Long-Term Follow-Up of a Case of Probable Aspergillus Skull Base Osteomyelitis With Galactomannan Test and Literature Review.

We report a probable case of Aspergillus basicranial infection diagnosed by pathogenic serological examination presenting atypical initial manifestations, and highlight the importance of serological examination to avoid treatment delay and disease management. An 84-year-old diabetic patient presented with right peripheral nerve palsy, intolerable otalgia, hearing loss, dysphagia, hoarseness, and bucking. The patient was diagnosed a probable Aspergillus skull base osteomyelitis with cranial neuritis and meningitis of central nervous system. Galactomannan test was used in combination with 1-3-ß-D-glucan and magnetic resonance imaging to follow-up during the continuous treatment of voriconazole. To date, the patient has remained in clinical remission for over 39 months but the drug cannot be stopped safely.

Cldn4 overexpression promotes penile cavernous smooth muscle cell fibrotic response via the JNK signaling pathway.

BACKGROUND: Erectile dysfunction (ED), defined as the inability to achieve or maintain a penile erection sufficient to satisfy sexual behavior, is prevalent worldwide. AIM: Using previous research, bioinformatics, and experimental confirmation, we aimed to discover genes that contribute to ED through regulating hypoxia in corpus cavernosum smooth muscle cells (CCSMCs). METHODS: We used the Gene Expression Omnibus to acquire the sequencing data of the corpus cavernosum transcriptome for diabetic ED and nerve injury type ED rats. We intersected the common differentially expressed genes. Further verification was performed using single cell sequencing. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate whether the differentially expressed genes are found in the corpus cavernosum. We used induced hypoxia to assess cell viability changes, and we developed a lentivirus overexpressing Cldn4 for in vitro and in vivo experiments to measure changes in JNK signaling, fibrosis, hypoxia, and erectile function. OUTCOMES: Our results indicate that targeting the JNK pathway and decreasing local hypoxia may be better options for therapeutic intervention to improve erectile function. RESULTS: We identified Cldn4 and found its expression increased in the corpora cavernosa of the 2 datasets. In addition, we found that hypoxia can increase the expression of Cldn4, activate the JNK signaling pathway, and exacerbate fibrosis in CCSMCs. Cldn4 overexpression in CCSMCs activated the JNK signaling pathway and increased fibrotic protein expression. Last, rat corpus cavernosum overexpressing Cldn4 activated the JNK signaling pathway, increased local fibrosis, and impaired erectile function. CLINICAL IMPLICATIONS: Through bioinformatics and in vitro and in vivo experiments, we found that Cldn4 has a negative effect on ED, and targeting Cldn4 may provide new ideas for ED treatment. STRENGTHS AND LIMITATIONS: Although we have identified Cldn4 as a potential target for ED treatment, we have only conducted preliminary validation on CCMSCs, and we still need to further validate in other cell lines. CONCLUSION: CCSMC hypoxia leads to increased Cldn4, in both nerve injury and diabetic ED rat models, and promotes fibrosis by activating the JNK signaling pathway.

Inhibition of PPP1R15A alleviates osteoporosis via suppressing RANKL-induced osteoclastogenesis.

