Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective:To automatically classify hypertensive heart disease (HHD) and hypertrophic cardiomyopathy (HCM) based on mul-titask learning algorithm using native T1 mapping images.Methods:A total of 203 patients admitted to Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University from January 2017 to December 2021 were enrolled, including 53 patients with HHD, 121 patients with HCM, and 29 patients with normal control (NC). Native T1 mapping images of all enrolled patients were acquired using MRI and processed by a multi-task learning algorithm. The classification performance of each model was validated using ten-fold crossover, confusion matrix, and receiver operator characteristic (ROC) curves. The Resnet 50 model based on the original images was established as a control.Results:The ten-fold crossover validation results showed that the MTL-1 024, MTL-64, and MTL-all models showed better performance in terms of area under the curve (AUC), accuracy, sensitivity, and specificity compared to the Resnet 50 model. In the classification task, the MTL-64 model showed the best performance in terms of AUC (0.942 1), while the MTL-all model reached the highest value in terms of accuracy (0.852 2). In the segmentation task, the MTL-64 model achieved the best results with the Dice coefficient (0.879 7). The confusion matrix plot showed that the MTL model outperforms the Resnet 50 model based on the original image in terms of overall performance. The ROC graphs of all MTL models were significantly higher than the original image input Resnet 50 model.Conclusions:Multi-task learning-based native T1 mapping images are effective for automatic classification of HHD and HCM.

Objective:To investigate the protective effect of berberine hydrochloride on intestinal mucosal barrier damage in sepsis rats and its mechanism.Methods:Forty-eight male SD rats were divided into a control group (Sham group, 6 cases), a sepsis model group (LPS group, 14 cases), a berberine hydrochloride intervention group (Ber group, 14 cases), and a Notch signaling pathway inhibition group (DAPT group, 14 cases) according to random number table method. The DAPT group was intraperitoneally injected with 5 mg/kg Notch signaling pathway inhibition DAPT 2 hours before modeling. The sepsis model was established by intraperitoneal injection of 10 mg/kg lipopolysaccharide (LPS); Sham group was injected with an equal amount of saline (2 mL). The Ber group and DAPT group were treated with gavage of 50 mg/kg berberine hydrochloride 2 hours after modeling; Sham group and LPS group were treated with gavage of an equal amount of saline (2 mL). The temperature, weight, behavior and survival rate of rats were observed at 0, 6, 12 and 24 hours of modeling. After 24 hours of modeling, abdominal aortic blood was collected under anesthesia, and intestinal tissues were obtained after euthanasia. The pathological changes of ileum were observed under light microscope. The ultrastructure of ileum was observed under transmission electron microscope. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of serum diamine oxidase (DAO), intestinal fatty acid binding protein (iFABP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Real time-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the mRNA and protein expressions of tight junction proteins (Occludin and Claudin1), Notch1 and their downstream target signals in the ileum tissue.Results:After 24 hours of modeling, compared with the Sham group, the LPS group, Ber group, and DAPT group showed a decrease in weight and an increase in temperature. Among them, the LPS group showed the most significant changes, followed by the DAPT group, and the Ber group showed the least significant changes. The survival rates of the LPS group, Ber group, and DAPT group were all lower than those of the Sham group [42.9% (6/14), 57.1% (8/14), 57.1% (8/14) vs. 100% (6/6)], and six rats were taken from each group for subsequent testing. Macroscopic observation of the intestine showed that the LPS group had the most severe edema in the ileum tissue and abdominal bleeding, with significant improvement in the Ber group and followed by the DAPT group. Under the light microscope, the LPS group showed disordered arrangement of glandular tissue in the ileum mucosa, significantly reduced goblet cells, and extensive infiltration of inflammatory cells, which were significantly improved in the Ber group but less improved in the DAPT group. Under electron microscopy, the LPS group showed extensive shedding of ileal microvilli and severe damage to the tight junction complex structure of intestinal epithelial cells, which was significantly improved in the Ber group but less improved in the DAPT group. The levels of serum DAO, iFABP, TNF-α, IL-6 