Autoimmune pancreatitis is a special type of chronic pancreatitis that can lead to abnormal pancreatic exocrine function in patients. Autoimmune pancreatitis comorbid with pancreatic exocrine insufficiency has a complex pathogenesis， and there is limited research on this topic， leading to the lack of understanding of such patients in clinical practice. This article introduces the epidemiology of autoimmune pancreatitis， briefly describes the pathogenesis of pancreatic exocrine insufficiency caused by autoimmune pancreatitis， and summarizes the various detection methods for pancreatic exocrine function， nutritional assessments， lifestyle management， and drug therapy， in order to strengthen the understanding of autoimmune pancreatitis comorbid with pancreatic exocrine insufficiency and improve the clinical diagnosis and treatment of pancreatic exocrine insufficiency.

Objective:To investigate the effect and safety of pancreatic extracorporeal shock wave lithotripsy (P-ESWL) in treating the chronic pancreatitis (CP) patients with main pancreatic duct (MPD) stones and to analyze the influencing factors of success of lithotripsy.Methods:Clinical data of 132 patients with CP complicated with MPD stones treated with P-ESWL in the Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2022 to December 2023 were retrospectively analyzed, including 103 males and 29 females, aged (50.3±16.9) years. The times of P-ESWL, the success rate of stone fragmentation, the necessity of combining endoscopic retrograde cholangiopancreatograhy (ERCP), clearance rate of MPD stones, and incidence of post-P-ESWL complications (acute pancreatitis, abdominal hematoma, infection, steinstrasse, perforation, etc.) were evaluated. The factors influencing the success rate of lithotripsy were analyzed using univariate and multivariate logistic regression.Results:All patients underwent P-ESWL treatment, with (2.23±0.82) times of P-ESWL per person. The success rate of stone fragmentation was 87.1%(115/132). Of 107 CP patients (81.1%, 107/132) were treated with their first P-ESWL. Of 12 patients (9.1%, 12/132) underwent single P-ESWL, and 120 (90.9%, 120/132) underwent P-ESWL combined with ERCP. There were 95 cases (72.0%, 95/132) with effective removal of stones, and 62 (47.0%, 62/132) with complete removal of stones. Post-P-ESWL complications included eight cases (6.1%, 8/132) of acute pancreatitis, two (7.6%, 2/132) of steinstrasse complicated with acute pancreatitis and one (0.8%, 1/132) of abdominal hematoma. No infection or perforation occurred. Multivariate logistic regression analysis showed that the higher CT value of stones ( OR=1.239, 95% CI: 1.040-1.477, P=0.017) was associated with the lower success rate of stone fragmentation. Conclusion:P-ESWL is safe and effective in treating patients with CP complicated with MPD stones. The CT value of stones is a risk factor for the success rate of P-ESWL.

Obejective To explore whether it is possible to detect the 123I-prostate-specific membrane antigen(PSMA)radiation value of the puncture tissue during prostate biopsy to achieve real-time,rapid,and accurate identification of benign and malignant prostate tissues,so as to improve the current clinical biopsy strategy and achieve accurate diagnosis of prostate cancer during operation with fewer puncture needles.Method In this prospective,diagnostic trial,we included 29 patients with suspected prostate cancer.All patients underwent transperineal biopsy guided by ultrasound within 24 hours after injection of 123I-PSMA,a total of 435 punctures were performed.The radiation value of punctured tissue was measured in real-time with a gamma counter.Pearson test is used to correlate radiation value with histopathology.Result The median radiation value of prostate cancer tissue(1 906.50 cpm)was significantly higher than that of benign prostate tissue(415.00 cpm).The optimal cut-off value for distinguishing benign and malignant prostate tissues was 828.50 cpm.The median radiation value of clinically significant prostate cancer tissue(2 652.50 cpm)was significantly higher than that of clinically insignificant prostate cancer(1 386.00 cpm).The optimal cut-off value for distinguishing clinically significant and clinically insignificant prostate cancer tissues was 1 767.00 cpm.In additional,there was a significant positive correlation between the radiation value of puncture tissue and ISUP pathological grade(r=0.834).Conclusion It is preliminarily confirmed that detection of 123I-PSMA radiation value of prostate puncture tissue can realize real-time,rapid and accurate identification of benign and malignant prostate tissues during operation.

