Targeting T-cell is a strategy to control allogeneic response disorders, such as acute graft-versus-host disease (GVHD) which is an important cause of therapy-failure after allogeneic hematopoietic cell transplants. Free fatty acid receptor-4 (FFAR4) is a regulator of obesity but its role in T-cell and allogeneic reactions is unknown. Here, we found knockout of Ffar4 in donor T-cells in a mouse allograft model increased acute GVHD whereas the natural FFAR4 ligands and the synthetic FFAR4 agonists decreased it. FFAR4 agonist-mediated anti-acute GVHD effects depended on FFAR4-expression in donor T-cells. The FFAR4 agonist CpdA suppressed donor T-cell-mediated alloreaction by activating an aryl hydrocarbon receptor (AhR) pathway. CpdA recruited β-Arrestin2 to FFAR4 which facilitated nuclear translocation of AhR and upregulation of IL-22. The CpdA-mediated anti-acute GVHD effect was absent in mice receiving Ahr-knockout or Il22-knockout T-cells. Recipient-expressing Ffar4 was also important for the anti-acute GVHD effect of CpdA which inhibited activation of antigen presenting cells. Importantly, CpdA decreased acute GVHD in obese mice, an effect also depended on Ffar4-expression in donor T-cells and recipients. Our study shows the immunoregulatory effect of FFAR4 in T-cell, and targeting FFAR4 might be a relative option for controlling allogeneic reactions in obese patients.

Objective To explore the feasibility of radiomics nomogram based on magnetic resonance diffusion weighted imaging for predicting the expression of Ki-67 in breast cancer.Methods A retrospective study was conducted on patients with breast cancer confirmed by surgery and pathology in the Second Affiliated Hospital of Guangdong Medical University.All patients were detected by Ki-67 expression staining,and then divided into group A(n=28,low-level expression of Ki-67)and group B(n=73,high-level expression of Ki-67).The apparent diffusion coefficient(ADC)graph was generated from diffusion weighted images,and the two groups were compared for radiomics features of ADC images and clinical data.The expression level of Ki-67 in breast cancer was predicted using the features of LASSO after dimensionality reduction,and a nomogram model was established,whose diagnostic efficiency was analyzed with receiver operating characteristic curve.Results No significant difference was observed in ADC value,age,carbohydrate antigen 199,carbohydrate antigen 153,carbohydrate antigen 125 and carcinoembryonic antigen between two groups(P>0.05).LASSO regression identified two radiomics features as predictors for the expression level of Ki-67 in breast cancer.The best tuning Lambda of LASSO was-0.125 690 135 478 682,and the included radiomics features for nomogram establishment were MinIntensity and Quantile95.The established nomogram had an area under ROC curve of 0.917,achieving a sensitivity of 91.7%and a specificity of 83.3%.Conclusion The expression of Ki-67 in breast cancer can be predicted based on the radiomics features of ADC images,which can provide a noninvasive detection method for evaluating the proliferation degree and treatment prognosis of breast cancer.

Objective:To illustrate the clinical modeling and commissioning results of Monte Carlo dose calculation algorithm in RayStation treatment planning system (TPS) for a domestically developed synchrotron-based spot scanning proton therapy system (SAPT-PS-01).Methods:The proton pencil beam model in RayStation required integral depth dose curves, spot profiles and absolute dose as the input beam data. It was not necessary to collect beam parameters with range shifter. The integral depth dose curves of a single spot were measured by an 8 cm parallel ion chamber. A 2-dimensional scintillation detector was used to measure the in-air spot profile at 5 different depths including the isocenter plane. The absolute dose was calibrated by a 0.25 cm parallel ion chamber under the single energy layer irradiation with a field size of 10 cm × 10 cm. After modeling, the results of the beam model and the Monte Carlo dose calculation algorithm were validated from the range, spot profile, point-dose in a spread-out Bragg peak, planar dose in a clinical plan, point dose in an end-to-end test.Results:For the 94 energy layers, the maximum deviation between the calculated and measured range was 0.03 cm. The maximum difference between the calculated and measured in-air spot sigma was 0.015 cm, and the deviation of in-water spot sigma was measured within ±15%. Compared with the measured values, the calculated dose deviation of 138 measured points in the spread-out Bragg peak was within 3%. For the planar dose verification of clinical plans, the TPS-calculated dose distribution of 285 planes agreed well with the measurement with a minimum gamma-passing rate of 90%, and the gamma passing rate of almost 95% of planes were greater than 95%. The point dose measurements for 8 beams in the end-to-end tests under 4 clinical scenarios were within 5%.Conclusions:The acceptable beam model validation results and successful end-to-end test confirm that the Monte Carlo dose calculation algorithm modeling for the synchrotron-based spot scanning proton therapy system is accurate, which is applicable for the design of patient treatment plan.

