Pathologically triggered in situ aggregation of nanoparticles for inflammation-targeting amplification and therapeutic potentiation

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.

A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

Inducible co-stimulatory molecules participate in mesenteric vascular endothelial-mesenchymal transition and sclerosis of mesenteric vessels in spontaneously hypertensive rats / 南方医科大学学报

OBJECTIVE@#To investigate the correlation of inducible co-stimulatory molecules (ICOS) with mesenteric vascular endothelial- mesenchymal transition (EndMT) and sclerosis in spontaneously hypertensive rats (SHR).@*METHODS@#Twenty 4-week-old WKY rats and 20 SHRs of the same strain were both randomly divided into 4 groups for observation at 4, 6, 10 and 30 weeks of age. ICOS expression frequency in rat spleen CD4+T cells was analyzed using flow cytometry, and the expressions of ICOS, VE-cad, α-SMA and Col3 mRNA in rat mesentery were detected by RT-PCR. The distributions of ICOS, IL-17A and TGF-β in rat mesentery were detected by immunohistochemistry. The levels of IL-17A and TGF-β in rat plasma were measured using ELISA. The morphological changes of rat mesenteric vessels were observed with Masson staining. Spearman or Pearson correlation analyses were used to evaluate the correlation between ICOS expression and the expressions of the markers of vascular EndMT and sclerosis.@*RESULTS@#Compared with the control WKY rats, the SHRs began to show significantly increased systolic blood pressure and ICOS expression frequency on CD4+T cells at 6 weeks of age (P < 0.05). In the SHRs, the mRNA and protein expressions of ICOS, α-SMA, Col3, IL-17A and TGF-β in the mesentery were significantly higher than those in control group (P < 0.05), while the mRNA and protein expressions of VE-cad started to reduce significantly at 10 weeks of age (P < 0.05). The plasma levels of IL-17A and TGF-β were significantly increased in SHRs since 6 weeks of age (P < 0.05) with progressive worsening of mesenteric vascular sclerosis (P < 0.05). ICOS mRNA and protein expression levels in the mesenteric tissues of SHRs began to show positive correlations with α-SMA and Col3 expression levels and the severity of vascular sclerosis at 6 weeks of age (P < 0.05) and a negative correlation with VE-cad expression level at 10 weeks (P < 0.05).@*CONCLUSION@#ICOS play an important pathogenic role in EndMT and sclerosis of mesenteric vessels in essential hypertension by mediating related immune responses.

A multi-center analysis of thyroid-stimulating hormone level in apparently healthy elderly population in China / 南方医科大学学报

OBJECTIVE@#To investigate serum thyroid stimulating hormone (TSH) level and its changes with age in apparently healthy Chinese elderly population and analyze the differences between TSH levels detected using Roche and Snibe electrochemiluminescence immunoassay analyzers.@*METHODS@#General clinical data and frozen fasting serum samples were collected from 5451 apparently healthy Chinese elderly individuals (> 60 years) from 10 centers in different geographic regions in China. Thyroid function indexes including TSH level were detected using Roche and Snibe electrochemiluminescence immunoassay analyzer, and the median (2.5% and 97.5% quantiles) TSH level was calculated. The variations of TSH level among the participants with geographic regions, gender, and age (with an interval of 5 years) were analyzed to determine the influence of these factors on TSH level.@*RESULTS@#The reference ranges of serum TSH level established using Roche and Snibe electrochemiluminescence immunoassay analyzers were 0.42-9.47 mU/L and 0.36-7.98 mU/L, respectively, showing significant differences between the two methods (P < 0.001). The TSH levels measured at two centers in Western China were significantly higher than those at the other centers (P < 0.05). In elderly male population, serum TSH level tended to increase with age, which was not observed in elderly female population. At the age of 60-75 years, women generally had higher serum TSH level than men, but this difference was not observed in the population beyond 75 years.@*CONCLUSION@#In elderly population, serum TSH level can vary with geographic region, gender, and age, but there was no need for establishing specific reference ranges for these factors. The differences between different detection methods should be evaluated when interpreting the detection results of TSH level.

Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B, endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.

Active Ingredients of Reduning Injection Maintain High Potency against SARS-CoV-2 Variants / 中国结合医学杂志

OBJECTIVE@#To investigate the anti-coronavirus potential and the corresponding mechanisms of the two ingredients of Reduning Injection: quercetin and luteolin.@*METHODS@#A pseudovirus system was designed to test the efficacy of quercetin and luteolin to inhibit SARS-CoV-2 infection and the corresponding cellular toxicity. Luteolin was tested for its activities against the pseudoviruses of SARS-CoV-2 and its variants. Virtual screening was performed to predict the binding sites by Autodock Vina 1.1.230 and PyMol. To validate docking results, surface plasmon resonance (SPR) was used to measure the binding affinity of the compounds with various proteins of the coronaviruses. Quercetin and luteolin were further tested for their inhibitory effects on other coronaviruses by indirect immunofluorescence assay on rhabdomyosarcoma cells infected with HCoV-OC43.@*RESULTS@#The inhibition of SARS-CoV-2 pseudovirus by luteolin and quercetin were strongly dose-dependent, with concentration for 50% of maximal effect (EC50) of 8.817 and 52.98 µmol/L, respectively. Their cytotoxicity to BHK21-hACE2 were 177.6 and 405.1 µmol/L, respectively. In addition, luetolin significantly blocked the entry of 4 pseudoviruses of SARS-CoV-2 variants, with EC50 lower than 7 µmol/L. Virtual screening and SPR confirmed that luteolin binds to the S-proteins and quercetin binds to the active center of the 3CLpro, PLpro, and helicase proteins. Quercetin and luteolin showed over 99% inhibition against HCoV-OC43.@*CONCLUSIONS@#The mechanisms were revealed of quercetin and luteolin inhibiting the infection of SARS-CoV-2 and its variants. Reduning Injection is a promising drug for COVID-19.

Advances of development and application amino acid biosensors / 生物工程学报

Amino acids are the basic building blocks of protein that are very important to the nutrition and health of humans and animals, and widely used in feed, food, medicine and daily chemicals. At present, amino acids are mainly produced from renewable raw materials by microbial fermentation, forming one of the important pillar industries of biomanufacturing in China. Amino acid-producing strains are mostly developed through random mutagenesis- and metabolic engineering-enabled strain breeding combined with strain screening. One of the key limitations to further improvement of production level is the lack of efficient, rapid, and accurate strain screening methods. Therefore, the development of high-throughput screening methods for amino acid strains is very important for the mining of key functional elements and the creation and screening of hyper-producing strains. This paper reviews the design of amino acid biosensors and their applications in the high-throughput evolution and screening of functional elements and hyper-producing strains, and the dynamic regulation of metabolic pathways. The challenges of existing amino acid biosensors and strategies for biosensor optimization are discussed. Finally, the importance of developing biosensors for amino acid derivatives is prospected.

Efficacy and safety of secondary allogeneic hematopoietic stem cell transplantation in 70 patients with recurrent hematologic malignancies after transplantation / 中华血液学杂志

