Background and aims:Environmental pollutants,particularly organochlorine insecticides like endosulfan(ENDO),are increasingly linked to liver toxicity and related diseases.Despite its widespread historical use,the mechanisms underlying ENDO-induced liver damage remain poorly understood.This study aims to elucidate the cellular and molecular mechanisms of ENDO-induced hepatotoxicity.Methods:C57BL/6 mice were exposed to ENDO for two weeks.Single-cell RNA sequencing(scRNA-seq)was subsequently performed on mouse livers to explore ENDO-induced hepatotoxicity at the single-cell level.Differentially expressed genes(DEGs)across cell types and treatments were identified and then subjected to pathway enrichment to uncover key biological processes affected by ENDO.Transcription factor(TF)regulatory network,pseudotime trajectory,and cellular communication analysis were used to explore the molecular and cellular changes after ENDO exposure.Results:ENDO not only caused direct hepatocyte injury but also activated hepatic stellate cells and lymphocytes,triggering inflammatory responses with upregulation of multiple key chemokines and cytotoxic genes.Additionally,ENDO exposure led to the recruitment and activation of myeloid cells,contributing to the inflammatory milieu.An increase in intercellular communication and changes to the hepatic microenvironment,especially the interaction between activated hepatic stellate cells and CD8+T cells were observed,further implicating these processes in ENDO-induced liver damage.Conclusions:This study provides new insights into the cellular and molecular mechanisms underlying liver injury induced by organochlorine insecticides like ENDO.Key genes and pathways involved in ENDO-associated liver toxicity have been identified at a single-cell resolution.These findings suggest that altered cellular communications and inflammatory responses may play pivotal roles in the pathogenesis of ENDO-induced liver injury.

Purpose: The genomic characteristics of uterine sarcomas have not been fully elucidated. This study aimed to explore the genomic landscape of the uterine sarcomas (USs). Materials and Methods: Comprehensive genomic analysis through RNA-sequencing was conducted. Gene fusion, differentially expressed genes (DEGs), signaling pathway enrichment, immune cell infiltration, and prognosis were analyzed. A deep learning model was constructed to predict the survival of US patients. Results: A total of 71 US samples were examined, including 47 endometrial stromal sarcomas (ESS), 18 uterine leiomyosarcomas (uLMS), three adenosarcomas, two carcinosarcomas, and one uterine tumor resembling an ovarian sex-cord tumor. ESS (including high-grade ESS [HGESS] and low-grade ESS [LGESS]) and uLMS showed distinct gene fusion signatures; a novel gene fusion site, MRPS18A–PDC-AS1 could be a potential diagnostic marker for the pathology differential diagnosis of uLMS and ESS; 797 and 477 uterine sarcoma DEGs (uDEGs) were identified in the ESS vs. uLMS and HGESS vs. LGESS groups, respectively. The uDEGs were enriched in multiple pathways. Fifteen genes including LAMB4 were confirmed with prognostic value in USs; immune infiltration analysis revealed the prognositic value of myeloid dendritic cells, plasmacytoid dendritic cells, natural killer cells, macrophage M1, monocytes and hematopoietic stem cells in USs; the deep learning model named Max-Mean Non-Local multi-instance learning (MMN-MIL) showed satisfactory performance in predicting the survival of US patients, with the area under the receiver operating curve curve reached 0.909 and accuracy achieved 0.804. Conclusion USs harbored distinct gene fusion characteristics and gene expression features between HGESS, LGESS, and uLMS. The MMN-MIL model could effectively predict the survival of US patients.

