Zoledronic acid (ZA), a nitrogen-containing bisphosphonate with established clinical utility in osteoporosis management, exhibits emerging antitumor potential in estrogen receptor-positive breast cancer. However, the molecular mechanisms underlying its nonapoptotic anticancer effects remain poorly characterized. This study revealed that ZA induced ferroptosis in ER+ breast cancer cells through dual suppression of cystine-glutamate antiporter SLC7A11 and glutathione peroxidase 4 (GPX4), key repressors of ferroptosis. Pharmacological inhibition of ferroptosis using Ferrostatin-1 significantly attenuated ZA-induced cytotoxicity, while combinatorial treatment with the GPX4 inhibitor RSL3 synergistically enhanced lipid peroxidation and cell death. Mechanistically, ZA activated the Hippo-YAP signaling pathway, promoting YAP phosphorylation, proteasomal degradation, and cytoplasmic retention, thereby silencing SLC7A11 and GPX4. We established a novel metabolic vulnerability in hormone-responsive malignancies.These findings position ZA as a bifunctional ferroptosis inducer in ER+ breast cancer, offering a promising strategy to overcome endocrine resistance.

BACKGROUND: The role of inflammation in the development of gestational diabetes mellitus (GDM) has recently become a focus of research. The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI), novel indices, reflect the body's chronic immune-inflammatory state. This study aimed to investigate the associations between the SII or SIRI and GDM. METHODS: A prospective birth cohort study was conducted at Beijing Obstetrics and Gynecology Hospital from February 2018 to December 2020, recruiting participants in their first trimester of pregnancy. Baseline SII and SIRI values were derived from routine clinical blood results, calculated as follows: SII = neutrophil (Neut) count × platelet (PLT) count/lymphocyte (Lymph) count, SIRI = Neut count × monocyte (Mono) count/Lymph count, with participants being grouped by quartiles of their SII or SIRI values. Participants were followed up for GDM with a 75-g, 2-h oral glucose tolerance test (OGTT) at 24-28 weeks of gestation using the glucose thresholds of the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Logistic regression was used to analyze the odds ratios (ORs) (95% confidence intervals [CIs]) for the the associations between SII, SIRI, and the risk of GDM. RESULTS: Among the 28,124 women included in the study, the average age was 31.8 ± 3.8 years, and 15.76% (4432/28,124) developed GDM. Higher SII and SIRI quartiles were correlated with increased GDM rates, with rates ranging from 12.26% (862/7031) in the lowest quartile to 20.10% (1413/7031) in the highest quartile for the SII ( Ptrend <0.001) and 11.92-19.31% for the SIRI ( Ptrend <0.001). The ORs (95% CIs) of the second, third, and fourth SII quartiles were 1.09 (0.98-1.21), 1.21 (1.09-1.34), and 1.39 (1.26-1.54), respectively. The SIRI findings paralleled the SII outcomes. For the second through fourth quartiles, the ORs (95% CIs) were 1.24 (1.12-1.38), 1.41 (1.27-1.57), and 1.64 (1.48-1.82), respectively. These associations were maintained in subgroup and sensitivity analyses. CONCLUSION The SII and SIRI are potential independent risk factors contributing to the onset of GDM.
Humans ; Female ; Pregnancy ; Diabetes, Gestational/immunology* ; Prospective Studies ; Adult ; Inflammation/immunology* ; Glucose Tolerance Test ; Birth Cohort

