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Purpose: This study evaluates the efficacy and patient satisfaction of intravitreal conbercept (IVC) as adjunctive treatment before panretinal photocoagulation (PRP) for Chinese proliferative diabetic retinopathy (PDR) with or without clinically significant macular edema. Methods: We enrolled 94 patients and categorized them into 2 groups: eyes that received PRP with single-dose IVC (0.5 mg/0.05 mL) 1 week before PRP (Plus group) or PRP only (PRP group). We measured the central macular thickness (CMT) by optical coherence tomography and best-corrected visual acuity. Satisfaction of PRP after 3 months was evaluated by a satisfaction questionnaire. Results: Single-dose IVC 1 week before PRP significantly increased the PRP completion rate and satisfaction of treatment after 3 months in PDR patients. The average CMT significantly decreased in the Plus group but increased in the PRP group. No average visual changes were detected in the Plus group, but significant average visual loss was detected in the PPR group. The most important factors that determined satisfaction were the PRP completion rate in the short term and better vision gain after PRP. Conclusions: IVC is a promising adjunctive treatment to PRP in the treatment of PDR. Single-dose IVC 1 week before PRP was suggested to improve PRP completion rate and patient satisfaction in the short term. [ABSTRACT FROM AUTHOR]

Abstract Background Intramural hematomas (IMHs) are reported to dynamically evolve into different clinical outcomes ranging from regression to aortic rupture, but no practice guidelines are available in China. Objective To determine the evolution of IMHs after long-term follow-up and to identify the predictive factors of IMH outcomes in the Chinese population. Methods A total of 123 IMH patients with clinical and imaging follow-up data were retrospectively studied. The primary endpoints were aortic disease-related death, aortic dissection, penetrating aortic ulcer (PAU), thickening of the aortic hematoma and aortic complications requiring surgical or endovascular treatment. Results All 123 IMH patients were monitored clinically. The follow-up duration ranged from 1.4 to 107 months (median, 20 months). Thirty-nine patients had type A IMH, and 84 had type B. The multivariate analysis showed that a baseline MAD ≥ 44.75 mm (2.9% vs 61.4%, P < 0.001) and acute PAUs (2.9% vs 34.1%, P = 0.008) were independent predictors of aorta-related events. Conclusions Medication and short-term imaging are recommended for Chinese IMH patients with a hematoma thickness < 10.45 mm and a baseline MAD < 44.75 mm. Rigorous medical observation should also be performed during the acute phase of IMH. Graphical abstract Figure legend IMH evolution to AD over a 12-day period. A, C, E, and G, in the acute phase, MDCT shows a high signal intensity suggestive of IMH. B, Twelve days later, MDCT reveals a typical dissection; D, at 8 days of follow-up, MDCT shows an atherosclerotic ulcerated plaque (arrow) with IMH in the upper part of the descending aorta; F, at 2 months of follow-up, a CT scan shows that the intima has almost completely disappeared; H, 15 days later, the intima became enlarged. Unlabelled Image Highlights • Most adverse aorta-related events occur within 30 days in Chinese aortic intramural hematomas patients • The cutoff values for predicting aorta-related events are a hematoma thickness of 10.45 mm and a baseline maximal aorta diameter of 44.75 mm • An acute penetrating aortic ulcer and a maximal aorta diameter ≥44.75 mm in aortic intramural hematoma patients predict a poor prognosis [ABSTRACT FROM AUTHOR]

In lamivudine-refractory chronic hepatitis B (CHB) patients, discontinuation of lamivudine therapy may lead to loss of lamivudine-resistant hepatitis B virus (HBV) and reappearance of wide-type HBV as dominant strains, yet the underlying mechanism remains unclear. In this study, we cloned wide-type and lamivudine-resistant HBV genomes from the sera of a CHB patient who stopped lamivudine therapy after occurrence of resistant virus and determined the biologic properties of the two isolates in hepatoma cell lines. Sequencing reverse transcriptase region of HBV revealed that the patient developed lamivudine-resistant mutations (rtV173 L, rtL180 M, and rtM204 V) 36 months after the start of lamivudine therapy, and lamivudine-resistant mutants reversed to wild-type after the treatment was stopped for 8 months. Our data showed that the wild-type and mutant isolates had similar transcriptional and translational activity. However, comparison of intracellular and released HBV DNA levels showed that replication efficiency of the mutant virus was approximately 50% of wild-type HBV, while the infectivity of released virus was not affected by the lamivudine-resistant mutations. In conclusion, the reversion of lamivudine-resistant mutants to wild-type HBV after discontinuation of lamivudine in hepatitis B patients may be attributed to better replication fitness of wild-type HBV. [ABSTRACT FROM AUTHOR]

