Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic strategy for targeted protein degradation. However, the clinical application of PROTACs may be hindered by off-target toxicity resulting from non-tissue-specific protein degradation and ingenious prodrug strategies may open new avenues to addressing this concern. Herein, we propose a light-induced positive feedback strategy to use photodynamic therapy (PDT) to improve the activation efficiency of PROTAC prodrugs, monitor PROTAC release, and combine PROTAC to induce tumor cell apoptosis. In the hypoxic tumor microenvironment, the azo bond in AZO-PRO selectively cleaves, triggering the release of the potent protein degrader PRO and the multifunctional photosensitizer. Once activated, the fluoresce signal of the photosensitizer dramatically recovers, allowing monitoring of prodrug activation. Additionally, upon irradicating the tumor site using near-infrared (NIR) laser, PDT exacerbates tumor hypoxia, further promoting AZO-PRO activation. Our work introduces a novel approach to efficiently track and activate PROTAC prodrugs, enhance their antitumor efficacy, and mitigate off-target systemic toxicity.

Objective To explore the risk factors of adverse pregnancy outcomes in the patients with cervical incompetence(CI),and to establish a risk warning model of adverse pregnancy outcomes in CI pa-tients based on decision tree model.Methods The clinical data of 159 patients with CI admitted and treated in this hospital from February 2022 to April 2023 were retrospectively analyzed,and the risk factors for adverse pregnancy outcomes were screened and the decision tree model for postoperative adverse pregnancy outcomes was constructed.The internal verification method was 5-fold cross-validation.Results The incidence rate of adverse pregnancy outcome was 22.64%.The pregnant weeks of cervical cerclage,amniotic cystocele,multiple cervical cerclage,preoperative cervical length and amniotic fluid sediment were all influential factors for ad-verse pregnancy outcome occurrence(P＜0.05).The amniotic fluid sediment was the most important factor affecting the postoperative adverse pregnancy outcome in CI patients,and the preoperative cervical length had little influence on the postoperative adverse pregnancy outcomes in CI patients.The area under the curve(AUC)value of logistic regression model was slightly higher than that of the decision tree model.The accura-cy rate of the 5-fold cross-validation model was 78.3%.Conclusion During clinical treatment,the above two models can be combined to find the influencing factors of postoperative adverse pregnancy outcomes in CI pa-tients from different aspects,and provide references for clinical medical staff to evaluate the disease condition of CI patients and formulate the intervention plans.

Objective To identify the key biomarkers for diagnosing chronic obstructive pulmonary disease(COPD)complicated with pulmonary arterial hypertension(PAH)using bioinformatics,and validate their clinical significance.Methods High-throughput sequencing data analysis was employed to identify differentially expressed genes(DEGs)in COPD-PAH.Functional enrichment analysis was then conducted to explore the biological functions of these DEGs.Machine learning methods,including least absolute shrinkage and selection operator(LASSO),random forest(RF),and support vector machine-recursive feature elimination(SVM-RFE),were utilized to screen 5 potential biomarkers.Single-cell analysis was performed to reveal the expression patterns of these key genes in macrophages.The clinical significance of these biomarkers was further validated using peripheral blood mononuclear cells(PBMC)data.A mouse model of COPD-PAH was established using hypoxia exposure.Sixteen mice(either sexes,8 weeks old,weighing 20～22 g)were randomly divided into a hypoxia group[O2(10.0±0.5)%,COPD-PAH,n=8]and a normoxia group(COPD,n=8).Immunofluorescence assay was used to label the key biomarkers,and their expression levels were quantified.Results A total of 28 DEGs(|Log2FC|≥2,P<0.05)were identified in COPD-PAH patients.Functional enrichment analysis indicated that DEGs in COPD were primarily associated with major histocompatibility complex(MHC)Ⅱ and cell division,and involved in lysosomes,oxidative phosphorylation,and cell cycle pathways(P<0.05).Machine learning identified 5 potential biomarkers(GRN,KLF4,SHTN1,LRP1,and GPNMB),and subsequent single-cell analysis revealed that these markers exhibited reverse expression patterns during disease progression.A nomogram model constructed based on PBMC data yielded an area under the curve(AUC)of 0.907 in diagnosing COPD-PAH.GRN,KLF4,SHTN1,LRP1 and GPNMB were significantly upregulated in the COPD-PAH group(P<0.05).Conclusion GRN,KLF4,SHTN1,LRP1 and GPNMB are identified as key biomarkers for the prediction and diagnosis of COPD-PAH,which providing new insights for the clinical and treatment of the condition.

