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.

Coronaviruses are important pathogens that cause respiratory diseases in humans,such as common cold or severe respiratory symptoms.After coronavirus infects host cells,innate immune system recognizes invading virus through sensing its patho-gen-associated molecular patterns with various pattern recognition receptors,and antiviral immune response is activated.Increased production of IFN and pro-inflammatory will inhibit proliferation of coronavirus.In addition,coronavirus has ability to escape innate immune response,which is conducive to proliferation of virus.In this review,we describe relevant studies on regulation of IFN response and inflammatory response of coronaviruses,to provide new ideas for prevention and treatment of coronavirus infection.

Objective:To evaluate the predictive value of proximal ureteral diameter (D1)to distal ureteral diameter (D2)ratio (DDR) for impacted stones in the middle and upper ureter.Methods:The clinical data of 173 patients with middle and upper ureteral calculi admitted to the Third Hospital of Shanxi Medical University from January 2014 to November 2021 were retrospectively analyzed. There were 75 males and 98 females, with the median age of 56.0 (51.0, 62.0) years old and median body mass index of 26.1 (24.8, 27.2) kg/m 2. The imaging data of the patients were analyzed. The impacted stones were defined as the inability of the contrast agent to pass through the site of obstruction when intravenous urography or CT urography was performed, resulting in the inability of the ureter to visualize normally in parts below the site of obstruction. D1 was defined as the proximal ureteral diameter at the lower pole of the kidney on horizontal CT images. D2 was defined as the ureteral diameter 3 cm from the calculi. The stone diameter, stone CT value, D1, D2, and DDR were compared between impacted stone group and non-impacted stone group. Univariate logistic regression analysis was used to analyze the different indicators. Random number table was used to divide the training set and validation set according to the ratio of 7∶3. Through least absolute shrinkage and selection operator(LASSO) regression analysis, the independent influencing factors were obtained and the nomogram model was established (Model 1). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to verify the predictive efficacy of the model, and the other three effective models (Model 2-4) were constructed by stepwise multivariate logistic regression. The deLong test was used to compare whether there was a significant difference in the AUC between Model 1 and the other three models, and the net benefit of patients was analyzed by clinical decision curve analysis(DCA). Results:In this study, 64 cases (37.0%) were impacted ureteral calculi and 109 cases (63.0%) were non-impacted ureteral calculi, and there were significant differences in diameter[7.8(6.2, 8.8)mm vs. 6.3(5.2, 8.1)mm] , CT value[878.5(763.8, 940.5)HU vs.764.0 (613.0, 854.0) HU], D1[11.1(8.9, 14.9) mm vs. 9.1(7.1, 10.8) mm], D2[4.1(3.1, 4.9) mm vs. 5.0(4.1, 5.9) mm] and DDR[3.1(2.3, 3.9) vs. 1.8(1.4, 2.4)] between the two groups( P < 0.05). The results of univariate logistic regression analysis showed that stone diameter ( OR = 1.333, P < 0.001), CT value ( OR = 1.002, P=0.002), D1 ( OR = 1.146, P<0.001), D2 ( OR = 0.652, P < 0.001) and DDR ( OR = 2.995, P<0.001) were the influencing factors of impacted stones. The training set and validation set included 122 cases and 51 cases, respectively, without significant differences in their image characteristics and outcomes ( P > 0.05). The results of LASSO regression analysis showed that λ corresponding to the simplest result in the optimal range was 0.0908, and three variables were included at this time, and the influencing factors of impacted stones were stone diameter (coefficient 0.0700, OR = 1.073), CT value (coefficient 0.0003, OR = 1.001) and DDR (coefficient 0.5960, OR = 1.815). Moreover, Model 1 was established. According to the model fitting results, ROC curves were plotted, and the AUC of Model 1 was 0.862, and the AUCs of Model 2-4 were 0.859, 0.762, and 0.793, respectively. After deLong test, there was no significant difference between Model 1 and Model 2 ( Z = 0.248, P = 0.804). The AUC of Model 1 was superior to that of Model 3 ( Z = 2.888, P = 0.004) and Model 4 ( Z = 2.321, P = 0.020). The DCA suggested that Model 1 could improve the net benefit rate by up to approximately 21% of patients. Conclusions:DDR is the influencing factor of impacted ureteral calculi, and the model constructed by DDR, stone CT value and stone diameter can effectively predict the probability of impacted ureteral calculi in the middle and upper ureter.

