Targeting drug delivery systems mediated by nanoparticles has shown great potential in the diagnosis and treatment of cancer. However, influences of different tumor progressions on the accumulation of nanoparticles, especially the ligand-modified active targeting nanoparticles are seldom exploited. In this work, the accumulation and penetration of RGD-modified gold nanoparticles (active AuNPs) with different sizes were investigated in orthotopic breast cancer with different tumor progressions. The results showed that the smallest active AuNPs had better accumulation and permeation effects in early tumor tissues with the relatively looser extracellular matrix, larger gaps, lower interstitial fluid pressure, and less receptor expression, which was due to size effects. However, the larger active AuNPs had better accumulation and penetration effects in late tumor tissues with highly expressed target receptors integrin α _v β ₃ because of the multivalent interactions between larger active nanoparticles and integrin α _v β ₃. In the midterm, tumor accumulation of active AuNPs was equally influenced by size effects and multivalent interactions. Therefore, RGD-modified nanoparticles with sizes of 7 and 90 nm accumulated more in tumors. This study will guide a rational design of active targeting nanoparticles for enhancing the diagnosis and treatment of tumors based on their progressions.

OBJECTIVE To observe the effects of liraglutide on cardiovascular metabolism， left ventricular structure and function of non-alcoholic fatty liver disease （NAFLD） patients with type 2 diabetes mellitus （T2DM）. METHODS Totally 351 NAFLD patients with T2DM were enrolled retrospectively， who visited the Department of Endocrinology in our hospital from January 2019 to December 2022. They were divided into control group （196 cases） and observation group （155 cases） according to different treatment regimens. The control group received conventional standard treatment， and the observation group was additionally given Liraglutide injection 0.6 mg/d subcutaneously once a day based on the control group， adjusted to 1.2 mg/d after 7 days. Both groups received regular treatment for more than 12 months. The propensity matching method was used to match the two groups of patients at a ratio of 1∶1. The cardiovascular metabolism indexes and cardiac ultrasound parameters were compared， and the correlation between left ventricular structure， function parameters and cardiovascular metabolism indexes was analyzed. RESULTS After propensity score matching， there was no significant difference in baseline clinical data between the two groups （each 155 cases） before treatment （P＞0.05）. After 12 months of treatment， the waist circumference， weight， body mass index （BMI）， systolic blood pressure （SBP）， fasting blood glucose （FBG）， glycosylated hemoglobin （HbA1c） and triglyceride （TG） of both groups， as well as the diastolic blood pressure （DBP）， total cholesterol （TC）， uric acid （UA） and left ventricular mass （LVM） of the observation group， exhibited a significant decrease compared to pre-treatment levels （P＜0.05）. The high-density lipoprotein cholesterol （HDL-C）， estimated glomerular filtration rate （eGFR）， and E/A ratio in both groups， as well as the aspartate aminotransferase （AST） in the control group and the left ventricular ejection fraction （LVEF） in the observation group， were all significantly increased compared with before treatment in the same group （P＜0.05）. Moreover， the improvement of the above indicators （except for TG and SBP） in the observation group was generally more significant than those in the control group （P＜0.05）. The left ventricular structure and functional parameters （LVM， LVEF， E/A ratio） of the two groups before and after treatment had varying degrees of correlation with the patients’ waist circumference， body weight， BMI， SBP， FBG and HbA1c. Moreover， BMI （observation group： β＝ 0.229， P＝0.004） and SBP （control group： β＝0.240， P＝0.004； observation group： β＝0.226， P＝0.007） were independent influential factors for LVM of the patients. CONCLUSIONS Liraglutide combined with conventional standard treatment can effectively control blood glucose in NAFLD patients with T2DM， reduce waist circumference， body weight and blood pressure， improve blood lipid disorders， and protect their cardiac structure and function.

