OBJECTIVE To provide a basis for aligning Chinese pharmacoeconomic research on heart failure （HF） with international standards. METHODS A qualitative comparison o f domestic and global HF pharmacoeconomic studies was conducted across four dimensions： research methods and model application， research perspectives and endpoints， data sources and parameter selection， and policy translation and practical impact. RESULTS & CONCLUSIONS Global studies predominantly utilize long-term dynamic models， societal perspectives， real-world data integration， and directly inform reimbursement decisions. Conversely， domestic research often relies on short-term simplified models， a single healthcare system perspectives， literature-derived data， and individual medicine recommendations. Future domestic studies should transition to long-term dynamic modeling， develop localized disease-specific utility databases via big data， establish reimbursement-linked closed-loop mechanisms， and foster multidisciplinary collaboration to optimize healthcare resource allocation.

OBJECTIVE To compare the predictive accuracy and clinical applicability of four vancomycin individualized dosing tools （SmartDose， ClinCalc， Gulou， Pharmado） and provide a basis for rational clinical medication use. METHODS A retrospective cohort study was conducted， enrolling 479 adult patients who received vancomycin therapy and underwent steady-state trough concentration monitoring in Zhongshan Hospital， Fudan University （Xiamen Branch） from January 1， 2022， to June 30， 2024. The predictive accuracy of each tool was evaluated using indicators， such as mean error （ME）, mean absolute error （MAE）， mean percentage error （MPE）， mean absolute percentage error （MAPE）， the proportion of patients with an absolute percentage error （APE） of less than 30%， the 95% limits of agreement， and the overall relative percentage difference between predicted and measured values. Using indicators such as accessibility， patient management， and recommendation of multiple treatment options， the clinical panxso@163.com applicability of the tools for all patients was evaluated； using the discrepancy in accuracy between the predicted and actual measured blood drug concentrations as an indicator， the clinical applicability was assessed for patients in different renal function subgroups （hyperfunction， normal， mild impairment， moderate impairment， and severe impairment）. RESULTS In terms of accuracy， SmartDose demonstrated the best overall performance with an MAPE of 46.40% and a proportion of APE ＜30% （46.56%）. Bland-Altman analysis indicated that SmartDose had the smallest overall relative percentage difference （－7.25%）， although the 95% limits of agreement were broad for all tools， with differences between the upper and lower limits exceeding 200%. In terms of applicability， all four dosing tools were freely accessible and demonstrated good availability； SmartDose and Pharmado provided the most comprehensive solutions， offering features such as patient management， multiple regimen recommendations， and drug concentration-time curve plotting. Stratified analysis based on renal function revealed that Pharmado showed optimal prediction for hyperfiltration patients （mean difference： 0.11 mg/L）. SmartDose and ClinCalc showed relatively better performance in normal and mild renal impaiment （mean difference： 0.37， 0.51 mg/L and －1.13， －1.33 mg/L，respectively）. SmartDose performed best in moderate renal impairment （mean difference： －2.60 mg/L）. Pharmado and Gulou had smaller prediction biases in severe renal impairment （mean differences： 1.52 mg/L and －0.23 mg/L， respectively）. CONCLUSIONS The four individualized dosing tools demonstrated limited accuracy in the initial prediction of vancomycin concentrations. Among them， SmartDose demonstrates the highest overall prediction accuracy and possesses comprehensive clinical management features. It is recommended that Pharmado be preferred for patients with renal hyperfiltration； SmartDose or ClinCalc can be used for patients with normal or mildly impaired renal function； SmartDose is recommended for patients with moderately impaired renal function； Pharmado or Gulou may be considered for patients with severely impaired renal function.

Objective:To investigate the semen characteristics of male patients with autosomal dominant polycystic kidney disease (ADPKD) complicated by infertility and the impact of PKD1 mutations on their reproductive outcomes following preimplantation genetic testing for monogenic diseases (PGT-M). Methods:A retrospective cohort study was conducted to analyze the clinical data of ADPKD patients in the Clinical Center of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2023. The study included two groups: observation group consisting of male infertility patients with ADPKD aged 20-45 years ( n=78), and control group comprising ADPKD patients with PKD1 mutations who demonstrated normal semen parameters ( n=5). According to the type of mutation, the patients were further divided into the PKD1 truncated mutation group and the non-truncated mutation group. Baseline data, ovulation induction outcomes and PGT-M clinical outcomes were compared between the two groups. Binary logistic regression analysis was used to assess the effects of age, family history, mutation type and mutation position on semen quality and live birth rates. Results:In the observation group, there were 28 cases of asthenozoospermia, 38 cases of oligoasthenozoospermia, and 12 cases of azoospermia. The total sperm count and forward motility ratio of patients with asthenozoospermia, oligoasthenozoospermia, and azoospermia in the observation group were significantly different from those in control group (all P<0.001). Genetic diagnosis revealed PKD1 mutations in 70 cases, PKD2 mutation in 1 case, and no known pathogenic mutations were identified in 7 cases. Among the 70 ADPKD patients with PKD1 mutations, 52 couples underwent PGT-M assisted reproduction. The blastocyst formation rate was significantly lower in the non-truncating mutation group [44.74% (51/114)] than in the truncating mutation group [58.76% (161/274), P=0.011]. No statistically significant differences were observed between the two groups in other parameters including age of both partners, semen parameters, number of oocytes retrieved, two pronuclei (2PN) rate, number of available embryos, high-quality embryo rate, clinical pregnancy rate, miscarriage rate, and live birth rate (all P>0.05). Binary logistic regression analysis showed that neither PKD1 mutation type nor PKD1 mutation site was an independent factor affecting semen parameters and live birth rate in ADPKD patients (all P>0.05). Conclusions:Asthenospermia and oligoasthenospermia are the most common semen phenotypes in ADPKD-associated male infertility. The PKD1 mutation type and location are not associated with abnormal semen parameters in ADPKD-associated infertility patients. PKD1 mutation types do not affect the outcomes of PGT-M in infertile patients with ADPKD.