Objectives: To investigate the role of donor change in the second hematopoietic stem cell transplantation (HSCT2) for hematological relapse of malignant hematology after the first transplantation (HSCT1) . Methods: We retrospectively analyzed patients with relapsed hematological malignancies who received HSCT2 at our single center between Mar 1998 and Dec 2020. A total of 70 patients were enrolled[49 males and 21 females; median age, 31.5 (3-61) yr]. Results: Forty-nine male and 21 female patients were enrolled in the trial. At the time of HSCT2, the median age was 31.5 (3-61) years old. Thirty-one patients were diagnosed with acute myeloid leukemia, 23 patients with ALL, and 16 patients with MDS or other malignant hematology disease. Thirty patients had HSCT2 with donor change, and 40 patients underwent HSCT2 without donor change. The median relapse time after HSCT1 was 245.5 (26-2 905) days. After HSCT2, 70 patients had neutrophil engraftment, and 62 (88.6%) had platelet engraftment. The cumulative incidence of platelet engraftment was (93.1±4.7) % in patients with donor change and (86.0±5.7) % in patients without donor change (P=0.636). The cumulative incidence of CMV infection in patients with and without donor change was (64.0±10.3) % and (37.0±7.8) % (P=0.053), respectively. The cumulative incidence of grade Ⅱ-Ⅳ acute graft versus host disease was (19.4±7.9) % vs (31.3±7.5) %, respectively (P=0.227). The cumulative incidence of TRM 100-day post HSCT2 was (9.2±5.1) % vs (6.7±4.6) % (P=0.648), and the cumulative incidence of chronic graft versus host disease at 1-yr post-HSCT2 was (36.7±11.4) % versus (65.6±9.1) % (P=0.031). With a median follow-up of 767 (271-4 936) days, 38 patients had complete remission (CR), and three patients had persistent disease. The CR rate was 92.7%. The cumulative incidences of overall survival (OS) and disease-free survival (DFS) 2 yr after HSCT2 were 25.8% and 23.7%, respectively. The cumulative incidence of relapse, OS, and DFS was (52.6±11.6) % vs (62.4±11.3) % (P=0.423), (28.3±8.6) % vs (23.8±7.5) % (P=0.643), and (28.3±8.6) % vs (22.3±7.7) % (P=0.787), respectively, in patients with changed donor compared with patients with the original donor. Relapses within 6 months post-HSCT1 and with persistent disease before HSCT2 were risk factors for OS, DFS, and CIR. Disease status before HSCT2 and early relapse (within 6 months post-HSCT1) was an independent risk factor for OS, DFS, and CIR post-HSCT2. Conclusion: Our findings indicate that changing donors did not affect the clinical outcome of HSCT2.

Clinical characteristics of 11 patients with chronic lymphocytic leukemia with t (14;19) (q32;q13) / 中华血液学杂志

Objective: To analyze the clinicopathological characteristics of 11 cases of chronic lymphocytic leukemia (CLL) with t (14;19) (q32;q13) . Methods: The case data of 11 patients with CLL with t (14;19) (q32;q13) in the chromosome karyotype analysis results of the Blood Diseases Hospital, Chinese Academy of Medical Sciences from January 1, 2018, to July 30, 2022, were retrospectively analyzed. Results: In all 11 patients, t (14;19) (q32;q13) involved IGH::BCL3 gene rearrangement, and most of them were accompanied by +12 or complex karyotype. An immunophenotypic score of 4-5 was found in 7 patients and 3 in 4 cases. We demonstrated that CLLs with t (14;19) (q32;q13) had a mutational pattern with recurrent mutations in NOTCH1 (3/7), FBXW7 (3/7), and KMT2D (2/7). The very-high-risk, high-risk, intermediate-risk, and low-risk groups consisted of 1, 1, 6, and 3 cases, respectively. Two patients died, 8 survived, and 2 were lost in follow-up. Four patients had disease progression or relapse during treatment. The median time to the first therapy was 1 month. Conclusion: t (14;19) (q32;q13), involving IGH::BCL3 gene rearrangement, is a rare recurrent cytogenetic abnormality in CLL, which is associated with a poor prognosis.

Incidence and clinical characteristics of engraftment syndrome after syngeneic hematopoietic stem cell transplantation in patients with hematological diseases / 中华血液学杂志