Objective:To investigate the association of muscle mass loss with atherosclerosis in elderly patients with type 2 diabetes mellitus(T2DM).Methods:A total of 322 patients with T2DM aged≥60 years old were divided into muscle mass loss group( n=152) and non-muscle mass loss group( n=170) according to their appendicular skeletal muscle mass index(ASMI). All participants underwent physical examination, dual-energy X-ray absorptiometry check, carotid and lower extremity ultrasound, as well as laboratory tests. Results:Among 322 patients, 49(15.22%) patients were suffered from sarcopenia and 152(47.2%) patients with reduced muscle mass. The carotid and lower extremity atherosclerosis grades in the muscle mass loss group were significantly higher than those in the non-muscle mass loss group( P<0.05), with lower body mass index(BMI), T-score, ASMI, uric acid, and homeostasis model assessment of insulin resistance index( P<0.05). Multivariate logistic regression analysis showed that carotid atherosclerosis and lower extremity atherosclerosis were risk factors for muscle mass loss while BMI and 25-(OH)D 3 were protective factors for muscle mass loss. There existed a consistency in carotid atherosclerosis grade and lower extremity atherosclerosis grade of elderly patients with T2DM( P<0.01). Conclusion:Atherosclerosis has a predictive value for early sarcopenia in elderly patients with T2DM.

Objective:To explore the role of transgelin(TAGLN) in the occurrence and development of papillary thyroid carcinoma (PTC) and its possible signal pathway.Methods:One hundred cases of PTC tissues and corresponding paracancerous normal thyroid tissues were collected. Realtime quantitative PCR (RT-qPCR), Western blotting, and immunohistochemistry were used to analyze the expression of TAGLN in PTC tissues and corresponding paracancerous normal thyroid tissues. PTC cells were transfected with plasmid and shRNA lentivirus vector respectively to up-regulate or down-regulate the expression of TAGLN in order to detect the effects of them on the proliferation, invasion, and migration by cell proliferation assay(cell counting kit-8, CCK-8)and cell invasion and migration assays (Transwell). The effects of TAGLN on mitogen-activated protein kinase (MAPK)/extracellular-signal regulating kinase (ERK) signal pathway was detected with Western blotting.Results:RT-qPCR showed that there was no difference in the expression of TAGLN mRNA between PTC and corresponding paracancerous normal thyroid tissues ( P>0.05); Western blotting demonstrated that the expression of TAGLN protein in PTC tissues was significantly lower than that in corresponding paracancerous normal thyroid tissues ( P<0.01). Immunohistochemical results revealed that the expression of TAGLN in PTC tissues was significantly lower than that in corresponding paracancerous normal thyroid tissues. Overexpression of TAGLN inhibited the proliferation, invasion, and migration of PTC cells ( P<0.01), but knockdown of TAGLN promoted the proliferation, invasion, and migration of PTC cells ( P<0.01). Overexpression of TAGLN decreased the expression of phosphorylated ERK ( P<0.05), whereas silencing TAGLN increased phosphorylated ERK level in PTC cells( P<0.01). Conclusion:The expression of TAGLN in PTC is significantly decreased. It is related to the occurrence and development of PTC, and its mechanism may be related to MAPK/ERK signal pathway.

Objective:To explore the related factors of muscle mass loss in patients with type 2 diabetes mellitus, and to provide evidence for prevention of sarcopenia in type 2 diabetic patients.Methods:A cross-sectional survey was used to select type 2 diabetic patients admitted to the Department of Endocrinology, Affiliated Hospital of Qingdao University from January 2019 to August 2019. All subjects underwent dual-energy X-ray absorptiometry check. According to the diagnostic criteria of the Asian Working Group for Sarcopenia (AWGS), the subjects were divided into a muscle reduction group and a non-muscle reduction group. Data including age, gender, body mass index, course of disease, blood index, urinary albumin-creatinin ration (UACR), and appendicular skeletal muscle index (ASMI) were collected. The relevant clinical data of viscera fat/subcutaneous fat (VAT/SAT), percentage of abdominal fat/percentage of hip fat (A/G), grip strength, and pace were analyzed for the related factors of muscle mass loss in type 2 diabetic patients.Results:A total of 369 patients with type 2 diabetes were enrolled, including 42 patients with sarcopenia (an incidence rate of 11.38%), and 155 patients with reduced muscle mass (an incidence of 42.01%). Age, systolic blood pressure, high density lipoprotein-cholesterol, UACR, VAT/SAT, and A/G in the muscle reduction group were higher than those in the non-muscle reduction group ( P<0.05). The parameter of body mass index, homeostasis model assessment for insulin resistance, estimated glomerular filtration rate (eGFR), ASMI, and grip strength were lower in the muscle reduction group than in the non-muscle reduction group ( P<0.05). Multivariate logistic regression analysis showed age, UACR, A/G, and VAT/SAT were risk factors for muscle loss, body mass index, eGFR, and grip strength were protective factors for muscle mass reduction. Conclusion:It is of great practical significance for type 2 diabetic patients, especially those with advanced age, central obesity, low body mass index, low grip strength, low glomerular filtration rate, and high UACR to perform an early screening and to begin an early intervention.

