Objective To investigate the clinical characteristics of colorectal polyps in patients with melanosis coli(MC),analyze the recurrence risk after polypectomy,and construct a prediction model for polyp recurrence.Methods A total of 1,763 patients who underwent colorectal polypec-tomy at the First Hospital of Handan from January 2017 to June 2023 were divided into MC group(n=149)and non-MC group(n=1,614).Among them,122 patients in the MC group underwent colonoscopic re-examination one year later and were further divided into recurrence group(n=52)and non-recurrence group(n=70)based on polyp recurrence.The characteristics of colorectal polyps and recurrence risk after polypectomy in MC patients were analyzed.A multivariable Logistic regression analysis was used to construct a polyp recurrence risk model,and the nomogram model was plotted using R studio software.The receiver operating characteristic(ROC)curve,calibration curve,and decision curve analysis were employed to evaluate the discrimination,calibration,and clinical practicality of the model.Results The detection rates of large polyps(≥1.0 cm),right-sided colon polyps,multiple polyps(≥3 polyps),and Yamada type Ⅰ polyps in the MC group were significantly higher than those in the non-MC group,while the detection rates of left-sided co-lon polyps and Yamada type Ⅳ polyps were significantly lower(P＜0.05).The detection rates of adenomatous polyps and polyps with mild dysplasia in the MC group were significantly higher than those in the non-MC group,whereas the detection rate of polyps with moderate dysplasia in the MC group was significantly lower(P＜0.05).Significant differences were observed between the recur-rence and non-recurrence groups in terms of a history of cholecystectomy,Helicobacter pylori(Hp)in-fection,and family history of colorectal cancer(P＜0.05).There were also significant differences in the distribution,size,and the number of initial polyps between the two groups(P＜0.05).Multivari-able Logistic regression analysis identified cholecystectomy,Hp infection,first-degree relatives with colorectal cancer,polyp size(≥1 cm),and multiple polyps(≥3 polyps)as independent risk factors for polyp recurrence after polypectomy(P＜0.05).Based on these factors,a recurrence prediction model was constructed.The area under the curve(AUC)of this model was 0.824(95％CI,0.753 to 0.895),indicating good discrimination.The calibration curve showed a good fit.Decision curve anal-ysis demonstrated a high net benefit within the threshold range of 0.1 to 0.8,suggesting that the mod-el had a wide range of beneficial thresholds and clinical practical value.Conclusion Compared with the non-MC group,the MC group has higher detection rates of large polyps,right-sided colon pol-yps,multiple polyps,Yamada type Ⅰ polyps,adenomatous polyps,and polyps with low-grade dys-plasia,but lower detection rates of left-sided colon polyps,Yamada type Ⅳ polyps,and polyps with moderate dysplasia.Cholecystectomy,Hp infection,first-degree relatives with colorectal cancer,large polyps(≥1 cm),and multiple polyps(≥3 polyps)are independent risk factors for polyp re-currence after colorectal polypectomy in MC patients.The recurrence prediction model constructed based on these factors has high practical value.