Objective: To explore the incidence and clinical characteristics of engraftment syndrome (ES) after syngeneic hematopoietic stem cell transplantation (syn-HSCT) in patients with hematological diseases. Methods: The clinical data of 21 patients who received syn-HSCT at People's Hospital of Peking University from January 1994 to May 2018 were retrospectively analyzed. Results: Seven (33.3% ) of 21 patients developed ES. The onset of ES symptoms occurred at a median of 8 (range: 5-13) days after HSCT, and the diagnosis of ES occurred at a median of 10 (range: 7-14) days after HSCT. Steroids were administered immediately after the diagnosis of ES, the median time of symptom continuance was 2 (range: 1-5) days, and all patients showed complete resolution of ES symptoms. In the multivariate analysis, patients with acute myeloid leukemia and faster neutrophil reconstitution were the risk factors for ES (HR=15.298, 95% CI 1.486-157.501, P=0.022, and HR=17.459, 95% CI 1.776-171.687, P=0.014) . Meanwhile, there was no significant difference in the overall survival and disease-free survival between patients with ES and those without ES. Conclusion: A high incidence of ES was observed in syn-HSCT recipients. Moreover, the prognosis of ES was excellent.

Dynamic monitoring of plasma Epstein-Barr Virus DNA load can predict the occurrence of lymphoproliferative disorders after haploidentical hematopoietic stem cell transplantation / 中华血液学杂志

Objective: To determine the optimal cutoff value of Epstein-Barr virus (EBV) DNA load that can assist in the diagnosis of post-transplant lymphoproliferative disease (PTLD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) . Methods: The data of patients with EBV infection after haplo-HSCT from January to December 2016 were retrospectively analyzed. Through constructing the receiver operating characteristic (ROC) curve and calculating the Youden index to determine the cutoff value of EBV-DNA load and its duration of diagnostic significance for PTLD. Results: A total of 94 patients were included, of whom 20 (21.3% ) developed PTLD, with a median onset time of 56 (40-309) d after transplantation. The median EBV value at the time of diagnosis of PTLD was 70,400 (1,710-1,370,000) copies/ml, and the median duration of EBV viremia was 23.5 (4-490) d. Binary logistic regression was used to analyze the peak EBV-DNA load (the EBV-DNA load at the time of diagnosis in the PTLD group) and duration of EBV viremia between the PTLD and non-PTLD groups. The results showed that the difference between the two groups was statistically significant (P=0.018 and P=0.001) . The ROC curve was constructed to calculate the Youden index, and it was concluded that the EBV-DNA load ≥ 41 850 copies/ml after allogeneic hematopoietic stem cell transplantation had diagnostic significance for PTLD (AUC=0.847) , and the sensitivity and specificity were 0.611 and 0.932, respectively. The duration of EBV viremia of ≥20.5 d had diagnostic significance for PTLD (AUC=0.833) , with a sensitivity and specificity of 0.778 and 0.795, respectively. Conclusion: Dynamic monitoring of EBV load in high-risk patients with PTLD after haplo-HSCT and attention to its duration have important clinical significance, which can help clinically predict the occurrence of PTLD in advance and take early intervention measures.

Review on exposure characteristics and health effects of per- and poly-fluoroalkyl substances / 环境与职业医学

Per- and poly-fluoroalkyl substances (PFAS) are a new type of persistent organic pollutants that have received extensive attention in recent years. This article reviewed the population characteristics of environmental exposure to PFAS, as well as the potential health effects. Previous studies have verified that people are exposed to PFAS mainly through ingestion, and food and water are the dominant contributors. In terms of exposure characteristics, geographical, gender, age, and occupational differences have an impact on the level of PFAS exposure in the corresponding populations by influencing their behavioral characteristics and metabolic levels, with occupational exposure receiving more attention, especially in the exploration of novel PFAS. PFAS associate with a variety of adverse health effects caused by hepatorenal toxicity, immunotoxicity, reproductive toxicity, neurotoxicity, and carcinogenicity. However, some of the conclusions are not completely consistent, and the published epidemiological studies have focused on children and young people, lacking relevant data of the elderly. Future research can pay more attention to the elderly population and carry out validation exploration on controversial conclusions.

