Objective:To study the effects of cathepsin K(CTSK)on the healing process of tooth extraction socket and type H blood vessel angiogenesis in mice.Methods:Ctsk knockout(Ctsk-/-)mice were generated by CRISPR/Cas9 technology,and genotype sequen-cing,general observation,Micro-CT and immunohistochemistry were performed to confirm successful knockout of Ctsk.Then 8 week-old WT and Ctsk-/-mice were used to establish the tooth extraction modle by extracting the left maxillary first molars,and the mice were sac-rificed at the day 7,10,14,21,28 and 35 respectively(n=3)after tooth extraction.Then samples were subjected to stereo microscope and Micro-CT examination.Immunofluorescence staining was used to study the effect of Ctsk knockout on type H blood vessel angiogene-sis.Results:Ctsk knockout did not affect the soft tissue healing of tooth extraction socket,but significantly promoted the bone healing process,and Ctsk deficency significantly enhanced type H blood vessel angiogenesis in the tooth extraction socket.Conclusion:Ctsk knockout can enhance type H vessel angiogenesis,and promote bone healing process of tooth extraction socket in mice.

Objective:To construct a prognostic model for lung squamous cell carcinoma (SqCLC) based on autophagy-related genes analyzed by bioinformatics and validate it.Methods:Expression profile data and clinical information of 268 SqCLC patients were downloaded from The Cancer Genome Atlas (TCGA) database and a dataset of normal lung tissues of 336 healthy people was downloaded from the Genotype Tissue Expression (GTEx) database; the autophagy-related genome was obtained from the GO_AUTOPHAGY genome of the Human Autophagy Database (HADb) and the Molecular Signature Database (MSigDB) 6.2. R 4.0.3 software was applied to analyze the differentially expressed genes between SqCLC tissues in TCGA database and normal lung tissues in GTEx database. Screening of autophagy-related genes differentially expressed between SqCLC tissues and normal lung tissues in the TCGA database (referred to as differentially expressed autophagy genes) was performed using R 4.0.3 software. The Cox proportional risk model was applied to analyze the relationship between the differentially expressed autophagy genes and prognosis of SqCLC patients in TCGA database, and a prognostic model was constructed. The SqCLC patients in TCGA database were divided into high-risk group and low-risk group based on the median risk score of the prognostic model, and the Kaplan-Meier method was used to compare the overall survival of the two groups; the time-dependent receiver operating characteristic (ROC) curve of the 3-, 5- and 10-year overall survival rates of 268 patients in TCGA database predicted by the prognostic model was plotted. Cox regression was used to analyze the independent influencing factors of overall survival of SqCLC patients in TCGA database, and the prognostic index formula was established. Based on the consistency index and restricted mean survival (RMS) curve, the predictive efficacy for the survival of patients in TCGA database between prognostic index of prognostic model risk score alone and prognostic index of risk score combined with independent influencing factors was compared. R 4.0.3 software was used to construct the nomogram for predicting patients' 3-, 5- and 10-year overall survival rates.Results:Six prognosis related differentially expressed autophagy genes were screened, and a prognostic model was constructed as: risk score=PEX14×0.337+CASPASE-8×(-0.280)+TM9SF1×0.292+UBB×0.472+P4HB×0.163+CTSA×0.173. In TCGA database, the overall survival of high-risk group was worse than that of low-risk group ( P < 0.001). Time-dependent ROC curve analysis showed that the area under the curve (AUC) of the prognostic model risk score for predicting the 3-, 5- and 10-year overall survival rates of 268 patients in TCGA database was 0.715, 0.715 and 0.831, respectively. Multivariate Cox regression analysis showed that age, staging and prognostic model risk score were independent factors affecting the overall survival of SqCLC patients in TCGA database, and the prognostic index=0.998×risk score+0.725×staging+0.559×age. The RMS curve showed that compared with the prognostic model risk score, the prognostic index combined with 3 independent prognostic factors had a better effect on predicting the overall survival (consistency index: 0.68 vs. 0.65, P =0.045). Using age, staging and prognostic model risk score, a nomogram was constructed to predict the survival of patients with SqCLC, and its calibration curve was close to the ideal curve. Conclusions:A prognostic model of SqCLC based on 6 characteristic differentially expressed autophagy-related genes has been successfully established. Internal validation shows that this model combined with other clinicopathological factors could be helpful in predicting the survival of SqCLC patients.

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.