Diabetic patients with poor glycemic control are exposed to media containing mold spores, and spores enter the body, which may lead to refractory infections. This article combines case and literature reviews, proposes the diagnosis and treatment method of mold infection, and provides some guidances for subjects who long-term exposure to mold groups such as farmers and immunocompromised people.

Objective To investigate the effect of liraglutide on glucagon release in obese type 2 diabetes (T2DM). Methods A multi-center, prospective, and self-comparison study was conducted in four hospitals in Qingdao. Twenty-four patients with T2DM were selected and treated with liraglutide for 12 weeks. Glucagon levels before and after treatment were detected before and 30 min, 60 min and 120 min after meals. Results After 12 weeks of treatment, the overall level of glucagon decreased, in which the differences in glucagon levels at 30 min [(220±79) ng/L vs. (203±77) ng/L, P<0.05] and 60 min [(248±119) ng/L vs. (203±82)ng/L, P<0.05] reached significance, respectively, comparing to those before treatment. The area under the curve of glucagon after treatment was significantly lower than that before treatment (438±190 vs. 389 ± 153, P<0.05). In contrast, after treatment, the overall level of C-peptide increased, especially the levels at 30 min [(1.53±1.02) nmol/L vs.(2.03±1.29) nmol/L ], 60 min [(1.93±1.19) nmol/L vs. (2.48±1.75) nmol/L] and 120 min [(2.36±1.47) nmol/L vs. (2.96±1.84) nmol/L], all P<0.05. The area under C-peptide curve increased significantly (3.6±2.2 vs. 4.6±2.9, P<0.05). Fasting plasma glucose, postprandial 2 h plasma glucose and glycosylated hemoglobin A1c were all lower than before, and the differences were statistically significant (P<0.05). Waist circumference and body mass index were significantly lower than before (P<0.05). The amount of insulin used for the treatment decreased by approximately 55.1% compared with that before liraglutide, and the difference was statistically significant (P<0.05). Conclusions Liraglutide inhibits glucagon secretion and lowers blood glucose. It can also reduce body weight, improve islet cell function and reduce insulin use in T2DM.

The occurrence and development of malignant tumors is closely related to the tumor microenvironment. Tumor-associated neutrophils (TAN) are important inflammatory cells in the tumor microenvironment. Studies have confirmed that TAN plays an important role in tumor growth, invasion, metastasis, pathological angiogenesis, and immunity escapes. TAN can be activated as an anti-tumor N1 type and a tumor-promoting N2 type. This article reviews the biological characteristics of TAN and the role of TAN in the malignant tumors and its mechanism.

Objective The purpose of this study is to investigate the molecular mechanisms of p.C310R(c.T928C) and p.E396V(c.A1187T) lipoprotein lipase(LPL) gene mutations in vitro, which may help to construct the spectrum of LPL gene mutations and phenotype. It also can provide accurate early diagnosis for high-risk population of familial hypertriglyceridemia and provide the basis for the development of gene targeted therapy. Methods Genomic DNA was extracted from proband′s family members′ peripheral blood cells and screened by whole-exome sequencing to verify candidate gene variations. PCR products were afterwards directly sequenced again to confirm corresponding LPL variants. At the cellular level, lentiviruses containing LPL mutations were constructed and then transfected into COS-1 cells. Functional significance of the mutants was corroborated by analyzing LPL activity and mass in the cell medium and lysates via ELISA and enzyme-fluorescent method. mRNA was assayed by RT-PCR to confirm the effect on gene transcription. Results DNA sequence analysis revealed that the proband was a heterozygote for a novel c.T928C mutation in exon 6 of LPL gene, while his nephew was a compound heterozygote for the c.T928C mutation in exon 6 and a novel c.A1187T mutation in exon 8. In vitro studies, these two mutations can cause decreased activity and mass of extracellular LPL(P<0.05). Moreover, further investigation indicated that LPL C310R mutation tremendously affected post-transcriptional modification of LPL gene, whereas LPL E396V mutation dampened intracellular LPL trafficking. Conclusion Both the mutations are pathogenic by reducing the activity and mass of LPL in the plasma, which affected normal metabolism of triglycerides.