A clinical randomized controlled trail of an intelligent robot-assisted minimally invasive reduction system for treatment of unstable pelvic fractures / 中华创伤骨科杂志

Objective:To compare the short-term efficacy between our self-designed intelligent robot-assisted minimally invasive reduction system and conventional freehand reduction assisted by fluoroscopy in the treatment of unstable pelvic fractures by robot or fluoroscopy-assisted internal fixation with percutaneous screws.Methods:A prospective randomized controlled trial was conducted to include eligible 35 patients with unstable pelvic fracture who were admitted to Department of Orthopaedic Trauma, Beijing Jishuitan Hospital from December 2021 to October 2022. They were randomized into 2 groups. The observation group[17 cases, 10 males and 7 females with an age of (44.0±17.4) years] was treated with robot-assisted minimally invasive reduction, followed by robot-assisted or fluoroscopic internal fixation with percutaneous screws; the control group[18 cases, 12 males and 6 females with an age of (38.8±15.0) years] was treated with freehand reduction assisted by fluoroscopy, followed by robot-assisted or fluoroscopic internal fixation with percutaneous screws. The 2 groups were compared in terms of operation time, intraoperative bleeding, successful reduction, reduction quality, incidence of surgical complications and postoperative functional scores.Results:The 2 groups were comparable because there were no significant differences in the preoperative general data between them ( P>0.05). The intraoperative fluoroscopy frequency[(32.4±17.5) times] and fluoroscopy time [(19.8±10.4) s] in the observation group were significantly lower or shorter than those in the control group [(60.8±26.6) times and (38.2±16.1) s], and the rate of successful reduction in the observation group was 100.0% (17/17), significantly higher than that in the control group[72.2% (13/18)] ( P<0.05). There was no significant difference between the 2 groups in intraoperative bleeding, operation time, reduction error, excellent and good rate of reduction after operation by Matta scoring, or Majeed functional score at 12 weeks after operation ( P>0.05). Conclusion:In the treatment of unstable pelvic fractures, since our self-designed intelligent robot-assisted minimally invasive reduction system can plan autonomously the reduction paths and accomplish minimally invasive reduction of the fracture with 3D images real-time monitoring, it is advantageous over conventional reduction methods in a higher success rate and less radiation exposure.

Comparison of efficacy and safety of BR regimen and R-CHOP regimen in the treatment of newly diagnosed follicular lymphoma / 中国综合临床

Objective:Compare the clinical efficacy and safety of bendamustine combined with rituximab (BR regimen) and rituximab combined with standard CHOP regimen (R-CHOP regimen) in the treatment of newly diagnosed follicular lymphoma (FL).Methods:Adopting a prospective case-control study method. 104 newly diagnosed FL patients admitted to Beijing Aerospace General Hospital from January 2018 to January 2022 were selected and randomly divided into an observation group and a control group using a random number table method, with 52 patients in each group. The observation group was treated with bendamustine combined with rituximab, while the control group was treated with rituximab combined with standard CHOP regimen. Both groups were treated for 6 consecutive courses of treatment, with a 21 day treatment period. Compare the serum lactate dehydrogenase (LDH) levels before and after treatment between two groups β 2-Microglobulin (β 2-microglobulin, β 2-MG level, improvement in quality of life after treatment, long-term survival, clinical efficacy, and incidence of adverse reactions. Measurement data is represented by paired t-tests for intra group comparisons, and independent sample t-tests for inter group comparisons; Counting data is represented as an example (%), and inter group comparisons are made using χ 2-test, Wilcoxon rank sum test was used for comparing rank data. Survival analysis was conducted using the Log Rank test. Results:After treatment, serum LDH and The levels of β 2-MG were lower than before treatment [LDH: (262.34±37.24) U/L ratio (323.45±44.46) U/L, (287.23±43.19) U/L ratio (318.28±52.35) U/L; β 2-MG: (2.72±0.30) mg/L compared to (3.45±0.37) mg/L, (2.93±0.28) mg/L compared to (3.37±0.42) mg/L, t-values of 7.60, 3.30, 11.05, 6.29, P values of <0.001, 0.001, <0.001, <0.001, <0.001], and the observation group was lower than the control group ( t-values of 3.15, 3.69, P values of 0.002, <0.001, respectively). After 6 courses of treatment, the quality of life in the observation group improved in 27 cases, stabilized in 22 cases, and decreased in 3 cases; The quality of life in the control group improved in 18 cases, stabilized in 26 cases, and decreased in 8 cases. The improvement of quality of life in the observation group was better than that in the control group ( Z=-2.03, P=0.042). The progression free survival period in the observation group was longer than that in the control group [52.53 months (95% confidence interval: 49.16-55.89 months) compared to 38.84 months (95% confidence interval: 32.44-45.24 months)], and the difference was statistically significant (Log Rank χ 2=4.06, P=0.044), there was no statistically significant difference in overall survival between the two groups ( P=0.217). The complete remission rate in the observation group was higher than that in the control group [88.46%(46/52) vs 71.15%(37/52)], χ 2=4.83, P=0.028], there was no statistically significant difference in objective response rates between the two groups ( P=0.485). The incidence of nausea, vomiting, leukopenia, neutropenia, alopecia, and fatigue in the observation group was lower than that in the control group, and the differences were statistically significant (all P<0.05). Conclusions:Both the BR regimen and R-CHOP regimen can significantly reduce serum tumor marker levels in the treatment of newly diagnosed FL. However, the BR regimen has a higher complete response rate, better patient quality of life, longer PFS, fewer toxic side effects, and more significant overall efficacy.

