A probe for NIR-II imaging and multimodal analysis of early Alzheimer's disease by targeting CTGF.

To date, earlier diagnosis of Alzheimer's disease (AD) is still challenging. Recent studies revealed the elevated expression of connective tissue growth factor (CTGF) in AD brain is an upstream regulator of amyloid-beta (Aß) plaque, thus CTGF could be an earlier diagnostic biomarker of AD than Aß plaque. Herein, we develop a peptide-coated gold nanocluster that specifically targets CTGF with high affinity (KD ~ 21.9 nM). The probe can well penetrate the blood-brain-barrier (BBB) of APP/PS1 transgenic mice at early-stage (earlier than 3-month-old) in vivo, allowing non-invasive NIR-II imaging of CTGF when there is no appearance of Aß plaque deposition. Notably, this probe can also be applied to measuring CTGF on postmortem brain sections by multimodal analysis, including fluorescence imaging, peroxidase-like chromogenic imaging, and ICP-MS quantitation, which enables distinguishment between the brains of AD patients and healthy people. This probe possesses great potential for precise diagnosis of earlier AD before Aß plaque formation.

Enhancing Liver Delivery of Gold Nanoclusters via Human Serum Albumin Encapsulation for Autoimmune Hepatitis Alleviation.

Peptide-protected gold nanoclusters (AuNCs), possessing exceptional biocompatibility and remarkable physicochemical properties, have demonstrated intrinsic pharmaceutical activity in immunomodulation, making them a highly attractive frontier in the field of nanomedicine exploration. Autoimmune hepatitis (AIH) is a serious autoimmune liver disease caused by the disruption of immune balance, for which effective treatment options are still lacking. In this study, we initially identified glutathione (GSH)-protected AuNCs as a promising nanodrug candidate for AIH alleviating in a Concanavalin A (Con A)-induced mice model. However, to enhance treatment efficiency, liver-targeted delivery needs to be improved. Therefore, human serum albumin (HSA)-encapsulated AuNCs were constructed to achieve enhanced liver targeting and more potent mitigation of Con A-induced elevations in plasma aspartate transaminase (AST), alanine transaminase (ALT), and liver injury in mice. In vivo and in vitro mechanism studies indicated that AuNCs could suppress the secretion of IFN-γ by Con A-stimulated T cells and subsequently inhibit the activation of the JAK2/STAT1 pathway and eventual hepatocyte apoptosis induced by IFN-γ. These actions ultimately protect the liver from immune cell infiltration and damage caused by Con A. These findings suggest that bio-protected AuNCs hold promise as nanodrugs for AIH therapy, with their liver targeting capabilities and therapeutic efficiency being further improved via rational surface ligand engineering.

Clinical prediction models of radiation-induced rectal injury after brachytherapy combined with external beam radiation therapy for cervical cancer / 中华放射医学与防护杂志

Objective:To explore the dosimetric differences of different dose accumulation method for brachytherapy combined with external beam radiation therapy (EBRT) of cervical cancer and establish clinical prediction models for radiation-induced late rectal injury (RLRI) after radiotherapy.Methods:A retrospective analysis was conducted for the clinical data of patients who received radical concurrent chemoradiotherapy (CCRT) for cervical cancer in the Department of Oncology of the Affiliated Hospital of North Sichuan Medical College from January 1, 2020 to November 30, 2021. EBRT combined with brachytherapy was employed for the patients, and dose assessment was performed in two means: the direct accumulation using equivalent dose in 2-Gy fractions (EQD2) and deformable image registration (DIR)-based dose accumulation of 3D planning images. The toxicity criteria of the Radiation Therapy Oncology Group were adopted as the RLRI grading criteria. The prediction models of RLRI using both dose assessment method were constructed. The areas under the receiver operating characteristic (ROC) curves were calculated to assess the predictive accuracy of the different dose assessment method.Results:In the case of brachytherapy, the D95% and D90% EQD2 doses to high-risk clinical target volumes (HR-CTVs) were 2.18 and 2.92 Gy higher respectively and the D2 cm 3, D1 cm 3, and D0.1 cm 3 EQD2 doses to the rectal were 1.74, 2.28, and 2.26 Gy higher, respectively compared to DIR-based dose accumulation ( t = 3.82, 5.21, 4.58, 5.17, 2.05, P < 0.05). For EBRT combined with brachytherapy, the D2 cm 3, D1 cm 3, and D0.1 cm 3 EQD2 doses to the rectal were 6.22, 7.61, 9.56 Gy higher than DIR-based doses, respectively, and the dosimetric differences were statistically significant ( t = 9.40, 10.59, 7.87, P < 0.001). The joint prediction model yielded an area under the ROC curve of 0.788. The sensitivity and specificity of the optimal cut-off value were 0.850 and 0.660, respectively. Furthermore, the Hosmer-Lemeshow goodness-of-fit tests indicated high goodness-of-fit ( P > 0.05). The prediction model for DIR-based dose accumulation of traditional predictors yielded areas under the ROC curves for D2 cm 3 and D1 cm 3 to the rectal of 0.784 and 0.763, respectively. The sensitivities of the optimal cut-off values were 0.850 and 0.750, respectively, and the specificities were 0.679 and 0.717, respectively. Conclusions:There are dosimetric differences between the direct dose accumulation using EQD2 and DIR-based dose accumulation of 3D planning images for brachytherapy combined with EBRT. Both the joint prediction model and the DIR-based dose accumulation of D2 cm 3 and D1 cm 3 to the rectal are effective in predicting RLRI. Given the complex calculation of the joint prediction model, it is recommended that RLRI should be predicted through DIR-based dose accumulation of D2 cm 3 and D1 cm 3 to the rectal clinically.