Objective To identify risk factors for colorectal adenomatous polyps using logistic regression analysis,construct a prediction model based on these identified factors,and subsequently evaluate the performance of the model.Methods Encompassed 1,023 patients who underwent large intestine polyp resection at the First Hospital of Handan between January 2017 and January 2022.Among these patients,676 had adenomatous polyps(adenomatous polyp group)and 347 had non-adenomatous polyps(non-adenomatous polyp group).We collected data on basic information,medical history,colonoscopy results,and polyp pathology.By comparing the two groups,we identified significant differences in various indicators,which were selected as candidate factors for model construction.Patients were randomly divided into a training set and a validation set at an 8∶2 ratio.Using the training set data,we constructed a risk prediction model and developed a nomogram using R Studio software to visually present the model.Finally,we internally validated the model using the validation set.The model's discrimination ability was evaluated using the ROC curve,its accuracy was assessed via the calibration curve,and its clinical utility was evaluated through decision curve analysis(DCA).Results Significant differences were observed between the two groups in terms of age,drinking habits,family history of colorectal cancer,hyperlipid-emia,history of cholecystectomy,HP infection,and history of appendectomy(P<0.05).These variables were included in the model construction.A total of 818 participants were randomly assigned to the training set,while 205 were allocated to the validation set.Multivariate logistic regression analysis on the training set confirmed that age(OR=1.021,95%CI:1.006～1.036,P=0.006),alcohol consumption(OR=3.440,95%CI:2.251～5.257,P<0.001),first-degree relatives with colorectal cancer(OR=3.775,95%CI:1.881～7.577,P<0.001),hyperlipidemia(OR=3.428,95%CI:2.443～4.808,P<0.001),history of cholecystectomy(OR=3.916,95%CI:1.756～8.735,P<0.001),Helicobacter pylori(HP)infection(OR=3.292,95%CI:2.309～4.693,P<0.001),and history of appendectomy(OR=3.819,95%CI:2.002～7.286,P<0.001)were independent risk factors for adenomatous polyps.Consequently,a prediction model for large intestine adenomatous polyps was developed using the formula P=1/(1+e-Y),where Y=0.020×age+1.328×first-degree relatives with colorectal cancer+1.235×alcohol consumption+1.232×hyperlipidemia+1.365×cholecystectomy+1.192×HP infection+1.340×appendectomy-1.995.The model demonstrated good performance with AUC values of 0.763(95%CI:0.729～0.797)for the training set and 0.769(95%CI:0.644～0.787)for the validation set.The calibration curve indicated a good fit,and decision curve analysis showed that the model could achieve positive net benefit across a wide range of threshold probabilities,confirming its clinical utility.Conclusions Age,alcohol consumption,a family history of colorectal cancer in first-degree relatives,hyperlipidemia,cholecystectomy,HP infection,and appendectomy were identified as independent risk factors for adenomatous polyps.A prediction model incorporating these risk factors holds significant practical value for predicting the occurrence of colorectal adenomatous polyps.

Objective To identify risk factors for colorectal adenomatous polyps using logistic regression analysis,construct a prediction model based on these identified factors,and subsequently evaluate the performance of the model.Methods Encompassed 1,023 patients who underwent large intestine polyp resection at the First Hospital of Handan between January 2017 and January 2022.Among these patients,676 had adenomatous polyps(adenomatous polyp group)and 347 had non-adenomatous polyps(non-adenomatous polyp group).We collected data on basic information,medical history,colonoscopy results,and polyp pathology.By comparing the two groups,we identified significant differences in various indicators,which were selected as candidate factors for model construction.Patients were randomly divided into a training set and a validation set at an 8∶2 ratio.Using the training set data,we constructed a risk prediction model and developed a nomogram using R Studio software to visually present the model.Finally,we internally validated the model using the validation set.The model's discrimination ability was evaluated using the ROC curve,its