Genetic inhibition of MLKL exerts protective effects against cognitive impairment and neuroinflammation in a cerebral small vessel disease model / 中国药理学与毒理学杂志

OBJECTIVE To identify the role of mixed lineage kinase domain like protein(MLKL)in cerebral small vessel disease(CSVD)and explore the underlying mechanism.METHODS Transient bilateral common carotid artery occlusion(tBCCAO)was used to establish a mouse model of CSVD.Immunofluorescence staining and Western blotting were used to observe the expres-sions of RIPK3/MLKL signaling molecules in brain tissues at 7,14 and 28 d after tBCCAO.Open field test,rotarod test,Y-maze and novel object recognition test were used to observe the effect of MLKL knockout on cognitive func-tion after tBCCAO.Blood-brain barrier(BBB)disruption was observed by sodium fluorescein permeability test and the expressions of tight junction proteins.Immunoflu-orescence staining and Western blotting were used to detect the expression of microglia marker Iba-1,astro-cyte marker GFAP,and NLRP3/Caspase-1 signaling mol-ecules in the hippocampus of CSVD mice.ELISA was used to detect the level of inflammatory factors(TNF-α,IL-1β,IL-18)in hippocampus.RESULTS The expres-sions of RIPK3/MLKL signaling molecules increased in cortex and hippocampus after tBCCAO,especially on day 14.The expression of pMLKL mainly increased in neurons,glia cells and endothelial cells in CSVD mice.MLKL knockout improved the cognitive functions such as motor learning,spatial learning and working memory,and object recognition ability in CSVD mice.MLKL knock-out alleviated the leakage of sodium fluorescein and attenuated the down-regulation of tight junction proteins at 1 d and 14 d after tBCCAO.At 14 d after tBCCAO,MLKL knock out inhibited the activations of microglia and astrocytes,attenuated the expressions of NLRP3/cas-pase-1 molecules,and decreased the levels of inflamma-tory factors in the hippocampus of mice.CONCLUSION Genetic inhibition of MLKL exerts protective effects against cognitive impairment by ameliorating BBB dam-age and neuroinflammation in a mouse cerebral small vessel disease model.