Colon-Accumulated Gold Nanoclusters Alleviate Intestinal Inflammation and Prevent Secondary Colorectal Carcinogenesis via Nrf2-Dependent Macrophage Reprogramming.

Inflammatory bowel disease (IBD) is one of the main factors leading to colitis-associated colorectal cancer (CAC). Therefore, it is critical to develop an effective treatment for IBD to prevent secondary colorectal carcinogenesis. M2 macrophages play crucial roles in the resolution phase of intestinal inflammation. However, traditional drugs rarely target intestinal M2 macrophages, and they are not easily cleared. Gold nanoclusters are known for their in vivo safety and intrinsic biomedical activities. In this study, a glutathione-protected gold nanocluster is synthesized and evaluated, namely, GA. Interestingly, GA specifically accumulates in the colon during IBD. Furthermore, GA not only promotes M2 differentiation of IL-4-treated peritoneal macrophages but also reprograms macrophage polarization from M1 to M2 in a pro-inflammatory environment. Mechanistically, this regulatory effect is exerted through activating the antioxidant Nrf2 signaling pathway, but not traditional STAT6. When applied in IBD mice, we found that GA elevates M2 macrophages and alleviates IBD in an Nrf2-dependent manner, evidenced by the abolished therapeutic effect upon Nrf2 inhibitor treatment. Most importantly, GA administration significantly suppresses AOM/DSS-induced CAC, without causing obvious tissue damage, providing critical evidence for the potential application of gold nanoclusters as nanomedicine for the treatment of IBD and CAC.

Virtual reality-induced motor function of the upper extremity and brain activation in stroke: study protocol for a randomized controlled trial.

Background: The benefits of virtual reality (VR)-based rehabilitation were reported in patients after stroke, but there is insufficient evidence about how VR promotes brain activation in the central nervous system. Hence, we designed this study to explore the effects of VR-based intervention on upper extremity motor function and associated brain activation in stroke patients. Methods/design: In this single-center, randomized, parallel-group clinical trial with a blinded assessment of outcomes, a total of 78 stroke patients will be assigned randomly to either the VR group or the control group. All stroke patients who have upper extremity motor deficits will be tested with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and clinical evaluation. Clinical assessment and fMRI will be performed three times on each subject. The primary outcome is the change in performance on the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE). Secondary outcomes are functional independence measure (FIM), Barthel Index (BI), grip strength, and changes in the blood oxygenation level-dependent (BOLD) effect in the ipsilesional and contralesional primary motor cortex (M1) on the left and right hemispheres assessed with resting-state fMRI (rs-fMRI), task-state fMRI (ts-fMRI), and changes in EEG at the baseline and weeks 4 and 8. Discussion: This study aims to provide high-quality evidence for the relationship between upper extremity motor function and brain activation in stroke. In addition, this is the first multimodal neuroimaging study that explores the evidence for neuroplasticity and associated upper motor function recovery after VR in stroke patients. Clinical trial registration: Chinese Clinical Trial Registry, identifier: ChiCTR2200063425.

Peptide-Protected Gold Nanoclusters Efficiently Ameliorate Acute Contact Dermatitis and Psoriasis via Repressing the TNF-α/NF-κB/IL-17A Axis in Keratinocytes.

Immune-mediated skin diseases have a high prevalence and seriously affect patients' quality of life. Gold compounds have been considered promising therapeutic agents in dermatology, but the high incidence of adverse reactions have limited their clinical application. There is a great need to develop more effective and less toxic gold-based drugs. Gold nanoclusters fabricated by using peptides (pep-AuNCs) have appeared as potential biomedical nanomaterials because of their excellent biocompatibility, ease of fabrication and unique physicochemical properties. Glutathione (GSH) is an endogenous tripeptide and has been used for lightening the skin color. Therefore, we fabricated a well-defined gold nanocluster with GSH as an example to explore the immunomodulatory effect of AuNCs on a TNF-α-treated human keratinocyte cell line (HaCaT) in vitro, the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritant contact dermatitis (ICD) model and the oxazolone (OXA)-induced psoriatic model in vivo. The results indicated that topically applied AuNCs successfully attenuated the severity of ICD and psoriasis-like lesions. In vitro and in vivo, AuNCs effectively inhibited the abnormal activation of the NF-κB pathway and the consequent overexpression of proinflammatory cytokines in keratinocytes. In particular, the transactivation of IL-17A, the most important cytokine in psoriasis pathology, was effectively inhibited by AuNCs treatment. In addition, AuNCs did not show any obvious cytotoxicity in HaCaT cells at doses even up to 100 µM and did not induce any irritation in the healthy skin and major organs, which indicated their favorable biosafety. These results indicate that biocompatible pep-AuNCs might be a promising gold-based nanomedicine for the treatment of inflammatory skin diseases.