ObjectiveTo investigate the difference in the level of biliary calprotectin between patients with cholangiocarcinoma and those with choledocholithiasis. MethodsClinical data and bile samples were collected from 34 patients with cholangiocarcinoma and 78 patients with choledocholithiasis who were diagnosed and treated with endoscopic retrograde cholangiopancreatography in The First Affiliated Hospital of Anhui Medical University from May 2021 to September 2022. Fluorescence lateral flow immunoassay was used to measure the levels of calprotectin， hemoglobin， and lactoferrin in bile. The Mann-Whitney U test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between two groups； the Spearman correlation test was used for correlation analysis； the DeLong test was used for comparison of the area under the ROC curve （AUC）. ResultsCompared with the choledocholithiasis group， the cholangiocarcinoma group had significant increases in the levels of calprotectin ［4 795.50 （2 286.79‍ ‍—‍ ‍20 179.73） ng/mL vs 411.16 （67.03‍ ‍—‍ ‍1 991.88） ng/mL， Z=5.572， P<0.001］ and fluoride ［115.70 （109.10‍ — ‍125.50） mmol/L vs 106.60 （98.60‍ ‍—‍ ‍114.40） mmol/L， Z=2.702， P=0.007］. The patients with cholangiocarcinoma were further divided into high cholangiocarcinoma group and low cholangiocarcinoma group， and there was no significant difference between the two groups in the level of calprotectin ［3 867.71 （2 235.66‍ — ‍26 407.40） ng/mL vs 4 795.50 （2 361.15‍ — ‍13 070.53） ng/mL， Z=0.129， P>0.05］. Biliary calprotectin level was correlated with white blood cell count， hemoglobin concentration， and lactoferrin concentration in bile （r=0.316， 0.353， and 0.464， all P<0.05）. The ROC curve analysis showed that biliary calprotectin （with a sensitivity of 79.4% and a specificity of 75.6%）， blood CA19-9 （with a sensitivity of 82.4% and a specificity of 78.2%）， and their combination （with a sensitivity of 88.2% and a specificity of 73.1%） had good sensitivity and specificity in the diagnosis of cholangiocarcinoma. ConclusionThere is an increase in the level of biliary calprotectin in patients with cholangiocarcinoma， and therefore， it might become a biomarker for the diagnosis of cholangiocarcinoma.

Objective To observe the clinical efficacy and safety of external application of Piyan Formula in treating epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKIs)-related rashes.Methods Sixty cases of EGFR-TKIs-related rash patients were randomly allocated into either a treatment group or a control group.The treatment group received external application of Piyan Formula to the rash area twice daily for 14 days.The control group received external application of fucidic acid cream to the rash area twice daily for 14 days.Changes in rash grading,itching grading,quality of life scores and adverse event were observed and recorded in both groups.At the same time,levels of hypersensitive C-reactive protein,interleukin(IL)-6,and IL-1β were measured before treatment and 24 hours after treatment.Results After treatment,the rash severity,itching severity,and quality of life scores were notably lower in the treatment group compared to the control group(P<0.05).The levels of hypersensitive C-reactive protein,IL-6,and IL-1β exhibited a significant decrease compared to their pre-treatment values.(P<0.05).Compared with the control group,the levels of hypersensitive C-reactive protein,IL-6,and IL-1β decreased in the treatment group,with statistically significant differences(P<0.05).No adverse events related to Piyan Formula or fucidic acid cream occurred during the treatment process.Conclusion External application of Piyan Formula in treating EGFR-TKIs-related rashes shows significant clinical efficacy,can effectively reduce the levels of inflammatory factors,and has high safety,thus warranting clinical promotion.

A 36-year-old healthy male served as an allogeneic hematopoietic stem cell donor was given recombinant human granulocyte colony-stimulating factor injection (rhG-CSF) 300 μg by subcutaneous injection once daily for 5 consecutive days. On day 4 of stem cell mobilization, peripheral stem cell collection was performed and rhG-CSF 250 μg was given in addition. The donor experienced dry cough, dyspnea, and difficulty breathing on the next day. Chest CT scan showed diffuse patchy and nodular shadows in both lungs, and relevant tests excluded bacterial/viral infection of the lungs and heart failure. It was considered to be acute lung injury caused by rhG-CSF. After giving glucocorticoids and symptomatic treatments, the symptoms gradually subsided, and the peripheral blood stem cell collection was successful. In the continuing treatment of glucocorticoids, the symptoms of the donor were further improved, and chest CT scan showed marked improvement. At a 3 years of follow-up, the donor' work and life were normal, and no lung discomfort symptoms recurred.