accuracy was assessed via the calibration curve,and its clinical utility was evaluated through decision curve analysis(DCA).Results Significant differences were observed between the two groups in terms of age,drinking habits,family history of colorectal cancer,hyperlipid-emia,history of cholecystectomy,HP infection,and history of appendectomy(P<0.05).These variables were included in the model construction.A total of 818 participants were randomly assigned to the training set,while 205 were allocated to the validation set.Multivariate logistic regression analysis on the training set confirmed that age(OR=1.021,95%CI:1.006～1.036,P=0.006),alcohol consumption(OR=3.440,95%CI:2.251～5.257,P<0.001),first-degree relatives with colorectal cancer(OR=3.775,95%CI:1.881～7.577,P<0.001),hyperlipidemia(OR=3.428,95%CI:2.443～4.808,P<0.001),history of cholecystectomy(OR=3.916,95%CI:1.756～8.735,P<0.001),Helicobacter pylori(HP)infection(OR=3.292,95%CI:2.309～4.693,P<0.001),and history of appendectomy(OR=3.819,95%CI:2.002～7.286,P<0.001)were independent risk factors for adenomatous polyps.Consequently,a prediction model for large intestine adenomatous polyps was developed using the formula P=1/(1+e-Y),where Y=0.020×age+1.328×first-degree relatives with colorectal cancer+1.235×alcohol consumption+1.232×hyperlipidemia+1.365×cholecystectomy+1.192×HP infection+1.340×appendectomy-1.995.The model demonstrated good performance with AUC values of 0.763(95%CI:0.729～0.797)for the training set and 0.769(95%CI:0.644～0.787)for the validation set.The calibration curve indicated a good fit,and decision curve analysis showed that the model could achieve positive net benefit across a wide range of threshold probabilities,confirming its clinical utility.Conclusions Age,alcohol consumption,a family history of colorectal cancer in first-degree relatives,hyperlipidemia,cholecystectomy,HP infection,and appendectomy were identified as independent risk factors for adenomatous polyps.A prediction model incorporating these risk factors holds significant practical value for predicting the occurrence of colorectal adenomatous polyps.

OBJECTIVE To investigate the biodistribution of lipid nanoparticles(LNPs)with different surface charges and different particle sizes in mice.METHODS LNPs were prepared using microfluidic technology by incorporating positively charged phospholipids,negatively charged phospholipids,ioniz-able phospholipids,and neutral phospholipids into the formulation to create LNPs with corresponding surface charges.The particle size of the LNPs was controlled by polyethylene glycol(PEG)modifica-tion and measured using dynamic light scattering(DLS)and transmission electron microscopy(TEM),while the surface charge was analyzed using a zeta potential analyzer.The LNPs were labeled with a fluorescent dye,and the mice were intravenously injected with 0.625 μmol·kg-1 of LNPs.At 1,4,12 and 24 h post-injection,the brain,heart,livers,spleen,lungs and kidneys were collected.The fluorescence distribution in different organs was detected using an in vivo imaging system to reflect the distribution of LNPs in various organs.RESULTS Particle size analysis showed that,except the ionizable lipid nanoparticles without PEG modification(LNP-MC3),which had a particle size>200 nm,the particle sizes of positively charged LNPs without PEG modification(LNP-Pos),PEG-modified positively charged LNPs(LNP-Pos-P),PEG-modified neutral LNPs(LNP-Neu-P),PEG-modified ionizable LNPs(LNP-MC3-P),and PEG-modified negatively charged LNPs(LNP-Neg-P)were all<200 nm.Zeta potential analysis revealed that the surface charges of the LNPs were the highest in LNP-Pos,followed by LNP-Pos-P,LNP-MC3-P,LNP-Neu-P,LNP-MC3 and LNP-Neg-P.In vivo imaging results indicated that LNP-Pos-P,LNP-Pos and LNP-MC3-P were primarily distributed in the livers,lungs and kidneys,respectively,while LNP-Neu-P and LNP-Neg-P in the livers,kidneys,and lungs,respectively.The distribution of LNP-MC3-P in the brain,heart,spleen and kidneys peaked at 12 h post-injection,but at 24 h in the livers.The distribution of LNP-Pos-P in the lungs peaked at 1 h post-injection.CONCLUSION LNPs are primarily distributed in the livers.Surface charges influence the second most highly-distributed organs.LNP-Pos-P and LNP-MC3-P are the second most highly-distributed in the lungs,and LNP-Neu-P and LNP-Neg-P in the kidneys.

