Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

Ischemic stroke (IS), a leading cause of morbidity and mortality worldwide, primarily results from blood clot formation in cerebral vessels, leading to vessel occlusion, reduced cerebral blood flow, and subsequent tissue ischemia. While thrombolytic therapies and mechanical thrombectomy remain cornerstone treatments for restoring blood flow, their clinical efficacy is significantly limited by the narrow therapeutic window, which underscores the critical need for novel, safe, and effective therapeutic strategies. In this review, we present an intensive analysis of four pathophysiological stages of IS progression and their intervention targets, and evaluate both established and emerging therapeutic strategies with the molecular mechanisms underpinning these methods, aiming to enhance the understanding of IS intervention. Additionally, we discuss current challenges in IS therapy, emphasizing the importance of timely, stage-specific approaches to optimize therapeutic outcomes. Finally, we highlight some promising research directions and innovations to advance IS field.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy predominantly managed via chemotherapy. Our clinical sample analysis revealed a significant correlation between elevated CD24 expression in TNBC tumor cells and patient survival rates. We developed a novel antibody-drug conjugate (ADC), named HN03, consisting of an antibody with engineered cysteines for site-specific conjugation with a low toxic nitric oxide (NO) precursor as its payload through a novel Pt(IV)-mediated bioorthogonal self-cleavable linker. HN03 specifically targets tumor cells expressing high levels of CD24, concurrently generating cisplatin and releasing NO upon activation. HN03 also exhibited potent in vitro and in vivo antitumor activity. It significantly reduced tumor growth at various doses, prevented tumor metastasis, with markedly lower toxicity than traditional chemotherapy agents. We found that a key mechanism of its action involved inducing apoptosis and endoplasmic reticulum stress, substantially decreasing the number of M2-type macrophages. Overall, HN03 stands out as a promising therapeutic option for TNBC, offering a targeted treatment with reduced side effects and the potential for improved outcomes. Furthermore, using Pt(IV) in the linker and an NO precursor as the payload enhances the versatility of the Antibody-NO donor Conjugate (ANC), offering new avenues for the design of the next generation of ADCs.

[Purpose]To analyze the diagnostic yield of quantitative fecal immunochemical test(FIT)at different cut-offs in colorectal cancer(CRC)screening.[Methods]The sequential screening method was adapted in Jiashan CRC screening program for local residents aged 40～74 years old,which included a quantitative FIT and high-risk factor questionnaire for primary screening and subsequent colonoscopy for the diagnostic screening.Subjects who participated in quantitative FIT were included in this study between September,2021 and August,2023.The positive predictive values(PPVs)for colorectal neoplasms were calculated at the cut-offs of 100,120,140,160,180 and 200 ng/mL of FIT.The Cochran-Armitage trend test was performed to compare the trend of PPVs at different cut-offs.The effects of different starting age and FIT cut-offs on requirement of colonoscopy and advanced neoplasia detection were assessed.[Results]A total of 58 256 individuals completed the quantitative FIT,and 3 106 had fecal hemoglobin concentrations＞100 ng/mL,among whom 2 186 underwent colonoscopic examination with a compliance rate of 70.38％.The colonoscopy detected 588 cases of non-advanced adenomas and 355 cases of advanced neoplasms(AN),in-cluding 30 cases of CRC and 325 cases of advanced adenomas.Progressively increasing the cut-off showed a decrease in PPVs of non-advanced adenomas and an increase of AN.The ratio of the rate of reduced requirement of colonoscopy to the missed rate of the progressive lesions was the smallest when the screening start age was 45 years old and the positive FIT threshold was set at 100 ng/mL.[Conclusion]There were significant differences in the diagnostic yield at different cut-offs of FIT.Increasing the cut-offs of FIT will elevate PPVs for the advanced neoplasms.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

To analyze the relationship between serum non-HDL-C levels and cardiovascular disease (CVD) mortality in community populations. A retrospective cohort study was conducted using the Yuecheng District Health Information Platform in Shaoxing City, Zhejiang Province. The study cohort included individuals aged 40 years or older with no prior history of CVD who underwent physical examinations at Yuecheng District healthcare institutions between January and December 2019. A total of 39 038 participants were included, including 19 085 males (48.9%) and 19 953 females (51.1%), with a mean age of (73.64±9.10) years. The mean follow-up duration was 52.3 months. During follow-up, 1 227 CVD death events occurred. The results indicated a significant overall association between non-HDL-C levels and the risk of CVD mortality, including coronary heart disease (CHD) and stroke. Cox models indicated that, using the ideal level of non-HDL-C as the reference, the hazard ratios (HRs) for risk of CVD death in the suitable level, borderline elevated level and elevated level groups were 1.24 (95% CI: 1.08-1.42), 1.57 (95% CI: 1.34-1.85) and 2.31 (95% CI: 1.87-2.86), respectively. The corresponding HRs for CHD death were 1.39 (95% CI: 1.10-1.76), 1.69 (95% CI: 1.28-2.12) and 2.53 (95% CI: 1.76-3.64), respectively. Subgroup analysis revealed significant interaction effects between non-HDL-C and sex, smoking, alcohol consumption, and diabetes (all P interaction<0.05). Sensitivity analyses confirmed that results were consistent with the primary findings regarding the association between non-HDL-C and CVD mortality risk. In conclusion, increasing non-HDL-C levels are associated with higher risks of death from cardiovascular diseases, including stroke and CHD. The risk of CVD death associated with elevated non-HDL-C is greater among males, individuals with a history of diabetes, smokers or drinkers. In the future, attention should be paid to the monitoring of non-HDL-C in community health management, and the intensive and personalized management of blood lipids in high-risk population should be strengthened.

Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.

To analyze the relationship between serum non-HDL-C levels and cardiovascular disease (CVD) mortality in community populations. A retrospective cohort study was conducted using the Yuecheng District Health Information Platform in Shaoxing City, Zhejiang Province. The study cohort included individuals aged 40 years or older with no prior history of CVD who underwent physical examinations at Yuecheng District healthcare institutions between January and December 2019. A total of 39 038 participants were included, including 19 085 males (48.9%) and 19 953 females (51.1%), with a mean age of (73.64±9.10) years. The mean follow-up duration was 52.3 months. During follow-up, 1 227 CVD death events occurred. The results indicated a significant overall association between non-HDL-C levels and the risk of CVD mortality, including coronary heart disease (CHD) and stroke. Cox models indicated that, using the ideal level of non-HDL-C as the reference, the hazard ratios (HRs) for risk of CVD death in the suitable level, borderline elevated level and elevated level groups were 1.24 (95% CI: 1.08-1.42), 1.57 (95% CI: 1.34-1.85) and 2.31 (95% CI: 1.87-2.86), respectively. The corresponding HRs for CHD death were 1.39 (95% CI: 1.10-1.76), 1.69 (95% CI: 1.28-2.12) and 2.53 (95% CI: 1.76-3.64), respectively. Subgroup analysis revealed significant interaction effects between non-HDL-C and sex, smoking, alcohol consumption, and diabetes (all P interaction<0.05). Sensitivity analyses confirmed that results were consistent with the primary findings regarding the association between non-HDL-C and CVD mortality risk. In conclusion, increasing non-HDL-C levels are associated with higher risks of death from cardiovascular diseases, including stroke and CHD. The risk of CVD death associated with elevated non-HDL-C is greater among males, individuals with a history of diabetes, smokers or drinkers. In the future, attention should be paid to the monitoring of non-HDL-C in community health management, and the intensive and personalized management of blood lipids in high-risk population should be strengthened.

[Purpose]To analyze the diagnostic yield of quantitative fecal immunochemical test(FIT)at different cut-offs in colorectal cancer(CRC)screening.[Methods]The sequential screening method was adapted in Jiashan CRC screening program for local residents aged 40～74 years old,which included a quantitative FIT and high-risk factor questionnaire for primary screening and subsequent colonoscopy for the diagnostic screening.Subjects who participated in quantitative FIT were included in this study between September,2021 and August,2023.The positive predictive values(PPVs)for colorectal neoplasms were calculated at the cut-offs of 100,120,140,160,180 and 200 ng/mL of FIT.The Cochran-Armitage trend test was performed to compare the trend of PPVs at different cut-offs.The effects of different starting age and FIT cut-offs on requirement of colonoscopy and advanced neoplasia detection were assessed.[Results]A total of 58 256 individuals completed the quantitative FIT,and 3 106 had fecal hemoglobin concentrations＞100 ng/mL,among whom 2 186 underwent colonoscopic examination with a compliance rate of 70.38％.The colonoscopy detected 588 cases of non-advanced adenomas and 355 cases of advanced neoplasms(AN),in-cluding 30 cases of CRC and 325 cases of advanced adenomas.Progressively increasing the cut-off showed a decrease in PPVs of non-advanced adenomas and an increase of AN.The ratio of the rate of reduced requirement of colonoscopy to the missed rate of the progressive lesions was the smallest when the screening start age was 45 years old and the positive FIT threshold was set at 100 ng/mL.[Conclusion]There were significant differences in the diagnostic yield at different cut-offs of FIT.Increasing the cut-offs of FIT will elevate PPVs for the advanced neoplasms.

Objective To optimize the preparation process of Jiawei Suoquan mixture and determine the quality standard.Methods The preparation technology of Jiawei Suoquan mixture was determined by orthogonal test with the yield of paste,the total amount of morroniside and loganin as indexes.The column was Diamonsil Plus 5μm C18 (250mm×4.6mm).Acetonitrile as mobile phase A,0.3％ phosphoric acid solution as mobile phase B,gradient elution;The detection wavelength was 240nm;The flow rate was 1.0ml/min.The column temperature was 35℃.Results The determined extraction process conditions were extracted twice,with 10 times of water and 8 times of water,respectively,for 1.5h and 1.0h.The established methods for the determination of morroniside and loganin were specific,reproducibility and accurate.The linear relationship of morroniside was good in the range of 0.1962 to 0.9810μg,the average recovery was 100.83％,relative standard deviation (RSD) was 1.26％,and the precision and stability met the requirements.The linear relationship of loganin in the sample size range from 0.0995 to 0.7960μg was good.The average recovery was 97.10％ and RSD was 0.84％.The precision and stability met the requirements.Conclusion The preparation process of Jiawei Suoquan mixture is simple and feasible.The content determination method is specific,accurate and reliable,and can be used for quality control of Jiawei Suoquan mixture.