in the LPS group were significantly higher than those in the Sham group, while the above indicators in the Ber group were significantly lower than those in the LPS group [DAO (μg/L): 4.94±0.44 vs. 6.53±0.49, iFABP (ng/L): 709.67±176.97 vs. 1 417.71±431.44, TNF-α (ng/L): 74.70±8.15 vs. 110.36±3.51, IL-6 (ng/L): 77.34±9.80 vs. 101.65±6.92, all P < 0.01], while the above indicators in the DAPT group were significantly higher than those in the Ber group. The results of RT-PCR and Western blotting showed that the mRNA and protein expressions of Occludin, Claudin1, Notch1, and Hes1 in the ileum tissue of LPS group rats were decreased compared to the Sham group, which were significantly increased in the Ber group compared with the LPS group [mRNA expression: Occludin mRNA (2 -ΔΔCt): 1.61±0.74 vs. 0.30±0.12, Claudin1 mRNA (2 -ΔΔCt): 1.97±0.37 vs. 0.58±0.14, Notch1 mRNA (2 -ΔΔCt): 1.29±0.29 vs. 0.36±0.10, Hes1 mRNA (2 -ΔΔCt): 1.22±0.39 vs. 0.27±0.04; protein expression: Occludin/GAPDH: 1.17±0.14 vs. 0.74±0.04, Claudin1/GAPDH: 1.14±0.06 vs. 0.58±0.10, Notch1/GAPDH: 0.87±0.11 vs. 0.56±0.09, Hes1/GAPDH: 1.02±0.13 vs. 0.62±0.01; all P < 0.05], while those in the DAPT group were significantly lower than those in the Ber group. Conclusion:Early use of berberine hydrochloride can significantly improve intestinal mucosal barrier damage in sepsis rats, and its mechanism may be related to inhibiting inflammatory response and regulating the expression of intestinal mechanical barrier tight junction protein through Notch1 signal.

Objective:To observe the efficacy and safety of Tofacitinib in treating elderly rheumatoid arthritis(RA), in order to provide clinical evidence.Methods:In the randomized control trial, a total of 90 elderly RA patients admitted to the Department of Rheumatology of the First Affiliated Hospital of Soochow University from January 2019 to January 2021 were selected and divided into Methotrexate group(MTX group, MTX 10mg, qw, n=45)and Tofacitinib group(TOF group, oral 5mg, bid, n=45). The efficacy and safety of the two groups were evaluated at week 12.The primary endpoint was the proportion of patients meeting the American College of Rheumatology 50%(ACR50)improvement response criteria at week 12.Secondary endpoints included ACR20/70 improvement response, proportion of patients who met treat-to-target(T2T)criteria, including Disease Activity Score in 28 joints using erythrocyte sedimentation rate(DAS28-ESR), Disease Activity Score in 28 joints using C-reactive protein level(DAS28-CRP), clinical disease activity index(CDAI), and simplified disease activity index(SDAI), and patient-reported outcomes(PROs)which included changes compared to baseline in pain visual analog scale(VAS)and Health Assessment Questionnaire Disability Index(HAQ-DI)score, at week 12.Safety outcomes including drug-related adverse events, serious adverse events, dropping out due to adverse events, and deaths were assessed throughout.Results:Five patients in each group withdrew from the trial due to adverse events, and the number of patients who finally completed the observation was 40 in each group.At week 12, the ACR50 response rate was higher in TOF group than in MTX group[35%(14/40) vs.12.5%(5/40), χ2=5.591, P=0.018)], achieving the primary endpoint.When comparing TOF vs.MTX group, the ACR20 response rate[55%(22/40) vs.25%(10/40), χ2=7.500, P=0.006]and ACR70 response rate[25%(10/40) vs.7.5%(3/40), χ2=4.501, P=0.034], and proportions of indexes of disease remission including DAS28-ESR<2.6[25%(11/40) vs.7.5%(3/40), χ2=4.501, P=0.034], or DAS28-CRP<2.6[27.5%(11/40) vs.7.5%(3/40), χ2=5.541, P=0.019], or CDAI≤2.8[30%(12/40) vs.10%(4/40), χ2=5.000, P=0.025], or SDAI≤3.3[27.5%(11/40) vs.7.5%(3/40), χ2=5.541, P=0.019], and the proportions of patients with low disease activity including DAS28-ESR≤3.2[32.5%(14/40) vs.12.5%(5/40), χ2=5.591, P=0.018], or DAS28-CRP≤3.2[32.5%(14/40) vs.12.5%(5/40), χ2=5.591, P=0.018], or CDAI≤10[37.5%(15/40) vs.17.5%(7/40), χ2=4.013, P=0.045], or SDAI≤11[37.5%(15/40) vs.15%(6/40), χ2=5.230, P=0.022], as well as changes compared to baseline data in pain VAS[(26.51±8.32)scores vs.(14.16±4.39)scores, t=8.371, P<0.001]and in HAQ-DI score(0.65±0.24 vs.0.32±0.06, t=9.387, P<0.001)were all better in the TOF group than in the MTX group at week 12.During the 12-week observation period, the number of patients with infection and hyperlipidemia was higher in TOF group than in MTX group, while the number of patients with abnormal blood cell count and liver function was lower than that in MTX group, but the differences were not statistically significant(all P<0.05). Conclusions:Tofacitinib has good efficacy and safety in the elderly RA.In patients over 70 years of age who are at high risk of infection, tofacitinib should be used with caution.