OBJECTIVE To investigate the biodistribution of lipid nanoparticles(LNPs)with different surface charges and different particle sizes in mice.METHODS LNPs were prepared using microfluidic technology by incorporating positively charged phospholipids,negatively charged phospholipids,ioniz-able phospholipids,and neutral phospholipids into the formulation to create LNPs with corresponding surface charges.The particle size of the LNPs was controlled by polyethylene glycol(PEG)modifica-tion and measured using dynamic light scattering(DLS)and transmission electron microscopy(TEM),while the surface charge was analyzed using a zeta potential analyzer.The LNPs were labeled with a fluorescent dye,and the mice were intravenously injected with 0.625 μmol·kg-1 of LNPs.At 1,4,12 and 24 h post-injection,the brain,heart,livers,spleen,lungs and kidneys were collected.The fluorescence distribution in different organs was detected using an in vivo imaging system to reflect the distribution of LNPs in various organs.RESULTS Particle size analysis showed that,except the ionizable lipid nanoparticles without PEG modification(LNP-MC3),which had a particle size>200 nm,the particle sizes of positively charged LNPs without PEG modification(LNP-Pos),PEG-modified positively charged LNPs(LNP-Pos-P),PEG-modified neutral LNPs(LNP-Neu-P),PEG-modified ionizable LNPs(LNP-MC3-P),and PEG-modified negatively charged LNPs(LNP-Neg-P)were all<200 nm.Zeta potential analysis revealed that the surface charges of the LNPs were the highest in LNP-Pos,followed by LNP-Pos-P,LNP-MC3-P,LNP-Neu-P,LNP-MC3 and LNP-Neg-P.In vivo imaging results indicated that LNP-Pos-P,LNP-Pos and LNP-MC3-P were primarily distributed in the livers,lungs and kidneys,respectively,while LNP-Neu-P and LNP-Neg-P in the livers,kidneys,and lungs,respectively.The distribution of LNP-MC3-P in the brain,heart,spleen and kidneys peaked at 12 h post-injection,but at 24 h in the livers.The distribution of LNP-Pos-P in the lungs peaked at 1 h post-injection.CONCLUSION LNPs are primarily distributed in the livers.Surface charges influence the second most highly-distributed organs.LNP-Pos-P and LNP-MC3-P are the second most highly-distributed in the lungs,and LNP-Neu-P and LNP-Neg-P in the kidneys.

Conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family proteins leads to the accumulation of 5hmC in the central nervous system; however, the role of 5hmC in the postnatal brain and how its levels and target genes are regulated by TETs remain elusive. We have generated mice that lack all three Tet genes specifically in postnatal excitatory neurons. These mice exhibit significantly reduced 5hmC levels, altered dendritic spine morphology within brain regions crucial for cognition, and substantially impaired spatial and associative memories. Transcriptome profiling combined with epigenetic mapping reveals that a subset of genes, which display changes in both 5hmC/5mC levels and expression patterns, are involved in synapse-related functions. Our findings provide insight into the role of postnatally accumulated 5hmC in the mouse brain and underscore the impact of 5hmC modification on the expression of genes essential for synapse development and function.
