Pancreatic cancer is a kind of highly malignant tumor with a low survival rate and poor prognosis. The effectiveness of gemcitabine as a first-line chemotherapy drug is limited; however, it can activate dendritic cells and improve antigen presentation which increase the sensitivity of tumor cell to immunotherapy. Although immunotherapy has made some advancements in cancer treatment, the therapeutic benefit of programmed cell death receptor 1/programmed death receptor-ligand 1 (PD-1/PD-L1) blockade therapy remains relatively low. The chemokine C-X-C chemokine ligand 12 (CXCL12) contributes to an immunosuppressive tumor microenvironment by recruiting immunosuppressive cells. The receptor C-X-C motif chemokine receptor 4 (CXCR4), highly expressed in various tumors including pancreatic cancer, plays a crucial role in tumor development and progression. In this study, the anti-tumor immune response of human peripheral blood mononuclear cell (hPBMC) was enhanced using the combination of BsNb PX4 (anti-PD-L1&CXCR4 bispecific nanobody) and gemcitabine. In a co-culture system of gemcitabine-pretreated hPBMCs with tumor cells, the BsNb PX4 synergized gemcitabine to improve the cytotoxic activity of hPBMCs against tumor cells. Flow cytometry analysis confirmed increased ratio of CD8⁺ to CD4⁺ T cells in combination treatment. In NOD/SCID mice bearing pancreatic cancer, the combination treatment exhibited more infiltration of CD8⁺ T cells into tumor tissues, contributing to an effective anti-tumor response. This study presents potential new therapies for the treatment of pancreatic cancer. Ethical approval was obtained for collection of hPBMC samples from the Local Ethics Committee of Shanghai Jiao Tong University. All animal experiments were approved by the Animal Ethic Committee of Shanghai Jiao Tong University (authorizing number: A2024246).

Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.

Sesquiterpenes are natural terpenoids with 15 carbon atoms in the basic skeleton, which mainly exist in plant volatile oil and have important physiological and medicinal value. Cytochrome P450 (CYP450) is a kind of monooxygenase encoded by supergene family, which is one of the largest gene families in plants. It is involved in the synthesis and metabolism of terpenoids, alkaloids and other secondary metabolites. In the process of terpene biosynthesis, CYP450 participates in the post-modification stage of terpenes by introducing functional groups such as hydroxyl, carboxyl and carbonyl, which plays an important role in enriching the diversity of terpenes. The CYP450 enzymes involved in sesquiterpene synthesis and their substrate catalytic specificity mechanisms have been partially investigated. In this paper, the biosynthetic pathway of plant sesquiterpenes, the structure and classification of CYP450 enzymes were briefly introduced, and the CYP450 enzymes involved in sesquiterpene biosynthesis were summarized, in order to provide a reference for intensive study of the role of CYP450 enzymes in the synthesis of sesquiterpenoids.

Twelve compounds were isolated from the ethyl acetate fraction of the 80% aqueous ethanol extract of the roots and stems of Dalbergia rimosa Roxb. by silica gel, MCI, Sephadex LH-20 column chromatography, and semi-preparative HPLC. Their structures were identified by spectral analysis such as UV, IR, MS, 1D/2D NMR and by comparison with literature information as dalbergiquinol A (1), dalbergiquinol B (2), R-(-)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol (3), neokhriol A (4), mucronulatol (5), (3R)-7,2′,3′-trihydroxy-4′-methoxy-isoflavane (6), isomucronulatol (7), (3S)-violanone (8), 3′-O-methylviolanone (9), eryvarin M (10), (±)-α,3,4,2′,4′-pentahydroxydihydrochalcone (11) and (-)-butin (12). Compound 1 and 2 are new compounds, and compounds 3-12 were isolated from this plant for the first time. Compounds 1, 2, 4, 6, 8, 11, 12 showed good scavenging effect on DPPH free radical.