Objective: : The surgical management of trigeminal neuralgia (TN) caused by petrous apex meningioma (PAM) is still a challenge because of the lesion’s deep location and the surrounding complex structures. The authors describe the intradural anterior transpetrosal approach (ATPA) and its effect on the treatment of TN secondary to PAM. Methods: : A retrospective analysis of 15 patients with TN secondary to PAM who underwent surgery via the intradural ATPA was conducted. The key techniques, which included drilling off the petrosal apex (PA) and opening the upper wall of Meckel’s cave (MC), are described in detail. Results: : Total removal of the tumor and complete pain relief (Barrow Neurological Institute I) were achieved in all 15 patients without significant morbidity. Five patients developed new facial numbness postoperatively, which disappeared within three months after surgery. The postoperative magnetic resonance imaging showed temporal lobe swelling in three patients, but no clinical symptoms. One patient had cerebrospinal fluid leakage and was managed with bed rest and temporary lumbar drainage. One patient had an intracranial infection and was treated with antibiotics. By the last follow up, no patients had pain relapse or/and tumor recurrence. It is worth noting that the vascular compression at the root of the trigeminal nerve was found in one patient during the operation. Conclusion : Our experience suggests that drilling off the PA and opening the upper wall of the MC are key elements for a good outcome of the treatment of TN secondary to PAM. The intradural ATPA has the advantages for both tumor resection and pain relief.

ObjectiveTo investigate the abnormal changes of gray matter structure covariant network in post-stroke aphasia (PSA) patients. MethodsFrom June, 2019 to March, 2022, 15 PSA patients (patient group) from Dongzhimen Hospital, Beijing University of Chinese Medicine and Beijing Bo'ai Hospital were recruited, as well as 15 healthy subjects (control group). Their brain structure magnetic resonance imaging data were collected. The brain covariant network was constructed based on gray matter volume correlation, and graph theory analysis method was used to evaluate the global and node network level topology properties of structural covariant network. The differences of gray matter covariant network properties between patients and controls were compared. ResultsThere was no significant difference in the global network level topology properties between two groups (P > 0.05). At the nodal level, compared with the control group, the betweenness decreased in the right middle frontal gyrus, right posterior cingulate gyrus, right amygdala, left middle occipital gyrus, and increased in the right inferior frontal gyrus and the right suboccipital gyrus of the insula operculum (P < 0.05); the node degree decreased in the left superior frontal gyrus, left anterior cingulate and paracingulate gyrus, left hippocampus and left amygdala, while it increased in the right inferior frontal gyrus, left supplementary motor area, right superior occipital gyrus, right inferior occipital gyrus, and right lentiform pallidus (P < 0.05); the node efficiency decreased in the left anterior cingulate and paracingulate gyrus, left hippocampus, left amygdala, left temporal pole: superior temporal gyrus, and increased in the inferior frontal gyrus of right insula, left supplementary motor area and right suboccipital gyrus (P < 0.05). ConclusionThe abnormal reduction of node network properties in some brain regions in the left hemisphere of PSA patients may be a characteristic structural covariation pattern, and there may be some compensation in the right hemisphere of the structural network in some brain regions.

