C-reactive Protein/Albumin Ratio as a Prognostic Indicator in Posttraumatic Shock and Outcome of Multiple Trauma Patients

Objective C-reactive protein(CRP)/albumin ratio(CAR)is a new inflammation-based index for predicting the prognosis of various diseases.The CAR determined on admission may help to predict the prognostic value of multiple trauma patients.Methods A total of 264 adult patients with severe multiple trauma were included for the present retrospective study,together with the collection of relevant clinical and laboratory data.CAR,CRP,albumin,shock index and ISS were incorporated into the prognostic model,and the receiver operating characteristic(ROC)curve was drawn.Then,the shock index for patients with different levels of CAR was analyzed.Finally,univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for the 28-day mortality of multiple trauma patients.Results A total of 36 patients had poor survival outcomes,and the mortality rate reached 13.6%.Furthermore,after analyzing the shock index for patients with different levels of CAR,it was revealed that the shock index was significantly higher when CAR was≥4,when compared to CAR<2 and 2≤CAR<4,in multiple trauma patients.The multivariate logistic analysis helped to identify the independent association between the variables CAR(P=0.029)and shock index(P=0.019),and the 28-day mortality of multiple trauma patients.Conclusion CAR is higher in patients with severe multiple trauma.Furthermore,CAR serves as a risk factor for independently predicting the 28-day mortality of multiple trauma patients.The shock index was significantly higher when CAR was≥4 in multiple trauma patients.

Predictive value of C-reactive protein/albumin ratio in acute pancreatitis

BACKGROUND:Serum C-reactive protein(CRP) increases and albumin decreases in patients with inflammation and infection.However,their role in patients with acute pancreatitis is not clear.The present study was to investigate the predictive significance of the CRP/albumin ratio for the prognosis and mortality in acute pancreatitis patients.METHODS:This study was performed retrospectively with 192 acute pancreatitis patients between January 2002 and June 2015.Ranson scores,Atlanta classification and CRP/albumin ratios of the patients were calculated.RESULTS:The CRP/albumin ratio was higher in deceased patients compared to survivors.The CRP/albumin ratio was positively correlated with Ranson score and Atlanta classification in particular and with important prognostic markers such as hospitalization time,CRP and erythrocyte sedimentation rate.In addition to the CRP/albumin ratio,necrotizing pancreatitis type,moderately severe and severe Atlanta classification,and total Ranson score were independent risk factors of mortality.It was found that an increase of 1 unit in the CRP/albumin ratio resulted in an increase of 1.52 times in mortality risk.A prediction value about CRP/albumin ratio >16.28 was found to be a significant marker in predicting mortality with 92.1% sensitivity and 58.0% specificity.It was seen that Ranson and Atlanta classification were higher in patients with CRP/albumin ratio >16.28 compared with those with CRP/albumin ratio ≤16.28.Patients with CRP/albumin ratio >16.28 had a 19.3 times higher chance of death.CONCLUSION:The CRP/albumin ratio is a novel but promising,easy-to-measure,repeatable,non-invasive inflammationbased prognostic score in acute pancreatitis.

C-reactive protein to albumin ratio predict responses to programmed cell death-1 inhibitors in hepatocellular carcinoma patients