Osteoporosis results from overactivation of osteoclasts. There are currently few drug options for treatment of this disease. Since the successful development of allosteric inhibitors, phosphatases have become attractive therapeutic targets. Protein phosphatase 1, regulatory subunit 15 A (PPP1R15A), is a stress-responsive protein, which promotes the UPR (unfolded protein response) and restores protein homeostasis. In this study we investigated the role of PPP1R15A in osteoporosis and osteoclastogenesis. Ovariectomy (OVX)-induced osteoporosis mouse model was established, osteoporosis was evaluated in the left femurs using micro-CT. RANKL-stimulated osteoclastogenesis was used as in vitro models. We showed that PPP1R15A expression was markedly increased in BMMs derived from OVX mice and during RANKL-induced osteoclastogenesis in vitro. Knockdown of PPP1R15A or application of Sephin1 (a PPP1R15A allosteric inhibitor in a phase II clinical trial) significantly inhibited osteoclastogenesis in vitro. Sephin1 (0.78, 3.125 and 12.5 µM) dose-dependently mitigated the changes in NF-κB, MAPK, and c-FOS and the subsequent nuclear factor of activated T cells 1 (NFATc1) translocation in RANKL-stimulated BMMs. Both Sephin1 and PPP1R15A knockdown increased the phosphorylated form of eukaryotic initiation factor 2α (eIF2α); knockdown of eIF2α reduced the inhibitory effects of Sephin1 on NFATc1-luc transcription and osteoclast formation. Furthermore, Sephin1 or PPP1R15A knockdown suppressed osteoclastogenesis in CD14+ monocytes from osteoporosis patients. In OVX mice, injection of Sephin1 (4, 8 mg/kg, i.p.) every two days for 6 weeks significantly inhibited bone loss, and restored bone destruction and decreased TRAP-positive cells. This study has identified PPP1R15A as a novel target for osteoclast differentiation, and genetic inhibition or allosteric inhibitors of PPP1R15A, such as Sephin1, can be used to treat osteoporosis. This study revealed that PPP1R15A expression was increased in osteoporosis in both human and mice. Inhibition of PPP1R15A by specific knockdown or an allosteric inhibitor Sephin1 mitigated murine osteoclast formation in vitro and attenuated ovariectomy-induced osteoporosis in vivo. PPP1R15A inhibition also suppressed pathogenic osteoclastogenesis in CD14+ monocytes from osteoporosis patients. These results identify PPP1R15A as a novel regulator of osteoclastogenesis and a valuable therapeutic target for osteoporosis.

Two-dimensional liquid chromatography measurement of meropenem concentration in synovial fluid of patients with periprosthetic joint infection.

Periprosthetic joint infection (PJI) is a catastrophic complication following joint replacement surgery. One potential treatment approach for PJI could be the combination of one-stage revision and intra-articular infusion of antibiotics. Meropenem is one of the commonly used intra-articular antibiotics in our institution. Determining the concentration of meropenem in the joint cavity could be crucial for optimizing its local application, effectively eradicating biofilm infection, and improving PJI treatment outcomes. In this study, we developed a simple, precise, and accurate method of two-dimensional liquid chromatography (2D-LC) for determining the concentration of meropenem in human synovial fluid. The method was then validated based on the guidelines of the Food and Drug Administration and the Chinese Pharmacopoeia. Meropenem showed good linearity in the range of 0.31-25.01 µg/mL (r ≥ .999). Selectivity, intra-day and inter-day precision and accuracy, extraction recovery, and stability validation results were all within the acceptance range. This method has been successfully applied to the determination of synovial fluid samples from PJI patients, providing a useful detection method for meropenem therapeutic drug monitoring (TDM) in PJI patients.

Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

The effect of bivalirudin on coagulation function in male patients with coronary heart disease undergoing percutaneous coronary intervention.

Aim of this study was to explore the effect of bivalirudin on coagulation function with the treatment of percutaneous coronary intervention (PCI) in male coronary heart disease (CHD) patients. There were 90 male CHD cases treated with PCIas study object and were randomly divided into bivalirudin and unfractionated heparin group (n=45). Unfractionated heparin group patients were given unfractionated heparin and bivalirudin group cases were treated with bivalirudin. Activated clotting time (ACT), thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), platelet count (PLT) were determined and the major adverse cardiovascular events (MACCE) were observed in two group patients. There was no significant (p<0.05) difference with ACT, TT, PT, PLT, APTT and Fib between the two groups before and after 6h, 24h and 72h of operation. The incidence of stent thrombosis and general bleeding with in 24h after PCI in bivalirudin group was lower than in heparin group. After 13 months of follow-up, there was no significant (p<0.05) difference in the incidence of MACCE between the two groups. Compared with the treatment of unfractionated heparin in CHD patients after PCI in 24h, the bivalirudin had more remarkable effect, such as rapid onset, short half-life, lower incidence of thrombosis and bleeding.

An unusual signal transducer GIV/Girdin engages in the roles of adipocyte-derived hormone leptin in liver fibrosis.

