Colorectal cancer(CRC)is a common malignancy of the digestive system,with increasing morbidity and mortality worldwide.The standard treatment for CRC has,in the past,been surgery,chemotherapy,and radiotherapy.However,these treatments have significant side effects and are particularly challenging for patients with advanced metastatic CRC(mCRC).Therefore,it is crucial to explore alternative and more effective treatments.In recent years,with the development of molecular technology,numerous biomarkers have been identified,and targeted therapy and immunotherapy have achieved surprisingly positive results in the treatment of mCRC.Patients receiving targeted ther-apy and immunotherapy have an improved prognosis and quality of life.On this basis,this article reviews the latest research progress in tar-geted therapy and immunotherapy for mCRC,providing a reference for precision treatment of mCRC.

Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor agents a research hotspot.In this study,artificial intelligence(AI)technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline,which combined Voting strategy based on compound-protein interaction(CPI)prediction models,cascade molecular docking,and molecular dynamic(MD)simulations.The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays.Among the identified compounds,Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity(IC50=5.41 nM)than that of tubastatin A(TubA)(IC50=15.11 nM),along with a favorable subtype selectivity profile(selectivity index ≈ 117.23 for HDAC1),which was further verified by the Western blot analysis.Additionally,Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells,exerting desirable antiproliferative activity(IC50=2.59 μM).Furthermore,based on long-term MD simulation trajectory,the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis,thereby elucidating its binding mechanism.Moreover,the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation,thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

The focus of green analytical chemistry(GAC)is to minimize the negative impacts of analytical pro-cedures on human safety,human health,and the environment.Several factors,such as the reagents used,sample collection,sample processing,instruments,energy consumed,and the quantities of hazardous materials and waste generated during analytical procedures,need to be considered in the evaluation of the greenness of analytical assays.In this study,we propose a greenness evaluation metric for analytical methods(GEMAM).The new greenness metric is simple,flexible,and comprehensive.The evaluation criteria are based on both the 12 principles of GAC(SIGNIFICANCE)and the 10 factors of sample prep-aration,and the results are presented on a 0-10 scale.The GEMAM calculation process is easy to perform,and its results are easy to interpret.The output of GEMAM is a pictogram that can provide both qualitative and quantitative information based on color and number.

Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the"therapeutic module"of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Colorectal cancer(CRC)is a common malignancy of the digestive system,with increasing morbidity and mortality worldwide.The standard treatment for CRC has,in the past,been surgery,chemotherapy,and radiotherapy.However,these treatments have significant side effects and are particularly challenging for patients with advanced metastatic CRC(mCRC).Therefore,it is crucial to explore alternative and more effective treatments.In recent years,with the development of molecular technology,numerous biomarkers have been identified,and targeted therapy and immunotherapy have achieved surprisingly positive results in the treatment of mCRC.Patients receiving targeted ther-apy and immunotherapy have an improved prognosis and quality of life.On this basis,this article reviews the latest research progress in tar-geted therapy and immunotherapy for mCRC,providing a reference for precision treatment of mCRC.

OBJECTIVE To investigate the expression levels of nucleotide-binding oligomerization domain-like recep-tor pyrin domain-associated protein 3(NLRP3)inflammasome pathway and toll-like receptors(TLRs)pathway in serofast patients with syphilis infection,and their correlation with helper T lymphocytes(Th)1/Th2.METHODS A total of 549 patients with syphilis admitted to Tianjin Chest Hospital and Tianjin Medical University General Hospital from Jan.2021 to Dec.2022 were selected.Among them,62 patients who had not received anti-syphilis treatment were assigned to the syphilis group,238 patients whose serum remained positive after anti-syphilis treatment were selected as the fixed group,249 patients whose serum turned negative after anti-syphilis treatment were selected as the negative conversion group,and another 565 healthy people who underwent medical examina-tion in the hospital during the same period were selected as the control group.TLR2,TLR4,nuclear factor(NF)-κB,NLRP3,apoptosis-associated speck-like protein(ASC),cysteinyl aspartate proteolytic enzyme 1(Caspase-1),in-terleukin(IL)-1β mRNA and interferon-γ(IFN-γ),IL-12,IL-13 and IL-10 levels were compared between each group.Pearson's analysis was used to analyze the correlation between the mRNA expression of TLR2,TLR4,NF-κB,NLRP3,ASC,Caspase-1,and IL-1β and the levels of IFN-γ,IL-12,IL-13,and IL-10 in serologically fixed patients with syphilis.RESULTS Compared with the control group,the mRNA expression of TLR2,TLR4,NF-κB,NLRP3,ASC,Caspase-1 and IL-1β was elevated in the negative conversion and the syphilis groups,and the expres-sion of the above indicators was decreased in the fixed group(P＜0.05).Compared with negative conversion group,mR-NA expressions of TLR2,TLR4,NF-κB,NLRP3,ASC,Caspase-1 and IL-1β were increased in syphilis group,while the expression of the above indicators was decreased in fixed group(P＜0.05).Compared with fixed group,mRNA ex-pressions of TLR2,TLR4,NF-κB,NLRP3,ASC,Caspase-1 and IL-1β in syphilis group were increased in the syphilis group(P＜0.05).Compared with the control group,IFN-γ and IL-12 levels were decreased in the negative conversion group,syphilis group and fixed group,and IL-13 and IL-10 levels were increased(P＜0.05).Compared with the nega-tive conversion group,IFN-γ and IL-12 levels in the syphilis group and fixed group were decreased,while IL-13 and IL-10 levels were increased(P＜0.05).Compared with the fixed group,the levels of IFN-γ and IL-12 in syphilis group were increased,while the levels of IL-13 and IL-10 were decreased(P＜0.05).The mRNA levels of TLR2,TLR4,NF-κB,NLRP3,ASC,Caspase-1 and IL-1β were positively correlated with the levels of IFN-γ and IL-12 in serum fixed patients with syphilis infection(r=0.698,0.602,0.636,0.702,0.645,0.617,0.583 and 0.669,and 0.693,0.641,0.702,0.623,0.618 and 0.647,respectively,all P＜0.05),and negatively correlated with the levels of IL-13 and IL-10(r=-0.639,-0.705,-0.614,-0.590,-0.598,-0.651 and-0.628,and-0.704,-0.649,-0.606,-0.655,-0.650,-0.641 and-0.539,respectively,all P＜0.05).CONCLUSION The NLRP3 inflammasome pathway and TLRs pathway are abnormally expressed in sero-fast patients with syphilis infection,positively correlated with the expression of Th1 cytokines IFN-γ and IL-12,and negatively correlated with the expression of Th2 cytokines IL-13 and IL-10.