BACKGROUND Over the years,programmed cell death-1(PD-1)inhibitors have been routinely used for hepatocellular carcinoma(HCC)treatment and yielded improved survival outcomes.Nonetheless,significant heterogeneity surrounds the outcomes of most studies.Therefore,it is critical to search for biomarkers that predict the efficacy of PD-1 inhibitors in patients with HCC.AIM To investigate the role of the C-reactive protein to albumin ratio(CAR)in evaluating the efficacy of PD-1 inhibitors for HCC.METHODS The clinical data of 160 patients with HCC treated with PD-1 inhibitors from January 2018 to November 2022 at the First Affiliated Hospital of Guangxi Medical University were retrospectively analyzed.RESULTS The optimal cut-off value for CAR based on progression-free survival(PFS)was determined to be 1.20 using x-tile software.Cox proportional risk model was used to determine the factors affecting prognosis.Eastern Cooperative Oncology Group performance status[hazard ratio(HR)=1.754,95%confidence interval(95%CI)=1.045-2.944,P=0.033],CAR(HR=2.118,95%CI=1.057-4.243,P=0.034)and tumor number(HR=2.932,95%CI=1.246-6.897,P=0.014)were independent prognostic factors for overall survival.CAR(HR=2.730,95%CI=1.502-4.961,P=0.001),tumor number(HR=1.584,95%CI=1.003-2.500,P=0.048)and neutrophil to lymphocyte ratio(HR=1.120,95%CI=1.022-1.228,P=0.015)were independent prognostic factors for PFS.Two nomograms were constructed based on independent prognostic factors.The C-index index and calibration plots confirmed that the nomogram is a reliable risk prediction tool.The ROC curve and decision curve analysis confirmed that the nomogram has a good predictive effect as well as a net clinical benefit.CONCLUSION Overall,we reveal that the CAR is a potential predictor of short-and long-term prognosis in patients with HCC treated with PD-1 inhibitors.If further verified,CAR-based nomogram may increase the number of markers that predict individualized prognosis.

Protein nanoparticles as potent delivery vehicles for polycytosine RNA-binding protein one

Ma et al recently reported in the World Journal of Diabetes that ferroptosis occurs in osteoblasts under high glucose conditions,reflecting diabetes pathology.This condition could be protected by the upregulation of the gene encoding polycytosine RNA-binding protein 1(PCBP1).Additionally,Ma et al used a lentivirus infection system to express PCBP1.As the authors’method of administration can be improved in terms of stability and cost,we propose delivering PCBP1 to treat type 2 diabetic osteoporosis by encapsulating it in protein nanoparticles.First,PCBP1 is small and druggable.Second,intravenous injection can help deliver PCBP1 across the mucosa while avoiding acid and enzyme-catalyzed degradation.Furthermore,incorporating PCBP1 into nanoparticles prevents its interaction with water or oxygen and protects PCBP1’s structure and activity.Notably,the safety of the protein materials and the industrialization techniques for large-scale production of protein nanoparticles must be comprehensively investigated before clinical application.

RGS4 promotes the progression of gastric cancer through the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition

BACKGROUND Regulator of G protein signaling(RGS)proteins participate in tumor formation and metastasis by acting on theα-subunit of heterotrimeric G proteins.The speci-fic effect of RGS,particularly RGS4,on the progression of gastric cancer(GC)is not yet clear.AIM To explore the role and underlying mechanisms of action of RGS4 in GC develop-ment.METHODS The prognostic significance of RGS4 in GC was analyzed using bioinformatics based public databases and verified by immunohistochemistry and quantitative polymerase chain reaction in 90 patients with GC.Function assays were employed to assess the carcinogenic impact of RGS4,and the mechanism of its possible influence was detected by western blot analysis.A nude mouse xenograft model was established to study the effects of RGS4 on GC growth in vitro.RESULTS RGS4 was highly expressed in GC tissues compared with matched adjacent normal tissues.Elevated RGS4 expression was correlated with increased tumor-node-metastasis stage,increased tumor grade as well as poorer overall survival in patients with GC.Cell experiments demonstrated that RGS4 knockdown suppressed GC cell proliferation,migration and invasion.Similarly,xenograft experiments confirmed that RGS4 silencing significantly inhibited tumor growth.Moreover,RGS4 knockdown resulted in reduced phosphorylation levels of focal adhesion kinase,phosphatidyl-inositol-3-kinase,and protein kinase B,decreased vimentin and N-cadherin,and elevated E-cadherin.CONCLUSION High RGS4 expression in GC indicates a worse prognosis and RGS4 is a prognostic marker.RGS4 influences tumor progression via the focal adhesion kinase/phosphatidyl-inositol-3-kinase/protein kinase B pathway and epithelial-mesenchymal transition.

