Efficacy and safety of PD-1/PD-L1 inhibitor-based immune combination therapy versus sorafenib in the treatment of advanced hepatocellular carcinoma: a meta-analysis.

Objective: To systematically evaluate the safety and efficacy of PD-1/PD-L1 inhibitor-based immunotherapy (hereafter referred to as "combination immunotherapy") compared with that of sorafenib in the treatment of hepatocellular carcinoma (HCC). Methods: Databases such as PubMed, Embase, and the Cochrane Library were searched from the date of their establishment to September 2023 to identify randomized controlled trials (RCTs) of combination immunotherapy versus sorafenib for the treatment of advanced HCC. Two reviewers independently evaluated the quality of the included studies, extracted the data, and cross-checked the information. The meta-analysis was performed using RevMan 5.3 software. Results: A total of 5 RCTs were included. The results of the meta-analysis showed the following: (1) Effectiveness. Compared to sorafenib, combination immunotherapy significantly improved overall survival (OS, HR = 0.69, 95% CI: 0.58 ~ 0.82, p < 0.01) and progression-free survival (PFS, HR = 0.62, 95% CI: 0.50 ~ 0.78, p < 0.001) in patients with advanced HCC. (2) Safety. Both groups had comparatively high incidences of adverse events (AEs), but the difference in any treatment-related adverse events was not significant between the two arms (OR = 0.98, 95% CI: 0.95 ~ 1.02, p = 0.34). The difference in the incidence of grade 1-2 adverse reactions was statistically significant (OR = 0.66, 95% CI = 0.49-0.90, p = 0.001). There were no differences in grade 3/4 TRAEs or grade 5 TRAEs (OR = 1.46, 95% CI = 0.78 ~ 2.71, p = 0.24; OR = 1.08, 95% CI = 0.73 ~ 1.58, p = 0.71). Conclusion: Combined immunotherapy can significantly prolong the OS and PFS of patients with advanced HCC without increasing the incidence of adverse effects in terms of safety, but the incidence of AEs in different systems is different.

Pathological changes of highly pathogenic Bacillus cereus on Pelodiscus sinensis.

An outbreak of a disease with a high mortality rate occurred in a Chinese Softshell Turtle (Pelodiscus sinensis) farm in Hubei Province. This study isolated a highly pathogenic Bacillus cereus strain (Y271) from diseased P. sinensis. Y271 has ß hemolysis, containing both Hemolysin BL (hblA, hblC, and hblD), Non-hemolytic enterotoxin, NHE (nheA, nheB, and nheC), and Enterotoxin FM (entFM) genes. Y271 is highly pathogenic against P. sinensis with an LD50 = 6.80 × 103 CFU/g weight. B. cereus was detected in multiple tissues of the infected P. sinensis. Among them, spleen tissue showed the highest copy number density (1.54 ± 0.12 × 104 copies/mg). Multiple tissues and organs of diseased P. sinensis exhibited significant pathological damage, especially the spleen, liver, kidney, and intestine. It showed obvious tissue structure destruction, lesions, necrosis, red blood cells, and inflammatory cell infiltration. B. cereus proliferating in the spleen, liver, and other tissues was observed. The intestinal microbiota of the diseased P. sinensis was altered, with a greater abundance of Firmicutes, Fusobacterium, and Actinomyces than in the healthy group. Allobaculum, Rothia, Aeromonas, and Clostridium abundance were higher in the diseased group than in the healthy group. The number of unique microbial taxa (472) in the disease group was lower than that of the healthy group (705). Y271 was sensitive to multiple drugs, including florfenicol, enrofloxacin, neomycin, and doxycycline. B. cereus is the etiological agent responsible for the massive death of P. sinensis and reveals its potential risks during P. sinensis cultivation.

T2SS-peptidase XcpA associated with LasR evolutional phenotypic variations provides a fitness advantage to Pseudomonas aeruginosa PAO1.

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa possesses hierarchical quorum sensing (QS) systems. The intricate QS network of P. aeruginosa synchronizes a suite of virulence factors, contributing to the mortality and morbidity linked to the pathogenicity of this bacterium. Previous studies have revealed that variations in the lasR gene are frequently observed in chronic isolates of cystic fibrosis (CF). Specifically, LasRQ45stop was identified as a common variant among CF, lasR mutants during statistical analysis of the clinical lasR mutants in the database. In this study, we introduced LasRQ45stop into the chromosome of P. aeruginosa PAO1 through allelic replacement. The social traits of PAO1 LasRQ45stop were found to be equivalent to those of PAO1 LasR-null isolates. By co-evolving with the wild-type in caseinate broth, elastase-phenotypic-variability variants were derived from the LasRQ45stop subpopulation. Upon further examination of four LasRQ45stop sublines, we determined that the variation of T2SS-peptidase xcpA and mexT genes plays a pivotal role in the divergence of various phenotypes, including public goods elastase secretion and other pathogenicity traits. Furthermore, XcpA mutants demonstrated a fitness advantage compared to parent strains during co-evolution. Numerous phenotypic variations were associated with subline-specific genetic alterations. Collectively, these findings suggest that even within the same parental subline, there is ongoing microevolution of individual mutational trajectory diversity during adaptation.