Animals ; Macaca mulatta ; Optic Disk ; Glaucoma ; Craniocerebral Trauma ; Intraocular Pressure ; Low Tension Glaucoma

Objective To explore the influence of different hardness surfaces on gait coordination in patients with functional ankle instability(FAI). Methods Qualisys Infrared Optical Motion Capture System was used to test the coordination and variability of 15 FAI patients on the right side at Nanjing Normal University from May to July,2023.The gait cycle data were collect-ed and intercepted,and coupling angle(CA)and standard deviation of coupling angle(SDCA)were calculated by Matlab to compare the differences on different hardness surfaces. Results On coronal plane,CA of hip-ankle joint was higher on the hard surface than on the soft surface during middle stage of support and early stage of swing,and lower on its rest stages and the gait stages of hip-knee joint and knee-ankle joint than on the soft surface(P<0.01).On sagittal plane,CA of hip-ankle joint and knee-ankle joint was smaller on the hard surface than on the soft surface during middle and late stages of support,and larger than on the soft surface during their rest stages,and the gait stages of hip-knee joint(P<0.01).On horizontal plane,CA of hip-knee joint was lower on the hard surface than on the soft surface during the late stage of support,and higher than on the soft surface during its early stage of swing and bearing stage of hip-ankle joint(P<0.01).Compared with the hard surface,SDCA was smaller on the soft surface than on the hard surface only in the hip-ankle on the sagittal plane and during bearing stage of hip-knee joint,and was greater than on the hard surface for the rest(P<0.01). Conclusion FAI patients showed more distal dominance on soft surface than on hard surface during most gait cycle on 3D plane,i.e.,advantage of ankle varus and plantar flexion increased,and advantage of hip joint decreased;the coordination variability was generally higher on soft surface than on hard surface.These findings suggested that FAI patients may increase the risk of recurrent lateral ankle sprain walking on soft surface.

Objective:To investigate the efficacy of arthroscopic superior capsular reconstruction using composite autologous patch graft combined with tenodesis of the long head of the biceps tendon in the treatment of irreparable massive rotator cuff tears (IMRCT).Methods:A retrospective case series study was performed on 11 IMRCT patients who were admitted to Affiliated Fuyang Hospital of Bengbu Medical University (Fuyang People′s Hospital) from May 2020 to June 2022, including 7 males and 4 females, aged 54-74 years [(62.6±7.3)years]. All the patients were treated with arthroscopic superior capsular reconstruction using composite patch graft combined with tenodesis of the long head of the biceps tendon. The Visual Analogue Scale (VAS), Acromiohumeral Distance (AHD), Constant-Murley score and University of California Los Angeles (UCLA) score and active range of motion of the shoulder joint before, at 6 months after surgery and at the last follow-up were compared. At the last follow-up, the integrity of reconstructed superior capsule and the long head of the biceps tendon was evaluated using MRI of the shoulder joint. Postoperative complications were observed.Results:All the patients were followed up for 13-39 months [16(13, 36)months]. The VAS score, AHD, Constant-Murley score, and UCLA score were 2(2, 3)points, (9.1±1.1)mm, (56.1±5.4)points, and (19.7±2.8)points respectively at 6 months after surgery, which were all significantly improved from those before surgery [6(5, 7)points, (5.1±1.2)mm, (37.9±2.2)points, and (11.8±1.2)points] ( P<0.05). The VAS score, AHD, Constant-Murley score, and UCLA score were 0(0, 1)points, (8.4±0.9)mm, (83.6±3.8)points, and (28.2±2.3)points respectively at the last follow-up, which were all significantly improved from those before surgery ( P<0.05). At the last follow-up, the VAS score or AHD were not significantly improved from those at 6 months after surgery ( P>0.05); Constant-Murley score and UCLA score were both significantly improved from those at 6 months after surgery ( P<0.05). At 6 months after surgery, shoulder active ranges of motion in forward flexion, abduction and external rotation were (134.6±13.5)°, (124.6±18.6)° and 45(40, 50)° respectively, which were all significantly improved compared with those before surgery [(63.2±36.1)°, (65.0±23.1)°, and [30(20, 40)°] ( P<0.05). At the last follow-up, shoulder active ranges of motion in forward flexion, abduction and external rotation were (144.1±12.6)°, (139.6±15.4)° and 60(45, 65)° respectively, which were all significantly improved compared with those before surgery ( P<0.05). There were no significant differences in active range of motion of the shoulder in forward flexion, abduction and external rotation between 6 months after surgery and the last follow-up ( P>0.05). At the last follow-up, MRI revealed integrity of the reconstructed superior joint capsule and the long head of the biceps tendon in 10 patients. One patient developed resorption of the greater tuberosity and 1 showed a partial tear of the supraspinatus tendon at 1 year after surgery. Conclusion:Arthroscopic superior capsular reconstruction using composite autologous patch graft combined with tenodesis of the long head of the biceps tendon can relieve shoulder pain, decrease upward displacement of the humerus head, improve the function and range of motion of the shoulder joint, and reduce complications in the treatment of IMRCT.