Objective To construct 5 machine-learning models and compare their performance in predicting the associations between pre-pregnancy socio-psycho-behavioral exposures of both spouses and preconception outcomes.Methods Based on Chongqing Preconception Reproductive Health and Birth Outcome Cohort of volunteers recruited from Chongqing Health Center for Women and Children during January 2019 and March 2022,5 447 couples were recruited and surveyed through interviewer-interview for the demographic and social-psychological-behavioral data of both spouses(221 variables).According to the inclusion and exclusion criteria,4 097 couples were finally included,and randomly assigned into a training set(n=2 867 spouses)and a validation set(n=1 230 spouses)at a ratio of 7∶3.Feature analysis and collinear screening were applied to select the potential exposure factors.In consideration of difficulty to carry out semen parameters analysis in primary healthcare institutions,feature Set 1 including sperm parameters and feature Set 2 excluding semen parameters were constructed by including or excluding sperm quality simultaneously in the training set and the validation set.Five algorithms,that is,Logistic Regression,Naive Bayes,Random Forest,Gradient Boosting Machine,and Support Vector Machine,were used to construct preconception outcome prediction models,and the parameters of each model were optimized using random search combined with grid search.The predictive performance of each model was compared using precision,recall,F1 score,area under the receiver operating characteristic curve(AUC),and calibration curve.The optimal model was then selected by comparing the changes in the predictive ability of the questionnaire data for fertility outcomes with or without semen parameters.Results There were 24 variables screened out in feature Set 1,and 16 variables in feature Set 2.In feature Set 1,the gradient boosting machine performed better,with a relatively higher AUC value(0.651)and better F1 score(0.61).The logistic regression model performed stably(AUC value=0.647)and was suitable as the reference model.The random forest(AUC value=0.641),Naive Bayes(AUC value=0.641),and support vector machine(AUC value=0.634)performed second-best.By utilizing the gradient boosting machine,comparable results were found between the predictions from feature sets with or without semen parameters,as in feature Set 1,the AUC value of its validation set was 0.651(95%CI:0.629～0.681),the prediction accuracy was 0.63,the recall rate was 0.65,and the average precision value F1 was 0.61;and in feature Set 2,the AUC value of its validation set was 0.649(95%CI:0.624～0.663),and both the calibration curves were close to the ideal curve.The prediction results indicated that in feature Set 1,the features highly negatively correlated with preconception outcomes were female age,male age,and no pregnancy within 1 year without contraception,while the features highly positively correlated with preconception outcomes were female pregnancy history,total sperm vitality,and use of contraceptive measures before enrollment.Conclusion Among the 5 machine-learning algorithms performed in this cohort data,the gradient boosting machine shows slightly better performance.There are 24 factors being associated with preconception outcomes in both spouses,and the performance of the simplified model excluding semen parameters is not significantly declined.It is feasible to use machine-learning methods to predict human preconception outcomes through social-psychological-behavioral questionnaires.

Obejective To explore whether it is possible to detect the 123I-prostate-specific membrane antigen(PSMA)radiation value of the puncture tissue during prostate biopsy to achieve real-time,rapid,and accurate identification of benign and malignant prostate tissues,so as to improve the current clinical biopsy strategy and achieve accurate diagnosis of prostate cancer during operation with fewer puncture needles.Method In this prospective,diagnostic trial,we included 29 patients with suspected prostate cancer.All patients underwent transperineal biopsy guided by ultrasound within 24 hours after injection of 123I-PSMA,a total of 435 punctures were performed.The radiation value of punctured tissue was measured in real-time with a gamma counter.Pearson test is used to correlate radiation value with histopathology.Result The median radiation value of prostate cancer tissue(1 906.50 cpm)was significantly higher than that of benign prostate tissue(415.00 cpm).The optimal cut-off value for distinguishing benign and malignant prostate tissues was 828.50 cpm.The median radiation value of clinically significant prostate cancer tissue(2 652.50 cpm)was significantly higher than that of clinically insignificant prostate cancer(1 386.00 cpm).The optimal cut-off value for distinguishing clinically significant and clinically insignificant prostate cancer tissues was 1 767.00 cpm.In additional,there was a significant positive correlation between the radiation value of puncture tissue and ISUP pathological grade(r=0.834).Conclusion It is preliminarily confirmed that detection of 123I-PSMA radiation value of prostate puncture tissue can realize real-time,rapid and accurate identification of benign and malignant prostate tissues during operation.