The metonymic mechanism of English translation of Chinese intangible cultural heritage terms from the perspective of cognitive psychology.

The translation of Intangible Cultural Heritage (ICH) terms is an important practical aspect of cross-lingual expressions related to ICH knowledge. Chinese ICH terms are heavily loaded with specific historical and cultural knowledge and regional characteristics. Based on cognitive psychology, this paper analyzes the metonymic mechanism of traditional translation techniques such as substitution in the English translation of Chinese ICH terms. The English translation of Chinese ICH nominal terms can be realized based on the metonymic mechanism of replacing either a superordinate with a subordinate of the linguistic structure or a subordinate of the linguistic structure with a subordinate of the linguistic structure in the pair language, English-Chinese. The English translation of Chinese ICH verbal terms can regard the whole verbal action as an event process and can highlight one aspect of the process through a metonymic mechanism as well. This paper holds that metonymy is an important psychological motivation and cognitive mechanism for translation skills such as substitution as it brings the relationship between the corresponding items of the target language and the source language into a unified interpretation framework. Hence, this may add some significance to the research of translation theory and translation practice. This also contributes to the UN Sustainable Development Goal number 17 which seeks global parternship for sustainable development.

l-Cysteine-Modified Graphene Oxide-Based Membrane for Chiral Selective Separation.

A novel chiral separation membrane was fabricated by assembling l-cysteine (l-Cys)-modified graphene oxide sheets. l-Cys modification leads to an enantiomer separation membrane with an accessible interlayer spacing of 8 Å, which allows high solvent permeability. In the racemate separation experiments under isobaric conditions, the enantiomeric excess (ee) values of alanine (Ala), threonine (Thr), tyrosine (Tyr), and penicillamine (Pen) racemates in the permeation solution were 43.60, 44.11, 27.43, and 46.44%, respectively. In the racemate separation experiments under negative pressure, the separation performances of Ala, Thr, and Tyr were still maintained, and the enantiomeric excess (ee) values of the filtrate after separation were 56.80, 54.57, and 32.34%, respectively. These results indicate that the as-prepared GO-Cys membrane has a great practical value in the field of enantiomer separation.

Synthesis of membrane-type graphene oxide immobilized manganese dioxide adsorbent and its adsorption behavior for lithium ion.

Recently, there has been an urgent need to develop new materials and technologies for extracting lithium ions. Herein, the membrane-type adsorbent of manganese dioxide (MnO2) is prepared by a vacuum filtration method using graphene oxide (GO) as a binder and amino-ß-cyclodextrin (amino-ß-CD) as an adjuvant. The results of thermogravimetric analysis show that MnO2 is successfully immobilized on GO layers with a content of about 24 wt%, which enabled rapid adsorb lithium ions from the ionic solution. In addition, the permeation experiment shows the membrane has specific selectivity for lithium ion transport and adsorption, which is manifested in the selectivity ratios of K+/Li+, Na+/Li+ and K+/Na+ to 2.5, 3.2 and 0.8, respectively. Adsorption experiments show that GO-ß-CD/MnO2 membrane has a high adsorption capacity for lithium ions (37.5 mg g-1). The adsorption kinetic curve indicates that the lithium adsorption process is controlled by the chemical adsorption mechanism. In the enrichment experiment, the concentration of lithium ions from seawater can be enriched to 1.2 mg L-1 after 100 cycles. The results suggest that the developed GO-ß-CD/MnO2 membrane could effectively extract lithium ions from seawater.

FLNA promotes chemoresistance of colorectal cancer through inducing epithelial-mesenchymal transition and smad2 signaling pathway.

