Proteolysis-targeting chimeras (PROTACs) have emerged as a promising therapeutic strategy for targeted protein degradation. However, the clinical application of PROTACs may be hindered by off-target toxicity resulting from non-tissue-specific protein degradation and ingenious prodrug strategies may open new avenues to addressing this concern. Herein, we propose a light-induced positive feedback strategy to use photodynamic therapy (PDT) to improve the activation efficiency of PROTAC prodrugs, monitor PROTAC release, and combine PROTAC to induce tumor cell apoptosis. In the hypoxic tumor microenvironment, the azo bond in AZO-PRO selectively cleaves, triggering the release of the potent protein degrader PRO and the multifunctional photosensitizer. Once activated, the fluoresce signal of the photosensitizer dramatically recovers, allowing monitoring of prodrug activation. Additionally, upon irradicating the tumor site using near-infrared (NIR) laser, PDT exacerbates tumor hypoxia, further promoting AZO-PRO activation. Our work introduces a novel approach to efficiently track and activate PROTAC prodrugs, enhance their antitumor efficacy, and mitigate off-target systemic toxicity.

Objective To evaluate the effectiveness and safety of edaravone combined with oxiracetam in the treatment of acute cere-bral infarction.Methods PubMed,Embase,Cochrane Library,CNKI,Wanfang Data and other databases were comprehensively searched from database inception until October 27,2022,to collect randomized controlled trials of edaravone combined with oxiracetam in the treatment of acute cerebral infarction(ACI).RevMan5.4software was used to analyze the collected data.Results A total of9studies involving 887 patients were included.Meta-analysis results showed that the overall effective rate and Barthel index in the observation group were significantly higher than those in the control group(OR=4.66,95％CI:2.74-7.93,P＜0.001;MD=14.57,95％CI:8.58-20.56,P＜0.001),the NIHSS scores in the observation group were significantly lower than that in the control group(MD=-5.28,95％CI:-6.42--4.13,P＜0.001).There was no significant difference in adverse effect rate between the two groups(RR=1.11,95％CI:0.63-1.95,P=0.72).Conclusion The combination of edaravone and oxiracetam in the treatment of ACI can significantly reduce NIHSS scores,and improve Barthel index and overall effective rate.The efficacy is better than edaravone alone,and a more comprehensive evaluation of safety is needed in the future.

Objective To investigate the changes of blood lipid and glycosylated hemoglobin (HbA1c) levels in obese type 2 diabetes (T2DM) patients and their relationship with insulin resistance (Homa-IR). Methods A total of 120 cases of T2DM newly diagnosed in Motuo County, Tibet from February to October 2022 were selected as the observation group. According to BMI, the patients were divided into diabetes normal weight group (46 cases), overweight group (43 cases) and obesity group (31 cases); 145 healthy subjects were selected as the control group. The levels of HbA1c, fasting blood glucose (FPG), fasting insulin (FINS), serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C) were detected in the study subjects, and Homa-IR and Homa-β indices were calculated. The height, weight, and abdominal circumference were measured. The differences in the levels of the above indicators between the observation group patients and the control group, as well as among various subgroups within the observation group were compared. The influencing factors of Homa-IR in obese T2DM patients were analyzed. Results Compared with the control group, a significant increase in BMI, abdominal circumference, blood pressure, HbA1c, FBG, FINS, TC, TG, LDL-C, UA, visceral fat area, and the levels of Home-IR and Home-β was found in the observation group (all P<0.05). There were significant differences in BMI, abdominal circumference, and the levels of FINS, Homa IR, Homa-β, and HbA1c in diabetes patients with different BMI (all P<0.05). Correlation analysis showed that TG levels in obese T2DM patients in the observation group were significantly correlated with HbA1c (r=0.396, P=0.027), Homa-IR (r=0.405, P=0.024), and Home-β (r=-0.401, P=0.025); LDL-C was significantly correlated with Homa-IR (r=0.411, P=0.022) and Homa-β (r=-0.412, P=0.021); HbA1c was significantly positively correlated with BMI (r=0.371, P=0.040). Conclusion Insulin resistance is closely related to TG, LDL-C, and BMI in obese T2DM patients from the Motuo ethnic minority of Tibet, suggesting that these factors may play a role in the occurrence of T2DM.