Objective To investigate the association between single nucleotide polymorphisms(SNP)rs57095329 and rs6864584 of miR-146a gene and cervical intraepithelial neoplasia(CIN).Methods A total of 96 patients diagnosed with CIN were randomly collected as the CIN group,and 225 healthy individuals examined during the same period were selected as the control group using SPSS software.Genotyping of the above SNP loci was performed using the TaqMan probe method,and their correlation with CIN was analyzed.Results The allele and genotype distribution of rs57095329 showed a statistically significant differences compared to the control group,with the frequency of the allele A in the CIN group significantly lower than that in the control group(P<0.001;OR=0.48,95%CI:0.32～0.70).In the dominant model,individuals carrying the G allele(A/G-G/G)had a significantly increased risk of CIN(P<0.001;OR=2.67,95%CI:1.64～4.37).In contrast,no correlation was found between the rs6864584 and the risk of CIN.Conclusion The A allele of the miR-146a gene at the rs57095329 locus may be a protective factor for CIN.

Objective To explore the feasibility of radiomics nomogram based on magnetic resonance diffusion weighted imaging for predicting the expression of Ki-67 in breast cancer.Methods A retrospective study was conducted on patients with breast cancer confirmed by surgery and pathology in the Second Affiliated Hospital of Guangdong Medical University.All patients were detected by Ki-67 expression staining,and then divided into group A(n=28,low-level expression of Ki-67)and group B(n=73,high-level expression of Ki-67).The apparent diffusion coefficient(ADC)graph was generated from diffusion weighted images,and the two groups were compared for radiomics features of ADC images and clinical data.The expression level of Ki-67 in breast cancer was predicted using the features of LASSO after dimensionality reduction,and a nomogram model was established,whose diagnostic efficiency was analyzed with receiver operating characteristic curve.Results No significant difference was observed in ADC value,age,carbohydrate antigen 199,carbohydrate antigen 153,carbohydrate antigen 125 and carcinoembryonic antigen between two groups(P>0.05).LASSO regression identified two radiomics features as predictors for the expression level of Ki-67 in breast cancer.The best tuning Lambda of LASSO was-0.125 690 135 478 682,and the included radiomics features for nomogram establishment were MinIntensity and Quantile95.The established nomogram had an area under ROC curve of 0.917,achieving a sensitivity of 91.7%and a specificity of 83.3%.Conclusion The expression of Ki-67 in breast cancer can be predicted based on the radiomics features of ADC images,which can provide a noninvasive detection method for evaluating the proliferation degree and treatment prognosis of breast cancer.

Objective:To illustrate the clinical modeling and commissioning results of Monte Carlo dose calculation algorithm in RayStation treatment planning system (TPS) for a domestically developed synchrotron-based spot scanning proton therapy system (SAPT-PS-01).Methods:The proton pencil beam model in RayStation required integral depth dose curves, spot profiles and absolute dose as the input beam data. It was not necessary to collect beam parameters with range shifter. The integral depth dose curves of a single spot were measured by an 8 cm parallel ion chamber. A 2-dimensional scintillation detector was used to measure the in-air spot profile at 5 different depths including the isocenter plane. The absolute dose was calibrated by a 0.25 cm parallel ion chamber under the single energy layer irradiation with a field size of 10 cm × 10 cm. After modeling, the results of the beam model and the Monte Carlo dose calculation algorithm were validated from the range, spot profile, point-dose in a spread-out Bragg peak, planar dose in a clinical plan, point dose in an end-to-end test.Results:For the 94 energy layers, the maximum deviation between the calculated and measured range was 0.03 cm. The maximum difference between the calculated and measured in-air spot sigma was 0.015 cm, and the deviation of in-water spot sigma was measured within ±15%. Compared with the measured values, the calculated dose deviation of 138 measured points in the spread-out Bragg peak was within 3%. For the planar dose verification of clinical plans, the TPS-calculated dose distribution of 285 planes agreed well with the measurement with a minimum gamma-passing rate of 90%, and the gamma passing rate of almost 95% of planes were greater than 95%. The point dose measurements for 8 beams in the end-to-end tests under 4 clinical scenarios were within 5%.Conclusions:The acceptable beam model validation results and successful end-to-end test confirm that the Monte Carlo dose calculation algorithm modeling for the synchrotron-based spot scanning proton therapy system is accurate, which is applicable for the design of patient treatment plan.

