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.

Radiopharmaceuticals operate by combining radionuclides with carriers. The radiation energy emitted by radionuclides is utilized to selectively irradiate diseased tissues while minimizing damage to healthy tissues. In comparison to external beam radiation therapy, radionuclide drugs demonstrate research potential due to their biological targeting capabilities and reduced normal tissue toxicity. This article reviews the applications and research progress of radiopharmaceuticals in cancer treatment. Several key radionuclides are examined, including ²²³Ra, ⁹⁰Y, Lutetium-177 (¹⁷⁷Lu), ²¹²Pb, and Actinium-225 (²²⁵Ac). It also explores the current development trends of radiopharmaceuticals, encompassing the introduction of novel radionuclides, advancements in imaging technologies, integrated diagnosis and treatment approaches, and equipment-medication combinations. We review the progress in the development of new treatments, such as neutron capture therapy, proton therapy, and heavy ion therapy. Furthermore, we examine the challenges and breakthroughs associated with the clinical translation of radiopharmaceuticals and provide recommendations for the research and development of novel radionuclide drugs.
Humans ; Radiopharmaceuticals/therapeutic use* ; Neoplasms/radiotherapy* ; Radioisotopes/therapeutic use* ; Animals

[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.

Objective To address the limitations of conventional physics-informed neural network(PINN)in handling hemodynamic boundary constraints,an improved hard boundary-constrained PINN(HBC-PINN)framework was proposed to achieve precise prediction of blood flow fields within stenotic arteries.Methods An idealized stenosed vessel geometry model was established and computational fluid dynamic simulation was performed to obtain a validation dataset.Appropriate boundary dependent trial functions were designed according to the hard constraint method to embed the flow boundary conditions into the network output.Thus,an HBC-PINN model with the hard boundary constraint method was constructed to predict the velocity field and pressure field of stenosed blood flow.Meanwhile,an original PINN model with the soft constraint method was also built for comparison.By evaluating the accuracy of the two models on the validation dataset,the capability of the HBC-PINN model to simulate hemodynamics without using any labeled data for training was verified.Results The effectiveness of the HBC-PINN method in predicting hemodynamic parameters in stenosed blood flow tasks was validated.The relative L2 errors of the flow velocity and pressure predicted by the HBC-PINN in two different stenosis scenarios were both lower than 0.5％,representing an improvement of over 48.8％in accuracy compared to the original PINN model.Additionally,the prediction accuracy of the transverse velocity also increased by more than 35.4％.Conclusions Implementing hard constraints on boundary conditions in the PINN modeling process can effectively improve the prediction accuracy of hemodynamic parameters and the efficiency of model solving.

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.

Objective To address the limitations of conventional physics-informed neural network(PINN)in handling hemodynamic boundary constraints,an improved hard boundary-constrained PINN(HBC-PINN)framework was proposed to achieve precise prediction of blood flow fields within stenotic arteries.Methods An idealized stenosed vessel geometry model was established and computational fluid dynamic simulation was performed to obtain a validation dataset.Appropriate boundary dependent trial functions were designed according to the hard constraint method to embed the flow boundary conditions into the network output.Thus,an HBC-PINN model with the hard boundary constraint method was constructed to predict the velocity field and pressure field of stenosed blood flow.Meanwhile,an original PINN model with the soft constraint method was also built for comparison.By evaluating the accuracy of the two models on the validation dataset,the capability of the HBC-PINN model to simulate hemodynamics without using any labeled data for training was verified.Results The effectiveness of the HBC-PINN method in predicting hemodynamic parameters in stenosed blood flow tasks was validated.The relative L2 errors of the flow velocity and pressure predicted by the HBC-PINN in two different stenosis scenarios were both lower than 0.5％,representing an improvement of over 48.8％in accuracy compared to the original PINN model.Additionally,the prediction accuracy of the transverse velocity also increased by more than 35.4％.Conclusions Implementing hard constraints on boundary conditions in the PINN modeling process can effectively improve the prediction accuracy of hemodynamic parameters and the efficiency of model solving.

[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 investigate the expression of the novel immune checkpoint SIGLEC9 and SIGLEC9+T cells in cervical cancer and its clinical correlation.Methods:A total of 132 paraffin-embedded specimens of cervical tissue from patients with cervical cancer who under-went surgical treatment or pathological biopsy at The First Affiliated Hospital of Xinjiang Medical University from May 2022 to October 2023 were included for study.In addition,58 paraffin-embedded specimens of normal cervical tissue from patients with benign uterine leiomyomas who underwent total uterine excision during the same period were selected as normal controls.Furthermore,108 peripheral blood samples from patients with cervical cancer who underwent surgical treatment or pathological biopsy were collected for study,and 86 peripheral blood samples from healthy individuals during the same time period were selected as controls.Bioinformatics technology,im-munohistochemical(IHC)staining,flow cytometry,and double immunofluorescence(IF)staining were used to assess the expression of SIGLEC9 and SIGLEC9+T cells in cervical cancer,followed by correlation analysis with clinical indicators.Results:The bioinformatics,IHC,and double IF staining results showed that SIGLEC9 and SIGLEC9+T cells were highly expressed in cervical cancer tissues(P<0.05).The flow cyto-metry results showed that SIGLEC9+CD4+T and SIGLEC9+CD8+T cells were increased in the peripheral blood of patients with cervical cancer(P<0.05).SIGLEC9 expression correlated with tumor size,FIGO stage,lymph node metastasis,and human papillomavirus(HPV)infection(P<0.05).Conclusions:The novel immune checkpoint SIGLEC9 was highly expressed in cervical cancer tissues,and SIGLEC9+T cells infiltrated cervical cancer tissues.In vitro cell experiments showed that SIGLEC9 affects T cell function.In summary,SIGLEC9 provides a novel research direction for understanding the immune escape mechanism of cervical cancer and a novel therapeutic target for cervical cancer immuno-therapy.