Melatonin-loaded liposomes (MLL) were successfully prepared using rapid expansion of supercritical solution technology. The effects of supercritical pressure on encapsulation efficiency (EE) and average particle size were then analysed. Meanwhile, temperature, formation time and ethanol concentration in the products were studied and optimised based on the response surface methodology (RSM). Anin vitrosimulated digestion model was also established to evaluate the release performance of MLL. The results showed that 140 bar was the best pressure for maximising the EE value using RSM optimisation, reaching up to 82.2%. MLL characterisations were performed using analytic techniques including infrared spectroscopy, transmission electron microscopy, a laser scattering particle size analyser and gas chromatograph-mass spectrometer. The size distribution was uniform, with an average diameter of 66 nm. Stability tests proved that MLL maintained good preservation duration, and residual solvent experiments indicated that only 1.03% (mass ratio) of ethanol remained in the products. Simulated release experiments indicated the slow release feature in early digestive stages and more thorough characteristics in later stages of simulated digestion. [ABSTRACT FROM PUBLISHER]

The objective of this study was to evaluate the preventive effects of oral administration of lansoprazole on acute exacerbation of chronic obstructive pulmonary disease ( COPD). Patients with COPD in groups C and D in the stable phase were stratified into a group with neither gastroesophageal reflux nor lansoprazole therapy (group A) and a group subjected to oral lansoprazole therapy (group B1) and a group not subjected to oral lansoprazole therapy (group B2). The frequency scale for the symptoms of gastroesophageal reflux disease ( FSSG) questionnaire, COPD assessment test (CAT) questionnaire, pulmonary function test and the 6-minute walk test were applied; in addition, arterial blood gas, white blood cell ( WBC), hs- CRP, liver function and the levels of IL-1β, IL-6, IL-8, TNF-α and GM- CSF in sputum were monitored during follow-up. In the 12-month follow-up period, the frequency of exacerbation in group B2 was statistically higher than that in groups A and B1 ( P < 0.05). After a 3-month follow-up, the score of groups A and B1 in the FSSG questionnaire was significantly lower than that of group B2 ( P < 0.05). After the 1-year follow-up, the CAT score, FEV1, 6-min walk test, the total number of WBC, hs- CRP, alanine aminotransferase, aspartate aminotransferase, pH of the arterial blood, PaO2, Pa CO2 and the levels of IL-1β, IL-6, IL-8, TNF-α and GM- CSF in the sputum were statistically different in group B2 compared with groups A and B1 ( P < 0.05). Oral lansoprazole therapy decreased the frequency of acute exacerbation of COPD by alleviating gastroesophageal reflux and lowering the levels of IL-1β, IL-6, IL-8, TNF-α and GM- CSF in the sputum. [ABSTRACT FROM AUTHOR]

