Integrated molecular modeling techniques to reveal selective mechanisms of inhibitors to PI3Kδ with marketed Idelalisib.

Phosphatidylinositol-3-kinase (PI3K) is important for cell proliferation, differentiation, and apoptosis, and the diverse physiological roles of different PI3K isoforms have highlighted the significance of the development of PI3Kδ inhibitors. A large number of PI3Kδ inhibitors have been reported after the FDA approval of Idelalisib, but the clinical use of Idelalisib was limited because of its serious side effects. Therefore, great efforts have been made on the development of PI3Kδ inhibitors with higher selectivity and lower toxicity, but there is no new PI3Kδ inhibitor coming into the market so far. Even so, as the first listed PI3K inhibitor, Idelalisib could be used as an effective tool to investigate the selective inhibition mechanism of PI3Kδ. Thus, in this study, a modeling strategy integrated 3D-QSAR, pharmacophore model, and molecular dynamics simulation was employed to reveal the key chemical characteristics of Idelalisib analogs and the binding pattern between the inhibitors and PI3Kδ. First, the CoMFA model with high statistical significance was built to reveal the general structure-activity relationships. And then, a reliable pharmacophore model with a robust discrimination capability was constructed to expound the main chemical characteristics of the PI3Kδ inhibitors. Finally, molecular dynamics simulation was conducted to explore the binding modes and some key residues refer to δ-selective binding were highlighted with binding-free energy calculation. In summary, these models and results would provide some effective help for the discovery or the rational design of novel PI3Kδ inhibitors.

The effect of moving cupping on psoriasis vulgaris and its influence on PASI score: A protocol for systematic review and meta-analysis.

BACKGROUND: We aim to study the treatment of psoriasis vulgaris with moving cupping. METHODS: We will search PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, Wanfang Database, and Chinese Biomedical Literature Database of randomized controlled trials beginning from their inception to August 2020. The primary outcomes are that PASI score and clinical effective rate will be the main outcome indicators. Additional outcome is The Quality of life index score and safety assessment will be considered a secondary outcome. Two independent authors will based on the Cochrane system evaluation manual 5.1.0 version of RCT bias risk assessment tool to evaluate the risk of bias among the final included studies. And we will use the RevMan 5.3 software to analysis data. RESULTS: This study will provide an assessment of the current state of moving cupping for the psoriasis vulgaris, aiming to show the efficacy and safety of this treatment. CONCLUSION: This study will provide evidence to judge whether moving cupping is an effective therapy for psoriasis vulgaris. INPLASY REGISTRATION NUMBER: INPLASY2020120061.

Comparison of Outcomes between Fractional-Flow-Reserveand Angiography-Directed Intervention in Non-ST Elevation Acute Coronary Syndrome.

Among the sick patients suffering from non-ST segment elevation acute coronary syndrome (NSTEACS), the accuracy of fractional flow reserve (FFR)-directed percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is still ambiguous. Studies were obtained from PubMed, Embase, Wanfang Data, and Cochrane Library electronic statistics from their initiation up to April 2018, to explore the differences between the FFR-directed approach and the coronary angiography (CA)/stress perfusion scintigraphy (SPS)-directed approach in the outcomes of NSTACS patients. Odds ratio was determined for individual studies, quality assessments, heterogeneity, and publishing bias analyses. In total, there were 5 studies involving 1,366 patients (606 FFR patients and 760 CA patients). Compared with CA, the collection of the studies indicated that FFR had a lower incidence of myocardial infarction (MI) (OR, 0.61; 95% CI: 0.39-0.96; p <0.05). However, none showed important disparities in main adverse cardiovascular events (MACE, OR, 0.74; 95% CI: 0.53-1.03; p=0.07), all-cause death rate (OR, 0.83; 95% CI: 0.45-1.54; p = 0.56), and major bleeding (OR, 1.00; 95%CI: 0.25-4.03; p=1). The FFR-directed management of patients with NSTEACS had a close relationship with the serious decrease in incidence of MI without statistical significance. Future large-scale research, which is carried out at random and with a control, is needed to confirm these conclusions.

Liuwei Dihuang exhibits antidiabetic effects through inhibiting α-amylase and α-glucosidase.