Protein arginine methyltransferase-6 regulates heterogeneous nuclear ribonucleoprotein-F expression and is a potential target for the treatment of neuropathic pain

Protein arginine methyltransferase-6 participates in a range of biological functions,particularly RNA processing,transcription,chromatin remodeling,and endosomal trafficking.However,it remains unclear whether protein arginine methyl transferase-6 modifies neuropathic pain and,if so,what the mechanisms of this effect.In this study,protein arginine methyltransferase-6 expression levels and its effect on neuropathic pain were investigated in the spared nerve injury model,chronic constriction injury model and bone cancer pain model,using immunohistochemistry,western blotting,immunoprecipitation,and label-free proteomic analysis.The results showed that protein arginine methyltransferase-6 mostly co-localized withβ-tubulinⅢin the dorsal root ganglion,and that its expression decreased following spared nerve injury,chronic constriction injury and bone cancer pain.In addition,PRMT6 knockout(Prmt6~(-/-))mice exhibited pain hypersensitivity.Furthermore,the development of spared nerve injury-induced hypersensitivity to mechanical pain was attenuated by blocking the decrease in protein arginine methyltransferase-6 expression.Moreover,when protein arginine methyltransferase-6 expression was downregulated in the dorsal root ganglion in mice without spared nerve injury,increased levels of phosphorylated extracellular signal-regulated kinases were observed in the ipsilateral dorsal horn,and the response to mechanical stimuli was enhanced.Mechanistically,protein arginine methyltransferase-6 appeared to contribute to spared nerve injury-induced neuropathic pain by regulating the expression of heterogeneous nuclear ribonucleoprotein-F.Additionally,protein arginine methyltransfe rase-6-mediated modulation of hete rogeneous nuclear ribonucleoprotein-F expression required amino atids 319 to 388,but not classical H3R2 methylation.These findings indicated that protein arginine methyltransferase-6 is a potential therapeutic target fo r the treatment of peripheral neuro pathic pain.

Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway:a potential therapeutic approach for neurodegenerative diseases

The interaction between the gut microbiota and cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut–brain axis.The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites,which activates the vagus nerve and modulates the immune and neuroendocrine systems.Conversely,alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota,creating a dynamic network of microbial-host interactions.This reciprocal regulation affects neurodevelopment,neurotransmitter control,and behavioral traits,thus playing a role in the modulation of neurological diseases.The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation,mitochondrial dysfunction,abnormal energy metabolism,microglial activation,oxidative stress,and neurotransmitter release,which collectively influence the onset and progression of neurological diseases.This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway,along with its implications for potential therapeutic interventions in neurological diseases.Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders.This can be achieved through various methods such as dietary modifications,probiotic supplements,Chinese herbal extracts,combinations of Chinese herbs,and innovative dosage forms.These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

Application of myxovirus resistance protein A in the etiological diagnosis of infections in adults

BACKGROUND: Inappropriate antibiotic treatment for patients with viral infections has led to a surge in antimicrobial resistance, increasing mortality and healthcare costs. Viral and bacterial infections are often difficult to distinguish. Myxovirus resistance protein A(MxA), an essential antiviral factor induced by interferon after viral infection, holds promise for distinguishing between viral and bacterial infections. This study aimed to determine the ability of Mx A to distinguish viral from bacterial infections.METHODS: We quantified MxA in 121 infected patients via dry immunofluorescence chromatography. The Kruskal-Wallis test and receiver operating characteristic(ROC) curve analysis were used to determine the diagnostic value of Mx A, either alone or in combination with C-reactive protein(CRP) or procalcitonin(PCT), in patients with viral, bacterial, or co-infections.RESULTS: The value of MxA(ng/mL) was significantly higher in patients with viral infections than in those with bacterial and co-infections(82.3 [24.5–182.9] vs. 16.4 [10.8–26.5], P<0.0001)(82.3 [24.5–182.9] vs. 28.5 [10.2–106.8], P=0.0237). The area under the curve(AUC) of the ROC curve for distinguishing between viral and bacterial infections was 0.799(95% confidence interval [95% CI] 0.696–0.903), with a sensitivity of 68.9%(95% CI 54.3%–80.5%) and specificity of 90.0%(95% CI 74.4%–96.5%) at the threshold of 50.3 ng/mL. Combining the MxA level with the CRP or PCT level improved its ability. MxA expression was low in cytomegalovirus(15.8 [9.6–47.6] ng/mL) and Epstein-Barr virus(12.9 [8.5–21.0] ng/mL) infections.CONCLUSION: Our study showed the diagnostic efficacy of Mx A in distinguishing between viral and bacterial infections, with further enhancement when it was combined with CRP or PCT. Moreover, EpsteinBarr virus and human cytomegalovirus infections did not elicit elevated Mx A expression.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Regulation of Yield and Eating and Cooking Quality in Rice Through Seed Albumin OsRAL5

