Objective:To analyze the factors affecting delayed chemotherapy in children with Burkitt lymphoma (BL) and their influence on prognosis.Methods:Retrospective cohort study. Clinical data of 591 children aged ≤18 years with BL from May 2017 to December 2022 in China Net Childhood Lymphoma (CNCL) was collected. The patients were treated according to the protocol CNCL-BL-2017. According to the clinical characteristics, therapeutic regimen was divided into group A, group B and group C .Based on whether the total chemotherapy time was delayed, patients were divided into two groups: the delayed chemotherapy group and the non-delayed chemotherapy group. Based on the total delayed time of chemotherapy, patients in group C were divided into non-delayed chemotherapy group, 1-7 days delayed group and more than 7 days delayed group. Relationships between delayed chemotherapy and gender, age, tumor lysis syndrome before chemotherapy, bone marrow involvement, disease group (B/C group), serum lactate dehydrogenase (LDH) > 4 times than normal, grade Ⅲ-Ⅳ myelosuppression after chemotherapy, minimal residual disease in the interim assessment, and severe infection (including severe pneumonia, sepsis, meningitis, chickenpox, etc.) were analyzed. Logistic analysis was used to identify the relevant factors. Kaplan-Meier method was used to analyze the patients' survival information. Log-Rank was used for comparison between groups.Results:Among 591 patients, 504 were males and 87 were females, the follow-up time was 34.8 (18.6,50.1) months. The 3-year overall survival (OS) rate was (92.5±1.1)%,and the 3-year event-free survival (EFS) rate was (90.5±1.2)%. Seventy-three (12.4%) patients were in delayed chemotherapy group and 518 (87.6%) patients were in non-delayed chemotherapy group. The reasons for chemotherapy delay included 72 cases (98.6%) of severe infection, 65 cases (89.0%) of bone marrow suppression, 35 cases (47.9%) of organ dysfunction, 22 cases (30.1%) of tumor lysis syndrome,etc. There were 7 cases of chemotherapy delay in group B, which were seen in COPADM (vincristine+cyclophosphamide+prednisone+daunorubicin+methotrexate+intrathecal injection,4 cases) and CYM (methotrexate+cytarabine+intrathecal injection,3 cases) stages. There were 66 cases of chemotherapy delay in group C, which were common in COPADM (28 cases) and CYVE 1 (low dose cytarabine+high dose cytarabine+etoposide+methotrexate, 12 cases) stages. Multinomial Logistic regression analysis showed that the age over 10 years old ( OR=0.54,95% CI 0.30-0.93), tumor lysis syndrome before chemotherapy ( OR=0.48,95% CI 0.27-0.84) and grade Ⅲ-Ⅳ myelosuppression after chemotherapy ( OR=0.55,95% CI 0.33-0.91)were independent risk factors for chemotherapy delay.The 3-year OS rate and the 3-year EFS rate of children with Burkitt lymphoma in the delayed chemotherapy group were lower than those in the non-delayed chemotherapy group ((79.4±4.9)% vs. (94.2±1.1)%, (80.2±4.8)% vs. (92.0±1.2)%,both P<0.05). The 3-year OS rate of the group C with chemotherapy delay >7 days (42 cases) was lower than that of the group with chemotherapy delay of 1-7 days (22 cases) and the non-delay group (399 cases) ((76.7±6.9)% vs. (81.8±8.2)% vs. (92.7±1.3)%, P=0.002).The 3-year OS rate of the chemotherapy delay group (9 cases) in the COP (vincristine+cyclophosphamide+prednisone) phase was lower than that of the non-chemotherapy delay group (454 cases) ((66.7±15.7)% vs. (91.3±1.4)%, P=0.005). Similarly, the 3-year OS rate of the chemotherapy delay group (11 cases) in the COPADM1 phase was lower than that of the non-chemotherapy delay group (452 cases) ((63.6±14.5)% vs. (91.5±1.3)%, P=0.001). Conclusions:The delayed chemotherapy was related to the age over 10 years old, tumor lysis syndrome before chemotherapy and grade Ⅲ-Ⅳ myelosuppression after chemotherapy in pediatric BL. There is a significant relationship between delayed chemotherapy and prognosis of BL in children.