Early detection and intervention are key strategies to reduce mortality, increase long-term survival, and improve the therapeutic effects of hepatocellular carcinoma (HCC) patients. Herein, the isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative pro-teomic strategy was used to study the secretomes in conditioned media from HCC cancerous tissues, surrounding noncancerous tissues, and distal noncancerous tissues to identify diagnostic and prog-nostic biomarkers for HCC. In total, 22 and 49 dysregulated secretory proteins were identified in the cancerous and surrounding noncancerous tissues, respectively, compared with the distal non-cancerous tissues. Among these proteins, carbonic anhydrase Ⅱ (CA2) was identified to be signifi-cantly upregulated in the secretome of cancerous tissues; correspondingly, the serum concentrations of CA2 were remarkably increased in HCC patients compared with that in normal populations. Interestingly, a significant increase of serum CA2 in recurrent HCC patients after rad-ical resection was also confirmed compared with HCC patients without recurrence, and the serum level of CA2 could act as an independent prognostic factor for time to recurrence and overall sur-vival. Regarding the mechanism, the secreted CA2 enhances the migration and invasion of HCC cells by activating the epithelial mesenchymal transition pathway. Taken together, this study identi-fied a novel biomarker for HCC diagnosis and prognosis, and provided a valuable resource of HCC secretome for investigating serological biomarkers.

OBJECTIVE：To study the effects of augmented renal clearance （ARC）on blood trough concentration of patients receiving high-dose regimen of teicoplanin. METHODS ：Patients who received high-dose regimen of teicoplanin in the ICU were prospectively collected from the Affiliated Suzhou Hospital of Nanjing Medical University/Suzhou Municipal Hospital during Jul. 2018-Jun. 2020. They were divided into ARC group and normal renal function group according to corrected creatinine clearance. The dosage regimen of teicoplanin in the two groups were loading dose of 600 mg，q12 h×3 doses，maintenance dose of 6-10 mg/kg，qd，and the dosage was adjusted in combination with creatinine clearance rate and blood trough concentration. The trough concentration of blood samples which were collected 30 min before the 4th and 8th-10th dosage of teicoplanin were determined by HPLC. Trough concentration ，clinical efficacy ，Gram-positive bacterial clearance rate and the occurrence of ADR were compared between 2 groups. RESULTS ：A total of 56 patients were included and divided into ARC group （18 cases）and normal renal function group （38 cases）. ARC group had younger age （P＜0.001）and lower serum albumin level （P＝0.025）than normal renal function group. The trough concentrations before administration of the 4th and 8th-10th dosage in ARC group were lower than normal renal function group （P＝0.034；P＝0.035）. The trough concentrations in the ARC group and normal renal function group before 8th-10th dosage were all higher than 30 min before the 4th dosage （P＝0.003；P＜0.001）. The clinical efficacy rate and the clearance rate of Gram-positive bacteria in ARC group were 77.8％ and 76.2％，which were lower than those of the normal renal function group ，but there was no statistical difference （P＝0.195；P＝0.223）. There was no liver function damage ，hemocytopenia and allergic reaction in both groups ，but in the normal renal function group ，the causal relationship between acute renal damage and teicoplanin was assessed as “very likely ”in one patient. CONCLUSIONS ：ARC patients are younger ，most of them have hypoproteinemia，and the blood trough concentrations of teicoplanin in high-dose regimen are significantly lower than those of normal renal function patients. For critical ill ARC patients ，it is advisable to increase the loading dose of teicoplanin to make the trough concentration reach the target concentration range quickly.

Objective To explore the risk factors influencing the outcomes of radiation brain injury after intensity-modulated radiotherapy (IMRT) in patients diagnosed with nasopharyngeal carcinoma.Methods Clinical data of 1 300 nasopharyngeal carcinoma patients treated with IMRT in our hospital during 2006 and 2013 were retrospectively analyzed.Fifty-eight patients presented with radiation brain injury after IMRT.MRI data of these patients during 3-24 months follow-up were collected.The clinical efficacy in the treatment of radiation brain injury was evaluated according to RECIST guidelines.Results Forty-six patients with intact follow-up data were enrolled.The median latency of radiation brain injury was 34 months.Patients were divided into the response (CR+PR) and non-response groups.The risk factors influencing the response rate during 10-12 months and 18-24 months were identified and analyzed.Univariate analysis demonstrated that gender,age,smoking history,T stage,and high-intensity treatment exerted no significant effect upon the objective remission rate during these two time intervals periods.Patients treated with gangliosides obtained high response rate.The response rate was 68.8％ in 10-12 months (P=0.000),and 81.8％ in 18-24 months (P=0.008).Multivariate analysis revealed that use of gangliosides was a favorable factor for mitigating radiation brain injury in two time intervals (OR=19.8 and 13.5;P=0.001 and 0.005).Conclusions Use of gangliosides probably accelerates the healing of radiation brain injury,whereas the clinical efficacy remains to be elucidated by prospective clinical trials.