Seed storage proteins and their abundance are closely related to the formation of rice quality and grain size.A better understanding of the molecular basis of seed storage proteins will provide important information for developing new rice breeding strategies.In this study,we report that a seed storage protein albumin,named OsRAL5,positively regulates rice quality and grain size.OsRAL5 is specifically expressed during the grain-filling stage,suggesting its key role in regulating seed development.Gene editing of OsRAL5 using the CRISPR/Cas9 system diminished grain size and weight,resulting in the development of white-core endosperm and a reduction in eating and cooking quality(ECQ).Conversely,the endosperm appearance became transparent,and both grain weight and ECQ improved in the OsRAL5 over-expressed lines.The major seed storage components differed significantly between the OsRAL5-edited(dOsRAL5-TS)and OsRAL5-overexpressed(OsRAL5-OE)lines compared with the wild type.The protein and total lipid contents both decreased in the dOsRAL5-TS lines and increased in the OsRAL5-OE lines.Collectively,the over-expression of OsRAL5 significantly increased nutritional content and simultaneously improved yield and ECQ.These results imply that OsRAL5 might be a promising candidate gene for breeding super rice varieties with increased yield potential and superior quality.

AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice

The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.

Prognostic value of preoperative fibrinogen to albumin ratio in predicting postoperative outcomes in patients with gallbladder cancer

BACKGROUND Gallbladder cancer(GBC)is known for its poor prognosis and challenging management.The preoperative fibrinogen to albumin ratio(FAR)has been proposed as a potential prognostic marker for predicting postoperative outcomes in GBC patients,but its efficacy and prognostic value remain underexplored.AIM To evaluate the prognostic value of preoperative FAR in GBC outcomes.METHODS This retrospective cohort study included 66 patients who underwent curative surgery for GBC at our institution from January 2018 to January 2022.Preoperative FAR values were obtained within one week prior to surgery.Patients were followed through outpatient visits or telephone interviews,with overall survival(OS)as the primary endpoint.Statistical analyses,including receiver operating characteristic curve analysis and Kaplan-Meier survival estimates,were performed using SPSS software(version 27.0).RESULTS The cohort consisted of 36 male and 30 female patients,with a mean age of 61.81±8.58 years.The optimal FAR cut-off value was determined to be 0.088,with an area under the receiver operating characteristic curve of 0.7899,sensitivity of 68.96%,and specificity of 80.01%.Patients with FAR≤0.088 showed significantly better survival rates(1-year:60.5%,2-year:52.6%,3-year:25.9%)and a median OS of 25.6 months(95%confidence interval:18.8-30.5 months),compared to those with FAR>0.088 who had a median OS of 10.8 months(95%confidence interval:6.3-12.9 months).CONCLUSION Lower preoperative FAR is associated with longer OS in GBC patients,confirming its potential as a valuable prognostic indicator for improving outcome predictions and guiding patient management strategies in gallbladder cancer.

Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis,learning,and memory in a mouse model of Alzheimer’s disease

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.