Identification of hub genes in AR-induced tamoxifen resistance in breast cancer based on weighted gene co-expression network analysis.

BACKGROUND: Approximately 30% of patients with oestrogen receptor (ER)-positive breast cancer (BC) exhibit intrinsic or recurrent resistance to tamoxifen (TAM) adjuvant endocrine therapy. The androgen receptor (AR) is expressed in about 90% of ER-positive patients. Our previous studies found that BC patients with an AR:ER expression ratio ≥ 2.0 are more susceptible to TAM resistance. However, the specific mechanism by which a high AR:ER ratio promotes TAM resistance remains unknown. METHODS: RNA sequencing was performed on 10 cases of BC tissues with AR:ER ratios ≥ 2.0 and 3 cases with AR:ER ratios < 2.0. We then compared our data with the screened TAM-resistant and TAM-sensitive cases from the TCGA BC database. Bioinformatics methods were used to screen differentially expressed genes (DEGs) and to perform gene enrichment analysis. Weighted correlation network analysis (WGCNA) was used to screen hub genes in the AR-induced TAM resistance process. RESULTS: PAM50 analysis showed that the molecular phenotype of BC patients with AR:ER ratios ≥ 2.0 was similar to that of triple-negative breast cancer (TNBC), whereas the BC samples with AR:ER ratios < 2.0 were classified as the luminal subtype. Among the AR:ER ratio ≥ 2.0 and AR:ER < 2.0 BC tumours, 1855 DEGs were identified. Gene enrichment analysis showed that DEGs were enriched mainly in proliferation-related molecular pathways, such as the cell cycle, necroptosis, metabolic pathways and DNA replication. WGCNA analysis showed that SEC14L2, RIIAD1, STC2 and MAGEA6 served as hub genes in AR-induced TAM resistance and were associated with BC survival prognosis in the TCGA cohort. CONCLUSIONS: A high AR:ER expression ratio is a biomarker for patients who might develop TAM resistance, and AR expression seems to be a possible mechanism of resistance to endocrine therapy.

Risk factors of childhood systemic lupus erythematosus with thyroid dysfunction / 中华儿科杂志

Objective: To investigate the risk factors of childhood systemic lupus erythematosus (SLE) with thyroid dysfunction and to explore the relationship between thyroid hormone and kidney injury of lupus nephritis (LN). Methods: In this retrospective study, 253 patients who were diagnosed with childhood SLE and hospitalized in the First Affiliated Hospital of Zhengzhou University from January 2019 to January 2021 were enrolled in the case group, and 70 healthy children were the control cases. The patients in the case group were divided into the normal thyroid group and the thyroid dysfunction group. Independent t-test, χ2 test, and Mann-Whitney U test were used for comparison between the groups, Logistic regression analysis was used for multivariate analysis, and Spearman correlation. Results: A total of 253 patients, there were 44 males and 209 females in the case group, and the age of onset was 14 (12, 16) years; a total of 70 patients, 24 males and 46 females were in the control group, and the age of onset was 13 (10, 13) years. The incidence of thyroid dysfunction in the case group was higher than that in the control group (48.2% (122/253) vs. 8.6% (6/70), χ²=36.03, P<0.05). Of the 131 patients, there were 17 males and 114 females in the normal thyroid group, and the age of onset was 14 (12, 16) years. Of the 122 patients in the thyroid dysfunction group, 28 males and 94 females were in the thyroid dysfunction group, and the age of onset was 14 (12, 16) years. Of the 122 had thyroid dysfunction, including 51 cases (41.8%) with euthyroid sick syndrome, 25 cases (20.5%) with subclinical hypothyroidism, 18 cases (14.8%) patients with sub-hyperthyroidism, 12 cases (9.8%) with hypothyroidism, 10 cases (8.2%) with Hashimoto's thyroiditis, 4 cases (3.3%) with hyperthyroidism, and 2 cases (1.6%) with Graves disease. Compared to patients with normal thyroid function, the serum level of triglyceride, total cholesterol, urine white blood cell, urine red blood cell, 24 h urine protein, D-dimer, and fibrinogen, ferritin and systemic lupus erythematosus disease activity Index-2000 (SLEDAI-2K) score were higher in patients with thyroid dysfunction (Z=3.07, 3.07, 2.48, 3.16, 2.40, 3.99, 2.68, 2.55, 2.80, all P<0.05), while the serum level of free thyroxine and C3 were lower in thyroid disfunction patients (10.6 (9.1, 12.7) vs. 11.3 (10.0, 12.9) pmol/L, and 0.46 (0.27, 0.74) vs. 0.57 (0.37, 0.82) g/L, Z=2.18, 2.42, both P<0.05). The higher level of triglyceride and D-dimer were the independent risk factors for childhood SLE with thyroid dysfunction (OR=1.40 and 1.35, 95%CI 1.03-1.89 and 1.00-1.81, respectively, both P<0.05). There were 161 patients with LN in the case group, all of which were conducted with renal biopsies, including 11 cases (6.8%) with types Ⅰ LN, 11 cases (6.8%) with typesⅡLN, 31 cases (19.3%) with types Ⅲ LN, 92 cases (57.1%) with types Ⅳ LN, and 16 cases (9.9%) with types Ⅴ LN. There were significant differences in the level of free triiodothyronine and thyroid stimulating hormone among different types of kidney pathology (both P<0.05); compared with types I LN, the serum level of free triiodothyronine was lower in types Ⅳ LN (3.4 (2.8, 3.9) vs. 4.3 (3.7, 5.5) pmol/L, Z=3.75, P<0.05). The serum level of free triiodothyronine was negatively correlated with the acute activity index score of lupus nephritis (r=-0.228, P<0.05), while the serum level of thyroid stimulating hormone was positively correlated with the renal pathological acute activity index score of lupus nephritis (r=0.257, P<0.05). Conclusions: There is a high incidence of thyroid dysfunction in childhood SLE patients. The higher SLEDAI and more severe renal damage were found in SLE patients with thyroid dysfunction compared to these with normal thyroid functions. The risk factors of childhood SLE with thyroid dysfunction are the higher level of triglyceride and D-dimer. The serum level of thyroid hormone is possibly related to the kidney injury of LN.