Obese patients usually have hyperleptinemia and are prone to develop liver fibrosis. Leptin is intimately linked to liver fibrogenesis, a multi-receptor-driven disease. Gα-Interacting Vesicle-associated protein (GIV) functions as a multimodular signal transducer and a guanine nucleotide exchange factor for Gi controling key signalings downstream of diverse receptors. This study aimed to examine the roles of GIV in leptin-caused liver fibrosis and employed the culture-activated hepatic stellate cells (HSCs) and leptin-deficient mice, respectively. Results indicated that leptin upregulated GIV expression in HSCs. GIV was involved in leptin-induced HSC activation and liver fibrosis. GIV mediated leptin regulation of TIMP1, MMP9, PDGFß receptor and TGFß receptor and was required for leptin stimulating the pathways of Erk1/2, Akt1, and Smad3. GIV was also a mediator for leptin-regulation of Cyclin D1 and Caspase-3 activity but GIV reduced Caspase-3 level independently of leptin in vivo. Erk1/2 signaling, Egr1 and c-Jun were associated with the effect of leptin on GIV expression in HSCs. Leptin-induced Erk1/2 signaling increased Egr1 and p-c-Jun levels and promoted their binding to GIV promoter at the sites between -190 bp and -180 bp and between -382 bp and - 376 bp, respectively. Egr1 knockdown lessened leptin-upregulation of GIV in vitro and in vivo. In human cirrhotic livers, the increase in GIV protein level parallelled with the elevated p-Erk1/2 and Egr1 levels in HSCs. In summary, the unusual signal transducer GIV was identified as an important mediator in leptin-induced liver fibrosis. GIV may have significant implications in liver fibrosis progression of obese patients with hyperleptinaemia.

Curcumol inhibits breast cancer growth via NCL/ERα36 and the PI3K/AKT pathway.

Background: Breast cancer (BC) is the most common malignancy worldwide. ERα36 (ERα66 variant) is expressed in many breast cancer cells, especially highly expressed in tamoxifen (TAM)-resistant cell lines and triple-negative breast cancer, and our previous work revealed that nucleolin (NCL) is a protein target of curcumol. This study is aimed at investigating the effect and mechanism of curcumol on ERα36 positive breast cancer cells, and the relationship between curcumol's target protein NCL and ERα36. Study design: Application of in vivo and in vitro studies to reveal the mechanism of curcumol in inhibiting BC growth and the relationship between curcumol's target protein NCL and ERα36. Methods: The anti-tumor effect of curcumol was quantified via an MTT assay, colony formation and cycle arrest, respectively. The expressions of ERα36, NCL and the proteins involved in PI3K/AKT signaling were evaluated by western blotting. The interaction between two proteins was detected using co-immunoprecipitation (Co-IP) and an immunofluorescence assay. A mouse xenograft model was established to verify the role of ERα36 in breast cancer cells and curcumol's effect on ERα36 positive cancer cells. Results: Curcumol inhibited the cell growth, caused cell cycle arrest, decreased cell cycle related proteins and inactivated the PI3K/AKT pathway in ERα36 positive breast cancer cells. There is a positive correlation between NCL and ERα36 in breast cancer cells. In addition, ERα36 bound to NCL; the two proteins were distributed in the nucleus, cytoplasm and plasma membrane, where their expression was obviously decreased by curcumol. Moreover, NCL silenced by NCL siRNA blocked the cell cycle progress and inhibited the activation of PI3K/AKT in MDA-MB-231 cells, while overexpressed ERα36 increased the expression of NCL, promoted the cell cycle progress and enhanced the activity of PI3K/AKT in MCF-7 cells. NCL knockdown or ERα36 overexpression attenuated the effect of curcumol on breast cancer cells. Conclusion: Curcumol reduced the proliferation of breast cancer cells by targeting NCL/ERα36 and inactivating the PI3K/AKT pathway.

Real-World clinical features and survival outcomes associated with primary gastrointestinal natural killer/T-cell lymphoma from 1999 to 2020.