Chemoresistance is a leading cause of tumor relapse and treatment failure in colorectal cancer (CRC) patients and is correlated with epithelial-mesenchymal transition (EMT). This study was aimed to explore the mechanism of EMT in chemoresistant CRC. Bioinformatic method was used to screen differentially expressed genes between 5-FU sensitive and resistant CRC cells. Immunohistochemistry staining was utilized to analyze the expression of FLNA in CRC tissues. The roles of FLNA in chemoresistance were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic CRC animal model. The regulation of c-Met signaling by FLNA was explored via Co-Immunoprecipitation and luciferase reporter assays. Our results suggested FLNA directly regulated the metastasis and EMT of chemoresistant CRC cells. Moreover, c-Met-AKT mediated ser2152 phosphorylation of FLNA was demonstrated to be correlated with EMT. In turn, FLNA enhanced c-Met promoter activity by its interaction with smad2. Clinically, the expression of FLNA was significantly associated with c-Met protein levels in CRC tissues. These data established that FLNA could be a novel and reliable CRC marker and a potential therapeutic target against CRC.

Effects of nanoscale zero-valent iron on the performance and the fate of antibiotic resistance genes during thermophilic and mesophilic anaerobic digestion of food waste.

The effects of nanoscale zero-valent iron (nZVI) on the performance of food waste anaerobic digestion and the fate of antibiotic resistance genes (ARGs) were investigated in thermophilic (TR) and mesophilic (MR) reactors. Results showed that nZVI enhanced biogas production and facilitated ARGs reduction. The maximum CH4 production was 212.00 ±â€¯4.77 ml/gVS with 5 g/L of nZVI in MR. The highest ARGs removal ratio was 86.64 ±â€¯0.72% obtained in TR at nZVI of 2 g/L. nZVI corrosion products and their contribution on AD performance were analyzed. The abundance of tetracycline genes reduced significantly in nZVI amended digesters. Firmicutes, Chloroflexi, Proteobacteria and Spirochaetes showed significant positive correlations with various ARGs (p < 0.05) in MR and TR. Redundancy analysis indicated that microbial community was the main factor that influenced the fate of ARGs. nZVI changed microbial communities, with decreasing the abundance bacteria belonging to Firmicutes and resulting in the reduction of ARGs.

The Preparation and Study of Ethylene Glycol-Modified Graphene Oxide Membranes for Water Purification.

In this work, graphene oxide (GO)/ethylene glycol (EG) membranes were designed by a vacuum filtration method for molecular separation and water purification. The composite membranes were characterized by scanning electron microscopy (SEM), field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). The interlayer spacing of GO membranes (0.825 nm) and GO/EG membranes (0.634 nm) are measured by X-ray diffraction (XRD). Using the vacuum filtration method, the membrane thickness can be controlled by selecting the volume of the solution from which the membrane is prepared, to achieve high water permeance and high rejection of Rhodamine B (RhB). The membrane performance was evaluated on a dead-end filtration device. The water permeance and rejection of RhB of the membranes are 103.35 L m-2 h-1 bar-1 and 94.56% (GO), 58.17 L m-2 h-1 bar-1 and 97.13% (GO/EG), respectively. The permeability of GO/EG membrane is about 40 × 10-6 L m-1 h-1 bar-1. Compared with the GO membrane, the GO/EG membrane has better separation performance because of its proper interlayer spacing. In this study, the highest rejection of RhB (99.92%) is achieved. The GO/EG membranes have potential applications in the fields of molecular separation and water purification.

TRIM29 facilitates the epithelial-to-mesenchymal transition and the progression of colorectal cancer via the activation of the Wnt/ß-catenin signaling pathway.

BACKGROUND: Tripartite Motif 29 (TRIM29) has been newly identified as being implicated in cancer progression. However, the biological role and molecular mechanism of TRIM29 in the invasion and metastasis of colorectal cancer (CRC) remain to be determined. METHODS: The expression levels of TRIM29 and ß-catenin in CRC patient specimens were detected by immunohistochemistry. Recombinant lentivirus vectors containing the TRIM29 gene and its small hairpin interfering RNAs were constructed and transduced into CRC cells. Wound-healing and Transwell assays were performed to evaluate the migration and invasion abilities of CRC cells in vitro. Hepatic metastasis models in nude mice were established to validate the function of TRIM29 in vivo. Moreover, the expressions of epithelial-to-mesenchymal transition (EMT)-associated proteins were detected by qRT-PCR and Western blotting in CRC cells. Finally, Western blotting, qRT-PCR, luciferase reporter assays, and immunofluorescence assays were used to explore the molecular mechanisms of TRIM29 in CRC progression. RESULTS: Increased TRIM29 expression positively correlated with lymph node metastasis and ß-catenin expression in patient CRC tissues. Overexpression of TRIM29 promoted invasion and metastasis of CRC cells in vitro and in vivo by regulating EMT, whereas the knockdown of TRIM29 had the opposite effect. Further mechanistic studies suggest that TRIM29 can activate the Wnt/ß-catenin signaling pathway via up-regulating CD44 expression in colorectal cancer. CONCLUSIONS: TRIM29 induces EMT through activating the Wnt/ß-catenin signaling pathway via up-regulating CD44 expression, thus promoting invasion and metastasis of CRC.