Network Meta-analysis of Chinese medicine injection combined with conventional western medicine in treatment of stable angina pectoris / 中国中药杂志

This study aimed to systematically evaluate the efficacy and safety of different Chinese medicine injections combined with conventional western medicine for stable angina pectoris. PubMed, Cochrane Library, EMbase, Web of Science, CNKI, Wanfang, VIP, and SinoMed were searched to collect randomized controlled trial(RCT) of Chinese medicine injection combined with conventio-nal western medicine in the treatment of stable angina pectoris from the inception of the databases to July 8, 2022. Two researchers independently screened the literature, extracted the data, and evaluated the risk of bias of the included studies. Stata 15.1 was used for network Meta-analysis. A total of 52 RCTs were included, involving 4 828 patients treated by 9 Chinese medicine injections(Danhong Injection, Salvia Miltiorrhiza Polyphenol Hydrochloride Injection, Tanshinone Sodium Ⅱ_A Sulfonate Injection, Salvia Miltiorrhiza Ligustrazine Injection, Dazhu Hongjingtian Injection, Puerarin Injection, Safflower Yellow Pigment Injection, Shenmai Injection and Xuesaitong Injection). The network Meta-analysis showed that:(1)in terms of improving the efficacy of angina pectoris, the surface under the cumulative ranking curve(SUCRA) followed the order of conventional western medicine combined with Salvia Miltiorrhiza Ligustrazine Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Danhong Injection>Salvia Miltiorrhiza Polyphenol Hydrochloride Injection>Xuesaitong Injection>Shenmai Injection>Puerarin Injection>Safflower Yellow Pigment Injection>Dazhu Hongjingtian Injection;(2)in terms of improving the efficacy of electrocardiogram(ECG), SUCRA followed the order of conventional western medicine combined with Salvia Miltiorrhiza Ligustrazine Injection>Puerarin Injection>Danhong Injection>Salvia Miltiorrhiza Polyphenol Hydrochloride Injection>Shenmai Injection>Xuesaitong Injection>Safflower Yellow Pigment Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Dazhu Hongjingtian Injection;(3)in terms of increasing high-density lipoprotein cholesterol(HDL-C), SUCRA followed the order of conventional western medicine combined with Danhong Injection>Shenmai Injection>Safflower Yellow Pigment Injection>Xuesaitong Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Dazhu Hongjingtian Injection;(4)in terms of lowering low-density lipoprotein cholesterol(LDL-C), SUCRA followed the order of conventional western medicine combined with Safflower Yellow Pigment Injection>Danhong Injection>Shenmai Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Dazhu Hongjingtian Injection>Xuesaitong Injection;(5)in terms of safety, the overall adverse reactions of Chinese medicine injection combined with conventional western medicine were less than those of the control group. Current evidence indicated that Chinese medicine injection combined with conventional western medicine could improve the curative effect of stable angina pectoris with higher safety. Limited by the number and quality of included studies, the above conclusion needed to be verified by more high-quality studies.

Clinicopathological features and prognosis of 128 children with idiopathic membranous nephropathy / 中华实用儿科临床杂志