BACKGROUND: Primary gastrointestinal natural killer (NK)/T-cell lymphoma (PGINKTL) is a rare T-/NK-cell lymphoma subtype, and the clinical features and survival outcomes remain largely unknown. METHODS: To summarize the clinical features and survival outcomes of PGINKTL, PGINKTL cases diagnosed at our hospital from May 1999 to December 2020 were reviewed; and the clinical data, information on treatment strategies, and survival were collected. Survival analysis was performed using the Kaplan-Meier method and multivariable Cox proportional hazards regression. We constructed a nomogram to visualize the survival prediction of PGINKTL. The discriminative ability and calibration of the nomogram for prediction were tested using the concordance index (C-index) and calibration plots. RESULTS: The cohort included 81 cases, the median age was 36 years (range, 7-80 years), and the male-to-female ratio was 1.7:1. The most common clinical symptom at the time of diagnosis was abdominal pain (71.6%). The most common lesion site was the colon (59.3%). During a median follow-up period of 37.7 months, the median overall survival (OS) time of 81 patients was 4.0 months (95% confidence interval [CI], 3.1-4.9 months), and the 2-year OS rate was 30.7% (95% CI, 20.3%-40.1%). The multivariate analyses indicated that patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≥2, serum lactic dehydrogenase (LDH) level ≥ the upper limit normal (ULN), and perforation had worse OS. We used these data to establish a nomogram to predict survival for PGINKTL. The nomogram displayed good accuracy, with a C-index of 0.726. CONCLUSION: The clinical features and poor outcomes of PGINKTL, which is a rare and fatal lymphoma type, are presented. The proposed nomogram provides an individualized estimate of survival for these patients. In the future, the study focused on exploring a better treatment strategy to improve survival is required in PGINKTL.

Morbidity and risk factors of de novo malignancy after heart transplantation / 中华器官移植杂志

Objective:To explore the morbidity and risk factors of de novo malignancy after heart transplantation (HT).Methods:From June 2004 to August 2021, 995 patients undergoing HT were selected and followed up.The epidemiological characteristics, the morbidity of de novo malignancy (DNM) and its risk factors were examined.Kaplan-Meier survival analysis was performed for calculating the cumulative incidence and mortality of DNM.Log rank test was utilized for comparing the survival rate of each subgroup.Cox regression model was employed for examining the relationship between the included factors and the endpoint of DNM.Results:The median follow-up period was 6.36(3.64, 10.18) years.Thirty-six patients (3.6%) developed DNM during follow-up.Lung cancer accounted for 22.2%(8/36) of DNM while digestive system tumors accounted for 38.9% (including gastric cancer 6/36, 16.7%; liver cancer 3/36, 8.3%; colon cancer 2/36, 5.6%). The cumulative morbidity of DNM at Year 1/5/10/15 post-HT was 0.1%, 2.3%, 4.9% and 7.6% respectively.The median survival time of DNM recipients was 83.32 months.The mean survival time was significantly lower than those without DNM[(115.32±13.12) vs.(194.22±2.58), P<0.001]. The mortality of DNM recipients was around 6.57 folds higher ( HR=6.57, 95% CI: 4.06-10.64, P<0.01). Age was an independent risk factor for an occurrence of DNM.Hypertension and diabetes were also correlated with DNM. Conclusions:DNM after HT is associated with shorter survival time.And age is an independent risk factor for DNM after HT.

Analysis of risk factors for kidney dysfunction after heart transplantation and its impact onprognosis / 中华器官移植杂志

Objective:To summarize the incidence and long-term outcomes of postoperative renal dysfunction(RD) and explore the clinical predictors of postoperative RD to provide reference for preoperative evaluation and perioperative management of heart transplantation(HT).Methods:The relevant clinical data are retrospectively reviewed for 1 095 HT recipients.They are grouped into two groups of RD(352 cases)and non-RD(normal, 743 cases)according to whether or not RD occurred after HT.Two groups are compared to explore the clinical predictors associated with postoperative RD.For further examining the prognostic impact of perioperative renal dysfunction, the recipients are assigned into four groups based upon perioperative renal function.The long-term outcomes of four groups are compared.Results:The median follow-up period is 5.6 years.Among 352 RD patients (32.1%), there are new-onset(276 cases, 25.2%), occurring during postoperative hospitalization (99, 28.1%)and post-discharge until Year 1(111 cases, 31.5%).Compared with normal group, RD group have advanced age, greater body mass index(BMI), higher preoperative serum creatinine, longer cardiopulmonary bypass time, a higher ratio of male, diabetic history, preoperative RD, transplantation for previous graft failure, preoperative extracorporeal membrane oxygenerator(ECMO)and intra-aortic balloon pump(IABP); donors in this group had advanced age and higher ratio of male (all P<0.05).In terms of postoperative data, RD group had higher ratios of ECMO/IABP implantation, tracheostomy, infection, longer postoperative mechanical ventilation time, intensive care unit(ICU)stay and in-hospital stay than normal group( P<0.05).Long-term survival of patients with postoperative RD is significantly lower than that with postoperative normal kidney function( P<0.01).Long-term survival rate of patients with preoperative RD is significantly lower than that of those without preoperative RD, regardless of whether or not kidney function normalized postoperatively; long-term survival rate of patients with postoperative new-onset RD is significantly lower than that in those with normal kidney function( P<0.01).Advanced recipient age, higher BMI, existence of preoperative RD, postoperative cyclosporine dosing(versus tacrolimus)and cold ischemic time≥6 h are independent risk factors of RD post-HT. Conclusions:RD occurs predominantly within the first year post-HT.Advanced recipient age, higher BMI, existence of preoperative RD and cold ischemic time≥6 h are independent predictors of RD post-HT.The incidence of RD post-HT significantly affects perioperative and long-term survivals.