Breast cancer is one of the most common and fatal malignancies among women worldwide, and its treatment efficacy is often limited by drug resistance and the presence of undruggable targets. Traditional small-molecule drugs have difficulty effectively modulating certain critical targets such as transcription factors and non-coding RNAs, necessitating new therapeutic strategies. Proteolysis-targeting chimeras (PROTACs) function by recruiting pathogenic proteins to the cellular ubiquitin-proteasome system, thereby inducing their specific degradation. In contrast, ribonuclease-targeting chimeras (RIBOTACs) utilize small-molecule ligands but bind to RNA and direct endogenous RNases to selectively degrade pathogenic RNA molecules. By employing a "degradation rather than inhibition" mechanism, targeting chimera technology broadens the druggable landscape and offers a novel precision therapeutic strategy for breast cancer, particularly for refractory and drug-resistant cases. This approach not only overcomes the limitations of traditional drugs, such as the absence of suitable binding sites or poor selectivity, but also reduces required dosages and potential adverse effects. Recent studies have preliminarily demonstrated the therapeutic potential of PROTACs and RIBOTACs in breast cancer, encompassing target design, mechanistic investigation, and preclinical as well as early clinical applications. Research into these technologies reveals their ability to tackle previously undruggable targets, thereby providing theoretical support for the development of safer and more effective precision therapies for breast cancer. In the future, with advances in drug delivery systems and clinical trials, PROTACs and RIBOTACs are expected to be used synergistically with immunotherapy and chemotherapy, offering breast cancer patients more promising comprehensive treatment options and potentially driving oncology toward broader intervention of undruggable targets.
Humans ; Breast Neoplasms/drug therapy* ; Female ; Proteolysis ; Ribonucleases/metabolism* ; Molecular Targeted Therapy/methods* ; Antineoplastic Agents/therapeutic use*

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Ionizing radiation occurs not only during nuclear and radiological terrorist attacks or nuclear accidents but also in medical applications and daily life. In recent years, the potential toxic effects of low-dose ionizing radiation on the male reproductive system have raised public health concerns. Most specifically, for the testis, a highly sensitive target organ to ionizing radiation, there is an urgent need to determine the mechanisms underlying the association between radiation-induced spermatogenic failure and male infertility. Focusing on the potential injurious effects of low-dose ionizing radiation on spermatogenesis, this review presents a summary and analysis of various underlying mechanisms including oxidative stress, apoptosis, and DNA damage repair and reviews recent domestic and international strategies for protecting against radiation-induced reproductive system damage in order to offer references for future research on the injurious effects of low-dose radiation on spermatogenesis and relevant protection.

Objective:To investigate the semen characteristics of male patients with autosomal dominant polycystic kidney disease (ADPKD) complicated by infertility and the impact of PKD1 mutations on their reproductive outcomes following preimplantation genetic testing for monogenic diseases (PGT-M). Methods:A retrospective cohort study was conducted to analyze the clinical data of ADPKD patients in the Clinical Center of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2023. The study included two groups: observation group consisting of male infertility patients with ADPKD aged 20-45 years ( n=78), and control group comprising ADPKD patients with PKD1 mutations who demonstrated normal semen parameters ( n=5). According to the type of mutation, the patients were further divided into the PKD1 truncated mutation group and the non-truncated mutation group. Baseline data, ovulation induction outcomes and PGT-M clinical outcomes were compared between the two groups. Binary logistic regression analysis was used to assess the effects of age, family history, mutation type and mutation position on semen quality and live birth rates. Results:In the observation group, there were 28 cases of asthenozoospermia, 38 cases of oligoasthenozoospermia, and 12 cases of azoospermia. The total sperm count and forward motility ratio of patients with asthenozoospermia, oligoasthenozoospermia, and azoospermia in the observation group were significantly different from those in control group (all P<0.001). Genetic diagnosis revealed PKD1 mutations in 70 cases, PKD2 mutation in 1 case, and no known pathogenic mutations were identified in 7 cases. Among the 70 ADPKD patients with PKD1 mutations, 52 couples underwent PGT-M assisted reproduction. The blastocyst formation rate was significantly lower in the non-truncating mutation group [44.74% (51/114)] than in the truncating mutation group [58.76% (161/274), P=0.011]. No statistically significant differences were observed between the two groups in other parameters including age of both partners, semen parameters, number of oocytes retrieved, two pronuclei (2PN) rate, number of available embryos, high-quality embryo rate, clinical pregnancy rate, miscarriage rate, and live birth rate (all P>0.05). Binary logistic regression analysis showed that neither PKD1 mutation type nor PKD1 mutation site was an independent factor affecting semen parameters and live birth rate in ADPKD patients (all P>0.05). Conclusions:Asthenospermia and oligoasthenospermia are the most common semen phenotypes in ADPKD-associated male infertility. The PKD1 mutation type and location are not associated with abnormal semen parameters in ADPKD-associated infertility patients. PKD1 mutation types do not affect the outcomes of PGT-M in infertile patients with ADPKD.

