Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.

Objective:To investigate the value of intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) and texture analysis for predicting BRAF gene mutation in rectal cancer.Methods:The clinical diagnositic trial was conducted. The clinicopathological data of 36 rectal cancer patients who were admitted to the First People's Hospital of Shangqiu from January 2016 to June 2021 were collected. There were 28 males and 8 females, aged (50±4)years. All the 36 patients were confirmed by pathological examination. After genetic testing, 12 patients with BRAF mutant type of BRAF V600E mutation were allocated into the mutation group, and 24 patients with BRAF wild type were allocated into the non-mutation group. All patients underwent MRI scan before surgery, and IVIM related post-processing images were received by Function Tool post-processing software. Observation indicators: (1) consistency test between observers of IVIM para-meters and texture parameters; (2) comparison of IVIM parameters on MRI between the two groups; (3) comparison of texture parameters on MRI between the two groups; (4) diagnostic efficacy of IVIM and texture parameters. The intraclass correlation coefficient (ICC) was used to evaluate the consistency between observers, with ICC >0.80 as good consistency. The average values of para-meters with ICC >0.80 were included for further analysis. Measurement data with normal distribu-tion were represented as Mean± SD, and comparison between groups was analyzed by the indepen-dent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was analyzed by the chi-square test. Comparison of ordinal data was analyzed by the non-parameter rank sum test. The texture parameters were combined using the Logistic regression model. Receiver operating charac-teristic curve was used to analyze the predictive performance and calculate the sensitivity and specificity. Results:(1) Consistency test between observers of IVIM parameters and texture parameters: the ICCs between two observers of IVIM parameters including apparent diffusion coefficient, diffusion related coefficient, perfusion-related diffusion coefficient and perfusion-related parameter were 0.91, 0.90, 0.91, 0.89, respectively. The ICCs of texture parameters including the minimum value, the maximum value, the 10th percentile and the 25th percentile between two observers were <0.80 while the ICCs of texture parameters including mean value, the 50th percentile, the 75th percentile, the 90th percentile, energy, entropy, skewness and kurtosis between two observers were >0.80. (2) Comparison of IVIM parameters on MRI between the two groups: IVIM parameters of diffusion related coefficient and perfusion-related parameter on MRI were (0.70±0.13)×10 -3 mm 2/s and 0.39±0.30 for the mutation group, versus (0.79±0.12)×10 -3 mm 2/s and 0.17±0.10 for the non-mutation group, showing significant differences between the two groups ( t=-2.17, 2.46, P<0.05). (3) Comparison of texture parameters on MRI between the two groups: the texture parameters of mean value and energy on diffusion related coefficient image were 0.54±0.23 and 0.00(0.00,0.01) for the mutation group, versus 0.77±0.34 and 0.01(0.00,0.01) for the non-mutation group, showing significant differences between the two groups ( t=-2.12, Z=-1.35, P<0.05). (4) Diagnostic efficacy of IVIM and texture parameters: the areas under the curve (AUCs) of diffusion related coefficient, perfusion-related parameter, IVIM parameters combination, mean value of diffu-sion related coefficient image, energy value of diffusion related coefficient image, texture parameters combination were 0.69[95% confidence interval ( CI) as 0.52-0.84], 0.76(95% CI as 0.59-0.88), 0.79(95% CI as 0.62-0.91), 0.71(95% CI as 0.52-0.85), 0.79(95% CI as 0.62-0.91), 0.84(95% CI as 0.68-0.94), which were all lower than the AUC of IVIM and texture parameters combination as 0.92(95% CI as 0.79-0.99). Conclusions:IVIM parameters and texture parameters of MRI can non-invasively predict the mutation status of BRAF gene in rectal cancer. The combination of IVIM and texture parameters has a better predictive efficacy.

Objective To investigate the effect of vascular endothelial growth factor (VEGF) on the leukocyle function in a rat denervated infect flap model and to investigate the action mechanison of VEGF in the flap anti-infection .Methods An island pedicle flap measured 2 cm × 2 cm was raised on the right abdomen of sixty wister rats ,which were divided into three groups .All flaps re-ceived intradermal inoculation of 107 Staphylococcus aureus ,and the animals were observed for 96 h .The indexes of the leukocyte count ,leukocyte vitality ,hemiluminescence of neutrophils ,tissue bacterial count ,naked eyes observation of falptissue and the light microscope observation were detected .Results The leukocyte count in the exudation at postoperative 96 h had no statistical differ-ences among 3 groups(P>0 .05);while in the indexes detection of the leukocyte vitality ,chemiluminescence of neutrophils ,tissue bacterial count ,etc .,the comparison between the chronic denervated group and the control group showed very significantly differ-ences(P<0 .01);the differences between the VEGF treatment group and the chronic denervated group was very significant (P<0 .01) .The falp pathological change in the control group and the VEGF treatment groups was slight .Conclusion The soft issue af-ter losing the innervation decreases the leukocyte function .VEGF might improve the flap micro circulation and play an important role in improving the leukocyte function .

Objective To explore the effect of the traumatic brain injury on the fracture healing and the related mechanism. Methods 64 12-week-old SD rats were randomly divided into 2 groups: The femoral fracture with a brain injury group and the femoral fracture group. The bone callus was obtained 1, 2, 3 and 4 week after operation respectively, and observed with the HE staining. The vascular endothelial growth factor (VEGF) and VEGF mRNA in the callus were detected with immunohistochemical staining and hybridization in situ. Results The formation and reforming of the callus in group with brain injury were ahead to only fracture. The percentages of the cells positive for VEGF and VEGF mRNA in the callus were more in group with brain injury than in pure fracture group at the same time point (P<0.05). Conclusion Traumatic brain injury can promote the healing of fracture, which is probably related to an increase in the expression of VEGF.