Inhibition of subicular seizure-labeled c-fos+ neurons alleviates cognitive deficit in epilepsy / 中国药理学与毒理学杂志

OBJECTIVE Cognitive deficit is a com-mon comorbidity in temporal lobe epilepsy(TLE)and that is not well controlled by current therapeutics.Currently,how epileptic seizure affects cognitive performance remains largely unclear.The subiculum is the major out-put of the hippocampus,which projects to entorhinal cor-tex and other more distinct brain regions.Physiologically,the subiculum codes spatial working memory and naviga-tion information including place,speed,and trajectory.Importantly,prior studies have noted the importance of the subiculum in the beginning,spreading,and generaliz-ing process of hippocampal seizure.How seizure-activated neurons in subiculum participate in cognitive impairment remains largely elusive.METHODS In this study,we sought to label the subicular seizure-activated c-fos+ neu-rons with a special promoter with enhanced synaptic activity-responsive element E-SARE in the subiculum,combined with chemogenetics and designer receptors exclusively activated by designer drugs(DREADDs),Ca2+ fiber photometry approaches,and behavioral tasks,to reveal the role of these neurons in cognitive impairment in epilepsy.RESULTS We found that chemogenetic inhibi-tion of subicular seizure-tagged c-fos+ neurons(mainly CaMK Ⅱ α+ glutamatergic neurons)alleviates seizure generalization and improves cognitive performance in the hippocampal CA3 kindling TLE model.While inhibition of seizure-labeled c-fos+ GABAergic interneuron shows no effect on seizure and cognition.As a comparison,che-mogenetic inhibition of the whole subicular CaMK Ⅱ α+ neuron impairs cognitive function in na?ve mice in basal condition.Notably,inhibition of subicular seizure-tagged c-fos+ neurons enhances the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks.CONCLUSION Our results dem-onstrate that subicular seizure-activated c-fos+ neurons contribute to cognitive impairment in TLE,suggesting sei-zure-tagged c-fos+ neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

Correlation analysis between muscle CT measurement parameters, energy expenditure and risk of acute exacerbation in patients with stable chronic obstructive pulmonary disease / 中国医师进修杂志

Objective:To explore the correlation between muscle CT measurement parameters, energy expenditure and acute exacerbation in patients with stable chronic obstructive pulmonary disease (COPD).Methods:The clinical data of 146 patients with stable COPD from March 2020 to November 2021 in Lu′an Hospital Affiliated to Anhui Medical University (Lu′an People′s Hospital) were retrospectively analyzed. The clinical data were recorded; the lung function was measured by bronchodilator test. The cross-sectional area and CT value of the pectoral muscle were measured by reconstructed CT images of the mediastinum; the total energy consumption was calculated by Weir formula. Acute exacerbations within 3 and 12 months were recorded. Multivariate Logistic regression was used to analyze the independent risk factors for acute exacerbation in patients with stable COPD. The receiver operating characteristic (ROC) curve was used to analyze the efficacy of total energy expenditure, pectoral muscle cross-sectional area and pectoral muscle CT value for predicting acute exacerbation in patients with stable COPD.Results:Among 146 patients with stable COPD, 38 cases (26.03%) developed acute exacerbation within 3 months (acute exacerbation group), and 108 cases (73.97%) did not develop acute exacerbation (non-acute exacerbation group). The proportion of age<60 years old, rate of acute exacerbation within 12 months and rate of pulmonary function grading Ⅲ to Ⅳ in acute exacerbation group were significantly higher than those in non-acute exacerbation group: 71.05% (27/38) vs. 47.22% (51/108), 52.63% (20/38) vs. 30.56% (33/108) and 63.16% (24/38) vs. 37.96% (41/108), the total energy consumption, pectoral muscle cross-sectional area and pectoral muscle CT value were significantly lower than those in non-acute exacerbation group: (2 036.28 ± 163.13) J/d vs. (2 389.59 ± 204.71) J/d, (28.79 ± 3.45) cm 2 vs. (31.61 ± 4.56) cm 2 and (29.79 ± 3.06) HU vs. (34.52 ± 4.38) HU, and there were statistical differences ( P<0.05 or <0.01). Multivariate Logistic regression analysis result showed that age ≥60 years old, lower total energy expenditure, smaller pectoral muscle cross-sectional area and lower pectoral muscle CT value were independent risk factors for acute exacerbation in patients with stable COPD ( OR = 26.493, 1.015, 1.245 and 1.437; 95% CI 3.745 to 187.405, 1.008 to 1.022, 1.002 to 1.546 and 1.109 to 1.861; P<0.01 or <0.05). The ROC curve analysis result showed that combined prediction of the total energy consumption, pectoral muscle cross-sectional area and pectoral muscle CT value for acute exacerbation in patients with stable COPD had the largest area under the curve (0.962), with a sensitivity of 86.1%, a specificity of 80.8%, and the optimal cutoff values of 2 206.12 J/d, 32.39 cm 2 and 31.63 HU, respectively. Conclusions:The elderly age, smaller pectoral muscle cross-sectional area, lower pectoral muscle CT value and lower total energy expenditure are independent risk factors for acute exacerbation in patients with stable COPD. The combination of pectoral muscle cross-sectional area, pectoral muscle CT value and total energy expenditure has a good predictive effect on the risk of acute exacerbation in patients with stable COPD, and relevant indexes can be paid attention to in clinical treatment.