Objective To investigate the clinical efficacy of Jia Yi Formula(composed of Trionycis Carapax,Ranunculi Ternati Radix,Pinelliae Rhizoma Praeparatum,Trichosanthis Pericarpium,Poria,Curcumae Radix,Fritillariae Thunbergii Bulbus,and Albiziae Cortex)in improving anxiety symptoms of patients with hyperthyroidism(HT).Methods A total of 84 HT patients with yin deficiency with internal heat and phlegm blended with stasis syndrome accompanied by anxiety were enrolled from the Endocrinology Outpatient and Inpatient Departments of The Affiliated Guangzhou Traditional Chinese Medicine Hospital of Guangzhou University of Chinese Medicine between February and December of 2024.Patients were randomly divided into treatment group and control group(n=42 each)using a random number table.Both groups received conventional therapy,while the control group additionally received oral methimazole,and the treatment group received Jia Yi Formula and methimazole.The treatment duration was 12 weeks for both groups.Changes in Hamilton Anxiety Scale(HAMA)scores,traditional Chinese medicine(TCM)syndrome scores,and serum thyroid hormone levels[free triiodothyronine(FT3),free thyroxine(FT4),and thyroid-stimulating hormone(TSH)]were observed.The improvement in anxiety status,TCM syndrome efficacy,and drug safety were evaluated.Results(1)In terms of TCM syndrome improvement,the total effective rate was 92.86％(39/42)in the treatment group versus 71.43％(30/42)in the control group.Intergroup comparison(by Mann-Whitney U test)showed that the TCM syndrome improvement in the treatment group was superior to the control group(P＜0.05).(2)For anxiety improvement,the total effective rate was 83.33％(38/42)in the treatment group versus 69.05％(29/42)in the control group.Intergroup comparison(by Mann-Whitney U test)showed that the anxiety improvement in the treatment group was superior to the control group(P＜0.01).(3)After treatment,both groups showed significant reductions in HAMA scores and TCM syndrome scores(P＜0.01),with greater reductions observed in the treatment group(P＜0.01).(4)Thyroid hormone levels(FT3,FT4,TSH)were significantly improved in both groups(P＜0.01),with FT3 and TSH showing greater improvement in the treatment group(P＜0.05 or P＜0.01),while FT4 improvement did not differ significantly between groups(P＞0.05).(5)The incidence of adverse reactions was 4.76％(2/42)in the treatment group and 7.14％(3/42)in the control group.Intergroup comparison(by Fisher's exact test)showed that the difference was not statistically significant(P＞0.05).Conclusion Jia Yi Formula demonstrates significant efficacy in improving anxiety,clinical symptoms,and thyroid function in HT patients with yin deficiency with internal heat and phlegm blended with stasis syndrome,showing superior benefits when used together with methimazole compared to methimazole alone.

Objective To design a tabletop exercise teaching toolkit for emergency rescue training for mass wounded at sea.Methods Guided by the competency-based education(CBE)theory,a preliminary tabletop exercise teaching toolkit was constructed by combining field research and literature analysis.The toolkit was tested and modified through expert meetings.Results A set of tabletop exercise teaching toolkit including tabletop exercise scheme,casualty pool,teaching aids and teaching evaluation tools was formed.Conclusion The tabletop exercise teaching toolkit developed in this study can be used for the training of medical personnels on large surface warships,and it provides new ideas for our military medical training.