A 36-year-old healthy male served as an allogeneic hematopoietic stem cell donor was given recombinant human granulocyte colony-stimulating factor injection (rhG-CSF) 300 μg by subcutaneous injection once daily for 5 consecutive days. On day 4 of stem cell mobilization, peripheral stem cell collection was performed and rhG-CSF 250 μg was given in addition. The donor experienced dry cough, dyspnea, and difficulty breathing on the next day. Chest CT scan showed diffuse patchy and nodular shadows in both lungs, and relevant tests excluded bacterial/viral infection of the lungs and heart failure. It was considered to be acute lung injury caused by rhG-CSF. After giving glucocorticoids and symptomatic treatments, the symptoms gradually subsided, and the peripheral blood stem cell collection was successful. In the continuing treatment of glucocorticoids, the symptoms of the donor were further improved, and chest CT scan showed marked improvement. At a 3 years of follow-up, the donor' work and life were normal, and no lung discomfort symptoms recurred.

Objective:To investigate the activation level of neutrophil extracellular trap (NET) in the bile of patients with choledocholithiasis and its clinical significance.Methods:From May 2021 to October 2022, 130 patients underwent endoscopic retrograde cholangiopancreatography (ERCP) at the Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University were enrolled. The patients were divided into choledocholithiasis group (90 cases) and non-choledocholithiasis group (40 cases), and the choledocholithiasis group was further divided into large stone group (maximum diameter >1 cm, 36 cases) and small stone group (maximum diameter≤1 cm, 54 cases). The bile samples were collected from 130 patients during operation and 16 choledocholithiasis patients with nasobiliary drainage at 24 h after operation.The levels of myeloperoxidase(MPO), neutrophilelastase(NE), and citrullinated histone H3(CitH3) in bile were detected by enzyme-linked immunosorbent assay.The levels of MPO, NE, and CitH3 were compared between choledocholithiasis group and non-choledocholithiasis group, between large stone group and small stone group, as well as between choledocholithiasis patients before ERCP and after ERCP. Mann-Whitney U test and Wilcoxon signed rank test were used for statistical analysis. Results:The levels of MPO, NE and CitH3 in the bile of choledocholithiasis group were 32.6 U/L(28.5 U/L), 30.6 ng/L(35.2 ng/L) and 0.37 μg/L(0.73 μg/L), respectively, which were all higher than those of non-choledocholithiasis group (19.9 U/L(36.4 U/L), 18.2 ng/L(27.4 ng/L), and 0.10 μg/L(0.25 μg/L)), and the differences were statistically significant ( Z=2.91, 3.20 and 3.34; P=0.004, 0.001 and 0.001). The levels of MPO, NE and CitH3 of large stone group were 47.0 U/L(49.4 U/L), 48.4 ng/L(39.5 ng/L) and 0.83 μg/L(1.08 μg/L), respectively, which were all higher than those of small stone group (29.3 U/L(17.5 U/L), 24.0 ng/L(25.8 ng/L), and 0.27 μg/L(0.45 μg/L)), and the differences were statistically significant ( Z=2.01, 3.58 and 3.63; P=0.044, <0.001 and <0.001). The levels of MPO, NE and CitH3 in the bile of choledocholithiasis patients after ERCP significantly decreased compare with those before ERCP (19.4 U/L(19.8 U/L) vs. 33.6 U/L(36.7 U/L), 12.7 ng/L(15.1 ng/L) vs. 22.7 ng/L(25.9 ng/L), 0.05 μg/L(0.12 μg/L) vs. 0.14 μg/L(0.27 μg/L)), and the differences were statistically significant ( Z=3.52, 3.30 and 3.18; all P<0.001). Conclusion:The activation level of NET in the bile of patients with choledocholithiasis increase, while the activation level of NET decrease after ERCP, which indicate that NET may be involved in the formation of choledocholithiasis.

