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 effect of endoscopic laryngeal mask on perioperative airway management and postoperative recovery in patients undergoing gastric endoscopic submucosal dissection(ESD).Methods Ninety patients,aged 18-64 years,BMI 18-25 kg/m2,ASA physical statusⅠorⅡ,who underwent elective gastric ESD were randomly divided into two groups:the endoscopic laryngeal mask group(group E)and the endotracheal tube group(group C),45 patients in each group.After induction of general anesthesia,group E received endoscopic laryngeal mask airway ventilation,and the endoscope was inserted through the endoscopic channel of the laryngeal mask,group C received tracheal intubation,and the endoscopy was inserted through the mouth.The successful time and one-time success rate of intubation,and the insertion time and withdrawal rate of endoscopy were recorded.The operative time,extubation time and PACU residence time were recorded.HR,MAP were recorded when the patient entered the room(T0),at the time of intubating(T1),inserting gastroscopy(T2),exiting gastroscopy(T3),extubation(T4),and leaving PACU(T5).The average airway pressure and peak airway pressure at T1-T3 were recorded.The airway sealing pressure and endoscopic view grading system(EVGS)grading of group E were recorded before and after changing the position,and at the end of surgery.The adverse reactions and the satisfaction of anesthesiologists and gastroenterologists were recorded.Results Compared with T0,HR and MAP were significantly increased at T1 and T4 between the two groups(P＜0.05).Compared with group C,the suc-cessful time of intubation,the extubation time,and PACU residence time were significantly shortened,HR and MAP were significantly decreased at T1 and T4,the incidence of choking cough during extubation,post-operative pharyngeal pain,and hoarseness were significantly decreased(P＜0.05).There were no signifi-cant differences in the one-time success rate of intubation,the insertion time and withdrawal rate of endosco-py between the two groups.Endoscopic laryngeal mask showed good sealing and alignment in group E.Conclusion Endoscopic laryngeal mask could shorten the success time of establishment of artificial airway in patients with gastric ESD,without interfering with digestive endoscopy operations,shorten extubation time and PACU retention time,maintain intraoperative hemodynamic stability,and reduce adverse reactions.

Objective To investigate the effect of the monoamine oxidase A(MAOA),Maoa c.1409 T＞C synonymous mutation on anxiety,fear,and other emotional behaviors in mice.Methods In this study,CRISPR/Cas9 technology was used to construct a mouse model of a single nucleotide polymorphism(SNP)synonymous mutation.We evaluated the differential effect of this gene between males and females through animal behavior and gene expression studies in animal models.In terms of animal behavior,an open field test,elevated plus maze test,defensive burial experiment,forced swimming test,and 3D behavioral analysis were used.Other method were used to evaluate behavioral differences between male and female mice with polymorphisms in Maoa synonymous mutant genes.Results The result of the open field experiment showed that the residence time of female SNP mice in the central area was significantly higher than that of male SNP mice(P＜0.001).In the elevated cross maze experiment,the EPM result showed that the time and frequency of male SNP mice entering the open arm were higher than those of female SNP mice,but there was no significant difference.The defensive burial test showed that the number and duration of excavations by female SNP mice in response to rat urine were significantly reduced(P＜0.01).The FST showed that SNP females had shorter immobility time and longer swimming time(P＜0.05),and thus their depression was lower than males.3D-AI fine behavior analysis showed no significant male and female differences,except for the movement trajectory and climbing behavior of mice.The MAOA enzyme content of female SNP mice was significantly lower than that of male SNP mice(P＜0.001),but there was no significant difference in enzyme activity between male and female SNP mice.Conclusions The synonymous mutation of Maoa c.1409 T＞C acts by affecting the expression of MAOA and may have different fear,anxiety,and mood effects in male and female SNP mice.

As endogenous chemical substances,neurotransmitters play a vital role in maintaining normal life activities.Abnormal levels of neurotransmitters can lead to physical,mental,and some neurodegenerative diseases.However,the ultralow concentration,complex chemical properties,and release modes of neurotransmitters make their accurate detection in vivo a great challenge.To accurately monitor neurotransmitters in the brain and accurately understand the release kinetics of neurotransmitters,we reviewed several method commonly used in the past five years to detect neurotransmitters in vivo and their research progress.The basic principle and applicability of microdialysis,electrochemical sensors,and fluorescence sensors are introduced in detail.