Nocardiosis is a collective term for tissue and organ damage caused by Nocardia infection.Solid organ transplant recipients(SOTR)are at an increased risk of various pathogen infections,including Nocardia infection,due to immunosuppressive therapy which weakens their immune function.The diagnosis of nocardiosis has been challenging in the past.With the advent of molecular biology and other diagnostic methods,the diagnostic rate has significantly improved.Nocardia not only prone to cause necrotic pulmonary lesions but also invade other organs and tissues,such as intracranial infections and skin soft tissue infections,and can develop into systemic disseminated infections.For SOTR,nocardiosis is a potentially fatal disease with a fatality as high as 30%.Therefore,this article reviews the clinical characteristics of common nocardiosis in SOTR,new diagnostic technologies,and different anti-infective treatment strategies,aiming to provide a reference for the prevention and treatment of nocardiosis in clinical SOTR.

ObjectiveTo investigate the structural and functional characteristics of gut microbiota in common traditional Chinese medicine （TCM） syndromes of irritable bowel syndrome with diarrhea （IBS-D）. MethodsIBS-D patients who visited the Hospital of Chengdu University of Traditional Chinese Medicine， and healthy participants from the Physical Examination Centre of the same hospital were recruited from 1st January 2020 to 31st March 2021.The IBS-D patients were classified into syndrome of liver constraint and spleen deficiency， and syndrome of spleen deficiency and dampness exuberance； together with the recruited healthy participants， there were liver-constraint group， dampness-exuberance group， and healthy group. General information， including age， gender and body mass index （BMI）， were collected， and Irritable Bowel Syndrome Symptom Severity Scale （IBS-SSS） as well as Irritable Bowel Syndrome Quality of Life Scale （IBS-QOL） scores were additionally collected from IBS-D patients. Fresh fecal samples were also collected and tested by macro-genome sequencing technology for abundance statistical display， PCoA， Anosim， LEfSe bioinformatic analysis of the annotated gut microbiota structure and function. ResultsThere was no statistically significant difference in the general information of the participants in the three groups （P＞0.05）； the difference in the IBS-SSS and IBS-QOL scores between liver-constraint group and dampness-exuberance group were not statistically significant （P＞0.05）. The study included 28 cases each in liver-constraint group， dampness-exuberance group， and healthy group. The number of specific genes to patients in liver-constraint group was 269 135， with 216 156 in dampness-exuberance group and 249 759 in healthy group， accounting of total 1 784 036 in the three groups. There were differences in the relative abundance distribution of the top ten species of gut microbiota among the three groups， with smaller differences at the phylum， class and order levels， and larger differences at the family， genus and species levels. There were differences in the relative abundance of structure and function of the gut microbiota among the three groups. Species PCoA and Anosim analyses at the species level showed significant differences in the composition of the microbiota among the three groups. Further LEfSe analyses showed that patients in liver-constraint group were screened for 14 dominant strains， of which Clostridium sp. CAG 217， Lachnospira pectinoschiza， Anaerotruncus sp. CAG 528， Paeniclostridium sordellii， Eubecterium sp. CAG 76， Bacillus cereus were affected to a greater extent in abundance differences； dampness-exuberance group screened 24 species of dominant bacteria， of which Roseburia inulinivorans， Eubacterium sp. CAG 251， Roseburia hominis， Unclassified Eubacterium rectale， Roseburia intestinalis， and Megamonas funiformis were affected to a greater extent in abundance differences； no dominant functional genes were screened for patients in liver-constraint group， and dampness-exuberance group was screened for flagellum assembly （ko02040）， porphyrin metabolism （ ko00860）， salmonella infection （ko05132）， and benzoic acid degradation （ko00362）. The differentially dominant functional genes in liver-constraint group and dampness-exuberance group may mainly focus on metabolism （including biodegradation and metabolism of exogenous substances， energy metabolism， lipid metabolism， etc.）. ConclusionIBS-D with syndrome of liver constraint and spleen deficiency is characterized by the enrichment of 14 gut microbiota， such as Clostridium sp. CAG 217， while IBS-D with syndrome of spleen deficiency and dampness exuberance is characterized by the enrichment of 24 gut microbiota， such as Roseburia inulinivorans， and 4 functional enrichments， such as flagellum assembly. Clostridium sp. CAG 217 and Roseburia inulinivorans are expected to be biomarkers for IBS-D patients in the two syndromes， respectively.

