Metal ion-promoted chemodynamic therapy(CDT) combined with photodynamic therapy(PDT) offers broad application prospects for enhancing anti-tumor effects. In this study, glycyrrhizic acid(GA), copper ions(Cu~(2+)), and norcantharidin(NCTD) were co-assembled to successfully prepare a natural small-molecule, carrier-free hydrogel(NCTD Gel) with excellent material properties. Under 808 nm laser irradiation, NCTD Gel responded to the tumor microenvironment(TME) and acted as an efficient Fenton reagent and photosensitizer, catalyzing the conversion of endogenous hydrogen peroxide(H_2O_2) within the tumor into oxygen(O_2), and hydroxyl radicals(·OH, type Ⅰ reactive oxygen species) and singlet oxygen(~1O_2, type Ⅱ reactive oxygen species), while depleting glutathione(GSH) to stabilize reactive oxygen species and alleviate tumor hypoxia. In vitro and in vivo experiments demonstrated that NCTD Gel exhibited significant CDT/PDT synergistic therapeutic effects. Further safety evaluation and metabolic testing confirmed its good biocompatibility and safety. This novel hydrogel is not only simple to prepare, safe, and cost-effective but also holds great potential for clinical transformation, providing insights and references for the research and development of metal ion-mediated hydrogel-based anti-tumor therapies.
Hydrogels/chemistry* ; Animals ; Photochemotherapy ; Humans ; Mice ; Antineoplastic Agents/administration & dosage* ; Photosensitizing Agents/chemistry* ; Neoplasms/metabolism* ; Female ; Copper/chemistry* ; Reactive Oxygen Species/metabolism* ; Tumor Microenvironment/drug effects* ; Cell Line, Tumor ; Male

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.

Background: Twenty-four-hour urinary free cortisol (UFC) measurement is the initial diagnostic test for Cushing’s syndrome (CS). We compared UFC determination by both direct and extraction immunoassays using Abbott Architect, Siemens Atellica Solution, and Beckman DxI800 with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, we evaluated the value of 24-hr UFC measured by six methods for diagnosing CS. Methods: Residual 24-hr urine samples of 94 CS and 246 non-CS patients were collected.A laboratory-developed LC-MS/MS method was used as reference. UFC was measured by direct assays (D) using Abbott, Siemens, and Beckman platforms and by extraction assays (E) using Siemens and Beckman platforms. Method was compared using Passing–Bablok regression and Bland–Altman plot analyses. Cut-off values for the six assays and corresponding sensitivities and specificities were calculated by ROC analysis. Results: Abbott-D, Beckman-E, Siemens-E, and Siemens-D showed strong correlations with LC-MS/MS (Spearman coefficient r = 0.965, 0.922, 0.922, and 0.897, respectively), while Beckman-D showed weaker correlation (r = 0.755). All immunoassays showed proportionally positive bias. The areas under the curve were 0.975 for Abbott-D, 0.972 for LCMS/MS, 0.966 for Siemens-E, 0.948 for Siemens-D, 0.955 for Beckman-E, and 0.877 for Beckman-D. The cut-off values varied significantly (154.8–1,321.5 nmol/24 hrs). Assay sensitivity and specificity ranged from 76.1% to 93.2% and from 93.0% to 97.1%, respectively. Conclusions Commercially available immunoassays for measuring UFC show different levels of analytical consistency compared to LC-MS/MS. Abbott-D, Siemens-E, and Beckman-E have high diagnostic accuracy for CS.