Animals ; Brain/growth & development* ; 5-Methylcytosine/metabolism* ; Mice ; Synapses/genetics* ; Proto-Oncogene Proteins/metabolism* ; DNA-Binding Proteins/metabolism* ; Dioxygenases/metabolism* ; Cognition/physiology* ; Gene Expression ; Mixed Function Oxygenases/metabolism* ; Epigenesis, Genetic ; Mice, Knockout ; Mice, Inbred C57BL

To explore the mechanism by which vinegar-processed Euphorbiae Pekinensis Radix regulates gut microbiota and reduces intestinal toxicity, this study aimed to identify key microbial communities related to vinegar-induced detoxification and verify their functions. Using a derivatization method, the study measured the content of short-chain fatty acids(SCFAs) in feces before and after vinegar-processing of Euphorbiae Pekinensis Radix. Combined with the results of previous gut microbiota sequencing, correlation analysis was used to identify key microbial communities related to SCFAs content. Through single-bacterium transplantation experiments, the role of key microbial communities in regulating SCFAs metabolism and alleviating the intestinal toxicity of Euphorbiae Pekinensis Radix was clarified. Fecal extracts were then added to a co-culture system of Caco-2 and RAW264.7 cells, and toxicity differences were evaluated using intestinal tight junction proteins and inflammatory factors as indicators. Additionally, the application of a SCFAs receptor blocker helped confirm the role of SCFAs in reducing intestinal toxicity during vinegar-processing of Euphorbiae Pekinensis Radix. The results of this study indicated that vinegar-processing of Euphorbiae Pekinensis Radix improved the decline in SCFAs content caused by the raw material. Correlation analysis revealed that Bifidobacterium was positively correlated with the levels of acetic acid, propionic acid, isobutyric acid, n-butyric acid, isovaleric acid, and n-valeric acid. RESULTS:: from single-bacterium transplantation experiments demonstrated that Bifidobacterium could mitigate the reduction in SCFAs content induced by raw Euphorbiae Pekinensis Radix, enhance the expression of tight junction proteins, and reduce intestinal inflammation. Similarly, cell experiment results confirmed that fecal extracts from Bifidobacterium-transplanted mice alleviated inflammation and increased the expression of tight junction proteins in intestinal epithelial cells. The use of the free fatty acid receptor-2 inhibitor GLPG0974 verified that this improvement effect was related to the SCFAs pathway. This study demonstrates that Bifidobacterium is the key microbial community responsible for reducing intestinal toxicity in vinegar-processed Euphorbiae Pekinensis Radix. Vinegar-processing increases the abundance of Bifidobacterium, elevates the intestinal SCFAs content, inhibits intestinal inflammation, and enhances the expression of tight junction proteins, thereby improving the intestinal toxicity of Euphorbiae Pekinensis Radix.
Animals ; Mice ; Humans ; Acetic Acid/chemistry* ; Gastrointestinal Microbiome/drug effects* ; Fatty Acids, Volatile/metabolism* ; Bifidobacterium/genetics* ; Caco-2 Cells ; Intestines/microbiology* ; Drugs, Chinese Herbal/chemistry* ; Euphorbia/toxicity* ; RAW 264.7 Cells ; Male ; Feces/chemistry* ; Intestinal Mucosa/drug effects*

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

Aim To investigate the effect of overexpression of silent information regulator 1 (Sirtl) on cardiac function in mice with myocardial ischemia. Methods Myocardial specific Sirtl overexpression transgenic mice (Sirtl-Tg) and littermate control mice (C57BL/6J), half male and half female, were randomly divided into control sham operation group (Con), control model group (Con +ISO), Sirtl overexpression sham operation group (Sirtl-Tg) and Sirtl overexpression model group (Sirtl-Tg + ISO). Isoproterenol (ISO) was injected subcutaneously into the back of the neck at 100 mg • kg