Objective:To investigate the effect and safety of pancreatic extracorporeal shock wave lithotripsy (P-ESWL) in treating the chronic pancreatitis (CP) patients with main pancreatic duct (MPD) stones and to analyze the influencing factors of success of lithotripsy.Methods:Clinical data of 132 patients with CP complicated with MPD stones treated with P-ESWL in the Department of Gastroenterology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2022 to December 2023 were retrospectively analyzed, including 103 males and 29 females, aged (50.3±16.9) years. The times of P-ESWL, the success rate of stone fragmentation, the necessity of combining endoscopic retrograde cholangiopancreatograhy (ERCP), clearance rate of MPD stones, and incidence of post-P-ESWL complications (acute pancreatitis, abdominal hematoma, infection, steinstrasse, perforation, etc.) were evaluated. The factors influencing the success rate of lithotripsy were analyzed using univariate and multivariate logistic regression.Results:All patients underwent P-ESWL treatment, with (2.23±0.82) times of P-ESWL per person. The success rate of stone fragmentation was 87.1%(115/132). Of 107 CP patients (81.1%, 107/132) were treated with their first P-ESWL. Of 12 patients (9.1%, 12/132) underwent single P-ESWL, and 120 (90.9%, 120/132) underwent P-ESWL combined with ERCP. There were 95 cases (72.0%, 95/132) with effective removal of stones, and 62 (47.0%, 62/132) with complete removal of stones. Post-P-ESWL complications included eight cases (6.1%, 8/132) of acute pancreatitis, two (7.6%, 2/132) of steinstrasse complicated with acute pancreatitis and one (0.8%, 1/132) of abdominal hematoma. No infection or perforation occurred. Multivariate logistic regression analysis showed that the higher CT value of stones ( OR=1.239, 95% CI: 1.040-1.477, P=0.017) was associated with the lower success rate of stone fragmentation. Conclusion:P-ESWL is safe and effective in treating patients with CP complicated with MPD stones. The CT value of stones is a risk factor for the success rate of P-ESWL.

Objective:To study the reproductive toxicity of lithium chloride (LiCl) in male mice and to explore the molecular mechanism of the protective effect of quercetin on testosterone production dysfunction.Methods:Twenty-five male C57BL/6 mice aged 4-5 weeks were randomly divided into five groups according to the random number table method: control group, LiCl infected group [38.4 mg/(kg·d) LiCl+corn oil, noted as LiCl group], quercetin control group [50 mg/(kg·d) quercetin, noted as High-Quer group], low-dose quercetin combined with LiCl infection group [38.4 mg/(kg·d) LiCl+10 mg/(kg·d) quercetin, noted as Low-Quer+LiCl group] and high dose quercetin combined with LiCl infected group [38.4 mg/(kg·d) LiCl+50 mg/(kg·d) quercetin, noted as High-Quer+LiCl group]. The structure of testicular tissue, semen parameters, and the ultrastructure of Leydig cells in mice were detected by HE staining, computer-aided sperm analysis system (CASA), and transmission electron microscopy, respectively. TM3 mouse Leydig cells were treated with 0 mmol/L, 5 mmol/L, 10 mmol/L, 20 mmol/L LiCl for 24 h. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), mitochondrial membrane potential (MMP), lipid peroxidation levels, and expression levels of testosterone-related protein were measured by SOD and GSH-Px kits, TMRE probe, Image-iT TM lipid peroxidation probe, and Western blotting, respectively. Intracellular Fe 2+ concentration was detected by Fe 2+ detection kit and FerroOrange probe. The levels of testosterone, progesterone, and estradiol were measured using enzyme-linked immunosorbent assay kits. Results:In the LiCl group, the total sperm count [(36.78±1.81)×10 6], sperm concentration [(18.39±0.90)×10 6/mL], sperm