Objective:To analyze the clinicopathological features and prognosis of idiopathic membranous nephropathy (IMN) in children, and to investigate the factors influencing their prognosis.Methods:The clinical and pathological data of 128 children with IMN hospitalized in the First Affiliated Hospital of Zhengzhou University from January 2012 to December 2019 were retrospectively analyzed.They were divided into 2 groups according to the pathological manifestations: group A[typical membranous nephropathy(MN) group] and group B (atypical MN group), and the clinicopathological characteristics of the 2 groups were compared.Different treatment regimens and their efficacy were summarized, and the prognosis and its influencing factors were analyzed.The primary endpoint event at follow-up was the occurrence of end stage renal disease (ESRD), and the secondary endpoint event was the occurrence of renal insufficiency.Children with IMN were further divided into endpoint event group and non-endpoint event group according to the presence or absence of endpoint events at the last follow-up.Survival analysis was performed using the Kaplan-Meier survival curve method.The Cox proportional risk model method was used to analyze the factors influencing the prognosis of poor kidney outcomes in children with IMN. Results:(1)A total of 128 children were included, with the male-to-female ratio of 1.13∶1.00.The median age of onset and peak age of onset were 13.0 (10.3, 15.0) years, and 12-16 years (68.8%), respectively.Massive proteinuria was detected in 119 cases (93.0%), including 103 cases (80.5%) with massive proteinuria and hematuria, 4 cases(3.1%) with simple hematuria, and 5 cases (3.9%) with non-renal proteinuria.There were 29 cases (22.7%) in group A and 99 cases (77.3%) in group B. (2)Blood triacylglycerol level was significantly higher in group B than that of group A[2.1 (1.5, 3.0) mmol/L vs.1.7(1.1, 2.5) mmol/L], while high-density lipoprotein[1.5(1.1, 1.8) mmol/L vs.1.8(1.4, 2.1) mmol/L], serum albumin[22.0(17.0, 27.3) g/L vs.25.5 (21.0, 32.5) g/L] and complement C3[(1.1±0.2) g/L vs.(1.2±0.2) g/L] were significantly lower in group B than those of group A (all P<0.05). (3)Complete clinical data during hospitalization and follow-up data were obtained from 91 children with IMN, with a median follow-up time of 87.0 (49.0, 104.5) months.Among them, 5 cases (5.5%) progressed to ESRD, involving 3 cases received renal transplantation, and 9 cases (9.9%) had secondary endpoints.Cumulative renal survival rate for ESRD at 5 and 10 years were 96.2% and 92.9%, respectively, which, for the secondary endpoints at 5 and 10 years were 95.2% and 84.8%, respectively.(4)Kaplan-Meier survival analysis showed no significant difference in the cumulative renal survival between group A and group B ( P>0.05). Multifactorial Cox regression analysis showed that tubular atrophy/interstitial fibrosis was an independent risk factor for renal insufficiency in children with IMN ( HR=0.102, 95% CI: 0.011-0.940, P<0.05). Conclusions:Massive proteinuria combined with hematuria is the major clinical manifestation of IMN in children, and atypical MN is the major pathological manifestation.Tubular atrophy/interstitial fibrosis is an independent risk factor for renal insufficiency in children with IMN.

Effect of rotational errors on dose of positive lymph nodes in cervical cancer VMAT plan and its coping strategies / 中华放射肿瘤学杂志

Objective:To evaluate the effect of rotational errors (antero-posterior) on dosimetric parameters of positive lymph nodes in the long target volumetric modulated arc therapy (VMAT) plan for advanced cervical cancer and investigate its coping strategies.Methods:Clinical data of patients with cervical cancer complicated with para-aortic or inguinal lymph node metastasis admitted to Affiliated Hospital of North Sichuan Medical College were randomly selected and retrospectively analyzed. The target areas of the lymph nodes at different distances from the center of the plan were outlined according to the requirements. After designing the VMAT plan on the CT images of each case, the rotational errors (antero-posterior) were introduced by changing the parameters of the treatment couch, and the dose distribution was reconstructed by dose calculation with other parameters unchanged. Then, the external boundary of the original lymph node target was added according to d=2πr(α/360) ( r is the distance from the center of the lymph node to the plan center), re-planned, and the changes of dosimetric parameters in the target area of the original lymph node were analyzed after the corresponding rotational errors were introduced. Results:When the distance between the lymph node target area and the plan center was 6 cm with an error of 3°, the distance was 9 cm and 12 cm with an error of 2.5°, the distance was 15 cm with an error of 2°, and the distance was 18 cm with an error of 1.5°, the mean change of D 95% was more than 5%. When the rotational errors were ≤1°, the mean change of D 95% in lymph node target area was less than 5%, and when the lymph node was 18 cm away from the treatment plan center, the mean change was more than 3%, reaching 3.75%. When the rotational errors were 0.5° and the distance from the plan center was 18 cm (0.5°, 18 cm), the dose change of lymph node target was more than 5%, reaching 5.58%. At (1°, 15 cm), the V 100% change reached 8.96%, and at (1°, 18 cm), the V 100% change was 14.5%. The D 95% and V 100% parameters of the original lymph node target were changed by less than 1% after adding the external boundary of the original lymph node target and introducing corresponding rotational errors. Conclusions:In the long target area radiotherapy of cervical cancer, the variation of dosimetric parameters of lymph node target was increased with the increase of rotational errors and with the increase of distance from the plan center. It is recommended to increase the efferent boundary of lymph nodes in different positions to avoid underdose by d=2πr(α/360).