AAV-mediated expression of p65shRNA and bone morphogenetic protein 4 synergistically enhances chondrocyte regeneration

BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene manipulation for the treatment of osteoarthritis may not produce satisfactory results.Previous studies have shown that nuclear factorκB could promote the inflammatory pathway in osteoarthritic chondrocytes,and bone morphogenetic protein 4(BMP4)could promote cartilage regeneration.OBJECTIVE:To test whether combined application of AAV-p65shRNA and AAV-BMP4 will yield the synergistic effect on chondrocytes regeneration and osteoarthritis treatment.METHODS:Viral particles containing AAV-p65-shRNA and AAV-BMP4 were prepared.Their efficacy in inhibiting inflammation in chondrocytes and promoting chondrogenesis was assessed in vitro and in vivo by transfecting AAV-p65-shRNA or AAV-BMP4 into cells.The experiments were divided into five groups:PBS group;osteoarthritis group;AAV-BMP4 group;AAV-p65shRNA group;and BMP4-p65shRNA 1:1 group.Samples were collected at 4,12,and 24 weeks postoperatively.Tissue staining,including safranin O and Alcian blue,was applied after collecting articular tissue.Then,the optimal ratio between the two types of transfected viral particles was further investigated to improve the chondrogenic potential of mixed cells in vivo.RESULTS AND CONCLUSION:The combined application of AAV-p65shRNA and AAV-BMP4 together showed a synergistic effect on cartilage regeneration and osteoarthritis treatment.Mixed cells transfected with AAV-p65shRNA and AAV-BMP4 at a 1:1 ratio produced the most extracellular matrix synthesis(P<0.05).In vivo results also revealed that the combination of the two viruses had the highest regenerative potential for osteoarthritic cartilage(P<0.05).In the present study,we also discovered that the combined therapy had the maximum effect when the two viruses were administered in equal proportions.Decreasing either p65shRNA or BMP4 transfected cells resulted in less collagen II synthesis.This implies that inhibiting inflammation by p65shRNA and promoting regeneration by BMP4 are equally important for osteoarthritis treatment.These findings provide a new strategy for the treatment of early osteoarthritis by simultaneously inhibiting cartilage inflammation and promoting cartilage repair.

Adenosine triphosphate-binding pocket inhibitor for mixed lineage kinase domain-like protein attenuated alcoholic liver disease via necroptosis-independent pathway

BACKGROUND Mixed lineage kinase domain-like protein(MLKL)serves as a critical mediator in necroptosis,a form of regulated cell death linked to various liver diseases.This study aims to specifically investigate the role of MLKL’s adenosine triphosphate(ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression.By focusing on this mechanism,we seek to identify potential therapeutic targets that can modulate MLKL activity,offering new strategies for the prevention and treatment of liver-related pathologies.AIM To investigate the possibility of using the ATP-binding pocket-associated,necro-ptosis-independent MLKL pathway as a target for liver diseases.METHODS Cell death following necroptosis stimuli was evaluated using cell proliferation assays,flow cytometry,and electron microscopy in various cells.The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation.Additionally,alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury.RESULTS While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells,it did reduce the necroptosis-led expression of CXCL2,ICAM,and VCAM.Notably,MLKL ATP pocket inhibitor diminishes the expression of CXCL2,ICAM,and VCAM by inhibiting the IκB kinase and nuclear factor kappa-B pathways without inducing necroptosis-induced cell death in two-dimensional cell culture as well as the human-derived liver organoid system.Although MLKL ATP-binding inhibitor was ineffective in non-alcoholic fatty liver disease animal models,MLKL ATP-binding inhibitor attenuated hepatic inflammation in the alcoholic liver disease model.CONCLUSION MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.

Accurate prediction of essential proteins using ensemble machine learning

Essential proteins are crucial for biological processes and can be identified through both experimental and computational methods.While experimental approaches are highly accurate,they often demand extensive time and resources.To address these challenges,we present a computational ensemble learning framework designed to identify essential proteins more efficiently.Our method begins by using node2vec to transform proteins in the protein–protein interaction(PPI)network into continuous,low-dimensional vectors.We also extract a range of features from protein sequences,including graph-theory-based,information-based,compositional,and physiochemical attributes.Additionally,we leverage deep learning techniques to analyze high-dimensional position-specific scoring matrices(PSSMs)and capture evolutionary information.We then combine these features for classification using various machine learning algorithms.To enhance performance,we integrate the outputs of these algorithms through ensemble methods such as voting,weighted averaging,and stacking.This approach effectively addresses data imbalances and improves both robustness and accuracy.Our ensemble learning framework achieves an AUC of 0.960 and an accuracy of 0.9252,outperforming other computational methods.These results demonstrate the effectiveness of our approach in accurately identifying essential proteins and highlight its superior feature extraction capabilities.