Objective:To further improve the understanding of paroxysmal nocturnal hemoglobinuria (PNH), we retrospectively analyzed and summarized the clinical characteristics, treatment status, and survival status of patients with PNH in Zhejiang Province.Methods:This study included 289 patients with PNH who visited 20 hospitals in Zhejiang Province. Their clinical characteristics, comorbidity, laboratory test results, and medications were analyzed and summarized.Results:Among the 289 patients with PNH, 148 males and 141 females, with a median onset age of 45 (16-87) years and a peak onset age of 20-49 years (57.8% ). The median lactic dehydrogenase (LDH) level was 1 142 (604-1 925) U/L. Classified by type, 70.9% (166/234) were classical, 24.4% (57/234) were PNH/bone marrow failure (BMF), and 4.7% (11/234) were subclinical. The main clinical manifestations included fatigue or weakness (80.8%, 235/289), dizziness (73.4%, 212/289), darkened urine color (66.2%, 179/272), and jaundice (46.2%, 126/270). Common comorbidities were hemoglobinuria (58.7% ), renal dysfunction (17.6% ), and thrombosis (15.0% ). Moreover, 82.3% of the patients received glucocorticoid therapy, 70.9% required blood transfusion, 30.7% used immunosuppressive agents, 13.8% received anticoagulant therapy, and 6.3% received allogeneic hematopoietic stem cell transplantation. The 10-year overall survival (OS) rate was 84.4% (95% CI 78.0% -91.3% ) . Conclusion:Patients with PNH are more common in young and middle-aged people, with a similar incidence rate between men and women. Common clinical manifestations include fatigue, hemoglobinuria, jaundice, renal dysfunction, and recurrent thrombosis. The 10-year OS of this group is similar to reports from other centers in China.

Objective:To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) .Methods:A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results:Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype ( P=0.02, OR=0.39, 95% CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation ( P=0.02, OR=0.22, 95% CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95% CI 21.14-30.19) months. HMA response ( P=0.036, HR=0.47, 95% CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype ( P=0.024, HR=2.14, 95% CI 1.10-4.15) , leukemia transformation ( P<0.001, HR=2.839, 95% CI 1.64-4.92) , and TP53 mutation ( P=0.012, HR=2.19, 95% CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion:Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Objective:To improve clinicians' understanding of congenital nephrogenital diabetes insipidus (CNDI) and to reduce missed and misdiagnosis. Methords 　Based on the literature, the clinical data and gene mutation of 2 patients with CNDI who were admitted to the Department of Endocrinology and Metabolism of the First Affiliated Hospital of Henan University of Science and Technology on July 30, 2020 were analyzed retrospectively. Results:(1) The presentee, 4 years old, had irritable thirst, polydipsia and polyuria for more than 3 years. The sister, 2.5 years old, had irritable thirst, polydipsia and polyuria for more than 2 years. The clinical diagnosis was “CNDI”, and the symptoms improved after treatment with hydrochlorothiazide. (2) The genetic test revealed that the congenital nephrogenic uremia and her sister had a heterozygous mutation of c.170A>C (p.Q57P) and c.211G>A (p.Vl71M) in the aquaporin-2 gene, and the mother carried the AQP2 gene. c.170A>C(p.Q57P) mutation.Conclusion:CNDI is a rare disease. Early diagnosis and treatment can improve the prognosis of patients to the greatest extent, and prenatal diagnosis can guide eugenics.

We report a case of a female teenage with monogenic diabetes mellitus caused by glucokinase regulator (GCKR) gene mutation who presented with diabetic ketosis and misdiagnosed as type 1 diabetes. The patient was treated with insulin for 3 years since diagnosis. The islet function was well preserved, but polycystic ovary syndrome was developed. Whole-exome gene sequencing revealed a GCKR gene c. 69delG heterozygous mutation. After molecular diagnosis, the insulin dosage was gradually reduced to full cessation, and only metformin sustained-release tablets were taken to control blood glucose. It is necessary to regular evaluate islet function of patient with type 1 diabetes, and genetic test is of significance for accurate diagnosis and treatment.