Beneficial effects of dual TORC1/2 inhibition on chronic experimental colitis.

BACKGROUND AND AIM: AZD8055, a new immunosuppressive reagent, a dual TORC1/2 inhibitor, had been used successfully in animal models for heart transplantation. The aim of this study was to evaluate the effects and mechanisms of AZD8055 on chronic intestinal inflammation. METHODS: Dextran sulfate sodium (DSS) - induced chronic colitis was used to investigate the effects of AZD8055 on the development of colitis. Colitis activity was monitored by body weight assessment, colon length, histology and cytokine profile analysis. RESULTS: AZD8055 treatment significantly alleviated the severity of colitis, as assessed by colonic length and colonic damage. In addition, AZD8055 treatment decreased the colonic CD4+ T cell numbers and reduced both Th1 and Th17 cell activation and cytokine production. The percentages of Treg cells in the colon were also expanded by AZD8055 treatment. Furthermore, AZD8055 effectively inhibited mTOR downstream proteins and signal transducer and activator of transcription related proteins in CD4+ T cells of intestinal lamina propria. CONCLUSIONS: These findings increased our understanding of DSS-induced colitis and shed new lights on mechanisms of digestive tract chronic inflammation. Dual TORC1/2 inhibition showed potent anti-inflammatory and immune regulation effects by targeting critical signaling pathways. The results supported the strategy of using dual mTOR inhibitor to treat inflammatory bowel disease.

MEMS Gyroscope Automatic Real-Time Mode-Matching Method Based on Phase-Shifted 45° Additional Force Demodulation.

In order to solve the problem where existing mode-matching methods in microelectromechanical systems (MEMS) vibrating gyroscopes fail to meet real-time and reliability requirements, this paper presents a novel method to accomplish automatic and real-time mode-matching based on phase-shifted 45° additional force demodulation (45° AFD-RM). The phase-shifted 45° additional force signal has the same frequency as the quadrature force signal, but it is phase-shifted by 45° and applied to the sense mode. In addition, two-way phase-shifted 45° demodulations are used at the sense-mode detection output to obtain a phase metric that is independent of the Coriolis force and can reflect the mode-matching state. Then, this phase metric is used as a control variable to adaptively control the tuning voltage, so as to change the sense-mode frequency through the negative stiffness effect and ultimately achieve real-time mode-matching. Simulation and experimental results show that the proposed 45° AFD-RM method can achieve real-time matching. The mode frequency split is controlled within 0.1 Hz, and the gyroscope scale factor, zero-bias instability, and angle random walk are effectively improved.

Prognostic Analysis of Duodenal Gastrointestinal Stromal Tumors.

AIM: This study aims to analyze factors possibly related to the prognosis of duodenal gastrointestinal stromal tumors (DGISTs). METHODS: We collected and retrospectively analyzed clinical and pathological data of 62 patients with primary DGISTs. All the patients were hospitalized and received complete surgical resection at Shanghai Ruijin Hospital from September 2003 to April 2015. We followed up the patients to determine survival outcomes. We also analyzed the effect of clinical and pathological factors on disease-free survival (DFS) and overall survival (OS) of the patients. RESULTS: Kaplan-Meier univariate survival analysis demonstrated that tumor size, mitotic index, Ki-67 index, and pathological risk were correlated with the DFS and OS of the patients (DFS P = 0.039, 0.001, <0.001, and 0.005, resp.; OS P = 0.027, 0.007, <0.001, and 0.012, resp.). Cox multivariate regression analysis revealed that Ki-67 index was an independent prognostic factor affecting DFS and OS (P = 0.007 and 0.028, resp.). Moreover, Kaplan-Meier survival analysis showed that imatinib treatment for patients with recurrence was correlated with prolonged OS (P = 0.002). CONCLUSION: Prognosis for DGIST treated by R0 resection is favorable. High level of Ki-67 can be an independent risk factor of DGIST prognosis. Adjuvant imatinib therapy for patients with tumor recurrence could probably lead to prolonged survival.

Correction: Inhibition of neddylation regulates dendritic cell functions via Deptor accumulation driven mTOR inactivation.

[This corrects the article DOI: 10.18632/oncotarget.9543.].

Comparison between Intestinal Behçet's Disease and Crohn's Disease in Characteristics of Symptom, Endoscopy, and Radiology.