motility [(25.70±3.32)%] and serum testosterone level [(7.26±0.29) μg/L] were lower than those of control group [(51.60±4.96)×10 6, P=0.002; (25.80±2.48)×10 6/mL, P=0.002; (41.47±2.83)%, P=0.001; (7.87±0.29) μg/L, P=0.013], the expression levels of Cyp11a1, StAR and Cyp17a1, Leydig cell biomarkers (3β-HSD1, 17β-HSD3) and ferroptosis regulatory proteins (GPX4, SLC7A11 and Nrf2) in testis were significantly down-regulated compared with control group (all P<0.001). LiCl also induced mitochondrial vacuoles and swelling of Leydig cells. However, low-dose quercetin intervention could significantly ameliorate the above LiCl-induced damage (total sperm count: P<0.001, sperm concentration: P<0.001, sperm motility: P=0.015, serum testosterone level: P=0.026, Cyp11a1, StAR, Cyp17a1, 3β-HSD1, 17β-HSD3, GPX4, SLC7A11, and Nrf2: all P<0.001). In 20 mmol/L LiCl group, the testosterone level [(7.28±0.24) μg/L] in TM3 cells was lower than that of 0 mmol/L LiCl group [(12.50±0.38) μg/L, P<0.001], the protein levels of Cyp11a1, StAR and Cyp17a1 were significantly down-regulated compared with 0 mmol/L LiCl group (all P<0.001), the activities of SOD [(2.42±0.11) U/mg], GSH-Px [(1.29±0.03) mU/mg] and MMP [(57.24±1.69)%] were lower than those of 0 mmol/L LiCl group [(3.11±0.09) U/mg, (1.54±0.01) mU/mg, (100.00±0)%, all P<0.001], the level of lipid peroxidation [(211.18±3.60)%] and the concentration of Fe 2+ [(26.44±0.94) μmol/L] were higher than those of 0 mmol/L LiCl group [(100.00±0)%, (7.12±0.29) μmol/L, all P<0.001], and the expression of ferroptosis regulatory proteins was significantly down-regulated compared with 0 mmol/L LiCl group (all P<0.001). Compared with 20 mmol/L LiCl group cells [lipid peroxidation: (194.46±3.16)%, (194.70±3.93)%; MMP: (78.74±0.52)%, (75.32±1.29)%], ferroptosis inhibitors Fer-1 and quercetin significantly decreased the level of lipid peroxidation [(181.71±3.80)%, P=0.004; (166.88±3.22)%, P<0.001], increased the level of MMP [(86.26±0.79)%, P=0.040; (81.09±1.32)%, P=0.001], and significantly up-regulated the expression of key enzymes in testosterone synthesis and ferroptosis regulatory proteins (all P<0.05). Conclusion:Quercetin may protect LiCl-induced Leydig cells injury and testosterone production dysfunction by inhibiting cell ferroptosis.

Objective:To study the reproductive toxicity of lithium chloride (LiCl) in male mice and to explore the molecular mechanism of the protective effect of quercetin on testosterone production dysfunction.Methods:Twenty-five male C57BL/6 mice aged 4-5 weeks were randomly divided into five groups according to the random number table method: control group, LiCl infected group [38.4 mg/(kg·d) LiCl+corn oil, noted as LiCl group], quercetin control group [50 mg/(kg·d) quercetin, noted as High-Quer group], low-dose quercetin combined with LiCl infection group [38.4 mg/(kg·d) LiCl+10 mg/(kg·d) quercetin, noted as Low-Quer+LiCl group] and high dose quercetin combined with LiCl infected group [38.4 mg/(kg·d) LiCl+50 mg/(kg·d) quercetin, noted as High-Quer+LiCl group]. The structure of testicular tissue, semen parameters, and the ultrastructure of Leydig cells in mice were detected by HE staining, computer-aided sperm analysis system (CASA), and transmission electron microscopy, respectively. TM3 mouse Leydig cells were treated with 0 mmol/L, 5 mmol/L, 10 mmol/L, 20 mmol/L LiCl for 24 h. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), mitochondrial membrane potential (MMP), lipid peroxidation levels, and expression levels of testosterone-related protein were measured by SOD and GSH-Px kits, TMRE probe, Image-iT TM lipid peroxidation probe, and Western blotting, respectively. Intracellular Fe 2+ concentration was detected by Fe 2+ detection kit and FerroOrange probe. The levels of testosterone, progesterone, and estradiol were measured using enzyme-linked immunosorbent assay kits. Results:In the LiCl group, the total sperm count [(36.78±1.81)×10 6], sperm concentration [(18.39±0.90)×10 6/mL], sperm motility [(25.70±3.32)%] and serum testosterone level [(7.26±0.29) μg/L] were lower than those of control group [(51.60±4.96)×10 6, P=0.002; (25.80±2.48)×10 6/mL, P=0.002; (41.47±2.83)%, P=0.001; (7.87±0.29) μg/L, P=0.013], the expression levels of Cyp11a1, StAR and Cyp17a1, Leydig cell biomarkers (3β-HSD1, 17β-HSD3) and ferroptosis regulatory proteins (GPX4, SLC7A11 and Nrf2) in testis were significantly down-regulated compared with control group (all P<0.001). LiCl also induced mitochondrial vacuoles and swelling of Leydig cells. However, low-dose quercetin intervention could significantly ameliorate the above LiCl-induced damage (total sperm count: P<0.001, sperm concentration: P<0.001, sperm motility: P=0.015, serum testosterone level: P=0.026, Cyp11a1, StAR, Cyp17a1, 3β-HSD1, 17β-HSD3, GPX4, SLC7A11, and Nrf2: all P<0.001). In 20 mmol/L LiCl group, the testosterone level [(7.28±0.24) μg/L] in TM3 cells was lower than that of 0 mmol/L LiCl group [(12.50±0.38) μg/L, P<0.001], the protein levels of Cyp11a1, StAR and Cyp17a1 were significantly down-regulated compared with 0 mmol/L LiCl group (all P<0.001), the activities of SOD [(2.42±0.11) U/mg], GSH-Px [(1.29±0.03) mU/mg] and MMP [(57.24±1.69)%] were lower than those of 0 mmol/L LiCl group [(3.11±0.09) U/mg, (1.54±0.01) mU/mg, (100.00±0)%, all P<0.001], the level of lipid peroxidation [(211.18±3.60)%] and the concentration of Fe 2+ [(26.44±0.94) μmol/L] were higher than those of 0 mmol/L LiCl group [(100.00±0)%, (7.12±0.29) μmol/L, all P<0.001], and the expression of ferroptosis regulatory proteins was significantly down-regulated compared with 0 mmol/L LiCl group (all P<0.001). Compared with 20 mmol/L LiCl group cells [lipid peroxidation: (194.46±3.16)%, (194.70±3.93)%; MMP: (78.74±0.52)%, (75.32±1.29)%], ferroptosis inhibitors Fer-1 and quercetin significantly decreased the level of lipid peroxidation [(181.71±3.80)%, P=0.004; (166.88±3.22)%, P<0.001], increased the level of MMP [(86.26±0.79)%, P=0.040; (81.09±1.32)%, P=0.001], and significantly up-regulated the expression of key enzymes in testosterone synthesis and ferroptosis regulatory proteins (all P<0.05). Conclusion:Quercetin may protect LiCl-induced Leydig cells injury and testosterone production dysfunction by inhibiting cell ferroptosis.

PI3Kγ and PI3Kδ have important regulatory roles in the immune system, and targeting these two subtypes helps to reshape the tumor microenvironment. PI3Kγ and PI3Kδ are potential targets for tumor immunotherapy. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors, resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor. Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC₅₀ values of 0.11 and 0.79 nmol·L^-1. In cell-based assays, it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC₅₀ values of 3 and 7 nmol·L^-1. In vivo, compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley (SD) rats and suppressed the tumor growth in a MC38 syngeneic mouse model. The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science, Chinese Academy of Sciences (approval number: DWLL-2000-06). In addition, no appreciable human ether-a-go-go-related gene (hERG) inhibition was observed for compound 16l even at 30 μmol·L^-1. These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD⁺), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD⁺ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.
Humans ; NAD/metabolism* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Nicotinamide Phosphoribosyltransferase/metabolism* ; Cytokines/metabolism* ; Quinones ; Oxidoreductases