OBJECTIVE To study effects of Jinshui Liujun decoction(JLD) on pulmonary water metabolism and TNF-α/NF-κB signaling pathway in asthmatic mice. METHODS After 1 week of acclimatization, 10 mice were randomly selected by body weight as a blank control group, and the rest of the mice were sensitized by intraperitoneal and subcutaneous injections of ovalbumin sensitizing solution on the 1st, 8th, and 15th day of the experiment. On the 22nd day, they were randomly divided into model control group, positive control group and JLD low, medium and high dose(4.1, 8.2, 16.4 g·kg−1) group, and replicated the asthma mouse model by inhaling nebulized excitation solution(1% ovalbumin) once every other day for 2 consecutive weeks, and at the same time, were given atomized excitation solution(1% ovalbumin) every other day for two weeks to replicate the asthmatic mouse model, and were given the test drug by gavage daily. The effects of JLD on the behavior, lung wet-dry weight ratio, AQP1, AQP5, TNF-α, NF-κB, and NF-κB mRNA expression in asthmatic mice were observed. RESULTS JLD reduced the number of animals with asthma attacks, alleviated asthma symptoms, decreased the lung index and lung wet-to-dry weight ratio, increased the expression level of AQP1 and AQP5 in lung tissues, reduced the content of TNF-α in bronchoalveolar lavage fluid and lung tissues, and down-regulated the expression level of NF-κB and its genes in lung tissues(P<0.05 or P<0.01). CONCLUSION JLD has an anti-asthma effect and its mechanism of action is partially due to its inhibition of the TNF-α/NF-κB signaling pathway, upregulation of AQP1 and AQP5, and improvement of pulmonary water metabolism.

Objective To generate and identify the Itgbl1(integrin beta-like)promoter-driven Cre knock-in mouse line.Methods Itgbll-Cre knock-in mice were generated using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)gene editing.The Itgbl1-Cre mice were crossed with the Cre reporter ROSALSL-tdTomato)mice to detect the expression profile of Cre activity.The tdTomato expression pattern across tissues and cell-specific markers were used to identify the cell types of Itgbl1-expressing cells and their progeny.Results and Conclusion tdTomato was specifically expressed in mucous acinar cells of the sublingual gland,pancreatic islet cells,and gastric endocrine cells.In addition,tdTomato expression was also found in some of the neurons of the retina and brain,as well as in a few cells in the serosal layer of the intestine,articular cartilage,periosteum,and bone marrow.The first Itgbl1-Cre recombinase transgenic mouse line was established,which can specifically label the mucous acinar cells of the sublingual gland.

Objective:To investigate the efficacy and safety of flumatinib in the treatment of imatinib-resistant or imatinib-intolerant patients with chronic phase chronic myelogenous leukemia (CML-CP).Methods:The clinical data of 9 CML-CP patients who received flumatinib after imatinib resistance or intolerance in Jining No. 1 People's Hospital from April 2020 to May 2021 were retrospectively analyzed. Patients were evaluated for the hematologic, cytogenetic and molecular responses, progression-free survival (PFS), event-free survival (EFS), and adverse reactions.Results:Among 9 CML-CP patients, there were 4 imatinib-resistant patients and 5 imatinib-intolerant patients. The median duration of flumatinib exposure was 17 months (1-25 months). Except for 1 case who discontinued flumatinib early due to grade 4 thrombocytopenia and other adverse reactions, 7 of the remaining 8 cases achieved the best response at 3, 6 and 12 months of flumatinib therapy. By the end of follow-up in April 2022, 7, 7 and 6 patients achieved complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4.5 (MR4.5), respectively. The median time to achieving CCyR, MMR and MR4.5 was 4.5 months (3-6 months), 12 months (3-12 months) and 15 months (3-21 months), respectively. Within 17 months (11-25 months) of follow-up, 7 of the 9 patients had EFS and 8 patients with continuous flumatinib had PFS. Among 9 patients treated with flumatinib, hematologic adverse reactions were observed in 6 cases, and grade 3-4 hematologic adverse reactions occurred in 2 cases. Non-hematologic reactions events mainly included diarrhea (4 cases), muscle ache (2 cases), fatigue (2 cases) and liver damage (2 cases), which were all grade 1-2.Conclusions:Flumatinib is effective and well tolerated in the treatment of imatinib-resistant or imatinib-intolerant CML-CP patients.