Comparison of dosimetric differences in unintended irradiation of ipsilateral axillary region between intensity modulated proton and photon therapy for whole breast irradiation / 肿瘤

Objective:This study aimed to compare the dosimetric differences in unintended irradiation to the ipsilateral axillary region between intensity-modulated radiation therapy(IMRT)and intensity-modulated proton therapy(IMPT)in patients receiving whole breast irradiation(WBI). Methods:A total of 20 patients with early breast cancer who received WBI at our center between August and September 2022 were included in this study.One IMPT plan and one IMRT plan were formulated for each patient,with prescription dose of 4005 cGy(RBE)in 1 5 fractions.Dosimetric parameters of axillary lymph nodes(ALN)level Ⅰ,Ⅱ,Ⅲ,Rotter's lymph nodes(RN),and the axillary-lateral thoracic vascular junction(ALTJ)were compared between IMPT and IMRT plans. Results:All plans met the criteria of CTV V95％Dose≥95％.IMPT showed significantly better conformity index(0.97 vs 0.95,P=0.0003)and homogeneity index(0.05 vs 0.07,P=0.0301)compared to IMRT.The mean dose of the heart[27.48 vs 114.74 cGy(RBE),P＜0.0001]and ipsilateral lung[356.66 vs 498.89 cGy(RBE),P＜0.0001]were significantly lower in the IMPT plan compared to the IMRT plan.The mean dose,V50％Dose,V80％Dose,V90％Dose,and V95％Dose of ALNⅠ,ALN Ⅱ,ALN Ⅲ and RN in the IMPT plan were significantly lower than those in the IMRT plan(all P＜0.01),with the most significant difference observed in the dosimetric parameters of the axillary region inferior to the axillary vein[mean dose:79.75 vs 995.31 cGy(RBE),P＜0.0001].The mean dose and serial dosimetric parameters(V5,V10,V15,V20,V25,V30,and V35)of the ALTJ were also significantly lower in IMPT plans compared to IMRT plans. Conclusion:IMPT demonstrates lower unintended irradiation dose in the inferior axillary region and reduces dose volume in the ALTJ region compared to IMRT.When employing IMPT,the clinical target volume(CTV)should be delineated based on the individual locoregional recurrence risk for patients with positive sentinel lymph nodes who omitted axillary lymph node dissection.For high-risk patients,the axillary region should be included in the CTV to ensure efficacy,while for low-risk patients,excluding the axillary region can help mitigate the risk of breast cancer-related lymphedema.

Breast cancer related lymphedema:from evaluation of risk to patient management / 肿瘤

Breast cancer-related lymphedema(BCRL)is one of the most common complications after multidiscipline treatment of breast cancer,which manifests as upper limb swelling and skin changes and significantly affects limb function and quality of life.The occurrence and development of BCRL are affected by many factors including surgery,radiotherapy,drugs,infection,trauma,and so on.Therefore,it is important to identify the potential risk factors to establish individualized prevention strategies.Evidence-based risk assessment models for BCRL could help clinicians to identify high-risk patients and apply prospective surveillance to treat BCRL at early stage.For patients with advanced lymphedema,conservative treatment and surgical treatment could be delivered to relieve symptoms and improve their conditions.This article comprehensively reviewed the risk factors,prospective surveillance,intervention,and research progress of BCRL,to provide reference for multidisciplinary collaboration as well as clinical diagnosis and treatment in this field.

Cell-Penetrating Peptide Conjugated Au Nanoclusters Selectively Suppress Refractory Lymphoma Cells via Targeting Both Canonical and Noncanonical NF-κB Signaling Pathways.

Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is the most aggressive form of DLBCL, with a significantly inferior prognosis due to resistance to the standard R-CHOP immunochemotherapy. Survival of ABC-DLBCL cells addicted to the constitutive activations of both canonical and noncanonical NF-κB signaling makes them attractive therapeutic targets. However, a pharmaceutical approach simultaneously targeting the canonical and noncanonical NF-κB pathway in the ABC-DLBCL cell is still lacking. Peptide-conjugated gold nanoclusters (AuNCs) have emerged unique intrinsic biomedical activities and possess a great potential in cancer theranostics. Here, we demonstrated a Au25 nanocluster conjugated by cell-penetrating peptides that can selectively repress the growth of ABC-DLBCL cells by inducing efficient apoptosis, more efficiently than glutathione (GSH)-conjugated AuNCs. The mechanism study showed that the cell-penetrating peptides enhanced the cellular internalization efficiency of AuNCs, and the selective repression in ABC-DLBCL cells is due to the inhibition of inherent constitutive canonical and noncanonical NF-κB activities by AuNCs. Several NF-κB target genes involved in chemotherapy resistance in ABC-DLBCL cells, including anti-apoptotic Bcl-2 family members and DNA damage repair proteins, were effectively down-regulated by the AuNC. The emerged novel activity of AuNCs in targeting both arms of NF-κB signaling in ABC-DLBCL cells may provide a promising candidate and a new insight into the rational design of peptide-conjugated Au nanomedicine for molecular targeting treatment of refractory lymphomas.

Performance of PRECISE-DAPT and Age-Bleeding-Organ Dysfunction Score for Predicting Bleeding Complication During Dual Antiplatelet Therapy in Chinese Elderly Patients.