Enlightenment on the Construction of Medical Professionalism from the Perspective of Moral Injury / 中国医学伦理学

The purpose of medicine is to preserve and develop the treatment in the process of saving lives and helping injuries. Medical professionalism is a comprehensive expression of physician’s clinical abilities, relationships and values between different subjects. In practice, white robed doctors utilize high standards of professionalism to practice the medical purpose and goals of "always centering on the interests of the patient" in specific diagnosis and treatment behaviors. At the same time, fulfilling the promises and expectations of medicine to the public. For these reasons, selfless dedication, self-sacrifice, and one-way pure altruism are all internalized into the basic requirements of medical professionalism: doctors should not only have the skill to revive the dead, but also have the benevolence of evangelists; they not only need to achieve maximum efficiency in technology, but also achieve the highest truth, goodness, and beauty in virtue. When these qualities are exaggerated or unattainable due to uncontrollable reasons, there will be a rift between the entrenched value systems and practical needs. In recent years, the global epidemic has had a huge impact on the medical system and medical staff, and the moral beliefs, role expectations, and value systems of doctors have also been impacted unprecedentedly, resulting in moral injury. The international research on moral injury in medical field has also received attention. China is currently in the adjustment period of epidemic related policies, with medical personnel bearing the brunt. Therefore, referring to relevant international research on moral injury to re-examine the relationship between the medical professionalism, which emphasizes one-way pure altruism, dedication and weakening or even neglecting personal well-being, and current medical practices. And constructing a moral injury early warning-repair system that focuses on doctors, patients, medical teams, medical institutions, medical environments, health systems, and other stakeholders, and ensuring its healthy operation. Not only in extreme periods, but also in ordinary daily diagnosis and treatment, it can support doctors to actively, safely, and healthily fulfill their mission of saving lives and helping injuries.

Cellular and Molecular Mechanisms of Intestinal Fibrosis

Intestinal fibrosis associated stricture is a common complication of inflammatory bowel disease usually requiring endoscopic or surgical intervention. Effective anti-fibrotic agents aiming to control or reverse intestinal fibrosis are still unavailable. Thus, clarifying the mechanism underpinning intestinal fibrosis is imperative. Fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins at the injured sites. Multiple cellular types are implicated in fibrosis development. Among these cells, mesenchymal cells are major compartments that are activated and then enhance the production of ECM. Additionally, immune cells contribute to the persistent activation of mesenchymal cells and perpetuation of inflammation. Molecules are messengers of crosstalk between these cellular compartments. Although inflammation is necessary for fibrosis development, purely controlling intestinal inflammation cannot halt the development of fibrosis, suggesting that chronic inflammation is not the unique contributor to fibrogenesis. Several inflammation-independent mechanisms including gut microbiota, creeping fat, ECM interaction, and metabolic reprogramming are involved in the pathogenesis of fibrosis. In the past decades, substantial progress has been made in elucidating the cellular and molecular mechanisms of intestinal fibrosis. Here, we summarized new discoveries and advances of cellular components and major molecular mediators that are associated with intestinal fibrosis, aiming to provide a basis for exploring effective anti-fibrotic therapies in this field.