Objective:To assess the applicability of fully automatic pipeline automated testing for internal quality control (automated quality control).Methods:Stability, assay efficiency and implementation costs of 18 biochemical tests, 5 immunoturbidimetric tests and 11 chemical illuminescent tests in the Department of Laboratory Medicine of Peking Union Hospital from January 2019 to July 2022 were evaluated using automated quality control implementation methods. The detailed method is as follows: quality control materials for biochemical, immunoturbidimetric and chemiluminescent tests were stored in the refrigerator in the pipeline which was controlled by the intermediate software, and were automatically retrieved and tested as pre-set followed by documenting and storing. The quality control setup for the biochemical tests included refreshing quality control materials daily and weekly,both of which were paralleled for 3 months. The on-line storage stability of quality control materials in the pipeline was evaluated by comparing the coefficients of variation ( CV) of the quality control results between the two patterns. Effect of automated quality control application was evaluated using 6 indicators, including the results′ variation of automatically performed and manually performed quality controls, the out-of-controlled rate, the consumption of quality control materials, the change of staff workload, the impact on the testing time of the first sample, and the failure rate of automated quality control. Results:(1) Storage stability of quality control materials in the pipeline: under the pattern of weekly refresh of the biochemical quality control materials, except for total carbon dioxide (TCO 2) (the CVs of low and high level quality control were respectively 20.24% and 21.82%) and sodium (the CV of low level quality control was 1.51%) that were greater than the allowable variation set by the laboratory, the CVs of the rest tests meet the lab requirements on the allowable variations. (2) The results′ variation of quality control in automatically performed and manually performed control patterns: in the patterns of daily refresh of biochemical quality control materials and weekly refresh of immunoturbidimetric and chemiluminescent quality control materials, the CVs of both low and high levels of quality control were lower in the automatically performed control pattern than that in manually performed pattern for 8 chemiluminescent items of dehydroepiandrosterone sulfate, estradiol, follicle stimulating hormone, luteinizing hormone, serum ferritin, serum folic acid, vitamin B12 and testosterone, 3 immunologic items of complement 3, C reactive protein and immunoglobulin G, and 10 biochemical items of alkaline phosphatase, glucose, calcium, chloride, potassium, lactate dehydrogenase, sodium, urea, low density lipoprotein cholesterol, and adenosine deaminase. The out-of-control rates of biochemistry, immunoturbidimetric and chemiluminescence tests in both quality control patterns conformed with the clinical routine work requirements. (3) Comparison of quality control materials′ consumption: compared with manually performed quality control, weekly consumption of automatically performed chemiluminescent quality control materials decreased 37.5% (from 8 ml to 5 ml); weekly consumption of automatically performed immunoturbidimetric quality control materials decreased 33.3% (from 3 ml to 2 ml). (4)Comparison of staff workload and first sample testing time: compared with manually performed quality control, automatical quality control reduced manual work by about 156 steps per week, and the daily initial testing time was earlier by 15 min on average. The failure rate was 54.5% (37/64) during the early-stage application of the automated quality control which dropped to 10.2% (13/128) in the late-stage. Conclusion:The results of automated quality control detected in the pipeline system meet the quality indicators′ requirements of the laboratory, and the application of automated quality control can improve the quality control, save costs, reduce workload, and improve work efficiency.

Objective:To investigate the vaccination status, characteristics and prognosis of patients suffering from a combination of COVID-19 and chronic lymphocytic anemia (CLL) in China.Methods:Clinical data of 328 patients with chronic lymphocytic leukemia (CLL) who were first diagnosed with COVID-19 and treated in the Department of Hematology of Jiangsu Provincial People’s Hospital between November 2022 and February 2023 were retrospectively analyzed. Univariate and multivariate analysis of data of patients with severe/critical COVID-19 were conducted by applying the binary logistic regression model.Results:The median age of the CLL patients was 60 (24-87) years. 23.5% (77/328) of these patients suffered from severe/critical COVID-19 infection. Univariate analysis of the data demonstrated that a combination of factors including age >67 years ( OR=2.15, 95% CI 1.24- 3.73, P=0.006), diabetes ( OR=2.09, 95% CI 1.05-4.20, P=0.037), chronic hepatitis B ( OR=2.91, 95% CI 1.30-6.51, P=0.010), CLL progressive ( OR=3.79, 95% CI 1.57-9.15, P=0.003) and CD20 antibody-based treatments within three months prior to the COVID-19 infection ( OR=2.79, 95% CI 1.35-5.77, P=0.006) were the risk factors for severe/critical COVID-19. According to the multivariate analysis, CLL progressive ( OR=2.98, 95% CI 1.10-8.10, P=0.033) was an independent risk factor for severe/critical COVID-19 and administration of the BTK (Bruton tyrosine kinase) inhibitor monotherapy might exert a protective effect and influence a positive outcome of the COVID-19 infection ( OR=0.38, 95% CI 0.16-0.90, P=0.028). Among the 242 patients who were followed up until October 2023, 9.1% (22/242) had multiple subsequent COVID-19 infections (≥3), and 2.1% (5/242) had persistent COVID-19 infections (patients with persistent positive test for the SARS-CoV-2 antigen testing until missing follow-up for any reason). The peak value of the anti-SARS-CoV-2-IgG titres was observed between three and four months post symptom onset (median: 3.511 S/CO vs 1.047 S/CO, P<0.05). The levels of immunoglobulin A gradually decreased following infection with COVID-19, and its trough levels were attained between two to four weeks post infection (median: 0.30 g/L vs 0.74 g/L, P<0.05). According to this study the mortality of patients suffering from a combination of COVID-19 infection and CLL was 2.7% (9/328), and the main reason for their death was respiratory failure and heart failure. Conclusions:A low rate of COVID-19 vaccination and a high rate of severe/critical COVID-19 infection was observed in the CLL patients. CLL progressive was associated with severe/critical COVID-19. Anti-CD20-based treatments received within the past three months might be a risk factor for exacerbation of COVID-19 infection, whereas a monotherapy with BTK inhibitors exert a protective effect and improve outcome of COVID-19 infection.