OBJECTIVE: To observe the effect of Tongdu Tiaoshen (promoting the circulation of the governor vessel and regulating the spirit) electroacupuncture (EA) pretreatment on pyroptosis mediated by peroxisome proliferators-activated receptor γ (PPARγ) of the cerebral cortex in rats with cerebral ischemia reperfusion injury (CIRI) and explore the potential mechanism of EA for the prevention and treatment of CIRI. METHODS: A total of 110 clean-grade male SD rats were randomly divided into a sham-operation group, a model group, an EA group, an EA + inhibitor group and an agonist group, 22 rats in each group. In the EA group, before modeling, EA was applied to "Baihui" (GV 20), "Fengfu" (GV 16) and "Dazhui" (GV 14), with disperse-dense wave, 2 Hz/5 Hz in frequency, 1 to 2 mA in intensity, lasting 20 min; once a day, consecutively for 7 days. On the base of the intervention as the EA group, on the day 7, the intraperitoneal injection with the PPARγ inhibitor, GW9662 (10 mg/kg) was delivered in the EA + inhibitor group. In the agonist group, on the day 7, the PPARγ agonist, pioglitazone hydrochloride (10 mg/kg) was injected intraperitoneally. At the end of intervention, except the sham-operation group, the modified thread embolization method was adopted to establish the right CIRI model in the rats of the other groups. Using the score of the modified neurological severity score (mNSS), the neurological defect condition of rats was evaluated. TTC staining was adopted to detect the relative cerebral infarction volume of rat, TUNEL staining was used to detect apoptosis of cerebral cortical nerve cells and the transmission electron microscope was used to observe pyroptosis of cerebral cortical neural cells. The positive expression of PPARγ and nucleotide-binding to oligomerization domain-like receptor protein 3 (NLRP3) in the cerebral cortex was detected with the immunofluorescence staining. The protein expression of PPARγ, NLRP3, cysteinyl aspartate specific protease-1 (caspase-1), gasdermin D (GSDMD) and GSDMD-N terminal (GSDMD-N) in the cerebral cortex was detected with Western blot. Using the quantitative real-time fluorescence-PCR, the mRNA expression of PPARγ, NLRP3, caspase-1 and GSDMD of the cerebral cortex was detected. The contents of interleukin (IL)-1β and IL-18 in the cerebral cortex of rats were determined by ELISA. RESULTS: Compared with the sham-operation group, the mNSS, the relative cerebral infarction volume and the TUNEL positive cells rate were increased (P<0.01), pyroptosis was severe, the protein and mRNA expression levels of PPARγ, NLRP3, caspase-1 and GSDMD were elevated (P<0.01); and the protein expression of GSDMD-N and contents of IL-1β and IL-18 were increased (P<0.01) in the model group. When compared with the model group, the mNSS, the relative cerebral infarction volume and the TUNEL positive cells rate were decreased (P<0.01), pyroptosis was alleviated, the protein and mRNA expression levels of PPARγ were increased (P<0.01), the protein and mRNA expression levels of NLRP3, caspase-1 and GSDMD were decreased (P<0.01), the protein expression of GSDMD-N was reduced (P<0.01); and the contents of IL-1β and IL-18 were lower (P<0.01) in the EA group and the agonist group; while, in the EA + inhibitor group, the protein expression of PPARγ was increased (P<0.01), the protein and mRNA expression levels of NLRP3 and GSDMD were decreased (P<0.01, P<0.05), the mRNA expression of caspase-1 was reduced (P<0.01); and the contents of IL-1β and IL-18 were lower (P<0.01). When compared with the EA + inhibitor group, the mNSS, the relative cerebral infarction volume and the TUNEL positive cells rate were decreased (P<0.05, P<0.01), pyroptosis was alleviated, the protein and mRNA expression levels of PPARγ were increased (P<0.01), the protein and mRNA expression levels of NLRP3, caspase-1 and GSDMD were decreased (P<0.01), the protein expression of GSDMD-N was reduced (P<0.01); and the contents of IL-1β and IL-18 were declined (P<0.01) in the EA group. Compared with the agonist group, in the EA group, the relative cerebral infarction volume and the TUNEL positive cells rate were increased (P<0.05, P<0.01), the mRNA expression of PPARγ was decreased (P<0.01) and the protein expression of GSDMD-N was elevated (P<0.05); and the contents of IL-1β and IL-18 were higher (P<0.01). CONCLUSION Tongdu Tiaoshen EA pretreatment can attenuate the neurological impairment in the rats with CIRI, and the underlying mechanism is related to the up-regulation of PPARγ inducing the inhibition of NLRP3 in the cerebral cortex of rats so that pyroptosis is affected.
Male ; Animals ; Rats ; Rats, Sprague-Dawley ; PPAR gamma/genetics* ; Pyroptosis ; Interleukin-18 ; Electroacupuncture ; NLR Family, Pyrin Domain-Containing 3 Protein ; Cerebral Cortex ; Cerebral Infarction/therapy* ; Caspases ; RNA, Messenger