Application of scenario simulation teaching based on PBL in communication ability training of Pediatric Hematology Department / 中华医学教育探索杂志

Objective:To explore the application of scenario simulation teaching based on PBL in communication skills training of hematology students in Children's Hospital.Methods:The training of doctor-patient communication skills was conducted among trainees who had the standardized residency training at the Department of Hematology of the Children's Hospital of Soochow University. All the residents were randomized into the control group and observation group by lottery, with 24 residents in each group. The control group adopted the traditional narrative teaching method, and the observation group adopted PBL combined with scenario simulation teaching method. The Liverpool communication skills assessment scale (LCSAS) was used to compare the differences between the two groups before and after training, and the differences between the two groups after training. Then the degree of residents' recognition of these two teaching methods was investigated. Finally, the examination results were used to evaluate knowledge mastery of doctors in department of hematology. SPSS 20.0 was used for Chi-square test and t-test. Results:LCSAS scores of the two groups before training were respectively (11.61±2.21) and (11.95±2.22), with no statistically significant difference ( P >0.05). After PBL-based scenario simulation teaching and training in the observation group, the LCSAS score of the observation group (27.41±2.53) was higher than that of the control group (23.30±1.81), and the difference between the two groups was statistically significant ( P<0.05). Questionnaire survey results showed that the favorable rating rate of PBL-based scenario simulation teaching was 91.67% (22/24), higher than that of the traditional narrative teaching method [62.50% (15/24)], and the difference was statistically significant ( P<0.05). The examination of students' mastery of professional knowledge showed that after the PBL-based scenario simulation teaching and training, the trainees had a better grasp of knowledge and a higher score, with excellence rate of 91.67% (22/24）, which was higher than 66.67% (16/24) of the control group, with a statistically significant difference ( P<0.05). Conclusion:The scenario simulation teaching based on PBL could improve the communication ability and professional knowledge of trainees taking standardized residency training in the department of hematology, and the trainees are highly satisfied with this teaching method.

Efficacy and safety evaluation of three medicated eye patches in Demodex blepharitis: a multicenter, double-blind, randomized controlled clinical trial / 中华实验眼科杂志

Objective:To evaluate and compare the clinical efficacy and safety of three different medicated eye patches in the treatment of Demodex blepharitis. Methods:A multicenter, randomized, double-blind, parallel-controlled clinical trial was conducted.A total of 140 patients (280 eyes) with Demodex blepharitis were recruited in Shanghai Jing'an District Shibei Hospital, Xi'an Fourth Hospital and Kunming First People's Hospital from July 2021 to December 2022.The affected eyes were randomly divided into tea tree oil group, okra oil group, basal fluid control group and metronidazole group by the random number table method.Eye patches containing 20% tea tree oil, 1% okra oil, prepared base solution and 2% metronidazole were applied to the eyes for 28 days by the double-blind method.The count of Demodex was evaluated before treatment and on days 14 and 28 of treatment.Ocular surface symptoms were scored according to Ocular Surface Disease Index (OSDI). The degree of congestion at the eyelid margin and cylindrical dandruff at the root of eyelashes were scored under a slit lamp microscope.The effective rate was calculated according to the comprehensive scores above, and the adverse reactions of the subjects were observed.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Shanghai Jing'an District Shibei Hospital (No.YL-20200320-05). All the subjects were informed of the significance, purpose and method of the study.Written informed consent was obtained from each subject before any medical examination. Results:All subjects completed the treatment and follow-up, and the loss to follow-up rate was 0%.After 14 and 28 days of treatment, the Demodex count was significantly decreased in all groups compared with before treatment (all at P<0.05). After 28 days of treatment, the number of Demodex in tea tree oil group, okra oil group and metronidazole group were significantly lower than that in basal fluid control group, with statistically significant differences (all at P<0.05). The OSDI score, palpebral margin congestion score and cylindrical dandruff score on 14 and 28 days after treatment in tea tree oil group, okra oil group and metronidazole group were significantly lower than before treatment, showing statistically significant differences (all at P<0.05). After 28 days of treatment, the effective rates of tea tree oil group, okra oil group and metronidazole group were 71.4%, 71.4% and 62.9%, respectively, which were significantly higher than 25.7% in basal solution control group.No serious local or systemic adverse reactions were found during the treatment and follow-up. Conclusions:Eye patches containing tea tree oil, okra oil and metronidazole have significant effects on the treatment of Demodex blepharitis, which can improve the biological environment of the palpebral margin and eliminate the inflammation related to blepharitis.