Protein tyrosine phosphatase nonreceptor 2:A New biomarker for digestive tract cancers

In this editorial,the roles of protein tyrosine phosphatase nonreceptor 2(PTPN2)in oncogenic transformation and tumor behavior and its potential as a therapeutic target in the context of gastrointestinal(GI)cancers are presented with respect to the article by Li et al published in ninth issue of the World Journal of Gastrointestinal Oncology.PTPN2 is a member of the protein tyrosine phosphatase family of signaling proteins that play crucial roles in the regulation of inflammation and immunity.Accordingly,early findings highlighted the contribution of PTPN2 to the pathogenesis of inflammatory and autoimmune disorders related to its dysfunction.On the other hand,recent studies have indicated that PTPN2 has many different roles in different cancer types,which is associated with the complexity of its regulatory network.PTPN2 dephosphorylates and inactivates EGFR,SRC family kinases,JAK1 and JAK3,and STAT1,STAT3,and STAT5 in cell type-and context-dependent manners,which indicates that PTPN2 can perform either prooncogenic or anti-oncogenic functions depending on the tumor subtype.While PTPN2 has been suggested as a potential therapeutic target in cancer treatment,to the best of ourknowledge,no clear treatment protocol has referred to PTPN2.Although there are only few studies that investigated PTPN2 expression in the GI system cancers,which is a potential limitation,the association of this protein with tumor behavior and the influence of PTPN2 on many therapy-related signaling pathways emphasize that PTPN2 could serve as a new molecular biomarker to predict tumor behavior and as a target for therapeutic intervention against GI cancers.In conclusion,more studies should be performed to better understand the prognostic and therapeutic potential of PTPN2 in GI tumors,especially in tumors resistant to therapy.

Unveiling expression patterns,mechanisms,and therapeutic opportunities of transmembrane protein 106C:From pan-cancers to hepatocellular carcinoma

BACKGROUND Although transmembrane protein 106C(TMEM106C)has been elucidated to be overexpressed in cancers,its underlying mechanisms have not yet been fully understood.AIM To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types,including liver hepatocellular carcinoma(LIHC).METHODS We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment.Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C.Chromatin immunoprecipitation followed by sequencing(ChIP-seq)analysis was conducted to identify upstream transcriptional regulators of TMEM106C.In LIHC,we examined mRNA profiles,performed in-house quantitative polymerase chain reaction,immunohistochemistry,and constructed a co-expression gene network.Functional assays,including cell counting kit-8,cell cycle,apoptosis,migration,and invasion,were conducted.The effect of nitidine chloride(NC)on LIHC xenograft was evaluated through RNA sequencing and molecular docking.Finally,potential therapeutic agents targeting TMEM106C were predicted.RESULTS TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types,including LIHC.Across pan-cancers,TMEM106C was inversely correlated to the abundances of immune and stromal cells.Furthermore,TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers.ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the TMEM106C gene in pan-cancers.Integrated analysis showed that TMEM106C was upregulated in 4657 LIHC compared with 3652 normal liver tissue[combined standardized mean difference=1.31(1.09,1.52)].Inhouse LIHC samples verified the expression status of TMEM106C.Higher TMEM106C expression signified worse survival conditions in LIHC patients treated with sorafenib,a tyrosine kinase inhibitor(TKI).Co-expressed analysis revealed that TMEM106C were significantly enriched in the cell cycle pathway.Knockout experiments demonstrated that TMEM106C plays a crucial role in LIHC cell proliferation,migration,and invasion,with cell cycle arrest occurring at the DNA synthesis phase,and increased apoptosis.Notably,TMEM106C upregulation was attenuated by NC treatment.Finally,TMEM106C expression levels were significantly correlated with the drug sensitivity of anti-hepatocellular carcinoma agents,including JNJ-42756493,a TKI agent.CONCLUSION Overexpressed TMEM106C was predicted as an oncogene in pan-cancers,which may serve as a promising therapeutic target for various cancers,including LIHC.Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC.Future research directions include in-depth experimental validation and exploration of TMEM106C’s role in other cancer types.