AIM: To evaluate different parameters in differentiating intestinal BD from CD. METHODS: The medical records of inpatients with intestinal BD and CD were retrospectively reviewed. The univariate value of different parameters was analyzed, respectively. A differentiation model was established by pooling all valuable parameters together. Diagnostic efficacy was evaluated, and a receiver operating curve (ROC) was plotted. RESULTS: Forty-two BD patients and ninety-seven CD patients were reviewed. Demographic and clinical parameters that showed significant value included diarrhea, fever, perianal disease, oral ulcers, genital ulcers, skin lesions, and musculoskeletal lesions. Endoscopic parameters reaching clinical significance included multiple-site lesions, lesions confined to the ileocecal region, longitudinal ulcers, round or oval ulcers, punch-out ulcers, ulcers with discrete margin, ulcer size > 2 cm, stricture of bowel, and anorectal involvement. Radiologic parameters aiding the differentiation included involvement segments ≤ 3, asymmetrical pattern of involvement, intraluminal pseudopolyp formation, target sign, stricture with proximal dilation, comb sign, and fistula. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the differentiation model were 90.5%, 93.8%, 92.8%, 86.4%, and 95.8%, respectively. The cutoff value was 0.5 while the area under the ROC curve was 0.981. CONCLUSION: The differentiation model that integrated the various parameters together may yield a high diagnostic efficacy in the differential diagnosis between intestinal BD and CD.

Potential model for differential diagnosis between Crohn's disease and primary intestinal lymphoma.

AIM: To evaluate the usefulness of different parameters to differentiate Crohn's disease (CD) from primary intestinal lymphoma (PIL). METHODS: The medical records of 85 patients with CD and 56 patients with PIL were reviewed retrospectively. Demographic, clinical, laboratory, endoscopic, and computed tomographic enterography (CTE) parameters were collected. The univariate value of each parameter was analyzed. A differentiation model was established by pooling all the valuable parameters. Diagnostic efficacy was analyzed, and a receiver operating characteristic (ROC) curve was plotted. RESULTS: The demographic and clinical parameters that showed significant values for differentiating CD from PIL included age of onset, symptom duration, presence of diarrhea, abdominal mass, and perianal lesions (P < 0.05). Elevated lactate dehydrogenase and serum ß2-microglobulin levels suggested a PIL diagnosis (P < 0.05). The endoscopic parameters that showed significant values for differentiating CD from PIL included multiple-site lesions, longitudinal ulcer, irregular ulcer, and intraluminal proliferative mass (P < 0.05). The CTE parameters that were useful in the identification of the two conditions included involvement of ≤ 3 segments, circular thickening of the bowel wall, wall thickness > 8 mm, aneurysmal dilation, stricture with proximal dilation, "comb sign", mass showing the "sandwich sign", and intussusceptions (P < 0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the differentiation model were 91.8%, 96.4%, 93.6%, 97.5%, and 88.5%, respectively. The cutoff value was 0.5. The area under the ROC curve was 0.989. CONCLUSION: The differentiation model that integrated the various parameters together may yield a high diagnostic efficacy in the differential diagnosis between CD and PIL.

The Efficacy of Infliximab Monotherapy versus Infliximab-Azathioprine Sequential Treatment in Crohn's Disease: Experience from a Tertiary Medical Center in China.

Objective. To evaluate the efficacy of infliximab (IFX) monotherapy versus infliximab-azathioprine sequential treatment in Crohn's disease (CD) patients. Methods. Patients newly diagnosed with CD using IFX as induction therapy were enrolled. After 6 times of IFX infusions, they were divided into IFX monotherapy group and IFX-AZA sequential therapy group. Clinical remission rates were assessed at weeks 57, 84, 111, and 138 while endoscopic remission rates were assessed at weeks 84 and 138 to evaluate the efficacy of these two groups. Results. A total of seventy-nine patients had accomplished 138-week follow-up. At weeks 84 and 138, the deep remission rate (18/22 and 17/22) of IFX monotherapy group was significantly higher compared to IFX-AZA sequential therapy group (26/57 and 21/57) (P = 0.004 and 0.001, resp.). Similar findings were found in complete endoscopic remission rate. The clinical remission rates of IFX monotherapy group were similar to that of IFX-AZA sequential therapy group (P > 0.05). At weeks 84 and 138, the endoscopic remission rate and the endoscopic improvement rate between these two groups displayed no significant difference (P > 0.05). Conclusion. IFX monotherapy provides higher deep remission rate compared with IFX-AZA sequential therapy in two-year maintenance therapy. For patients who could not receive prolonged IFX therapy, IFX-AZA sequential therapy is acceptable, though long-term efficacy remains to be seen.

Correction: mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile.

[This corrects the article DOI: 10.1371/journal.pone.0154564.].