Hepatocellular carcinoma (HCC) is the most common liver malignancy, where HCC segmentation and prediction of the degree of pathological differentiation are two important tasks in surgical treatment and prognosis evaluation. Existing methods usually solve these two problems independently without considering the correlation of the two tasks. In this paper, we propose a multi-task learning model that aims to accomplish the segmentation task and classification task simultaneously. The model consists of a segmentation subnet and a classification subnet. A multi-scale feature fusion method is proposed in the classification subnet to improve the classification accuracy, and a boundary-aware attention is designed in the segmentation subnet to solve the problem of tumor over-segmentation. A dynamic weighted average multi-task loss is used to make the model achieve optimal performance in both tasks simultaneously. The experimental results of this method on 295 HCC patients are superior to other multi-task learning methods, with a Dice similarity coefficient (Dice) of (83.9 ± 0.88)% on the segmentation task, while the average recall is (86.08 ± 0.83)% and an F1 score is (80.05 ± 1.7)% on the classification task. The results show that the multi-task learning method proposed in this paper can perform the classification task and segmentation task well at the same time, which can provide theoretical reference for clinical diagnosis and treatment of HCC patients.
Humans ; Carcinoma, Hepatocellular ; Liver Neoplasms ; Learning

Somatostatin (SST) is an inhibitory polypeptide hormone that plays an important role in a variety of biological processes. Somatostatin receptor 2 (SSTR2) is the most widely expressed somatostatin receptor. However, the specific cell types expressing Sstr2 in the tissues have not been investigated. In this study, we detected the expression pattern of SSTR2 protein in mouse at different development stages, including the embryonic 15.5 days and the postnatal 1, 7, 15 days as well as 3 and 6 months, by multicolour immunofluorescence analyses. We found that Sstr2 was expressed in some specific cells types of several tissues, including the neuronal cells and astrocytes in the brain, the mesenchymal cells, the hematopoietic cells, the early hematopoietic stem cells, and the B cells in the bone marrow, the macrophages, the type Ⅱ alveolar epithelial cells, and the airway ciliated cells in the lung, the epithelial cells and the neuronal cells in the intestine, the hair follicle cells, the gastric epithelial cells, the hematopoietic stem cells and the nerve fibre in the spleen, and the tubular epithelial cells in the kidney. This study identified the specific cell types expressing Sstr2 in mouse at different developmental stages, providing new insights into the physiological function of SST and SSTR2 in several cell types.
Mice ; Animals ; Receptors, Somatostatin/metabolism* ; Hematopoietic Stem Cells/metabolism* ; Epithelial Cells

Objective:To investigate surgical treatment of carotid artery diseases in neck tumor surgery. Methods:A retrospective analysis of the clinical data on carotid artery treatment was conducted in the five cases of neck tumor surgeries treated at Department of Surgical Oncology, the First Peoples Hospital of Lanzhou from March 2010 to May 2020. Surgical methods, including carotid artery resection and ligation, tumor-involved artery resection and vascular reconstruction, and tumor peeling and carotid rupture repairing were used, respectively. Results:Five cases were successfully operated on. One case of carotid artery ligation was followed by intermittent dizziness and decreased contra-lateral limb strength after the surgery. The remaining patients exhibited no neurological complications. A patient with cervical low-grade myofibroblastoma developed into lung metastases 8 months after the surgery. Another patient with cervical lymph node metastases in papillary thyroid cancer developed into lung metastases 24 months after the surgery. Conclusion:Currently, surgical methods for clinical treatment of diseased carotid arteries include carotid artery resection and ligation, simple tumor peeling, tumor invasion artery resection and vascular reconstruction, and interventional therapy. Each surgical method has its own advantages and disadvantages. Therefore, the choice of treatment depends on the patient's specific conditions, physician's clinical experience, and the equipment available.
Humans ; Retrospective Studies ; Carotid Arteries/pathology* ; Head and Neck Neoplasms/pathology* ; Thyroid Neoplasms/surgery* ; Lung Neoplasms/pathology*

Objective:Based on the concept of outcomes-based education (OBE), aiming to improve students' medical mathematical modeling ability, the teaching design and practice of mathematical modeling module for the course Medical Advanced Mathematics are carried out and the direction of improvement is defined. Methods:Taking infectious disease model as an example, teaching practice was carried out, and then questionnaires from 44 students were collected for feedback opinions. Statistical description, Mann-Whitney U test, one-way ANOVA and Scheffe method, as well as chi-square test and z-test were used to analyze data. Results:The results showed that 90.91% of the students were interested in the subject of the course, and 65.91% of the students thought that this mode significantly improved the learning effect. In this course, there was no significant difference in the learning initiative of students on the two levels of being or not being interested in the course topic, but it had a significant impact on their mastery of knowledge points and their willingness to continue to carry out flipped classroom.Conclusion:The teaching mode is generally effective, but it needs to be further improved in three aspects: emphasizing modeling and downplaying computation, enhancing students' participation and strengthening the classroom learning effect.