Objective The objective of this study was to establish a mouse model of allergic rhinoconjunctivitis and investigate the role of the NLRP3 signaling pathway in allergic rhinoconjunctivitis.Methods Thirty-three female C57 mice(SPF)were randomLy divided into 3 groups:the control group,the experimental group,and the NLRP3-/-group.On days 0,4,7,14,and 21,the experimental group and NLRP3-/-group received a 0.2 mL intraperitoneal injection of medicine containing OVA(100 μg)and adjuvant Al(OH)3(4 mg),respectively.After an interval of 3 days,each eye and nose were dosed with 10 μL of 5%OVA for five consecutive days a week to induce allergic symptoms.During sensitization and excitation stages,the control group was replaced with an equiva-lent amount of PBS.Ocular and nasal symptoms were observed and scored.The levels of OVA-specific IgE,IL-4,IL-17,and IL-18 in serum were measured using ELISA,while changes in palpebral conjunctiva and nasal mucosa were assessed by hematoxylin-eosin staining.The expression of NLRP3 mRNA in conjunctival tissue and nasal mucosa was determined using real-time PCR analysis.Statistical analysis was performed using SPSS17.0 software with P<0.05 considered as statistically significant difference.Results The experimental group and NLRP3-/-group exhibited induced nasal and ocular allergic symptoms.In the experimental group,the duration of nasal allergy symptoms was(10.500±1.080)days,while the duration of eye allergy symptoms was(20.300±2.058)days.In the NLRP3-/-group,the duration of nasal allergy symptoms was(13.400±1.955)days,and for eye allergy symp-toms it was(20.900±2.132)days.The duration of nasal allergies in the NLRP3-/-group significantly exceeded that in the experimental group(P<0.05),whereas there were no significant differences observed in eye allergy durations between these two groups(P>0.05).Levels of OVA-specific IgE,IL-4,and IL-17 were significantly higher in both the experimental and NLRP3-/-groups compared to those in the control group(P<0.05).Additionally,serum IL-18 content increased significantly in the experimental group when compared with both control and NLRP3-/-groups(P<0.05).Conjunctival tissue lesions as well as nasal mucosa damage were evident in both experimental and NLRP3-/-groups.mRNA expression levels of NLRP3 within conjunctival tissue and nasal mucosa from the experimental group showed a significant increase when compared to those from both control and NLRP3-/-groups(P<0.05).Conclusion Allergic rhinoconjunctivitis pathogenesis is influenced by various factors;however,the involvement of NLPR3 signaling pathway promotes its development.

The Ehlers-Danlos syndrome(EDS)is a rare inherent connective tissue disorder.The prev-alence of EDS in the population is estimated at one out of ten thousand to one out of a hundred thousand.The vascular EDS(vEDS)are rare among the subtypes but are the worst in prognosis.The article reports a case of vEDS admitted to the hospital.The patient was a young man complaining of a sudden onset of aphasia in right hemiparalysis and severe left abdominal pain for unknown reasons.The diagnosis was made after the genetic testing.The patient suffered from vEDS.Then,the multi-disciplinary team(MDT)made a treatment plan tailored to this young patient.The complexity in classification and delusive presentations of the EDS make the correct diagnosis very challenging.This article hopes to report this case and to share the experiences to the bet-ter understanding of this disease.