Recognition of the caudate lobe and reflections on related issues / 中华消化外科杂志

The hepatic caudate lobe is located in the deep back area of the liver. Due to the unique anatomical position of hepatic caudate lobe, surgical treatment for tumor of hepatic caudate lobe is particularly difficult. Non-surgical treatment, such as ablation, transarterial embolization, etc, is also challenging for tumor of hepatic caudate lobe, and the therapeutic effect is inferior to that of surgery. Therefore, surgical resection is the only treatment for tumor of hepatic caudate lobe. The authors discuss the research history of hepatic caudate lobe, the problems of laparoscopic technique in hepatic caudate lobe resection, etc, in order to provide a theoretical basis for improving the concept of accuracy of laparoscopic caudate lobectomy.

Clinical significance of next-generation sequencing-based IGH/IGK gene rearrangement analysis in the diagnosis of minimal residual disease of children with acute B-cell lymphoblastic leukemia / 中华实用儿科临床杂志

Objective:To assess the clinical significance of next-generation sequencing (NGS)-based IGH/ IGK gene rearrangement analysis versus flow cytometry (FCM) in diagnosing minimal residual disease (MRD) of children with acute B-cell lymphoblastic leukemia (B-ALL). Methods:Clinical data, NGS-MRD and FCM-MRD findings at the initial diagnosis and after induction chemotherapy of 85 children diagnosed as B-ALL in Children′s Hospital of Nanjing Medical University from July 2019 to July 2021, were retrospectively analyzed.The sensitivity of the two methods, and the positive rate were compared by χ2 test or Fisher′ s test.The correlation was identified by Spearman correlation analysis. Results:Dominant clone sequences were detected in all children at the initial diagnosis by NGS, while selection markers were identified by FCM in 75(88.2%) patients.Positive MRD rate detected by NGS-MRD was significantly higher than that of FCM-MRD at the same time point after induction chemotherapy[31.8%(27/85) vs.9.4%(8/85), P<0.001]. Compared with those of FCM-MRD, NGS-MRD had good sensitivity (100.0%), specificity (75.3%) and negative predictive value (100.0%), and the positive predictive value was 29.6%.MRD results detected by NGS were consistent with that of FCM ( r=0.569, P<0.001). By July 27, 2022, 2 patients with NGS-MRD (+ )FCM-MRD (-)relapsed during maintenance chemotherapy. Conclusions:NGS is highly consistent with FCM in the detection of MRD in children with B-ALL, which is more sensitive.The combination of NGS-MRD and FCM-MRD benefits more in monitoring MRD in children with B-ALL after induction chemotherapy.

HipBST Toxin-antitoxin System of Prokaryotes / 中国生物化学与分子生物学报

Toxin-antitoxin system (TA) is a genetic element widely found in chromosomes and plasmids of bacteria, archaea and prophages. TA usually consists a toxin that inhibits the growth of bacteria and an antitoxin that neutralizes its toxicity. Since the discovery of the first CcdB / CcdA TA in the 1980s, TA has been proved to exist in almost all sequenced microorganisms and plays an important role in maintaining plasmid stability, anti-phage and promoting biofilm formation. At present, TA is divided into type I-VIII, among which type IITA is the most widely studied. HipBA is a type II TA. The toxin HipA in Escherichia coli HipBA is a serine / threonine kinase, which inhibits protein translation by phosphorylating bacterial Glutamyl tRNA synthetase (GltX), and its toxicity can be specifically neutralized by HipB. Recently, it has been found that Escherichia coli HipA homologous proteins exist widely in microorganisms, and they form a potential novel TA with genes of the same promoter, in which HipBST has been confirmed by experiments. The toxin HipT and the antitoxin HipS in this TA are similar to the C-terminal and N-terminal of E. coli HipA respectively, and the neutralization mechanism and the substrate of the toxin are different from that of E. coli toxin HipA. This study summarizes the recent discovery of special TA, especially the neutralization mechanism of HipBST which widely exists in prokaryotes.