OBJECTIVE To provide reference for improving the pre-prescription review system and reducing the occurrence of medication error by analyzing the drug-related problems(DRPs)in the pre-prescription review orders of pediatric outpatient clinics using the Pharmaceutical Care Network Europe(PCNE)classification system.METHODS The data of pre-prescription review orders were retrospectively collected from outpatient department of Shanghai Children's Medical Center,Shanghai Jiao Tong University School of Medicine from July 2022 to June 2023;DRPs in the pre-prescription review orders were classified and summarized by using the PCNE classification system(version 9.1),and then analyzed in terms of types and causes of issues,and the acceptance of interventions.RESULTS A total of 66 017 DRPs orders were included,involving 41 165 patients.The proportion of DRPs orders in children aged ≤5 years old was the highest(58.25％),followed by children aged 6-12 years old(33.52％);the department with the highest proportion of DRPs was internal medicine of pediatrics department(71.41％);the department with the highest incidence of DRPs was thoracic surgery department(9.73％);top three drug categories of DRPs orders were systemic anti-infective drugs(25.26％),Chinese patent medicines(24.74％)and respiratory drugs(22.38％).Referring to PCNE classification system,the types of DRPs mainly focused on treatment safety(64.86％);the reasons of DRPs orders mainly focused on dose selection(82.09％),of which 41.26％were due to excessive drug dosage;92.13％of interventions could be accepted and fully executed by doctors.CONCLUSIONS DRPs orders identified by the pre-prescription review system can be effectively analyzed by using PCNE classification system.Pharmacists should focus on medication use in children aged＜5 years old,update and develop personalized prescription review rules timely,and meet the rational needs of clinical medication for children.

Objective:To investigate the clinical features and therapeutic efficacy of patients with hereditary leiomyomatosis and renal cell carcinoma(RCC) syndrome-associated RCC (HLRCC-RCC) in China.Methods:The clinical data of 119 HLRCC-RCC patients with fumarate hydratase (FH) germline mutation confirmed by genetic diagnosis from 15 medical centers nationwide from January 2008 to December 2021 were retrospectively analyzed. Among them, 73 were male and 46 were female. The median age was 38(13, 74) years. The median tumor diameter was 6.5 (1.0, 20.5) cm. There were 38 cases (31.9%) in stage Ⅰ-Ⅱand 81 cases (68.1%) in stage Ⅲ-Ⅳ. In this group, only 11 of 119 HLRCC-RCC patients presented with skin smooth muscle tumors, and 44 of 46 female HLRCC-RCC patients had a history of uterine fibroids. The pathological characteristics, treatment methods, prognosis and survival of the patients were summarized.Results:A total of 86 patients underwent surgical treatment, including 70 cases of radical nephrectomy, 5 cases of partial nephrectomy, and 11 cases of reductive nephrectomy. The other 33 patients with newly diagnosed metastasis underwent renal puncture biopsy. The results of genetic testing showed that 94 patients had FH gene point mutation, 18 had FH gene insertion/deletion mutation, 4 had FH gene splicing mutation, 2 had FH gene large fragment deletion and 1 had FH gene copy number mutation. Immunohistochemical staining showed strong 2-succinocysteine (2-SC) positive and FH negative in 113 patients. A total of 102 patients received systematic treatment, including 44 newly diagnosed patients with metastasis and 58 patients with postoperative metastasis. Among them, 33 patients were treated with tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI), 8 patients were treated with bevacizumab combined with erlotinib, and 61 patients were treated with TKI monotherapy. Survival analysis showed that the median progression-free survival (PFS) of TKI combined with ICI was 18 (5, 38) months, and the median overall survival (OS) was not reached. The median PFS and OS were 12 (5, 14) months and 30 (10, 32) months in the bevacizumab combined with erlotinib treatment group, respectively. The median PFS and OS were 10 (3, 64) months and 44 (10, 74) months in the TKI monotherapy group, respectively. PFS ( P=0.009) and OS ( P=0.006) in TKI combined with ICI group were better than those in bevacizumab combined with erlotinib group. The median PFS ( P=0.003) and median OS ( P=0.028) in TKI combined with ICI group were better than those in TKI monotherapy group. Conclusions:HLRCC-RCC is rare but has a high degree of malignancy, poor prognosis and familial genetic characteristics. Immunohistochemical staining with strong positive 2-SC and negative FH can provide an important basis for clinical diagnosis. Genetic detection of FH gene germ line mutation can confirm the diagnosis. The preliminary study results confirmed that TKI combined with ICI had a good clinical effect, but it needs to be confirmed by the results of a large sample multi-center randomized controlled clinical study.