Background To explore the efficacy and safety of crizotinib versus platinum-based double agent chemotherapy as the first-line treatment in patients with advanced anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma. Method We retrospectively analyzed data from 19 patients with advanced ALK-positive lung adenocarcinoma who had received no previous systemic treatment for advanced disease. Seven patients received oral crizotinib at a dose of 250 mg twice daily; 12 patients were administered standard chemotherapy (pemetrexed, paclitaxel, vinorelbine or gemcitabine plus either cisplatin or carboplatin) every three weeks for up to six cycles. The primary endpoint was overall response rate ( ORR), disease control rate ( DCR), and safety. Results The ORR was significantly higher with crizotinib than with chemotherapy (83.3% in the crizotinib vs. 25.0% in the chemotherapy group, P < 0.05); the DCRs were 100% and 75%, respectively ( P < 0.05). The common adverse events associated with crizotinib were visual abnormality and diarrhea, whereas those associated with chemotherapy were neutropenia and nausea. In the crizotinib group, liver aminotransferase elevation (adverse events grade 3 or 4) occurred in one patient (14.3%). In the chemotherapy group, the same grade neutropenia adverse event occurred in two patients (16.6%). The incidence of treatment-related grade 3 or 4 adverse events was similar in both groups. Compared with chemotherapy, crizotinib was associated with a greater reduction in lung cancer symptoms and a greater improvement in quality of life. Conclusion As a first-line treatment, crizotinib was superior to platinum-based double chemotherapy in patients with previously untreated advanced ALK-positive lung adenocarcinoma. Therefore, crizotinib is an optimal therapy as a first-line treatment in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Surgically menopausal women incur a 2- to 5-fold increased risk for dementia and mortality from neurological diseases, but the mechanisms underlying these increased risks remain unclear. Previously, we demonstrated that after global cerebral ischemia (GCI), 17β-estradiol (E2 or estrogen) suppresses hippocampal elevation of the Wnt antagonist Dickkopf-1 (Dkk1), a neurodegenerative factor. We, thus, hypothesized that prolonged loss of E2 may lead to dysregulation of neural Dkk1 and Wnt/β-Catenin signaling, which could contribute to an increased risk of neurodegeneration. To test this hypothesis, we examined the effect of short-term (1week – STED) and long-term E2 deprivation (10weeks – LTED) via ovariectomy upon basal and E2-regulated Dkk1 levels and Wnt/β-Catenin signaling in the hippocampal CA1 region following GCI. In STED rats, E2 exerted robust neuroprotection against GCI, suppressed post-ischemic elevation of Dkk1, and enhanced pro-survival Wnt/β-Catenin signaling, effects that were lost in LTED rats. Intriguingly, LTED rats displayed modest basal changes in Dkk1 and survivin expression. Further work showed that c-Jun N-terminal Kinase (JNK) mediated GCI-induced changes in Dkk1 and survivin, and JNK inhibition afforded neuroprotection in LTED rats. Finally, we extended our findings to natural aging, as 24-month-old, reproductively senescent female rats also displayed a modest increase in basal Dkk1 in the CA1, which consistently co-localized with the apoptotic marker TUNEL after GCI and coincided with a loss of E2 neuroprotection. As a whole, this study supports the “critical period hypothesis” and further suggests that perimenopausal estradiol replacement may prevent neurodegenerative changes in the hippocampus by maintaining favorable Wnt/β-Catenin signaling. [Copyright &y& Elsevier]

Abstract: A series of 4-aryl-6-chloro-quinoline derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activities, namely the abilities to inhibit the secretion of HBV surface antigen (HBsAg), HBV e antigen (HBeAg), and replication of HBV DNA in HepG 2.2.15 cells. Most of the compounds exhibited moderate inhibitory activity against the secretion of HBsAg and HBeAg. Nine compounds (3, 5, 6, 7, 10, 14, 17, 20, 24) showed significant inhibition against HBV DNA replication with IC50 values in the range of 4.4–9.8μM, which were comparative to that of positive control tenofovir. Of them, compounds 10, 17, and 20 had low cytotoxicities, resulting in high SI values, >551.2, >143.7, and >284.5, respectively. [Copyright &y& Elsevier]

Glioblastoma (GBM) is the deadliest and most common type of primary brain tumor in adults with a grim prognosis despite multimodal treatments. Dendritic cell (DC)-based immunotherapy has emerged as a promising therapeutic modality for GBM, whose efficacy is nonetheless fundamentally undermined by GBM-induced immunosuppression. Inducing emission of damage associated molecular patterns (DAMPs) is a highly effective strategy to subvert tumor-associated immunosuppression. The present work was carried out to explore the idea of subverting the GBM immunosuppressive microenvironment through DC-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites (Nano-DOX), a potent DAMPs inducer demonstrated by our previous study, and thereby eliciting enhanced DC-driven anti-GBM immune response. In the in-vitro work on human cell models, Nano-DOX-loaded DC were shown to be functionally viable and release cargo drug to co-cultured GBM cells (GC). Nano-DOX-treated GC displayed not only profuse DAMPs emission but also antigen release. Enhanced activation and acquisition and presentation of GC-derived antigen were then demonstrated in DC in co-culture with GC and Nano-DOX. Consistently, co-culture with GC and Nano-DOX also activated mouse bone marrow-derived DC (mDC) which in turn stimulated mouse spleen-derived lymphocytes which ultimately suppressed co-cultured GC. Next, athymic mice bearing orthotopic human GBM xenografts were intravenously injected with Nano-DOX-loaded mDC and, 48 h later, spleen-derived lymphocytes. The presence of Nano-DOX, DAMPs emission and enhanced infiltration and activation of mDC and lymphocytes were detected in the GBM xenografts. Taken together, our results demonstrate the efficacy of DC-mediated delivery of Nano-DOX to stimulate GC immunogenicity and elicit anti-cancer immune response in the GBM. By this work, we present a novel approach with great application potential to subverting the GBM immunosuppressive microenvironment and to anti-GBM immunotherapy. Investigation has also been conducted probing the mechanisms by which Nano-DOX stimulates GC immunogenicity, which is described in a follow-up paper. [ABSTRACT FROM AUTHOR]