Mechanism of autophagy induced by osthole through PINK1/Parkin pathway in HeLa cells / 中国药理学通报

Aim To investigate the potential mechanism of osthole promoting autophagy in cervical cancer HeLa cells. Methods HeLa cells were treated with various concentrations of Osthole(0,10,20,40,80,160,240,320 mg·L-1). MTT was used to detect cell vitality. Transmission electron microscopy(TEM)was used to observe the morphology of HeLa cells after osthole intervention. Mondane sulfonyl cadaverine(MDC)staining was used to dectect the level of autophagy. Western blot was employed to analyze the expression levels of mitochondrial protein MFN1 and DPR1. JC-1 flourescence probe was applied to detect mitochondrial membrane potential. Flow cytometry was used to deteminet the release of reactive oxygen species(ROS). A transplanted tumor model of cervical cancer was established in vivo in nude mice. Western blot was used to detect the protein expression levels of PINK1,Parkin and LC3Ⅱ/. Results Osthole could inhibit the proliferation of HeLa cells significantly. Transmission electron microscopy showed that typical autophagosomes were formed in HeLa cells after osthole intervention. The fluorescence intensity of MDC was enhanced. The expression of mitochondrial fusion protein MFN1 was down-regulated after HeLa cells pretreated with osthole,and mitochondrial fission protein DRP1 was up-regulated. Mitochondrial membrane potential decreased. ROS production of HeLa cells was increased by flow cytometry,which could be reversed by autophagy inhibitor 3-MA. Tumor weight in nude mice was inhibited by osthole obviously,which might restrain cervical cancer. Western blot result indicated that the key factors of mitochondrial autophagy PINK1,Parkin and LC3Ⅱ/ratio were up-regulated in HeLa cells. Conclusions Osthole could induce autophagy in HeLa cells and its mechanism may be related to ROS production and PINK1/Parkin pathway.

Clinical characteristics and prognosis of patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia arising from malignant tumors / 中华血液学杂志

Objective: To investigate the clinical characteristics, cytogenetics, molecular biology, treatment, and prognosis of patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) secondary to malignancies. Methods: The clinical data of 86 patients with t-MDS/AML in West China Hospital of Sichuan University between January 2010 and April 2023 were retrospectively analyzed. The clinical characteristics, primary tumor types, and tumor-related therapies were analyzed. Results: The study enrolled a total of 86 patients with t-MDS/AML, including 67 patients with t-AML, including 1 patient with M(0), 6 with M(1), 27 with M(2), 9 with M(3), 12 with M(4), 10 with M(5), 1 with M(6), and 1 with M(7). Sixty-two patients could be genetically stratified, with a median overall survival (OS) of 36 (95% CI 22-52) months for 20 (29.9%) patients in the low-risk group and 6 (95% CI 3-9) months for 10 (14.9%) in the intermediate-risk group. The median OS time was 8 (95% CI 1-15) months in 32 (47.8%) patients in the high-risk group. For patients with non-acute promyelocytic leukemia (APL) and AML, the median OS of the low-risk group was 27 (95% CI 18-36) months, which was significantly longer than that of the non-low-risk group (χ(2)=5.534, P=0.019). All 9 APL cases were treated according to the initial treatment, and the median OS was not reached, and the 1-, 2-, and 3-year OS rates were 100.0%, (75.0±6.2) %, and (75.0±6.2) % respectively. Of the 58 patients with non-APL t-AML (89.7%), 52 received chemotherapy, and 16 achieved complete remission (30.8%) after the first induction chemotherapy. The 1-, 2-, and 3-year OS rates of the non-APL t-AML group were (42.0 ± 6.6) %, (22.9±5.7) %, and (13.4±4.7) %, respectively. The median OS of patients who achieved remission was 24 (95% CI 18-30) months, and the median OS of those who did not achieve remission was 6 (95% CI 3-9) months (χ(2)=10.170, P=0.001). Bone marrow CR was achieved in 7 (53.8%) of 13 patients treated with vineclar-containing chemotherapy, with a median OS of 12 (95% CI 9-15) months, which was not significantly different from that of vineclar-containing chemotherapy (χ(2)=0.600, P=0.437). In 19 patients with t-MDS, the 1-, 2-, and 3-year OS rates were (46.8±11.6) %, (17.5±9.1) %, and (11.7±9.1) % with a median OS of 12 (95% CI 7-17) months, which was not significantly different from that in t-AML (χ(2)=0.232, P=0.630) . Conclusions: Breast cancer, bowel cancer, and other primary tumors are common in patients with t-MDS/AML, which have a higher risk of adverse genetics. Patients with APL had a high induction remission rate and a good long-term prognosis, whereas patients without APL had a low remission rate and a poor long-term prognosis.