Background: Recently, the Age-Bleeding-Organ Dysfunction (ABO) algorithm was recommended by the Asian Pacific Society of Cardiology Consensus as a binary approach to evaluate bleeding risk. This analysis made comparison of the predictive performances between the PRECISE-DAPT and ABO bleeding score in identifying the risk of 12-months major bleeding in Chinese elderly patients over 65 years old patients who underwent percutaneous coronary intervention (PCI) during dual-antiplatelet therapy period. Methods: A total of 2,037 elderly coronary artery disease (CAD) patients (≥65 years) receiving dual antiplatelet therapy (DAPT) after PCI were enrolled in the study. The predictive accuracy of the two bleeding risk scores (PRECISE-DAPT and ABO) was compared for identifying the risk of bleeding during the dual-antiplatelet therapy in patients who underwent PCI. Major clinically relevant bleeding events were defined according to the Bleeding Academic Research Consortium (BARC) criteria. Results: The PRECISE-DAPT score in the no bleeding, BARC = 1 bleeding, BARC ≥ 2 bleeding patients was 23.55 ± 10.46, 23.23 ± 10.03, and 33.54 ± 14.33 (p < 0.001), respectively. Meanwhile, the ABO score in the three groups was 0.72 ± 0.80, 0.69 ± 0.81, and 1.49 ± 0.99 (p < 0.001), respectively. The C-statistic of the PRECISE-DAPT model for prediction of BARC ≥ 2 bleeding in overall patients was 0.717 (95% CI, 0.656-0.777) and 0.720 (95% CI, 0.656-0.784) in acute coronary syndrome (ACS) patients. Similar discriminatory capacity was demonstrated in the ABO risk score [overall, patients, AUC: 0.712 (95% CI, 0.650-0.774); ACS patients, AUC: 0.703 (95% CI, 0.634-0.772)]. No differences were observed when the ABO model was in comparison with the PRECISE-DAPT model, regardless in overall patients (z = -0.199, p = 0.842) or ACS patients (z = -0.605, p = 0.545). The calibration for BARC ≥ 2 bleeding of the PRECISE-DAPT and ABO score were acceptable, regardless in overall patients [goodness-of-fit (GOF) Chi-square = 0.432 and 0.001, respectively; p-value = 0.806 and 0.999, respectively] or ACS patients (GOF Chi-square = 0.008 and 0.580, respectively; p-value = 0.996 and 0.748, respectively). Conclusion: No matter of clinical presentation in Asian 65-years older patients with DAPT, the PRECISE-DAPT, and ABO scores had the similar discriminative ability for 12-months BARC ≥ 2 bleeding. Considering the simplicity and reliability, the PRECISE-DAPT score might be more clinically applicable in the overall population and ACS patients in bleeding prediction.

Research progress of the application of anti-CD 20 monoclonal antibodies in the treatment of primary nephrotic syndrome in children / 中华实用儿科临床杂志

Primary nephrotic syndrome (PNS) is one of the common glomerular diseases in children.Glomerular disease treatment by anti-CD 20 monoclonal antibodies is currently a hot topic.There are three generations of anti-CD 20 monoclonal antibodies.As a representative of the first generation of anti-CD 20 monoclonal antibodies, Rituximab (RTX) has been proven effective in treating children with steroid-dependent/frequent-relapsing nephrotic syndrome (SDNS/FRNS). Ofatumumab (OFA) and Obinutuzumab (OBI) represent the second-and the third-generation anti-CD 20 monoclonal antibodies, respectively.OFA and OBI have showed good efficacy and safety in pediatric PNS.In this paper, clinical studies and applications of anti-CD 20 monoclonal antibodies in the treatment of children with PNS were reviewed, so as to provide a reference for the treatment of PNS in children.

Research progress of autophagy in intestinal ischemia-reperfusion injury / 中国临床药理学与治疗学

Intestinal ischemia/reperfusion injury (ll/RI) is a common pathological process in clinical practice. Ischemia/reperfusion causes damage to intestinal mucosa and distant organs, and induces systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Autophagy is a defense regulation mechanism under stress conditions, which can maintain the homeostasis of cytoplasm, proteins and organelles. The mechanism of autophagy is complex, which is Intestinal ischemia/reperfusion injury (II/RI) is a common pathological process in clinical practice. Ischemia/reperfusion causes damage to intestinal mucosa and distant organs, and induces systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Autophagy is a defense regulation mechanism under stress conditions, which can maintain the homeostasis of cytoplasm, proteins and organelles. The mechanism of autophagy is complex, which is co-regulated by protein complexes encoded by evolutionarily conserved autophagy-related gene (ATG) and a variety of signaling molecules and pathways. Studies have found that autophagy is involved in the process of intestinal ischemia-reperfusion injury. Therefore, revealing the mechanism of autophagy in II/RI can provide evidence for the prevention and treatment of II/RI.

Gold Cluster Capped with a BCL-2 Antagonistic Peptide Exerts Synergistic Antitumor Activity in Chronic Lymphocytic Leukemia Cells.