Objective:To compare the differences of reference intervals (RI) established by two types of indirect methods for 34 biochemical analytes, and to explore the possible factors that affect the consistency of the two methods.Methods:This was a retrospective study. Based on data of albumin (Alb), alkaline phosphatase (ALP), alanine aminotransferase (ALT), apolipoprotein A1(ApoA1), ApolipoproteinB (ApoB), aspartate aminotransferase (AST), calcium (Ca), cholinesterase (ChE), chloride (Cl), creatinine (Cr), high-sensitivity C-reactive protein (hsCRP), Cystatin (CysC), direct bilirubin (DBil), free fatty acid (FFA), glycated albumin(GA), gamma-glutamyltransferase (GGT), glucose (Glu), high density lipoprotein cholesterol (HDL-C), potassium (K), lactate dehydrogenase (LD), low density lipoprotein cholesterol (LDL-C), lipoprotein a [Lp (a)], sodium (Na), phosphorus (P), prealbumin (PA), superoxide dismutase (SOD), total bile acid (TBA), total bilirubin (TBil), total cholesterol (TC), total carbon dioxide (TCO 2), triglyceride (TG), total protein (TP), uric acid (UA) and urea (UR) of individuals who underwent physical examination at Peking Union Medical College Hospital from January 1, 2018 to December 31, 2019, Box-Cox algorithm was used to improve the data distribution and Tukey method was used to identify outliers. Variance component model was established, and standard deviation ratio (SDR) was calculated to determine whether the RIs of 34 biochemical analytes should be established according to age or sex The non-parametric method and kosmic algorithm were used to establish the RIs and 90% confidence intervals (CIs) of 34 biochemical analytes, and the coincidence of the 90% CIs of the reference limits for two methods was compared. Results:The skewness coefficients of ALP(male, female18-59), ALT, AST, hsCRP, DBil, GGT, Lp (a), TBA, TBil, TG, Glu, HDL-C(male) and CysC, GA, UR in the elderly group deviated from 0, and their kurtosis coefficients also deviated from 3. For these biochemical analytes, the point estimates of the RIs established by the two methods differed greatly and the 90% CIs did not overlap. The analytes with good normality were Alb, ApoA1, ApoB, Ca, ChE, Cl, Cr(E), CysC(18-59), FFA, GA(18-59), HDL-C(female), K, LDL-C, Na, P, PA, SOD, TC, TCO 2, TP and UR. The consistency is good. Except for Ca, 90% CIs of reference limits for some analyte between the two methods coincide with each other. Conclusions:The consistency of different indirect methods is affected by the normality of data.

OBJECTIVE: To investigate the expression and clinical significance of soluble Fas (sFas) and sFasL in patients with secondary hemophagocytic lymphohistiocytosis (sHLH). METHODS: From September 2015 to December 2020, 86 sHLH patients who met the HLH2004 diagnostic criteria were collected. They were divided into 55 cases in the MAHLH group and 31 cases in the NonMAHLH group according to the etiology. Thirty healthy persons were chosen as the normal control group, and 20 patients with systemic lupus erythematosus (SLE) were chosen as the disease control group. The expression levels of sFas and sFasL in the serum of patients with each group were detected by ELISA, and the clinical data were collected for statistical analysis. The significance of sFas and sFasL in sHLH was analyzed by ROC curve. RESULTS: Serum levels of sFas and sFasL in patients with newly diagnosed sHLH were significantly higher than those in disease control group and normal control group (P<0.01). The levels of sFas and sFasL in MAHLH group were significantly higher than those in nonMAHLH (infection related HLH and autoimmune disease related HLH) group (P<0.01). The serum levels of sFas and sFasL in 17 newly treated patients with sHLH (17/86) after treatment were significantly lower than those before treatment (P<0.01). The serum sFas level in newly diagnosed sHLH patients was positively correlated with SF(r=0.35), sCD25(r=0.79) and sFasL(r=0.73). The serum sFasL level was positively correlated with SF(r=0.39), sCD25(r=0.64) and sFas(r=0.73). Compared with the NonMAHLH group, the area under the ROC curve was 0.707 (95% CI: 0.593-0.821) (P=0.0015). The optimal critical value for diagnosing MAHLH by sFas level was 12 743 pg/ml, and the sensitivity and specificity were 70.9% and 71% respectively. Compared with the NonMAHLH group, the area under the ROC curve was 0.765(95% CI: 0.659-0.87)(P<0.01). The median OS time of sFas high expression group (≥16798.5 pg/ml) and sFasL high expression group (≥4 785 pg/ml) was significantly shorter than that of the low expression group (P<0.001). CONCLUSION Serum levels of sFas and sFasL can be used for the early diagnosis and differential diagnosis of sHLH disease, and are the factor related to the poor prognosis of sHLH.
Humans ; Lymphohistiocytosis, Hemophagocytic ; Clinical Relevance ; ROC Curve ; Sensitivity and Specificity ; Lupus Erythematosus, Systemic

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*