Objective:To evaluate the effect of autologous hematopoietic stem cell transplantation (ASCT) on the treatment of relapsed/refractory multiple myeloma (RRMM) with chimeric antigen receptor T cell (CAR-T) therapy.Methods:A retrospective cohort study. The clinical data of 168 patients with RRMM who underwent CAR-T therapy at the Department of Hematology, Xuzhou Medical University Hospital from 3 January 2020 to 13 September 2022 were analyzed. Patients were classified into a transplantation group (TG; n=47) and non-transplantation group (NTG; n=121) based on whether or not they had undergone ASCT previously. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the levels of CD3, CD4, CD8, CD19, CD56 and natural killer (NK) cells before CAR-T infusion were analyzed by χ2 test, Kaplan-Meier method and independent sample t-test. Results:Among 168 patients with RRMM, 98 (58.3%) were male. The median age of onset was 57 (range 30-70) years. After CAR-T therapy, the ORR of patients was 89.3% (92/103) in the NTG and 72.9% (27/73) in the TG. The ORR of the NTG was better than that of the TG ( χ2=5.71, P=0.017). After 1 year of CAR-T therapy, the ORR of the NTG was 78.1% (75/96), and that of the TG was 59.4% (19/32). The ORR of the NTG was better than that of the TG ( χ2=4.32, P=0.038). The median OS and PFS in the NTG were significantly longer than those in the TG (OS, 30 vs. 20 months; PFS, 26 vs. 12 months; both P<0.05). The CD4 level before CAR-T infusion in the TG was significantly lower than that in the NTG (25.65±13.56 vs. 32.64±17.21; t=-2.15, P=0.034), and there were no significant differences in the counts of CD3, CD8, CD19, CD56, and NK cells between the TG and NTG (all P>0.05). Conclusion:Among patients suffering from RRMM who received CAR-T therapy, patients who did not receive ASCT had significantly better outcomes than those who had received ASCT previously, which may have been related to the CD4 level before receiving CAR-T therapy.

Drug therapy is a common method to cure diseases and relieve symptoms.The value of patient-reported outcome(PRO)in evaluating the effect of drug therapy has been increasingly paid attention.The PRO scale is a standardized questionnaire,which can scientifically evaluate the experiences and subjective effects of drug use from a patient-centered perspective,and help patients and clinicians make more reasonable medication decisions.By reviewing and sorting out relevant global literature,this paper found that the content of the PRO scales relevant to drug therapy focused on five fields:"medication satisfaction""medication adherence""drug treatment burden""medication-related quality of life"and"adverse drug reactions".This paper described the basic information,measurement characteristics and application of common scales in recent years respectively,and summarized and analyzed the problems and enlightenment of scale development,aiming to provide theoretical reference for the selection,application and development of PRO scales.