Purpose: The genomic characteristics of uterine sarcomas have not been fully elucidated. This study aimed to explore the genomic landscape of the uterine sarcomas (USs). Materials and Methods: Comprehensive genomic analysis through RNA-sequencing was conducted. Gene fusion, differentially expressed genes (DEGs), signaling pathway enrichment, immune cell infiltration, and prognosis were analyzed. A deep learning model was constructed to predict the survival of US patients. Results: A total of 71 US samples were examined, including 47 endometrial stromal sarcomas (ESS), 18 uterine leiomyosarcomas (uLMS), three adenosarcomas, two carcinosarcomas, and one uterine tumor resembling an ovarian sex-cord tumor. ESS (including high-grade ESS [HGESS] and low-grade ESS [LGESS]) and uLMS showed distinct gene fusion signatures; a novel gene fusion site, MRPS18A–PDC-AS1 could be a potential diagnostic marker for the pathology differential diagnosis of uLMS and ESS; 797 and 477 uterine sarcoma DEGs (uDEGs) were identified in the ESS vs. uLMS and HGESS vs. LGESS groups, respectively. The uDEGs were enriched in multiple pathways. Fifteen genes including LAMB4 were confirmed with prognostic value in USs; immune infiltration analysis revealed the prognositic value of myeloid dendritic cells, plasmacytoid dendritic cells, natural killer cells, macrophage M1, monocytes and hematopoietic stem cells in USs; the deep learning model named Max-Mean Non-Local multi-instance learning (MMN-MIL) showed satisfactory performance in predicting the survival of US patients, with the area under the receiver operating curve curve reached 0.909 and accuracy achieved 0.804. Conclusion USs harbored distinct gene fusion characteristics and gene expression features between HGESS, LGESS, and uLMS. The MMN-MIL model could effectively predict the survival of US patients.

Purpose: The genomic characteristics of uterine sarcomas have not been fully elucidated. This study aimed to explore the genomic landscape of the uterine sarcomas (USs). Materials and Methods: Comprehensive genomic analysis through RNA-sequencing was conducted. Gene fusion, differentially expressed genes (DEGs), signaling pathway enrichment, immune cell infiltration, and prognosis were analyzed. A deep learning model was constructed to predict the survival of US patients. Results: A total of 71 US samples were examined, including 47 endometrial stromal sarcomas (ESS), 18 uterine leiomyosarcomas (uLMS), three adenosarcomas, two carcinosarcomas, and one uterine tumor resembling an ovarian sex-cord tumor. ESS (including high-grade ESS [HGESS] and low-grade ESS [LGESS]) and uLMS showed distinct gene fusion signatures; a novel gene fusion site, MRPS18A–PDC-AS1 could be a potential diagnostic marker for the pathology differential diagnosis of uLMS and ESS; 797 and 477 uterine sarcoma DEGs (uDEGs) were identified in the ESS vs. uLMS and HGESS vs. LGESS groups, respectively. The uDEGs were enriched in multiple pathways. Fifteen genes including LAMB4 were confirmed with prognostic value in USs; immune infiltration analysis revealed the prognositic value of myeloid dendritic cells, plasmacytoid dendritic cells, natural killer cells, macrophage M1, monocytes and hematopoietic stem cells in USs; the deep learning model named Max-Mean Non-Local multi-instance learning (MMN-MIL) showed satisfactory performance in predicting the survival of US patients, with the area under the receiver operating curve curve reached 0.909 and accuracy achieved 0.804. Conclusion USs harbored distinct gene fusion characteristics and gene expression features between HGESS, LGESS, and uLMS. The MMN-MIL model could effectively predict the survival of US patients.

Gastrointestinal (GI) cancers are a leading cause of cancer morbidity and mortality worldwide. Despite advances in treatment, cancer relapse remains a significant challenge, necessitating novel therapeutic strategies. In this study, we engineered nanobody-based chimeric antigen receptor (CAR) natural killer (NK) cells targeting cadherin 17 (CDH17) for the treatment of GI tumors. In addition, to enhance the efficacy of CAR-NK cells, we also incorporated CV1, a CD47-SIRPα axis inhibitor, to evaluate the anti-tumor effect of this combination. We found that CDH17-CAR-NK cells effectively eliminated GI cancers cells in a CDH17-dependent manner. CDH17-CAR-NK cells also exhibit potent in vivo anti-tumor effects in cancer cell-derived xenograft and patient-derived xenograft mouse models. Additionally, the anti-tumor activity of CDH17-CAR-NK cells is synergistically enhanced by CD47-signal regulatory protein α (SIRPα) axis inhibitor CV1, likely through augmented macrophages activation and an increase in M1-phenotype macrophages in the tumor microenvironment. Collectively, our findings suggest that CDH17-targeting CAR-NK cells are a promising strategy for GI cancers. The combination of CDH17-CAR-NK cells with CV1 emerges as a potential combinatorial approach to overcome the limitations of CAR-NK therapy. Further investigations are warranted to speed up the clinical translation of these findings.