Objective:To investigate the clinicopathological characteristics and prognosis of idiopathic membranous nephropathy (IMN) with or without C3 deposition.Methods:Clinical and pathological data of 576 patients with IMN diagnosed in Affiliated Hospital of Qingdao University from January 2017 to January 2021 were retrospectively analyzed. The patients were divided into C3 deposition group and non-C3 deposition group according to the immunofluorescence staining of C3. The clinical and pathological characteristics were compared between the two groups. Kaplan-Meier survival curve was used to compare the prognosis of the two groups.Results:A total of 576 IMN patients (male 364 (63.20%)) were enrolled, including 400 patients (69.44%) with C3 deposition and 176 patients (30.56%) without C3 deposition. Compared with the non-C3 deposition group, the levels of total blood cholesterol ( t=0.94, P=0.002) and the proportion of phospholipase A2 receptor ( χ2=9.99, P=0.002), IgG ( χ2=10.67, P=0.001), IgM ( χ2=7.00, P=0.008), IgA ( χ2=7.87, P=0.005) and C1q ( χ2=8.28, P=0.004) depositions in renal tissues was higher in C3 deposition group, while the levels of serum C3 ( t=2.87, P=0.004), albumin ( t=3.57, P<0.001) and IgG ( Z=3.55, P<0.001) were lower in C3 deposition group. There were no significant differences in other clinicopathological indicators between the two groups. The survival analysis was performed in 460 patients who were followed for>6 months, including 319 cases (69.35%) of C3 deposition and 141 cases (30.65%) of non-C3 deposition. The end point event was defined as an eGFR decline>30% or entry into end stage renal disease (ESRD). There was no statistically significant difference in treatment method between the two groups ( P>0.05). The median follow-up time was 22 (13,32) months, 327 (71.09%) patients achieved remission, and 22 patients had renal end-point events. Compared with the non-C3 deposition group, the proportion of urinary protein remission was lower ( χ2=10.85, P<0.05), the incidence of renal end-point events was higher ( χ2=5.05, P<0.05). Kaplan-Meier survival analysis showed that patients with C3 deposition had a lower cumulative remission rate (Log-rank χ2=6.68, P=0.010), and a lower cumulative renal survival than those without C3 deposition had ( χ2=5.42, P=0.020). Conclusions:Compared with patients without C3 deposition, IMN patients with C3 deposition have more severe clinical and pathological changes, lower renal cumulative remission rate, and are more likely to have poor prognosis.

Objective To analyze the modeling elements and subjects of the animal model of skin photoaging, and to provide a reference for the preparation and improvement of the model and a basis for the scientific evaluation of the subject.Methods By searching and collecting relevant literature on the preparation of animal models of skin photoaging from 2010 to 2022 in the China National Knowledge Infrastructure, Wanfang Database, and PubMed database, the model animal species, gender, modeling method, modeling cycle, radiation source and its distance from the modeling site, cumulative radiation volume, detection indicators, and subjects (drugs or treatments) recorded in the literature were collated and summarized, and a database was established for statistical analysis.Results 257 articles that met the inclusion criteria were selected. Among them, the most common animal model was SKH-1 hairless mice, followed by SD rats and KM mice; the gender of animals was mainly female, medium-wave ultraviolet B (UVB) was often used as the radiation source, the distance between the radiation source and the modelling site was mostly 30 cm, and the modelling period was usually 40-60 days. The cumulative dose of long-wave ultraviolet A (UVA) was between 100-150 J/cm², and the cumulative dose of UVB was between 5-10 J/cm². The tests used after model establishment were skin histopathological examination, skin tissue homogenization, fibre staining, immunoblotting, etc. Subjects included Chinese herbal medicines, Chinese herbal extracts, Chinese patent medicines, Chinese herbal compound medicines, chemical drugs, biological agents and other treatments, while the animal model of skin photoaging was also used for clinical efficacy studies of external Chinese medicine, physiotherapy and positive control drugs.Conclusion In skin photoaging animal experiments, female SKH-1 hairless mice are often used, and UVB is used as the radiation source. The modeling period is usually 40-60 days, and the minimum erythema dose (MED) is incremented week by week. The cumulative UVB irradiation dose ranges from 0 to 10 J/cm², which has the advantages of high success rate, good reproducibility and high similarity with clinical disease.