ObjectiveTo develop a highly sensitive method for detection of mutation of FMS-like tyrosine kinase-3-tyrosine kinase domain(FLT3-TKD)of acute myeloid leukemia(AML)and apply to the monitor of minimal residual disease(MRD).MethodsRecombinant plasmids containing wild FLT3 and mutant FLT3-D835Y were constructed respectively and mixed at certain ratios.The obtained standard plasmids with mutation rates of 50%,1%,0.1% and 0% respectively were determined by restriction fragment length polymorphism(RFLP)in combination with Sanger method.The plasmid DNA standards and blood DNA standards,at various FLT3-D835Y mutation rates,were determined by the developed method to verify the sensitivity.The genomic DNA samples of patients with AML before and after treatment were determined by the developed method to monitor the MRD.ResultsSequencing proved that both the recombinant plasmids containing wild FLT3 and mutant FLT3-D835Y were constructed correctly.The sensitivity of developed method increased to 0.1% through Sanger method combined with digestion with EcoR Ⅴ/Xho Ⅰ and recovery of mutant fragments in determination of purified plasmid DNA and collected blood DNA samples.MRD was detected in the peripheral blood sample of a patients with AML in complete remission period by the developed method but not by Sanger method.ConclusionA highly sensitive method for detection of FLT3-TKD mutation was developed,which was of an important clinical significance in guiding the treatment of AML and monitoring the MRD in complete remission period.

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC₅₀ values and achieved picomolar DC₅₀ values and >99% of maximum degradation (D_max) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^Y1230H and c-MET^D1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

OBJECTIVE To study the chemical composition and analgesia molecular mechanism of Shuanghu Zhongtongning tincture by UPLC-Q-TOF-MS/MS and network pharmacology. METHODS By comparing the chromatogram and blank chromatogram of Shuanghu Zhongtongning tincture, combined with PubChem, HMDB, MassBank database spectrum and the lysis information of reference substance, the chemical composition of Shuanghu Zhongtongning tincture was analyzed and identified. Protein-protein interaction network was constructed by using STRING database, and potential targets of analgesic effect of Shuanghu Zhongtongning tincture were screened. And GO and KEGG enrichment analysis were performed to analyze the core pathways related to analgesia. The network of "chemical composition-disease-target" was constructed by Cytoscape software to analyze the key compounds related to analgesia. RESULTS Seventeen core components of neochlorogenic acid, chlorogenic acid, hesperidin, neohesperidin, ferulic acid, berberine, ursolic acid, deoxyaconitine, mesaconitine, hypaconitine, benzoylmesaconine, benzoylhypacoitine, caffeic acid, quercetin, oleanolic acid, 4-hydroxycinnamic acid and mefenamic acid were identified, 3 core targets of STAT3, MAPK3 and MAPK1 were found, and 4 key signaling pathways of IL-17, TNF, PI3K-Akt and arachidonic metabolism were revealed. CONCLUSION This study preliminarily clarifies the chemical composition of Shuanghu Zhongtongning tincture and potential mechanism of analgesic effect, and provides a scientific theoretical basis for the study on the material basis and mechanism of Shuanghu Zhongtongning tincture.