OBJECTIVE To systematically review the background of bioequivalence assessment of nasal sprays and nasal aerosols and the guiding considerations for the bioequivalence assessment of these complex drug-device combination products by regulatory authorities in the United States, the European Union(EU) and China. METHODS This article provided detailed explanations on the innovative weight of evidence assessment approach adopted by the US Food and Drug Administration(FDA), and the statistical rationale, methods and considerations for the bioequivalence assessment of nasal sprays and nasal aerosols. Using the calculation methods described in the draft guidance for budesonide inhalation suspension and the draft guidance for fluticasone nasal spray propionate issued by FDA, the statistical parameters of two-sided and one-sided population bioequivalence calculation were realized through R language programming, and pseudo-code for the population bioequivalence (PBE) calculation programs was provided. This article also presented a comprehensive review of published guidelines and summaries review principles of the EU and China for nasal sprays and nasal aerosols equivalence assessment. RESULTS & CONCLUSION Nasal sprays/nasal aerosols is the focus of innovative and generic drug development in recent years. This paper provided valuable considerations references for the research and development, quality control and bioequivalence evaluation of generic preparations of nasal sprays/nasal aerosols.

ObjectiveTo investigate the impacts of circadian misalignment on glucose uptake of skeletal muscle and metabolism in rats. MethodsA total of 36 male Wistar rats were divided into circadian alignment (CA, normal light-dark cycles, n = 18) and circadian misalignment (CM, shifted light-dark cycles, n = 18) groups. ClockLab behavior analysis was performed for 18 days (61 to 78 days after modeling). Intraperitoneal injection glucose tolerance test and physiologic measures were performed 85 days after modeling. They were euthanized 91 to 92 days after modeling, at 8:00, 12:00, 16:00, 20:00, 24:00 and 4:00 next day. Gastrocnemius tissue was collected and measured for Bmal1, Clock, Per2, Tbc1d1, Glut4 and Pgc1α by reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR). ResultsThe circadian cycle increased (t = -6.557, P < 0.001), the amplitude decreased (t = 2.326, P = 0.030) and the area under curve (AUC) of the blood glucose of intraperitoneal glucose tolerance test decreased (t = -2.622, P = 0.016) in CM group. In gastrocnemius, there was difference in the expression of the Bmal1 (F = 6.691, P < 0.001), Clock (F = 4.188, P = 0.007), Per2 (F = 10.893, P < 0.001), Tbc1d1 (F = 3.411, P = 0.018), Glut4 (F = 5.439, P = 0.002) and Pgc1α (F = 15.376, P < 0.001) across different time; meanwhile, there was difference in the expression of Bmal1 (F = 5.020, P = 0.035), Per2 (F = 8.996, P = 0.006), Tbc1d1 (F = 51.111, P < 0.001) and Pgc1α (F = 10.177, P = 0.004) between groups, and the total Tbc1d1 expression decreased in CM group (t = 4.349, P < 0.001). ConclusionCM induced by shifted light-dark cycles may lead to glucose tolerance impairment in rats, which may be related to the decreased expression of Tbc1d1 and the changes of transcription rhythm of Bmal1, Per2 and Pgc1α in gastrocnemius.

Objective: To monitor the antimicrobial resistance and drug-resistance genes of Yersinia enterocolitis, Y. intermedia and Y. frederiksenii recovered from retailed fresh poultry of 4 provinces of China. Methods: The susceptibility of 25 isolated Yersinia spp. to 14 classes and 25 kinds of antibiotics was determined by broth microdilution method according to CLSI (Clinical and Laboratory Standards Institute). The antibiotic resistance genes were predicted with antibiotic resistance genes database (ARDB) using whole genome sequences of Yersinia spp. Results: In all 22 Y. enterocolitis tested, 63.7% (14 isolates), 22.8% (5 isolates), 4.6% and 4.6% of 1 isolates exhibited the resistance to cefoxitin, ampicillin-sulbactam, nitrofurantoin and trimethoprim-sulfamethoxazole, respectively. All the 25 isolates were multi-drug resistant to more than 3 antibiotics, while 64.0% of isolates were resistant to more than 4 antibiotics. A few Y. enterocolitis isolates of this study were intermediate to ceftriaxone and ciprofloxacin. Most Yersinia spp. isolates contained antibiotic resistance genes mdtG, ksgA, bacA, blaA, rosAB and acrB, and 5 isolates recovered from fresh chicken also contained dfrA1, catB2 and ant3ia. Conclusion The multi-drug resistant Yersinia spp. isolated from retailed fresh poultry is very serious in the 4 provinces of China, and their contained many kinds of drug-resistance genes.