Objective:To investigate the curative effect of red-blue light combined with intense pulsed light(IPL)in treating papular pustular rosacea,and its effect on quality of life.Methods:A total of 76 patients with papular pustular rosacea who admitted to PLA rocket force characteristic medical center and Qinghai provincial traffic hospital from August 2019 to July 2023 were retrospectively selected.According to the different treatment methods,all patients were divided into observation group and control group,with 38 patients in each group.The control group was treated with oral minocycline hydrochloride,while the observation group adopted respectively 87C type red-blue light instrument and M22 type photon therapy device to implement red-blue and IPL therapy on the basis of treatment of control group.The clinical efficacy,clinician's erythema assessment(CEA)scale,investigator's global assessment(IGA)scale,dermatology life quality index(DLQI)and the incidence of adverse reaction were compared between the two groups.Results:The overall effective rate of the observation group was 97.37%,which was significantly higher than 84.21%of the control group,and the difference was statistically significant(x2=3.934,P<0.05).The scores of IGA,CEA and DLQI in two groups after treatment were all lower than those before treatment,and the differences of them were all significant(t=3.820,6.725,7.937,P<0.05).There were no statistically significant differences in the incidence of adverse reactions included dizziness,dry skin,worsening itching and pain and pigmentation between the two groups after treatment(P>0.05).Conclusion:Red-blue light combined with IPL can significant enhance the clinically curative effect in treating papular pustular rosacea,which can significantly reduce the symptom of skin lesions of persistent with erythema,and improve quality of life of patients.It has favorable safety.

Objective:To investigate the clinical and pathological significance of the DICER1 mutation in follicular thyroid carcinoma (FTC).Methods:Sixty-eight cases of primary FTC resected between 2009 and 2023 were retrieved from The Affiliated Hospital of Qingdao University, Qingdao, China. Sanger sequencing was performed to identify DICER1 and TERT promoter mutations in all cases. Cases with DICER1 or TERT promoter mutations were subject to additional examination of potential mutations in KRAS, HRAS, and NRAS. The clinical and pathological features of DICER1-mutant FTCs were then analyzed. The relationship between DICER1 mutations and TERT-promoter/RAS mutations was also assessed.Results:DICER1 mutations were detected in 16 of the 68 FTC cases (23.5%), with 11 near E1813 at exon 25, 6 near D1709 at exon 24, and 1 in the splice region of exon 25. Two cases harbored two (distinct) mutations. All patients with DICER1-mutant FTC were female. Compared with patients with DICER1-wild-type FTC, those with DICER1-mutant were much younger, and had a higher proportion of minimally invasive subtype. Nine FTCs with DICER1 mutations were subject to further sequencing on adjacent non-cancerous tissues or lymph node tissues, but no mutations were detected. TERT-promoter or RAS hotspot mutations were not identified in any of the DICER1-mutant cases. However, TERT-promoter mutation was found in 6 DICER1-wild-type cases (8.8%, 6/68), with 3 cases also having RAS hotspot mutations and exhibiting highly aggressive biological behaviors.Conclusion:DICER1 mutations may occur in FTCs and appear mutually exclusive with RAS and TERT-promoter mutations, warranting further study as RAS-like mutations.

Objective:To investigate the curative effect of red-blue light combined with intense pulsed light(IPL)in treating papular pustular rosacea,and its effect on quality of life.Methods:A total of 76 patients with papular pustular rosacea who admitted to PLA rocket force characteristic medical center and Qinghai provincial traffic hospital from August 2019 to July 2023 were retrospectively selected.According to the different treatment methods,all patients were divided into observation group and control group,with 38 patients in each group.The control group was treated with oral minocycline hydrochloride,while the observation group adopted respectively 87C type red-blue light instrument and M22 type photon therapy device to implement red-blue and IPL therapy on the basis of treatment of control group.The clinical efficacy,clinician's erythema assessment(CEA)scale,investigator's global assessment(IGA)scale,dermatology life quality index(DLQI)and the incidence of adverse reaction were compared between the two groups.Results:The overall effective rate of the observation group was 97.37%,which was significantly higher than 84.21%of the control group,and the difference was statistically significant(x2=3.934,P<0.05).The scores of IGA,CEA and DLQI in two groups after treatment were all lower than those before treatment,and the differences of them were all significant(t=3.820,6.725,7.937,P<0.05).There were no statistically significant differences in the incidence of adverse reactions included dizziness,dry skin,worsening itching and pain and pigmentation between the two groups after treatment(P>0.05).Conclusion:Red-blue light combined with IPL can significant enhance the clinically curative effect in treating papular pustular rosacea,which can significantly reduce the symptom of skin lesions of persistent with erythema,and improve quality of life of patients.It has favorable safety.