Objective To evaluate clinical efficacy of lung transplantation for lung chronic graft-versus-host disease (cGVHD) after hematopoietic stem cell transplantation (HSCT). Methods Clinical data of 12 patients undergoing lung transplantation for lung cGVHD were retrospectively analyzed. Preoperative clinical manifestations and involved organs of patients were analyzed. The lung function before and after lung transplantation was compared, and the survival of patients after lung transplantation was analyzed. Results Eleven patients underwent HSCT due to primary hematological malignancies, including 9 cases of leukemia, 1 case of myelodysplastic syndrome, 1 case of lymphoma. And 1 case underwent HSCT for systemic lupus erythematosus. Among 12 cGVHD patients, skin involvement was found in 8 cases, oral cavity involvement in 5 cases, gastrointestinal tract involvement in 4 cases and liver involvement in 3 cases. All 12 patients developed severe respiratory failure caused by cGVHD before lung transplantation, including 9 cases of typeⅡ respiratory failure and 3 cases of type Ⅰ respiratory failure. Two patients underwent right lung transplantation, 2 cases of left lung transplantation and 8 cases of bilateral lung transplantation. The interval from HSCT to lung transplantation was 75 (19-187) months. Upon the date of submission, postoperative follow-up time was 18 (7-74) months. Ten patients survived, 1 died from severe hepatitis at postoperative 22 months, and 1 died from gastrointestinal bleeding at postoperative 6 months. No recurrence of primary diseases was reported in surviving patients. Conclusions Lung transplantation is an efficacious treatment for lung cGVHD after HSCT, which may prolong the survival time and improve the quality of life of the recipients.

Objective:To analyze the biological characteristics, phylogeny and the taxonomic status of strain 7712 (=CGMCC 1.17031=NBRC 113783=KCTC 15766) isolated from a clinical blood sample.Methods:Strain 7712 was identified by the cultural properties, cellular and colonial morphology, physiological and biochemical reactions, matrix-assisted laser desorption ionization time-of-flight mass spectrometry system, and genome correlation index analysis. The genomic phylogenetic tree was construct to analyze the taxonomic position. The virulence factors and resistance genes of strain 7712 and related strains were then compared by the online virulence factor database and online comprehensive antibiotic research database respectively.Results:Strain 7712 was urease negative, gram-negative nonfermenters, which was identified as Ochrobactrum anthropi by VITEK GN card. The 16S rRNA gene analysis showed that the strain was closely related to the members of genera Ochrobactrum and Brucella. The phylogenetic tree showed that strain 7712 was clustered together with Ochrobactrum teleogrylli LCB8 T and Ochrobactrum haematophilum CCUG 38531 T, along with genus Brucella and other Ochrobactrum species. The genome relatedness indexes analysis showed that the average nucleotide identity between strain 7712 and Ochrobactrum teleogrylli LCB8 T was 98.16%, which was higher than the threshold for prokaryotic species. Genetic prediction showed that strain 7712 carried several virulence-related genes and resistance-related genes, of which the existence of OCH gene might be responsible to the resistance to cephalosporin. Conclusions:A case of human infection caused by Ochrobactrum teleogrylli is identified, which would help promote the understanding of biodiversity of genus Ochrobactrum.