Preparation and evaluation of Indigo Naturalis dry suspension based on powder surface modification / 药学学报

A dry suspension of Indigo Naturalis (IN) based on lactose-IN composite particles was designed by powder modification technology to meet the clinical needs of IN. The contact angle was used as an evaluation index to investigate the effects of the type of modifier lactose, the amount of lactose, and the co-grinding time of lactose and IN on the hydrophilicity of IN. The difference between IN before and after modification was compared through physical properties such as particle size and scanning electron microscope, as well as hydrophilic properties such as surface free energy and multiple light scattering. The optimal process of lactose-IN composite particles is as follows: after lactose is ground alone for 2 minutes, it is co-ground with IN at a ratio of 1∶1 for 6 minutes. The results of the investigation of powder properties show that the particle size d0.9 of IN is reduced from 112.75 μm to 87.30 μm after modification. The BET and Langmuir specific surface areas decreased by 8.661 m2·g-1 and 12.512 m2·g-1, respectively. SEM shows that lactose is attached to the surface of modified IN (MIN); surface element analysis shows that Si, Ca, and Mg elements of MIN are smaller than IN, and O elements are larger. The infrared spectrum shows that the MIN possesses the characteristic peaks of both IN and lactose. Compared MIN with IN, the contact angle and the non-polar surface free energy decreased by 35.1° and 9.975 mJ·m-2, respectively; the polar surface free energy and the surface free energy increased by 36.956 and 26.950 mJ·m-2, respectively. The results of multiple light scattering showed that the light transmittance of MIN was 35% lower than that of IN, and the backscattered light intensity was increased by about 25%. Only one excipient was used to successfully prepare IN dry suspension with good wettability and suspending property, which provided a basis for the development of new preparations of IN.

The effect of Jiegeng decoction on lipopolysaccharide-induced acute lung injury in mice based on metabolomics / 药学学报

One of the traditional prescriptions for treating lung diseases, Jiegeng decoction (JGT), is still unknown in terms of its chemical makeup and mechanism. In this study, Q-Exactive-Orbitrap MS technology was used to identify the chemical constituents of JGT, and metabolomics was used to examine the effect of JGT on metabolites in the lung tissue of mice with acute lung injury (ALI) model. The potential biomarkers were screened by fold change (FC) > 1.5 or FC < 0.67 and P < 0.05, and enriched for metabolic pathways. A total of 40 compounds, including triterpenoid saponins, flavonoids and glycosides, were identified by mass spectrometry analysis of JGT. All animal experiments were approved by the Experimental Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine (No. TCM-LAEC2021106). The results showed that JGT improved the lung coefficient, and lung tissue morphology of mice with ALI, lowered the levels of malondialdehyde (MDA), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in bronchoalveolar lavage fluid (BALF), and reduced myeloperoxidase (MPO) content in lung tissue. The metabolomic results showed that JGT could regulate 22 metabolites associated with ALI, among which leukotriene D4, docosapentaenoic acid, hypoxanthine, L-5-oxoproline, and other metabolites were mainly associated with the body′s inflammatory response and oxidative stress, and were enriched in the pathways of glutathione metabolism, purine metabolism, and primary bile acid biosynthesis. This study analyzed the potential mechanism of JGT in the treatment of ALI through metabolomics, providing an important theoretical basis for the clinical application of JGT.