Objective:To explore risk factors for delayed onset of lactogenesis in prenatally overweight women and construct risk prediction models based on machine learning for early identification of high-risk individuals.Methods:Convenience sampling was adopted to select 338 prenatally overweight women who delivered in the Obstetrics Departments of four ClassⅢ Grade A hospitals in Hengyang City from October 2023 to June 2024 for the study. Delivery women were randomly divided into training set and test set in the ratio of 7∶3. The survey was conducted with the General Information Questionnaire, Breastfeeding Self-efficacy Scale Short Form, Edinburgh Postnatal Depression Scale, LATCH Scale and Pittsburgh Sleep Quality Index. One-way analysis and LASSO regression were used to screen predictors using delayed onset of lactogenesis as the outcome variable. Risk prediction models were constructed based on three machine learning algorithms of Logistic regression, support vector, and random forest, respectively. The models were tuned by ten-fold cross-validation to filter out the best models.Results:Delayed onset of lactogenesis occurred in 140 of 338 prenatally overweight women, an incidence of 41.4%. Among the three predictive model performances, the random forest model had the highest area under the receiver operating characteristic curve, accuracy, precision, recall, and F1 value. The importance of each predictor was ranked according to the fandom forest algorithm, and in descending order of importance, they were breastfeeding 1 h after the birth of the newborn, number of previous deliveries, age, feeding mode 3 d postpartum, pregnancy complications, mode of delivery, number of breastfeeding 24 h postpartum, and monthly household income.Conclusions:Risk prediction models for delayed onset of lactogenesis in prenatally overweight women are constructed based on three machine learning algorithms, aiming to help provide a scientific basis for clinical healthcare professionals to take relevant decisions.

Objective To investigate the effects of Echinococcus multilocularis infection on levels of memory T (Tm) cells and their subsets in lymph nodes of mice at different stages of infection, so as to provide new insights into immunotherapy for alveolarechinococcosis. MethodsTwenty-four C57BL/6J mice aged 6 to 9 weeks were randomly divided into the infection group and the control group, of 12 mice in each group. Mice in the infection group were administered with 3 000 E. multilocularis protoscoleces via portal venous injection, while animals in the control group were administered with an equal volume of physiological saline. Three mice from each group were sacrificed 4, 12 weeks and 24 weeks post-infection, and lymph nodes were sampled and stained with hematoxylin and eosin (HE) to investigate the histopathological changes of mouse lymph nodes in the infection group. The expression and localization of T lymphocyte surface markers CD3, CD4, and CD8 were observed in mouse lymph nodes using immunohistochemical staining. In addition, lymphocyte suspensions were prepared from mouse lymph nodes in both groups at different time points post-infection, and the levels of Tm cell subsets and their secreted cytokines were detected using flow cytometry. Results HE staining showed diffuse structural alterations in the subcapsular cortical and paracortical regions of mouse lymph nodes in the infection group 4 weeks post-infection with E. multilocularis. Immunohistochemical staining detected CD3, CD4 and CD8 expression in mouse lymph nodes in both groups. Flow cytometry revealed higher proportions of CD4⁺ Tm cells [(55.3 ± 4.8)% vs. (38.8 ± 6.1)%; t = -4.259, P < 0.05] and CD4⁺ tissue-resident Tm (Trm) cells [(57.7 ± 3.7)% vs. (34.1 ± 11.2)%; t = -3.990, P < 0.05] in mouse lymph nodes in the infection group than in the control group 4 weeks post-infection, and higher proportions of CD4⁺ Tm cells [(34.6 ± 3.2)% vs. (23.3 ± 7.5)%; t = -2.764, P < 0.05] and CD4⁺ Trm cells [(44.0 ± 1.9)% vs. (31.2 ± 1.5)%; t = -4.039, P < 0.05] in mouse lymph nodes in the infection group than in the control group 24 weeks post-infection. The proportions of CD8⁺ Tm cells were higher in the infection group than in the control group 4 weeks [(56.8 ± 2.7)% vs. (43.9 ± 5.2)%; t = -4.416, P < 0.01] and 12 weeks post-infection [(25.4 ± 2.7)% vs. (12.0 ± 2.6)%; t = -2.552, P < 0.05], while the proportions of tumor necrosis factor (TNF)-α⁺ CD4⁺ T cells [(15.7 ± 5.0)% vs. (49.4 ± 6.4)%; t = 7.150, P < 0.01], TNF-α⁺CD8⁺ T cells [(20.7 ± 5.5)% vs. (57.5 ± 8.4)%; t = -6.694, P < 0.01], and TNF-α⁺ CD8⁺ Tm cells [7.0% (1.0%) vs. 31.0% (11.0%); Z = -2.236, P < 0.05] were lower in the infection group than in the control group 24 weeks post-infection. Conclusions Tm cells levels are consistently increased in lymph nodes of mice at different stages of E. multilocularis infection, with Trm cells as the predominantly elevated subset. The impaired capacity of CD8⁺ Tm cells to secrete the effector molecule TNF-α in mouse lymph nodes at the late-stage infection may facilitate chronic parasitism of E. multilocularis.