Objective:To examine the characteristics of blood lipid profile and the correlation with clinic-pathological features of pancreatic cancer patients.Methods:The clinical and pathological data of 265 pancreatic cancer patients who received radical surgical treatment at Department of General Surgery,Qilu Hospital,Shandong University from January 2013 to September 2020 were collected and analyzed retrospectively. Among the 265 pancreatic cancer patients,there were 170 males and 95 females,with age of (61.0±9.6)years(range:28 to 86 years). General information,lipid indicators and clinic-pathological information were collected from electronic medical record system,and follow-up information gained by telephone. According to level of serum lipid in pancreatic cancer patients,265 patients were divided into dyslipidemia group( n=115) and normal lipid group( n=150). Pearson χ 2,Student′s t tests, variance analysis or univariate Logistic regression was used to analyze the correlation between dyslipidemia and clinico-pathological characteristics of pancreatic cancer,respectively. Kaplan-Meier survival curve was used to assessed the influence of dyslipidemia on prognosis of pancreatic cancer patients. Results:In 265 pancreatic cancer patients,115(43.4%)of them had dyslipidemias,and the most common form was increase of triglyceride(TG)(72.2%). In pancreatic cancer with dyslipidemias group,patients with body mass index ≥25 kg/m 2 had higher proportion than normal lipid group(36.1%(26/72) vs. 21.2%(21/99),χ2=4.643, P=0.031); The proportion of carcinoma located at head of pancreas(83.5%(96/115) vs. 40.7%(61/150),χ2=49.412, P<0.01), staging of T1/T2(79.1%(91/115) vs. 60.7%(91/150),χ2=10.316, P<0.01) and lymphatic metastasis(36.5%(42/115) vs. 22.7%(34/150),χ2=6.007, P<0.01) were higher. In patients of pancreatic cancer, dyslipidemias were closely associated with tumor location( OR=10.529, P<0.01)and body mass index( OR=3.671, P=0.008). Serum lipid profile results showed that TG,total cholesterol and high-density lipoprotein(HDL) disorders were associated with tumor location( P<0.05). TG disorder had association with body mass index( P<0.05), and HDL disorder had association with tumor stage( P<0.05). Moreover, the result of survival analysis showed that dyslipidemia was not a factor to impact the prognosis of pancreatic cancer patients underwent surgery( P>0.05). Conclusions:In pancreatic cancer patients,TG disorder was the most common type of dyslipidemia. Dyslipidemia has closely association with clinicopathologic features,including tumor location,body mass index,tumor stage. However,dyslipidemia had little effect on prognosis of pancreatic cancer patients.

Objective:To examine the characteristics of blood lipid profile and the correlation with clinic-pathological features of pancreatic cancer patients.Methods:The clinical and pathological data of 265 pancreatic cancer patients who received radical surgical treatment at Department of General Surgery,Qilu Hospital,Shandong University from January 2013 to September 2020 were collected and analyzed retrospectively. Among the 265 pancreatic cancer patients,there were 170 males and 95 females,with age of (61.0±9.6)years(range:28 to 86 years). General information,lipid indicators and clinic-pathological information were collected from electronic medical record system,and follow-up information gained by telephone. According to level of serum lipid in pancreatic cancer patients,265 patients were divided into dyslipidemia group( n=115) and normal lipid group( n=150). Pearson χ 2,Student′s t tests, variance analysis or univariate Logistic regression was used to analyze the correlation between dyslipidemia and clinico-pathological characteristics of pancreatic cancer,respectively. Kaplan-Meier survival curve was used to assessed the influence of dyslipidemia on prognosis of pancreatic cancer patients. Results:In 265 pancreatic cancer patients,115(43.4%)of them had dyslipidemias,and the most common form was increase of triglyceride(TG)(72.2%). In pancreatic cancer with dyslipidemias group,patients with body mass index ≥25 kg/m 2 had higher proportion than normal lipid group(36.1%(26/72) vs. 21.2%(21/99),χ2=4.643, P=0.031); The proportion of carcinoma located at head of pancreas(83.5%(96/115) vs. 40.7%(61/150),χ2=49.412, P<0.01), staging of T1/T2(79.1%(91/115) vs. 60.7%(91/150),χ2=10.316, P<0.01) and lymphatic metastasis(36.5%(42/115) vs. 22.7%(34/150),χ2=6.007, P<0.01) were higher. In patients of pancreatic cancer, dyslipidemias were closely associated with tumor location( OR=10.529, P<0.01)and body mass index( OR=3.671, P=0.008). Serum lipid profile results showed that TG,total cholesterol and high-density lipoprotein(HDL) disorders were associated with tumor location( P<0.05). TG disorder had association with body mass index( P<0.05), and HDL disorder had association with tumor stage( P<0.05). Moreover, the result of survival analysis showed that dyslipidemia was not a factor to impact the prognosis of pancreatic cancer patients underwent surgery( P>0.05). Conclusions:In pancreatic cancer patients,TG disorder was the most common type of dyslipidemia. Dyslipidemia has closely association with clinicopathologic features,including tumor location,body mass index,tumor stage. However,dyslipidemia had little effect on prognosis of pancreatic cancer patients.