OBJECTIVE: Liuwei Dihuang (LWDH) is a famous traditional herbal medicine formula in China that may regulate the balance of kidney yin yang and has been used to restore functional insufficiency of the kidney for a long time in China. METHODS: In this study, the water extract of LWDH was tested for its α-Amylase and α-Glucosidase inhibitory activities, and its anti-diabetic property in streptozotocin (STZ)-induced diabetic mice was also analyzed. RESULTS: LWDH extract inhibited α-Glucosidase and α-Amylase activities in a dose- dependent manner. Treatment of streptozotocin-induced diabetic mice with LWDH extract decreased camp, fasting blood glucose, TC, TG, LDL-c, HbA1C, Urine volume levels and Urine sugar, increased HDL-c level when compared to STZ induced diabetic mice. CONCLUSION: This study demonstrates that extract of LWDH can inhibit α-amylase and α-glucosidase activities and shows anti-diabetic effect in a mice preclinical model.

Pringle manoeuvre versus selective hepatic vascular exclusion in partial hepatectomy for tumours adjacent to the hepatocaval junction: a randomized comparative study.

OBJECTIVE: To compare the efficacy of selective hepatic vascular exclusion versus Pringle manoeuvre in partial hepatectomy for tumours adjacent to the hepatocaval junction. METHODS: A randomized comparative trial was carried out. The primary endpoint was intraoperative blood loss. The secondary endpoints were operation time, blood transfusion, postoperative liver function recovery, procedure-related morbidity and in-hospital mortality. RESULTS: 160 patients were randomized into 2 groups: the Pringle manoeuvre group (n = 80) and the selective hepatic vascular exclusion (SHVE) group (n = 80). Intraoperative blood loss and transfusion requirements were significantly less in the SHVE group. In the SHVE group, laceration of hepatic veins happened in 18 patients. Profuse intraoperative blood loss of over 2 L happened in 2 patients but no patient suffered from air embolism because the hepatic veins were controlled. In the Pringle group, the hepatic veins were lacerated in 20 patients, with profuse blood loss of over 2 L in 7 patients and air embolism in 3 patients. The rates of postoperative bleeding, reoperation, liver failure and mortality were significantly higher and the ICU stay and hospital stay were significantly longer in the Pringle group. CONCLUSIONS: SHVE was more efficacious than Pringle manoeuvre for partial hepatectomy in patients with tumours adjacent to the hepatocaval junction.

CT-guided radioactive ¹²5I seed implantation therapy of symptomatic retroperitoneal lymph node metastases.

PURPOSE: This study explored the clinical efficacy of CT-guided radioactive (125)I seed implantation in treating patients with symptomatic retroperitoneal lymph node metastases. METHODS: Twenty-five patients with pathologically confirmed malignant tumors received CT-guided radioactive (125)I seed implantation to treat metastatic lymph nodes. The diameter of the metastatic lymph nodes ranged from 1.5 to 4.5 cm. Treatment planning system (TPS) was used to reconstruct the three-dimensional image of the tumor and then calculate the corresponding quantity and distribution of (125)I seeds. RESULTS: Follow-up period for this group of patients was 2-30 months, and median time was 16 months. Symptoms of refractory pain were significantly resolved postimplantation (P < 0.05), and Karnofsky score rose dramatically (P < 0.05). Most patients reported pain relief 2-5 days after treatment. Follow-up imaging studies were performed 2 months later, which revealed CR in 7 patients, PR in 13 patients, SD in 3 patients, and PD in 2 patients. The overall effective rate (CR + PR) was 80 %. Median survival time was 25.5 months. Seven patients died of recurrent tumor; 16 patients died of multiorgan failure or other metastases. Two patients survived after 30 months follow-up. Two patients reported localized skin erythema 1 week postimplantation, which disappeared after topical treatment. CONCLUSIONS: CT-guided radioactive (125)I seed implantation, which showed good palliative pain relief with acceptable short-term effects, has proved in our study to be a new, safe, effective, and relatively uncomplicated treatment option for symptomatic retroperitoneal metastatic lymph nodes.

MicroPET-CT evaluation of interstitial brachytherapy in pancreatic carcinoma xenografts.