Objective:To explore the prognostic value of pretreatment albumin in extranodal nasal type NK/T cell lymphoma (ENKTL).Methods:The clinical data of 184 ENKTL patients in Shanxi Province Cancer Hospital from January 2002 to December 2018 were retrospectively analyzed. The Contal-O'Quigley change point method was used to determine the optimal cut-off value of albumin for predicting the prognosis of patients. The propensity score matching (PSM) was used to minimize selection biases. The Kaplan-Meier method was used for survival analysis, and Cox proportional hazards model was used to determine the factors affecting survival. The time-dependent receiver operating characteristic curve, Akaike information criterion and integrated Brier score were used to evaluate the efficacy of international prognostic index (IPI), Korean prognostic index (KPI) and prognostic index of NK cell lymphoma (PINK) models incorporating albumin for predicting the prognosis of patients.Results:The optimal cut-off value of pretreatment albumin for predicting the prognosis of ENKTL patients was 37.5 g/L. The 3-year and 5-year overall survival (OS) rates in >37.5 g/L group (126 cases) were 66.2% and 60.3%, and the progression-free survival (PFS) rates were 58.8% and 49.6%; the 3-year and 5-year OS rates in ≤37.5 g/L group (58 cases) were 35.0% and 32.4%, and the PFS rates were 32.5% and 30.0%. The OS and PFS in > 37.5 g/L group were better than those in ≤37.5 g/L group (both P<0.001). After PSM, the OS and PFS in >37.5 g/L group were still better than those in ≤37.5 g/L group (both P = 0.002). Multivariate analysis showed that albumin was an independent influencing factor for OS ( RR = 0.419, 95% CI 0.266-0.660, P < 0.001) and PFS ( RR = 0.493, 95% CI 0.322-0.755, P < 0.001). After PSM, albumin was still an independent influencing factor for OS ( RR = 0.305, 95% CI 0.156-0.598, P = 0.001) and PFS ( RR = 0.341, 95% CI 0.185-0.627, P = 0.001). The prognostic prediction performance of the IPI, KPI and PINK models incorporating albumin were all improved. Conclusions:Pretreatment albumin is an important prognostic indicator for ENKTL.

【Objective】 To understand the situation of free blood use of blood donors in Changsha to explore the correlation between free blood use of donors and repeated blood donation behaviors, so as to provide a theoretical basis for the recruitment of voluntary blood donations. 【Methods】 A total of 260 voluntary blood donors were selected by random sampling and divided into reimbursed group(n=97) and unreimbursed group(n=163), based on the results of a questionnaire, inquiring their using of free blood. 【Results】 The reimbursed group differed from the unreimbursed group in all dimensions, including behavioral attitude dimension(Z=3.250, P<0.05), subjective behavioral norm dimension(Z=4.576, P<0.05), and perceptual behavioral control dimension(Z=7.255, P<0.05) and the total score of the scale(Z=8.625, P<0.05), and the differences were statistically significant. 【Conclusion】 The intention to donate again was stronger in donors who experienced free blood use than those didn’t. Such donors are suitable candidates for blood donor recruitment. It is recommended to develop a suitable recruitment strategy for this population and further guarantee the clinical use of blood.

Objective:To investigate the value of a preoperatively MRI-based deep learning (DL) radiomics machine learning model to distinguish low-grade and high-grade soft tissue sarcomas (STS).Methods:From November 2007 to May 2019, 151 patients with STS confirmed by pathology in the Affiliated Hospital of Qingdao University were enrolled as training sets, and 131 patients in the Affiliated Hospital of Shandong First Medical University and the Third Hospital of Hebei Medical University were enrolled as external validation sets. According to the French Federation Nationale des Centres de Lutte Contre le Cancer classification (FNCLCC) system, 161 patients with FNCLCC grades Ⅰ and Ⅱ were defined as low-grade and 121 patients with grade Ⅲ were defined as high-grade. The hand-crafted radiomic (HCR) and DL radiomic features of the lesions were extracted respectively. Based on HCR features, DL features, and HCR-DL combined features, respectively, three machine-learning models were established by decision tree, logistic regression, and support vector machine (SVM) classifiers. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of each machine learning model and choose the best one. The univariate and multivariate logistic regression were used to establish a clinical-imaging factors model based on demographics and MRI findings. The nomogram was established by combining the optimal radiomics model and the clinical-imaging model. The AUC was used to evaluate the performance of each model and the DeLong test was used for comparison of AUC between every two models. The Kaplan-Meier survival curve and log-rank test were used to evaluate the performance of the optimal machine learning model in the risk stratification of progression free survival (PFS) in STS patients.Results:The SVM radiomics model based on HCR-DL combined features had the optimal predicting power with AUC values of 0.931(95%CI 0.889-0.973) in the training set and 0.951 (95%CI 0.904-0.997) in the validation set. The AUC values of the clinical-imaging model were 0.795 (95%CI 0.724-0.867) and 0.615 (95%CI 0.510-0.720), and of the nomogram was 0.875 (95%CI 0.818-0.932) and 0.786 (95%CI 0.701-0.872) in the training and validation sets, respectively. In validation set, the performance of SVM radiomics model was better than those of the nomogram and clinical-imaging models ( Z=3.16, 6.07; P=0.002,<0.001). Using the optimal radiomics model, there was statistically significant in PFS between the high and low risk groups of STS patients (training sets: χ2=43.50, P<0.001; validation sets: χ2=70.50, P<0.001). Conclusion:Preoperative MRI-based DL radiomics machine learning model has accurate prediction performance in differentiating the histopathological grading of STS. The SVM radiomics model based on HCR-DL combined features has the optimal predicting power and was expected to undergo risk stratification of prognosis in STS patients.