Chronic lymphocytic leukemia (CLL) is still incurable by conventional chemotherapy due to the resistance to apoptosis. We have previously found that a peptide-capped gold cluster (Au25Sv9) can target on the aberrant oxidative stress in CLL cells to specially inhibit thioredoxin reductase (TrxR) activity, resulting in significant apoptosis. However, the required doses of the gold cluster for inducing apoptosis are high, restricting its potential for further applications. Notably, the most recent studies suggested that CLL cells overexpressed antiapoptotic BCL-2 protein to prevent chemotherapy-induced apoptosis, indicating that BCL-2 could be a promising target for CLL therapy. Regrettably, the nonmitochondrial-targeted Au25Sv9 has little effect on BCL-2. In this study, we successfully screened a modified BADBH3 peptide (B1P) that could antagonize BCL-2 protein in CLL cells. We found that B1P could effectively sensitize MEC-1 cells to a subliminal dose of Au25Sv9. To simplify the treatment regimen, we directly fabricated a gold cluster capped with the B1P peptides by one-step synthesis to integrate the BCL-2 antagonistic activity into the gold the cluster, named BGC. We already found that low doses of BGC could significantly induce more apoptosis in MEC-1 cells than equivalent doses of the Au25Sv9 cluster or B1P peptide alone. Mechanistically, in addition to the inherent inhibitory effect of gold clusters on TrxR activity, BGC could bind to BCL-2 on mitochondria and activate the BCL-2 family-mediated mitochondrial apoptosis cascade more effectively. These results demonstrated that antagonizing the overexpressed BCL-2 in CLL cells, together with inhibiting TrxR simultaneously by a single gold cluster, is a promising strategy for the treatment of CLL cells. This study will provide a paradigm and reference for the development of functionalized gold clusters with rationally designed peptides, and opens up a new opportunity for the treatment of CLL in clinical settings.

Prognostic and predictive significance of tumor infiltrating lymphocytes for ductal carcinoma in situ.

This study aims to identify the density of TILs in ductal carcinoma in situ (DCIS) in terms of prognostic significance with recurrence and the benefit of whole breast irradiation (WBI). The clinicopathological data of DCIS patients from Jan 2009 to Dec 2016 who received breast-conserving surgery (BCS) were retrospectively reviewed. Cox regression analysis was used to confirm independent prognostic factors of ipsilateral breast tumor recurrence (IBTR). Kaplan-Meier method was utilized to analyze IBTR and values of WBI. Touching-tumor-infiltrating lymphocytes (TILs) were defined by TILs touching or within one lymphocyte cell thickness from the malignant ducts' basement membrane. In total, 129 patients were enrolled in this analysis with 98 patients who received WBI. After a median follow-up of 53.0 months, there were 16 IBTR events with five invasive IBTRs. Univariate and multivariate analyses showed that touching-TILs >5 were an independent prognostic factor for higher IBTR (HR = 6.17, 95%CI 1.95-19.56, p < .01). The whole cohort was classified into two subgroups: dense group (>5 touching-TILs per duct) and sparse group (≤5 touching-TILs per duct). Dense touching-TILs were associated with unfavorable biologic characteristics. The 5-y rate of IBTR between dense and sparse group was 29.0% versus 4.5% (p < .01). For the sparse group, WBI significantly reduced the rate of 5-y-IBTR risk from 13.2% to 1.7% (p = .02), but there was no benefit of WBI in the dense group. Touching-TILs density was heterogeneous in patients with DCIS. Sparse touching-TILs were associated with better prognosis and benefit from WBI. Dense touching-TILs not only were associated with a higher risk of IBTR but also lack of benefit from WBI.

Quantitative analysis of breathing patterns based on wearable systems / 生物医学工程学杂志

Breathing pattern parameters refer to the characteristic pattern parameters of respiratory movements, including the breathing amplitude and cycle, chest and abdomen contribution, coordination, etc. It is of great importance to analyze the breathing pattern parameters quantificationally when exploring the pathophysiological variations of breathing and providing instructions on pulmonary rehabilitation training. Our study provided detailed method to quantify breathing pattern parameters including respiratory rate, inspiratory time, expiratory time, inspiratory time proportion, tidal volume, chest respiratory contribution ratio, thoracoabdominal phase difference and peak inspiratory flow. We also brought in "respiratory signal quality index" to deal with the quality evaluation and quantification analysis of long-term thoracic-abdominal respiratory movement signal recorded, and proposed the way of analyzing the variance of breathing pattern parameters. On this basis, we collected chest and abdomen respiratory movement signals in 23 chronic obstructive pulmonary disease (COPD) patients and 22 normal pulmonary function subjects under spontaneous state in a 15 minute-interval using portable cardio-pulmonary monitoring system. We then quantified subjects' breathing pattern parameters and variability. The results showed great difference between the COPD patients and the controls in terms of respiratory rate, inspiratory time, expiratory time, thoracoabdominal phase difference and peak inspiratory flow. COPD patients also showed greater variance of breathing pattern parameters than the controls, and unsynchronized thoracic-abdominal movements were even observed among several patients. Therefore, the quantification and analyzing method of breathing pattern parameters based on the portable cardiopulmonary parameters monitoring system might assist the diagnosis and assessment of respiratory system diseases and hopefully provide new parameters and indexes for monitoring the physical status of patients with cardiopulmonary disease.