BACKGROUND: Interstitial brachytherapy (IBT) has been introduced as treatment for unresectable pancreatic cancers to maximize local dose and minimize irradiation of surrounding normal tissue. MicroPET-CT systems provide excellent anatomic and molecular information. PURPOSE: To use 18F-FDG micro-positron emission tomography (PET)/computed tomography (CT) to evaluate the therapeutic effect of (125)I interstitial brachytherapy on transplantation tumor of human pancreatic carcinoma in Balb/c-nu mice. MATERIAL AND METHODS: Xenograft models were created by subcutaneous injection of Swl990 human pancreatic cancer cell suspensions into the immunodeficient Balb/c-nu mice. The study was randomly divided into three groups: control group (n = 6), empty seed implant group (n = 6), and (125)I seed implant group (n = 6), respectively. Before and 1 week after treatment, 18F-FDG microPET-CT scan was performed. In-vivo cell proliferation and apoptosis were monitored by thymidine kinase 1 (TK1) immunostaining and Dutp-biotin nick end labeling (TUNEL) assay. RESULTS: Our results showed that before treatment the SUVmax and SUVmean values among three groups had no significant statistical difference. One week after treatment the SUVmax and SUVmean in (125)I seed implant group were significantly lower than before, while for the empty seed group and control group there were no significant difference compared with before treatment. Immunohistochemical analysis of tumor tissue revealed significantly less TK1 positive cells in (125)I seed implant group than in empty seed group and control group. The index of apoptosis was slightly higher in (125)I seed implant group than in empty seed group and control group as evaluated by TUNEL assay. CONCLUSION: These results suggest that 18F-FDG microPET-CT may be useful as a non-invasive imaging modality to assess early response to (125)I seed brachytherapy in a pancreatic carcinoma Xenograft.

Intraluminal radioactive stent compared with covered stent alone for the treatment of malignant esophageal stricture.

OBJECTIVE: This study was designed to compare the clinical effectiveness of intraluminal radioactive stent loaded with iodine-125 seeds implantation versus covered stent alone insertion in patients with malignant esophageal stricture. METHODS: We studied two groups of patients with malignant esophageal stricture. Group A comprised 28 patients (19 men and 9 women) who underwent intraluminal radioactive stent loaded with iodine-125 seeds implantation and were followed prospectively. Group B comprised 30 patients (18 men and 12 women) who had previously received covered stent alone insertion; these patients were evaluated retrospectively. There was no crossover between the two groups during follow-up. Informed consent was obtained from each patient, and our institutional review board approved the study. The dysphagia score, overall survival rates, complication rates, and reintervention rates were compared in the two groups. RESULTS: There were no significant differences between the two groups in terms of baseline characteristics. Stent placement was technically successful and well tolerated in all patients. The dysphagia score was improved in both groups after stent placement. The median survival was significantly longer in group A than in group B: 11 versus 4.9 months, respectively (P < 0.001). The complications of chest pain, esophageal reflux, and stent migration was more frequent in group B, but this difference did not reach statistical significance. There was no statistical difference in reintervention between two groups. CONCLUSIONS: Intraluminal radioactive stent loaded with iodine-125 seeds implantation was a feasible and practical management in treating malignant esophageal stricture and was superior to covered stent alone insertion, as measured by survival.

Prediction of calcium level in melamine-related urinary calculi with helical CT: diagnostic performance evaluation and clinical significance.

The aim of the study was to investigate the relationship between CT-attenuation and stone calcium level in melamine-related urinary calculi (MRUC). A total of 25 MRUC with known composition and calcium level were included (11 uric acid stones, 2 calcium oxalate stones and 12 mixture stones of uric acid and calcium oxalate). Of all, 18 renal stones accepted alkalization therapy except for 5 lower urinary tract stones and 2 stones of unknown position. With well-matched composition, 61 adult urinary stones were included as controls. Every stone was scanned by helical CT (80 kV/120 kV, 300 mA, pitch 0.625 mm) and the highest CT-attenuation value measured. CT-attenuation values of MRUC increased gradually from uric acid stones, mixture stones to calcium oxalate stones, but were always lower than the values of controls. Furthermore, a strong positive correlation was found between stone CT-attenuation value and stone calcium level (n = 25, r (80kV) = 0.883, p = 0.000; r (120kV) = 0.855, p = 0.000). Compared with alkalization-therapy-alone group, stone CT-attenuation values and stone calcium level in the comprehensive-therapy group were significantly greater (CT(80kV) 1,057 ± 639 vs. 172 ± 61 HU, p = 0.001; CT(120kV) 783 ± 476 vs. 162 ± 60 HU, p = 0.001; Ca 19.83 ± 7.48% vs. 1.30 ± 1.51%, p = 0.000). Fisher's exact test suggested that the stones with higher CT-attenuation values tended to resist alkalization when 400 HU served as the cutoff value (P (80kV) = 0.002, P (120kV) = 0.000). In conclusion, the study was the first to illustrate that the CT-attenuation value could reflect calcium level in MRUC and found that stones with higher CT-attenuation value were not amenable to alkalization because they probably contained greater calcium. For those patients, we believe that comprehensive therapy will be the best choice.

A prospective randomized controlled trial to compare Pringle maneuver, hemihepatic vascular inflow occlusion, and main portal vein inflow occlusion in partial hepatectomy.