Objective:To investigate the clinical features and prognosis of male with anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody.Methods:The clinical data of 246 patients with DM and anti-MDA5 autoantibodies hospitalized by Jiangsu Myositis Cooperation Group from 2017 to 2020 were collected and retrospectively analyzed. Chi-square test was performed to compared between counting data groups; Quantitative data were expressed by M ( Q1, Q3), and rank sum test was used for comparison between groups; Single factor survival analysis was performed by Kaplan-Meier method and Log rank test; Cox regression analysis were used for multivariate survival analysis. Results:①The male group had a higher proportion of rash at the sun exposure area [67.1%(47/70) vs 52.8%(93/176), χ2=4.18, P=0.041] and V-sign [50.0%(35/70) vs 30.7%(54/176), χ2=8.09, P=0.004] than the female group. The male group had higher levels of creatine kinase [112(18, 981)U/L vs 57 (13.6, 1 433)U/L, Z=-3.50, P<0.001] and ferritin [1 500 (166, 32 716)ng/ml vs 569 (18, 14 839)ng/ml, Z=-5.85, P<0.001] than the female group. The proportion of ILD [40.0%(28/70) vs 59.7%(105/176), χ2=7.82, P=0.020] patients and the red blood cell sedimentation rate[31.0(4.0, 101.5)mm/1 h vs 43.4(5.0, 126.5)mm/1 h, Z=-2.22, P=0.026] in the male group was lower than that of the female group, but the proportion of rapidly progressive interstitial lung disease (PR-ILD) [47.1%(33/70) vs 31.3%(55/176), χ2=5.51, P=0.019] was higher than that of the female group. ②In male patients with positive anti-MDA5 antibodies,the death group had a shorter course of disease[1.0(1.0, 3.0) month vs 2.5(0.5,84) month, Z=-3.07, P=0.002], the incidence of arthritis [16.7%(4/24) vs 42.2%(19/45), χ2=4.60, P=0.032] were low than those in survival group,while aspartate aminotransferase (AST)[64(22.1, 565)U/L vs 51(14,601)U/L, Z=-2.42, P=0.016], lactate dehydrogenase (LDH) [485(24,1 464)U/L vs 352(170, 1 213)U/L, Z=-3.38, P=0.001], C-reactive protein (CRP) [11.6(2.9, 61.7) mg/L vs 4.95(0.6, 86.4) mg/L, Z=-1.96, P=0.050], and ferritin levels [2 000(681, 7 676) vs 1 125 (166, 32 716)ng/ml, Z=-3.18, P=0.001] were higher than those in the survival group, and RP-ILD [95.8%(23/24) vs 22.2%(10/45), χ2=33.99, P<0.001] occurred at a significantly higher rate. ③Cox regression analysis indicated that the course of disease LDH level, and RP-ILD were related factors for the prognosis of male anti-MDA5 antibodies [ HR (95% CI)=0.203(0.077, 0.534), P=0.001; HR (95% CI)=1.002(1.001, 1.004), P=0.003; HR (95% CI)=95.674 (10.872, 841.904), P<0.001]. Conclusion:The clinical manifestations of male anti-MDA5 antibody-positive patients are different from those of female. The incidence of ILD is low, but the proportion of PR-ILD is high. The course of disease, serum LDH level, and RP-ILD are prognostic factors of male anti-MDA5 antibody-positive patients.