Background To evaluate the efficacy and safety of Icotinib - an orally administered, highly potent selective inhibitor of epidermal growth factor receptor ( EGFR) and its active mutations, in the treatment of patients with advanced non-small cell lung cancer ( NSCLC). Methods A total of 101 patients with stage IIIb/ IV NSCLC were treated with 125 mg Icotinib three times a day until disease progression or intolerable toxicity. Response rate was evaluated using response evaluation criteria in solid tumors and progression-free survival ( PFS) was collected. Results The overall response rate ( ORR) and disease control rate ( DCR) were 37.6% (38/101) and 79.2% (80/101), respectively. The median PFS was 6.5 months. Multivariate analysis showed that female gender ( P = 0.048, 95% confidence interval [ CI] 1.010-6.016) and occurrence of rash ( P = 0.002, 95% CI 1.667-9.809) were the independent predictive factors for ORR, while a performance status ( PS) score of 0-1 ( P = 0.001, 95% CI 0.024-0.402) and rash ( P = 0.042, 95% CI 1.089-76.557) were the independent predictive factors for DCR. In addition, PS scores of 0-1 ( P < 0.001, 95% CI 0.135-0.509), and non-smoking ( P = 0.017, 95% CI 0.342-0.900) were found to be independent influencing factors for PFS. Moreover, patients with EGFR mutations had better PFS than patients with wild type EGFR, while patients with EGFR exon 19 deletion had better survival than those with EGFR exon 21 mutation. The most common adverse effects of Icotinib were rash (35.6%) and diarrhea (17.8%), which was tolerable. Conclusion Treatment of stage IIIb/ IV NSCLC patients with Icotinib was effective and tolerable, specifically in patients with EGFR mutation. [ABSTRACT FROM AUTHOR]

We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC 50  = 0.039 nM vs. 0.069 nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC 50  = 0.25 nM and 0.26 nM vs. 0.11 nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d – 15f and oxadiazole compounds 24a – 24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC 50  = 0.14 μM and 0.05 μM vs. 8.98 μM). Compounds 15a and 24a also inhibited colony formation in MCF-7 cells and inhibited cell migration in the cell wound scratch assay in B16BL6 cells. Moreover, hydroxyl compounds 15a and 24a had low toxicity in vivo . [ABSTRACT FROM AUTHOR]

As a mitochondrial uncoupler, 2,4-dinitrophenol (DNP) is proven therapeutically effective against nonalcoholic fatty liver disease (NAFLD) by uncoupling oxidation and phosphorylation. However, a major factor that impedes the clinical application of DNP is the significant side effects derived from its frequent hyperthermia and even death. In this study, we developed an injectable liquid crystal gel (DNP-LC-gel) to reduce the toxicity of DNP. DNP-LC-gel achieved sustained release and maintained DNP plasma concentration at an effective drug level. In a rat model of NAFLD, DNP-LC-gel treated rats reduced hepatic steatosis, liver triglyceride content, plasma triacylglycerol (TG) and total cholesterol (TC) content. Compared with DNP solution (DNP-soln), rats after DNP-LC-gel treatment showed no body temperature toxicity and local irritation. All results above indicated that DNP-LC-gel has a great potential for NAFLD therapy. [ABSTRACT FROM AUTHOR]