BACKGROUND: blood loss during liver resection and the need for perioperative blood transfusions have negative impact on perioperative morbidity, mortality, and long-term outcomes. METHODS: a randomized controlled trial was performed on patients undergoing liver resection comparing hemihepatic vascular inflow occlusion, main portal vein inflow occlusion, and Pringle maneuver. The primary endpoints were intraoperative blood loss and postoperative liver injury. The secondary outcomes were operating time, morbidity, and mortality. RESULTS: a total of 180 patients were randomized into 3 groups according to the technique used for inflow occlusion during hepatectomy: the hemihepatic vascular inflow occlusion group (n = 60), the main portal vein inflow occlusion group (n = 60), and the Pringle maneuver group (n = 60). Only 1 patient in the hemihepatic vascular occlusion group required conversion to the Pringle maneuver because of technical difficulty. The Pringle maneuver group showed a significantly shorter operating time. There were no significant differences between the 3 groups in intraoperative blood loss and perioperative mortality. The degree of postoperative liver injury and complication rates were significantly higher in the Pringle maneuver group, resulting in a significantly longer hospital stay. CONCLUSIONS: all 3 vascular inflow occlusion techniques were safe and efficacious in reducing blood loss. Patients subjected to hemihepatic vascular inflow occlusion, or main portal vein inflow occlusion responded better than those with Pringle maneuver in terms of earlier recovery of postoperative liver function. As hemihepatic vascular inflow occlusion was technically easier than main portal vein inflow occlusion, it is recommended.

FDG-PET and other imaging modalities for the evaluation of breast cancer recurrence and metastases: a meta-analysis.

BACKGROUND AND PURPOSE: Breast carcinoma is the most common cancer in female patients with a propensity for recurrence and metastases. The accuracy of ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), scintimammography (SMM) and positron emission tomography (PET) in diagnosing the recurrent and/or breast cancer has never been systematically assessed, and present systematic review was aimed at this issue. METHODS: MEDLINE and EMBASE were searched for articles dealt with detection of recurrent and/or metastatic breast cancer by US, CT, MRI, SMM or PET whether interpreted with or without the use of CT. Histopathologic analysis and/or close clinical and imaging follow-up for at least 6 months were used as golden reference. We extracted data to calculate sensitivity, specificity, summary receiver operating characteristic curves and area under the curve and to test for heterogeneity. RESULT: In 42 included studies, US and MRI had highest pooled specificity (0.962 and 0.929, respectively); MRI and PET had highest pooled sensitivity (0.9500 and 0.9530, respectively). The AUC of US, CT, MRI, SMM and PET was 0.9251, 0.8596, 0.9718, 0.9386 and 0.9604, respectively. Results of pairwise comparison between each modality demonstrated that AUC of MRI and PET was higher than that of US or CT, p < 0.05. No statistical significance was found between MRI and PET. There was heterogeneity among studies and evidence of publication bias. CONCLUSION: In conclusion, MRI seemed to be a more useful supplement to current surveillance techniques to assess patients with suspected recurrent and/or metastatic breast cancer. If MRI shows an indeterminate or benign lesion or MRI was not applicable, FDG-PET could be performed in addition.

Clinical efficacy of CT-guided iodine-125 seed implantation therapy in patients with advanced pancreatic cancer.

OBJECTIVE: To examine the clinical efficacy of CT-guided radioactive iodine-125 (125I) seeds implantation treatment in patients with unresectable pancreatic cancer. METHODS: Thirty-one patients with inoperable pancreatic cancer were enrolled in this study. The 125I seeds were implanted into pancreatic tumor under CT guidance. In addition, 10 patients received routine gemcitabine and 5-fluorouracil chemotherapy 1 week after brachytherapy. Median diameter of the tumor was 5.8 cm. RESULTS: Follow-up period was 2 to 25 months. Symptoms of refractory pain were significantly resolved post-interventionally (P < 0.05), and Karnofsky physical score increased dramatically (P < 0.05). Tumor response which was demonstrated on repeated CT film 2 months post-treatment revealed complete response (CR) in 3 cases, partial response (PR) in 16 cases, stable disease (SD) in 9 cases, and progressive disease (PD) in 3 cases. Overall responding rate (CR+PR) was 61.3%. Median survival time for all patients was 10.31 months. Two seeds of radioactive 125I migrated to the liver in 2 patients. There were no serious complications detected during the follow-up period. CONCLUSIONS: This study suggests that CT-guided brachytherapy using 125I seeds implantation appears to be safe, effective, uncomplicated, and could produce adequate pain relief for treating unresectable pancreatic cancer.