This study aimed to explore the value of magnetic resonance imaging (MRI) T 2 mapping in the assessment of dermatomyositis (DM) and polymyositis (PM). Thirty-three confirmed cases (myosin group) and eight healthy volunteers (healthy control group) at the Department of Rheumatology and Immunology, the First Affiliated Hospital of Kunming Medical University, from October 2016 to December 2017, were collected and analyzed. Multiple parameters of the myosin group were quantified, including creatine kinase (CK), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement C3, and complement C4. Disease status was evaluated using a panel of tools: myositis disease activity assessment tool-muscle (MDAAT-muscle), myositis disease activity assessment tool-whole (MDAAT-all), health assessment questionnaire (HAQ), medical outcomes study health survey short form-36 item (SF-36), hand muscle strength test (MMT-8) score, and MRI T 2 mapping of muscle (22 muscles in the pelvis and thighs) T 2 values. The results showed that in the myositis group, the measurements for CK, ESR, CRP, complement C3, and complement C4 were 457.2 (165.6, 1 229.2) IU/L, 20 (10, 42) mm/1h, 3.25 (2.38, 10.07) mg/L, 0.90 (0.83, 1.06) g/L, and 0.18 (0.14, 0.23) g/L, respectively. The scores for MMT-8, MDAAT-muscle, MDAAT-all, HAQ, and SF-36 were 57.12±16.23, 5.34 (4.00, 6.00), 34.63±12.62, 1.55 (0.66, 2.59), and 44.66±7.98, respectively. T 2 values were significantly higher in all 22 muscles of the pelvis and thighs of patients with DM or PM compared with the healthy controls [(54.99±11.60)ms vs. (36.62±1.66)ms, P<0.001], with the most severe lesions in the satrorius, iliopsoas, piriformis, gluteus minimus, and gluteus medius muscles. The total muscle T 2 value in the myositis group was positively correlated with CK, MDAAT-muscle, MDAAT-all, and HAQ ( r=0.461, 0.506, 0.347, and 0.510, respectively, all P<0.05). There was a negative correlation between complement C4, SF-36, and MMT-8 scores ( r=-0.424, -0.549, and -0.686, respectively, all P<0.05). Collectively, the findings from this study suggest that MRI T 2 mapping can objectively reflect the disease status of DM and PM.

Hyperkalemia is one of the common ion metabolism disorders in clinical practice. Hyperkalemia is defined as serum potassium higher than 5.0 mmol/L according to the guidelines at home and abroad. Acute severe hyperkalemia can cause serious consequences, such as flaccid paralysis, fatal arrhythmia, and even cardiac arrest. The use of renin-angiotensin- aldosterone system inhibitors, β-blockers and diuretics, low-sodium and high-potassium diets, and the presence of related comorbidities increase the occurrence of hyperkalemia. Hyperkalemia risk exist in all clinical departments, but there is a lack of a standardization in the management of multi- department cooperation in hospital. Therefore, a number of domestic nephrology and cardiology department experts have discussed a management model for multi-department cooperation in hyperkalemia, formulating the management standard on hospital evaluation, early warning, diagnosis and treatment, and process. This can promote each department to more effectively participate in nosocomial hyperkalemia diagnosis and treatment, as well as the long-term management of chronic hyperkalemia, improving the quality of hyperkalemia management in hospital.