Severe upper gastrointestinal hemorrhage due to milk protein allergy: A case report

BACKGROUND Upper gastrointestinal hemorrhage is a life-threatening manifestation of cow’s milk protein allergy(CMPA).We analyze the clinical characteristics of a case of milk protein allergy manifested as severe upper gastrointestinal hemorrhage.CASE SUMMARY The hospital admitted a 2-month-old male infant due to“melena for 6 days,he-matemesis twice”.The main symptom was melena,initially occurring once or twice per day,then gradually increasing to five or six times per day at their peak.During the course of the illness,the infant vomited blood,but there were no re-ports of vomiting,fever,pale complexion,dyspnea,wheezing,or difficulty brea-thing.Laboratory tests showed hemoglobin level of 87 g/L,platelet count of 349×109/L,and eosinophil percentage of 0.031.Coagulation studies were normal.After avoiding certain foods and feeding with an amino acid formula for 2 weeks,a repeat gastroscopy revealed less bleeding.After six weeks,a positive oral food challenge test confirmed a severe CMPA.At the 4-month follow-up,there was no gastrointestinal bleeding,and the infant was growing and developing well.CONCLUSION The manifestations of milk protein allergy are diverse and nonspecific,with gas-trointestinal bleeding being less common,especially in infants.When infants present with unexplained massive hematemesis,it’s critical to investigate the possibility of CMPA.

Association between serum retinol-binding protein and lower limb atherosclerosis risk in type 2 diabetes mellitus

BACKGROUND Serum retinol-binding protein(RBP)is the primary transport protein of circulating vitamin A.RBP has a crucial role in maintaining nutrient metabolism and physiologic homeostasis.Several studies have indicated that serum RBP participates in the progression of diabetes and diabetes-related complications.However,the impact of serum RBP on lower limb atherosclerosis has not been determined in individuals with type 2 diabetes mellitus(T2DM).AIM To determine the association between serum RBP and lower limb atherosclerosis in individuals with T2DM.METHODS This retrospective study enrolled 4428 eligible T2DM patients and divided the patients into non-lower limb atherosclerosis(n=1913)and lower limb atherosclerosis groups(n=2515)based on lower limb arterial ultrasonography results.At hospital admission,baseline serum RBP levels were assessed,and all subjects were categorized into three groups(Q1-Q3)based on RBP tertiles.Logistic regression,restricted cubic spline regression,subgroup analysis,and machine learning were used to assess the association between RBP levels and lower limb atherosclerosis risk.RESULTS Among 4428 individuals with T2DM,2515(56.80%)had lower limb atherosclerosis.Logistic analysis showed that lower limb atherosclerosis risk increased by 1%for every 1 unit rise in serum RBP level(odds ratio=1.01,95%confidence interval:1.00-1.02,P=0.004).Patients in the highest tertile group(Q3)had a higher lower limb atherosclerosis risk compared to the lowest tertile group(Q1)(odds ratio=1.36,95%confidence interval:1.12-1.67,P=0.002).The lower limb atherosclerosis risk gradually increased with an increase in RBP tertile(P for trend=0.005).Restricted cubic spline analysis indicated a linear correlation between serum RBP levels and lower limb atherosclerosis risk(non-linear P<0.05).Machine learning demonstrated the significance and diagnostic value of serum RBP in predicting lower limb atherosclerosis risk.CONCLUSION Elevated serum RBP levels correlate with an increased lower limb atherosclerosis risk in individuals with T2DM.