Background Epidermal growth factor receptor-tyrosine kinase inhibitors ( EGFR-TKIs) effectively treat advanced non-small cell lung cancer with EGFR-mutation. However, most patients develop acquired resistance without effective therapy subsequent to EGFR-TKI failure. We evaluated the efficacy of subsequent treatment strategies for EGFR-TKI resistance. Methods We retrospectively analyzed 240 patients with advanced lung adenocarcinoma with EGFR-TKI failure and following subsequent treatment. According to the first subsequent strategies after EGFR- TKI failure, patients were divided into groups of EGFR-TKI continuation (21 cases), EGFR-TKI continuation with chemotherapy (23 cases), chemotherapy alone (143 cases), and best supportive care ( BSC) (53 cases). Results Except for 53 cases of BSC, the disease control rates ( DCR) of the remaining 187 patients in the EGFR-TKI continuation, EGFR-TKI continuation with chemotherapy, and chemotherapy alone groups were 66.7%, 73.9%, and 44.8%, respectively. The median post-progression progression-free survival ( PFS) for the three groups was 3.0, 3.3, and 2.0 months, respectively. The DCR for the EGFR-TKI continuation with chemotherapy group was significantly higher than the chemotherapy alone group ( P = 0.006). The post-progression PFS of the EGFR-TKI continuation with chemotherapy group was significantly longer than the chemotherapy alone group ( P = 0.037). The median overall survival in the EGFR-TKI continuation, EGFR-TKI continuation with chemotherapy, chemotherapy alone, and BSC groups were 6.9, 11.6, 8.8, and 0.9 months, respectively. Compared to the BSC group, all groups achieved a survival benefit ( P < 0.001). Conclusions EGFR-TKI continuation with chemotherapy could provide benefits for patients with acquired resistance to EGFR-TKI. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two heptamannosylated β-cyclodextrin derivatives (CD-Man7 and C 3 -CD-Man7) were synthesized. • Multivalent mannose ligands induced macrophages to differentiate into the M2 phenotype. • Both CD-Man7 and CD-Man-NPs could reduce the inflammatory response in wound tissue and accelerate wound healing. Macrophages have high plasticity and heterogeneity, and can suppress or mediate inflammation, depending on their cytokine secretion and phenotype. Regulating macrophage polarization into its M2 phenotype has a remarkable effect on inflammatory inhibition, inducing the regeneration of injured tissues. Here, we synthesized two heptamannosylated β-cyclodextrin derivatives (CD-Man7 and C 3 -CD-Man7) and demonstrated that their multivalent mannose ligands could induce M2 macrophage polarization to accelerate wound healing. Unlike hydrophilic CD-Man7, amphiphilic C 3 -CD-Man7 can self-assemble to form nanoparticles (CD-Man-NPs) in aqueous solution. Further, in vitro results confirmed that multivalent mannose ligands of either CD-Man7 or CD-Man-NPs stimulated RAW264.7 macrophages to differentiate into the M2 phenotype, which promoted fibroblast migration via a paracrine mechanism. In vivo results confirmed that both CD-Man7 and CD-Man-NPs reduced the inflammatory response in wound tissue and accelerated wound healing. The present study demonstrates multivalent effects of CD-Man7 and CD-Man-NPs on M2 macrophage polarization, indicating the therapeutic potential of these β-cyclodextrin glycoconjugates in the treatment of inflammatory diseases and wound healing. [ABSTRACT FROM AUTHOR]

This study compared the reliability, practicability and impact to donor site functionality of radial forearm (RF) and anterolateral thigh (ALT) flaps used for the reconstruction of head and neck soft-tissue defects. The clinical data of patients who underwent reconstruction using RF flaps ( n = 53) and ALT flaps (n = 21) after tumour ablation were reviewed. Pedicle length, skin area harvested and flap survival rate were compared between the two flap types. A questionnaire was used to compare the patients' perceptions of donor site functionality. Pedicle length did not significantly differ between RF and ALT flaps (7.5 vs. 9 cm, p = 0.733). A significantly larger mean area of skin was harvested in the ALT group than in the RF group (65 vs. 38 cm, p = 0.001). Flap survival rates did not differ between the two groups ( p = 0.554). Patients in the ALT group were more satisfied with the appearance of the donor sites than were those in the RF group ( p = 0.029). Significantly more patients in the RF group complained of donor site numbness than in the ALT group ( p = 0.014). No ALT group patients complained of movement impairment or weakness at the donor sites, but 10% of RF group patients experienced impairment ( p = 0.014) and 35% felt weakness ( p = 0.001). The ALT and RF flaps showed similar practicability and reliability for the reconstruction of soft-tissue defects, but ALT flaps had fewer impacts to donor site functionality than RF flaps. [ABSTRACT FROM AUTHOR]

Abstract: A series of 1-aryl-6,7-dihydroxyl(methoxy)-1,2,3,4-tetrahydroisoquinolines (compounds 1–36) were synthesized via Pictet–Spengler cyclization. All the synthesized compounds were assayed for activities against HIV-1IIIB in C8166 cell cultures by MTT method for the first time. The results of the anti-HIV screening revealed that 6,7-dihydroxytetrahydroisoquinolines possessed higher selective index than 6,7-dimethoxyl analogs due to the significantly decreased cytotoxicities. Compounds 6, 24, and 36 showed potent anti-HIV activities with EC50 values of 8.2, 4.6, and 5.3μM respectively, and the cytotoxicities (CC50) of these three compounds were 784.3, 727.3, and 687.3μM, which resulted in SI values larger than 95, 159, and 130 respectively. [Copyright &y& Elsevier]