Objective:To investigate the clinical and pathological significance of the DICER1 mutation in follicular thyroid carcinoma (FTC).Methods:Sixty-eight cases of primary FTC resected between 2009 and 2023 were retrieved from The Affiliated Hospital of Qingdao University, Qingdao, China. Sanger sequencing was performed to identify DICER1 and TERT promoter mutations in all cases. Cases with DICER1 or TERT promoter mutations were subject to additional examination of potential mutations in KRAS, HRAS, and NRAS. The clinical and pathological features of DICER1-mutant FTCs were then analyzed. The relationship between DICER1 mutations and TERT-promoter/RAS mutations was also assessed.Results:DICER1 mutations were detected in 16 of the 68 FTC cases (23.5%), with 11 near E1813 at exon 25, 6 near D1709 at exon 24, and 1 in the splice region of exon 25. Two cases harbored two (distinct) mutations. All patients with DICER1-mutant FTC were female. Compared with patients with DICER1-wild-type FTC, those with DICER1-mutant were much younger, and had a higher proportion of minimally invasive subtype. Nine FTCs with DICER1 mutations were subject to further sequencing on adjacent non-cancerous tissues or lymph node tissues, but no mutations were detected. TERT-promoter or RAS hotspot mutations were not identified in any of the DICER1-mutant cases. However, TERT-promoter mutation was found in 6 DICER1-wild-type cases (8.8%, 6/68), with 3 cases also having RAS hotspot mutations and exhibiting highly aggressive biological behaviors.Conclusion:DICER1 mutations may occur in FTCs and appear mutually exclusive with RAS and TERT-promoter mutations, warranting further study as RAS-like mutations.

OBJECTIVE To provide reference for medication therapy management （MTM） of diabetic patients complicated with cardiovascular disease. METHODS A 63-year-old male diabetic patient who suffered from temporary headache every morning after percutaneous coronary intervention （PCI） visited the neurology department of our hospital， and then was recommended to the pharmaceutical outpatient department. The pharmacists thought that the patient’s symptoms of headache， severe constipation and hyperuricemia were more likely induced by the medication used. The pharmacists further found that his atherosclerotic cardiovascular disease （ASCVD） influencing factors such as blood pressure， heart rate， blood glucose and blood lipids did not reach standard. The pharmacists provided MTM services for the patient through pharmacy inquiry and adverse drug reactions judgement， medication evaluation， medication reconciliation， medication education and pharmacy follow-up. RESULTS Through fifteen MTM services for thirteen weeks， the pharmacists reconciliated and optimized the medication therapy plan， discontinued the use of Isosorbide mononitrate sustained-release tablets， Nifedipine controlled-release tablets， and Indapamide tablets， which caused adverse drug reactions； the number of drugs was adjusted from fifteen to seven， and the symptom of headache disappeared； severe constipation had also been significantly improved， and hyperuricemia dropped to normal range. The ASCVD influencing factors of blood pressure， heart rate， fasting plasma glucose， glycosylated hemoglobin， low-density lipoprotein cholesterol and uric acid were reduced from ＞140/90 mmHg（1 mmHg＝0.133 kPa）， 70-80 beats per minute， 7.71 mmol/L， 7.2%， 2.13 mmol/L and 494 μmol/L before MTM services to ＜130/80 mmHg， 55-60 beats per minute， 6.22 mmol/L， 6.3%， 1.55 mmol/L and 348 μmol/L after MTM services. CONCLUSIONS The pharmacists providing MTM services to the patients can improve their quality of life and therapeutic efficacy， reduce medication risks， and enhance the level of rational drug use in hospitals and pharmaceutical service capabilities.