To facilitate noninvasive diagnosis of anemia, high-performance and portable near infrared (NIR) spectrometer for human blood constituents was designed and fabricated based on linear variable filter (LVF).Meanwhile, the performance of support vector regression (SVR) model for quantitative analysis of human hemoglobin (Hb) was investigated.Spectral data were collected noninvasively from 100 volunteers by self-designed LVF-NIR spectrometer, then divided into calibration set, validation set 1 and 2.To establish a robust SVR model, grid search method was applied to optimize the penalty parameter and kernel function parameter c=5.28, g=0.33.Then, Hb levels in the validation 1 and 2 sets were quantitatively analyzed.The results showed that the root mean square error of prediction (RMSEP) were 10.20 g/L and 10.85 g/L, respectively, and the relative RMSEP (R-RMSEP) were 6.85% and 7.48%, respectively.The results indicated that the SVR model had high prediction accuracy to Hb level and adaptability to different samples, and could satisfy the requirements of clinical measurement.Based on the SVR algorithm, the self-designed LVF-NIR spectrometer has a wide application prospect in the field of non-invasive anemia diagnosis.

Objective To evaluate the dosimetric effects of air cavity on primary tumor and organs at risk (OARs) during intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma patients.Methods Nine patients with nasopharyngeal carcinoma had CT simulation before treatment and on the 25 fraction of radiotherapy.Radiotherapy plan1 was first created by delineating the target volumes and OARs on the first CT image, which was then copied and merged with the second CT image.Air cavity that was formed following tumor volume regression was delineated on the first CT image, and the density of air cavity was set to zero.A new gross target volume (GTV) was formed by subtracting the air cavity from the original GTV, and the new CT image was named CTAir.Plan2 was then created by calculating the dose distribution on CTAir using the same portals and parameters as Plan1.Assuming that Plan1 and Plan2 were both used throughout the course of radiotherapy, the dosimetric parameters of nasopharyngeal tumor and OARs in the absence and presence of air cavity were then compared using the paired t-test.Results Dmean, D95, D90, D10, and D5 of tumor were significantly higher in plan2 than in plan1(P=0.000, 0.001, 0.001, 0.001, and 0.005, respectively), with a<0.5 Gy increase in dose.A dose build-up effect was observed within the tumor region posterior to the air cavity, where the highest dose was 1.4 cm posterior to the air cavity, resulting in a dose difference of 0.36 Gy.In addition, D2cc and D1cc of the brain stem were significantly higher in plan2 than in plan1(P=0.036 and 0.044, respectively).Dmax of the optical chiasm, left optical nerve, and right optical nerve were also increased in the presence of air cavity (P=0.438, 0.434, and 0.477, respectively), but the change in dose was<0.12 Gy.Conclusions Air cavity induces a small but negligible increase in the tumor and OARs dose in patients with nasopharyngeal carcinoma during IMRT.However, closer monitoring should be conducted for patients with OARs that is close to or has surpassed tolerance prior to radiotherapy.

Objective To investigate the influence of curcumin and its analogue H8 on glucose and lipid metabolism disorder in db/db mice. Methods The type 2 diabetes mouse model (db/db mice) was intragastrically administrated with curcumin and analogue H8 for 8 weeks.The blood biochemical indexes were measured.The expression of PEPCK and G6Pase mRNA was detected by real-time PCR in liver tissues.The expression of PEPCK and G6Pase protein was detected by Western blotting. Results Curcumin analogue H8 reduced blood glucose and lipids in db/db mice (P<0.01) and improved liver function related enzymes significantly.The levels of PEPCK and G6Pase mRNA in db/db mice were significantly decreased (P<0.01) and the expression levels of PEPCK and G6Pase protein were significantly decreased(P<0.01). Conclusion Curcumin analogue H8 improves the glucose and lipid metabolism disorder in db/db mice,and it is related to inhibiting the expression of PEPCK and G6Pase gene and protein.

This paper reported 13 cases of delayed traumatic chest wall abscess from January 2012 to January 2015.All the patients were associated with type 2 diabetes.After local puncture for confirmative diagnosis, a chest wall abscess dissection was carried out as soon as possible.At each site of upper and lower pole, an indwelling drainage tube was placed for irrigation and negative pressure suction.Sensitive antibiotics were selected based on susceptibility test results.The drainage tubes were removed 7-14 days after surgery.There were 8 cases of primary healing of incision and 5 cases of secondary healing of incision.All the patients were cured.Follow-ups for 6-36 months (average, 17 months) showed no recurrence.