th17 played a remarkable part in preventing S. aureus infection since the MntC-induced protective immunity decreased after neutralization of IL-17 by antibody in vivo and the Th17 adoptive transferred-mice could partly resist S. aureus challenge. In conclusion, we considered that the MntC-specific antibodies and MntC-specific Th17 cells play cooperative roles in the prevention of S. aureus infection.

Identification of a protective B-cell epitope of the Staphylococcus aureus GapC protein by screening a phage-displayed random peptide library.

The impact of epidemic Staphylococcus aureus (S. aureus) on public health is increasing. Because of the abuse of antibiotics, the antibiotic resistance of S. aureus is increasing. Thus, there is an urgent need to develop new immunotherapies and immunoprophylaxes. Previous studies showed that the GapC protein of S. aureus, which is a surface protein with high glyceraldehyde 3-phosphate dehydrogenase activity, transferrin binding activity, and other biological activities, is highly conserved. GapC induces an effective humoral immune response in vivo. However, the B-cell epitopes of S. aureus GapC have not been well identified. Here we used the bioinformatics tools to analyze the sequence of GapC, and we generated protective anti-GapC monoclonal antibodies (mAbs). A protective mAb (1F4) showed strong specificity to GapC and the ability to induce macrophages to phagocytose S. aureus. We screened the motif 272GYTEDEIVSSD282, which was recognized by mAb 1F4, using a phage display system. Then, we used site-directed mutagenesis to identify key amino acids in the motif. Residues G272 D276 E277 I278 and V279 formed the core of the 272GYTEDEIVSSD282 motif. In addition, we showed that this epitope peptide induced a protective humoral immune response against S. aureus infection in immunized mice. Our results will be useful for the further study of epitope-based vaccines against S. aureus infection.

Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs.

Using a highly effective binuclear Cu complex as the catalyst, the 1,3-dipolar cycloaddition reactions between 16 alkynes and two azides were successfully performed and resulted in the production of 25 new triazole-containing sorafenib analogs. Several compounds were evaluated as potent antitumor agents. Among them, 4-(4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)phenoxy)-N-methylpicolinamide (8f) potently suppressed the proliferation of HT-29 cancer cells by inducing apoptosis and almost completely inhibited colony formation at a low micromolar concentration.