Objective:To observe the effect of tenofovir disoproxil fumarate (TDF) antiviral therapy on HBV-specific CD8 +T cell function in peripheral blood of patients with HBeAg-positive chronic hepatitis B, and to assess its correlation with HBeAg sero-negativeness. Methods:Sixty-three cases with HLA-A02 restricted HBeAg-positive chronic hepatitis B who received TDF (300 mg/d) antiviral therapy were enrolled from October 2016 to July 2018. The peripheral blood CD8 +T cells were separated at baseline and 48 weeks after treatment. The peripheral blood T cells count were detected by flow cytometry. The frequency of HBV-specific CD8 +T cells secreting perforin, granzyme B, and interferon-γ (IFN-γ) were detected by enzyme-linked immunoblotting test. Direct and indirect contact co-culture system was established between HBV-specific CD8 +T cells and HepG2.2.15 cells. HBV DNA was detected in the culture supernatant. Target cell mortality was calculated by lactate dehydrogenase level. Cytokines expression was detected by enzyme-linked immunosorbent assay. Virus-specific CD8 +T cells cytokilling and non-cytokilling functions were evaluated. Measurement data of the two groups were compared by t-test or paired t-test. Results:Viral response, biochemical response, and HBeAg seroconversion rate at 48 weeks of TDF treatment were 100%, 90.48% (57/63), and 25.40% (16/63), respectively. There was no statistically significant difference in peripheral blood T cell count when compared with baseline and control group at 48 weeks of TDF treatment ( P > 0.05). At 48 weeks of TDF treatment, the frequency of HBV-specific CD8 +T cells secreting perforin, granzyme B, and IFN-γ in CHB patients was significantly higher than baseline ( P < 0.001). Furthermore, the frequency of HBV-specific CD8 +T cells secreting perforin, granzyme B, and IFN-γ was also significantly higher in CHB patients with HBeAg negative than that of non-negative ( P < 0.05). HBV-specific CD8 +T cells had induced significant down-regulation of HBV DNA in the supernatant of HepG2.2.15 cell culture ( P < 0.001) and remarkable IFN-γ and interleukin-2 secretion ( P < 0.05) at 48 weeks of TDF therapy in direct and indirect contact co-culture system. However, HepG2.2.15 cells death rate induced by virus-specific CD8 +T cells was increased only in the direct contact co-culture system (21.7% ± 6.18% vs. 16.1% ± 4.15%, P < 0.001). Compared with HBeAg non-negative patients, HBeAg negative CHB patients with HBV-specific CD8 +T cells had induced a strong decrease in HBV DNA ( P < 0.001) and an increase in IFN-γ secretion level ( P < 0.05). However, the target cell death proportion difference between HBeAg negative and non-negative patients was not statistically significant ( P > 0.05). Conclusion:During TDF treatment, with the viral load reduction, virus-specific CD8 +T cells cytokilling and non-cytokilling functions are significantly enhanced, and are closely related to HBeAg negative.

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared

In recent years, in the absence of venous component, dilated, overlapping, and tortuous arteries forming a mass of arterial loops with a coil-like appearance have been defined as pure arterial malformation (PAM). It is extremely rare, and its etiology and treatment have not yet been fully elucidated. Here, we reported 2 cases of PAM with associated aneurysmal subarachnoid hemorrhage in this paper. Both patients had severe headache as the first symptom. Subarachnoid hemorrhage was found by CT and computed tomography angiography (CTA) and PAM with associated aneurysm was found by digital subtraction angiography (DSA). In view of the distribution of blood and the location of aneurysms, the aneurysm rupture was the most likely to be considered. Based on the involvement of the lesion in the distal blood supply, only the aneurysm was clamped during the operation. It used to be consider that PAM is safety, because of the presentation and natural history of previously reported cases. Through the cases we reported, we have doubted about "the benign natural history" and discussed its treatment. PAM can promote the formation of aneurysms and should be reviewed regularly. The surgical indications for PAM patients with aneurysm formation need to be further clarified. Management of PAM patients with ruptured aneurysm is the same as that of ruptured aneurysm. Whether there are indications needed to treat simple arterial malformations remains to be further elucidated with the multicenter, randomized controlled studies on this disease.
Aneurysm, Ruptured/surgery* ; Angiography, Digital Subtraction ; Cerebral Angiography ; Humans ; Intracranial Aneurysm/surgery* ; Subarachnoid Hemorrhage/etiology*