Objective To evaluate the value of cardiac MRI in the diagnosis of Ebstein anomaly (EA). Methods Twenty patients from February 2014 to April 2017 with EA confirmed by surgery were enrolled into this study. The analysis in all patients was made according to preoperative cardiac MRI, 2D TTE and surgical data, including the changes of tricuspid valve leaflets, Carpentier classification, the size and function of atrioventricle, late Gadolinium enhancement, the total right/left-volume index and cardiopulmonary bypass time,etc.The numbers of apicaldisplaced leaflets and development condition of all the leaflets were compared using the R×C χ2among the three groups.With surgical results as the reference standard, the diagnostic accuracy of the two groups for the development condition of all the leaflets were evaluated. One-way ANOVA was performed to compare the differences of the apicaldisplaced distance of septal leaflet, using these three methods. Comparisons of the total right/left-volume index, surgery-related data between patients with or without late gadolinium enhancement were performed by independent t test.Results (1) The results in anatomicalstructures, such as distance of apicaldisplacedseptal leaflet,displacement of each leaflet and the Carpentier classification, showed nostatistical difference among MRI,2D TTE and operational findings. The leaflet dysplasia defined by MRI and 2D TTE areequivalent to surgically defined severe dysplasia, and surgically defined mild to moderate dysplasia can't be identified by the former two methods. The overall diagnostic accuracy of MRI and 2D TTE to identify leaflet dysplasia were 41.3%(19/46) and 34.7%(16/46), respectively.(2) Functional right ventricular volume index decreased in 1 case, normal in 8 cases, increased in 11 cases;functional right ventricula rejection fraction decreased in 15 cases. Six patients' left ventricular volume index decreased, 13 remained in normal range, 1 showed increased;left ventricula rejection fraction decreased in 14 cases. (3)LGE was identified in 8 patients and non-LGE in 12. Difference of the total right/left-volume index [(7.12 ± 4.06) vs. (3.84 ± 2.10), P=0.029] between two groups was statistically significant. However, there was no statistical difference in extracorporeal circulation time, aorticcross-clamping time, intubation time, ICU residence time and postoperative hospital staybetween the LGE and non-LGE groups.Conclusions Cardiac MRI can relatively accurately evaluate the apicaldisplacement of leaflets and the morphological changes of the atria and ventricles, as well as quantitatively evaluate the ventricular function, which can rovide references for clinical diagnosis and severity evaluation of EA.

Objective To study the ultramicrostructure change and keartin(KRT1) expression in skin lesion of symmetrical acral keratoderma(SAK) .Methods Thirteen cases of SAK in the First Affiliated Hospital of Fujian Medical University and the outpatient department of the Dongguan Municipal Sixth People′s Hospital were selected as the study subjects .The histopathological samples were taken from the wrist site .The retinoic acid preparation or corticosteroid preparation or Chinese medicine preparation were not externally used within 2 months before taking skin lesion sample .The healthy control skin samples were the normal skin in 12 cases by plastic surgical resection .The ultramicrostructural change were observed by the transmission electron microscopy .The KRT1 expression in skin lesion of 13 cases of SAK and healthy skin tissue of 12 cases were measured by immunohistochemistry method .Results The SAK ultramicrostructures manifested by the interruption of keratinizing envelope continuity in horny layer , and remarkable aggregation of keratin filament in upper stratum spinosum and surrounding nucleus of granular layer .KRT1 was ex-pressed in the cells of SAK skin lesion and basal layer ,spinous layer ,granular layer and horny layer .The cytoplasm and cytomem-brane staining was common .The KRT1 expression in skin lesion was significantly higher than that in normal skin (t=2 .210 ,P=0 .038) .Conclusion The ultramicrostructure features of SAK skin lesion are abnormal differentiation of epidermis keratin fila-ments ,which might be related with overexpression of KRT 1 .

Objective To investigate the efficacy of dexmedetomidine on sedation in post-cardiac surgery patients with NIV intolerance.The changes of respiratory function and hemodynamics of the patients as well as non-invasive ventilation (NIV) failure rate were also under evaluation.Methods Thirty-five post-cardiac surgery patients with NIV intolerance and hypoxemia were enrolled in this prospective study.All patients were sedated with dexmedetomidine.NIV was standardized according to the uniform protocol.The main outcome was NIV success (avoiding endotracheal intubation) or NIV failure (requiring endotracheal intubation or die).The cardiorespiratory parameters (BP,HtR and RR) and artery blood gas analysis were prospectively recorded before and after sedation.The respiratory function and hemodynamics changes in both groups (NIV success group and NIV failure group) were then evaluated.Factors independently associated with NIV failure were identified using a logistic regression model.Results Twenty out of 35 patients (57.14％) survived while 15 (42.86％) patients failed NIV.After 1 h and 4 h of NIV with dexmedetomidine sedation,respiratory rate in both groups were decreased compared with baseline,especially in NIV success group.The PaO2/FiO2 was also improved after 1h and 4h of NIV treatment compared with baseline.The improvement was more significantly in NIV success group.The heart rate was decreased compared with baseline with no differences between two groups.There were no significant changes on PaCO2 and mean arterial pressure (MAP) during the treatment.The respiratory and hemodynamics variables identified as predictors of NIV failure were included in a multivariate logistic regression.RR ＞ 23 time/min (OR =3.2,95％ CI:2.043 ～ 4.301,P ＜ 0.01) 1 h after NIV,RR ＞ 20 time/min (OR =2.1,95％ CI:1.659～3.231,P=0.025) 4 h after NIV,PaO2/FiO2 ＜178 mmHg (OR=2.4,95％CI:1.892 ～ 3.287,P ＜0.01) 1 h after NIV and PaO2/FiO2 ＜ 185 mmHg (OR =1.7,95％ CI:1.243 ～ 2.365,P =0.041) 4 h after NIV independendy predicted NIV failure.Conclusions Dexmedetomidine might be considered as an effective and safe sedative for post-cardiac surgery patients with NIV intolerance.Early identification of predictors of NIV failure may facilitate early intervention.

Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug-drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME) of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

Objective To evaluate the diagnostic value of multi-slice spiral CT (MSCT) in classifying coronary arteries of complete transposition of great arteries (D-TGA). Methods The clinical and imaging data of 367 patients with D-TGA who had undergone MSCT examination from March 2005 to June 2015 were retrospectively analyzed. The origin and course of the coronary arteries of the patients were classified according to the Marie Lannelongue classification. There were four patterns of courses: normal, looping, intramural and miscellaneous. And the four patterns were subdivided into eleven subgroups. The anatomic classification of coronary arteries in D?TGA were recorded, and the ratio of descriptive statistics was used according to categorical variable data. Results All the origin and course of the coronary arteries could be clearly displayed on MSCT. Of 367 patients with D-TGA, 209 cases (56.95%) were normal course (typeⅠ), 138 cases (37.60%) were looping course (typeⅡ), 16 cases (4.36%) were intramural course (typeⅢ), and 4 cases (1.09%) were miscellaneous course (typeⅣ). In looping course, the posterior looping (typeⅡA), anterior looping (typeⅡB) and double looping (typeⅡC) were found in 63 cases (17.17%), 30 cases (8.17%) and 45 cases (12.26%), respectively. The ratios of the anatomic classification of looping courses wereⅡA-1 44(11.99%),ⅡA-2 19(5.18%),ⅡB-1 12(3.27%),ⅡB-2 8(2.18%),ⅡB-3 10(2.72%),ⅡC-1 25 (6.81%),ⅡC-2 17(4.63%),ⅡC-3 3(0.82%). Conclusions MSCT is an effective technique to visualize and classify the coronary arteries in patients with D-TGA. And it is helpful for successful transfer of the coronary arteries and reducing the rate of coronary events after operation.

OBJECTIVE To investigate the effect of ketoconazole on the pharmacokinetic (PK) behaviors of midazolam and its metabolite through intranasal and intragastric(ig) routes in rats. METHODS Twenty-four rats were evenly divided into 4 groups. Two groups of rats were administrated singly with midazolam (1 mg?kg-1) through intranasal or ig route. The other two groups were concomitant with CYP3A inhibitor,ketoconazole(30 mg?kg-1),midazolam(1 mg?kg-1)through the same two routes. Blood samples were collected from different time points. Plasma concentration of midazolam and 1′-hydroxymidazolam was determined. Major pharmacokinetic parameters were calculated and statistical tests were performed by using t test. RESULTS Tmax was about 2 and 25 min for rats administered singly with midazolam via intranasal or ig routes,respectively and AUC was 296 and 179 μg?L-1?h, respectively. When concomitant with ketoconazole,AUC increased to 2.1 and 3.3 folds the original value for intranasal and ig routes,respectively. However,the Tmax value of midazolam via intranasally didn′t change after being coadministrated with ketoconazole,but Tmax increased to 1.14 h via ig. CONCLUSION Compared with administration via ig,intranasal route administrated midazolam displays significant advantages of faster absorption and higher exposure,which are vital for the first aid. Concomitant with CYP3A inhibitor and midazolam via intranasal route,the absorption speed is not affected,but with the metabolism blocked,the systemic exposure is greatly elevated. While via ig,both absorption speed and metabolism are inhibited. The dose should be cut down or the dosing interval increased in clinic practice in this concomitant situation.