Objective To translate self-care in spinal cord injuries inventory(SC-SCII)into Chinese and evaluate its reliability and validity,therefore to provide medical staff with a tool for evaluation of self-care behaviour of patients.Methods Brislin translation model was adopted for forward translation,back-translation,cultural adaptation and pilot testing in the development of Chinese version of SC-SCII.Convenience sampling was used to recruit 207 patients with spinal cord injury(SCI)from three Tier-IIIA hospitals in Xi'an between January 2024 and March 2025 for the purpose of assessing the reliability and validity of the translated inventory.Results A total of 202 patients completed the study.The finalised Chinese version of SC-SCII encompassed 4 dimensions with a total of 35 items,with the same structure as the original SC-SCII.Scale-level content validity index was 0.948,and the item-level content validity indices ranged from 0.912 to 1.000.Four common factors were extracted by exploratory factor analysis:self-care maintenance(12 items),self-care monitoring(8 items),self-care management(8 items)and self-care self-efficacy(7 items),cumulatively accounting for 61.402%of the total variance.The overall Cronbach's α coefficient was 0.820 and the Cronbach's α coefficients of the four dimensions were 0.935,0.905,0.921 and 0.892,respectively.The split-half reliability was 0.798,and the two-week retest reliability was 0.875.No statistically significant difference was observed between the original and sinicised scales(paired t-test,P>0.05),indicating a high cross-time stability of the sinicised scale.Conclusion The Chinese version of SC-SCII demonstrates a good reliability and validity,making it a suitable tool in evaluation of self-care abilities in SCI patients.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Objective·To explore the antitumor effects and potential mechanisms of combining phosphoinositide 3-kinase,FYVE-type zinc finger containing(PIKfyve)inhibitor YM201636 with the stimulator of interferon genes(STING)agonist diABZI in STING pathway-deficient melanoma.Methods·The mRNA and protein expression levels of STING in human cancer cell lines were obtained from the Cancer Cell Line Encyclopedia(CCLE)and UniProt databases.Based on median expression values,melanoma cell lines with high STING mRNA but low protein expression were identified.Quantitative real-time PCR(qRT-PCR)and Western blotting were performed to validate STING mRNA and protein expression in human melanoma cells.The murine melanoma cell line YUMM1.7,characterized by low STING protein expression,was selected through Western blotting.The ability of YM201636 to restore STING protein expression in YUMM1.7 cells was evaluated.STING agonist diABZI was then applied in combination with YM201636 to analyze the synergistic tumor cell-killing effect through CCK-8 assay.Western blotting was used to detect the phosphorylation of TANK-binding kinase 1(TBK1)and interferon regulatory factor 3(IRF3),and qRT-PCR was used to evaluate type Ⅰ interferon expression.A mouse melanoma model was established and treated with YM201636,diABZI,or their combination.Tumor volume was measured,and treatment efficacy was assessed.RNA sequencing and immunofluorescence staining were performed to analyze immune cell infiltration in the tumor microenvironment.Results·Database analyses,qRT-PCR,and Western blotting confirmed that some human melanoma cell lines exhibited high STING mRNA expression but low STING protein levels.YM201636 significantly increased STING protein expression in YUMM1.7 cells(P<0.001).Combined treatment with YM201636 and diABZI significantly enhanced phosphorylation of TBK1 and IRF3(P<0.05),indicating effective activation of the STING signaling pathway.This combination also promoted the expression of type Ⅰ interferons(P<0.001)and enhanced tumor cell killing in vitro.In vivo,the combination therapy markedly suppressed melanoma growth compared to monotherapy.Immune profiling of the tumor microenvironment revealed significantly increased infiltration of CD4? T cells and CD8? T cells in the combination treatment group(P<0.05).Conclusion·The PIKfyve inhibitor YM201636 could restore STING protein expression in STING-deficient melanoma and enhance the antitumor efficacy of the STING agonist diABZI,offering a promising therapeutic strategy for tumors with defective STING signaling.