Objective:To investigate the correlation between serum anti-phospholipase A2 receptor antibody (SAb) combined with glomerular complement C3 (GC3) deposition and clinicopathologic features and prognosis in patients with idiopathic membranous nephropathy (IMN).Methods:It was a retrospective cohort study. The patients diagnosed with IMN in Affiliated Hospital of Qingdao University from July 1, 2019 to April 30, 2022 were enrolled, and the clinical and pathological data were collected and analyzed. The patients were divided into negative SAb and negative GC3 (SAb -/GC3 -) group, negative SAb and positive GC3 (SAb -/GC3 +) group, positive SAb and negative GC3 (SAb +/GC3 -) group and positive SAb and positive GC3 (SAb +/GC3 +) group according to the status of SAb titer and GC3 deposition. Clinical and pathological characteristics among the groups were compared. Kaplan-Meier survival curve was used to compare the cumulative renal remission rates of different groups. Cox regression analysis model was used to analyze the related factors of renal remission. Results:A total of 143 IMN patients aged (53.35±12.34) years old were included in the study, including 94 males (65.7%). There were 17 patients (11.9%) in the SAb -/GC3 - group, 30 patients (21.0%) in the SAb -/GC3 + group, 19 patients (13.3%) in the SAb +/GC3 - group, and 77 patients (53.8%) in the SAb +/GC3 + group. Compared with SAb -/GC3 - group, the level of serum albumin was lower in the SAb +/GC3 + group, and the level of 24 h urine protein, SAb titer, and the proportions of glomerular anti-phospholipase A2 receptor antigen and renal tubule atrophy were higher in the SAb +/GC3 + group (all P<0.05). After 26.0 (19.0, 36.0) months of follow-up, a total of 96 patients (67.1%) attained remission. The proportion of patients receiving immunosuppressive therapy in the SAb +/GC3 + group was higher than that in the SAb -/GC3 - group [93.5% (72/77) vs. 70.6% (12/17), fisher value=8.974, P=0.016] and the proportion of renal remission rate in the SAb +/GC3 + group was lower than that in the SAb -/GC3 - group [49.4% (38/77) vs. 100% (17/17), χ2=25.438, P<0.001]. Kaplan-Meier survival curve result showed that the cumulative renal remission rate in the SAb +/GC3 + group was significantly lower than that in the SAb -/GC3 - group (Log-rank χ2=31.538, P<0.01). Multivariate Cox regression analysis result showed that 24 h urine protein level ( HR=0.891, 95% CI 0.803-0.988, P=0.029), SAb titer ( HR=0.996, 95% CI 0.992-1.000, P=0.042) and SAb +/GC3 + (with SAb -/GC3 - group as reference, HR=0.414, 95% CI 0.204-0.827, P=0.013) were independent related factors for renal remission in patients with IMN. Conclusions:IMN patients with positive SAb and GC3 deposition have more severe clinical and pathological changes, lower renal cumulative remission rates, and are more likely to have poor prognosis. The combined assessment of SAb and GC3 deposition may be helpful for evaluating prognosis and guiding treatment in IMN patients.

Micropenis is an objective diagnosis based on accurate measurement of the length of the penis. Micropenis can be caused by many factors, including the structure of the hypothalamic-pituitary-gonadal axis or hormone defects. Therefore, examination of the endocrine system is extremely important for the diagnosis of the etiology. Once the diagnosis is confirmed, a multidisciplinary team of endocrinologists, geneticists, pediatricians, pediatric surgeons, and urologists are required to jointly develop individualized treatment plans. This article reviews the etiology, diagnosis and treatment of micropenis, aiming to raise awareness and concern about micropenis.