Ionic Porous Aromatic Frameworks Embedding Polyoxometalates for Heterogeneous Catalysis.

Porous aromatic frameworks (PAFs) are promising functional porous solids known for their feasible amenability and extraordinary stability. When the framework modified by ionic functional groups, the given ionic PAFs (iPAFs) exhibited charged channels for adsorption, separation and catalysis. However, the surface areas of ionic porous frameworks are usually lower than the neutral ones, and their synthesis limited by specific strategies and complex modifying processes. To overcome these problems, we proposed an intuitive route to construct ionic porous framework with high specific surface area, through a multivariable synthesis strategy. Herein, multivariate ionic porous aromatic framework (MTV-iPAFs) material named PAF-270 was synthesized from readily available building units with ionic functional groups. PAF-270 exhibited hierarchical structure with the highest specific surface area among reported imidazolium functionalized PAFs. Leveraging its physical and chemical properties, we explored its availability for polyoxometalates loading and heterogeneous catalysis. PAF-270 exhibited high adsorption capacity up to 50% for both H3O40PW12 (HPW) and (NH4)5H6PV8Mo4O40 (V8). HPW@PAF-270 and V8@PAF-270 exhibited excellent catalytic abilities for oleic acid esterification and extractive oxidative desulfurization, respectively. Due to the stability of PAFs, these materials also showed remarkable resistance to temperature and pH changes. These results highlight the potential application of MTV-iPAFs as functional porous materials.

Multivariate Porous Aromatic Frameworks with High Porosity and Hierarchical Structures for Enzyme Immobilization.

As materials with permanently porous structures and readily modifying availability, porous aromatic frameworks (PAFs) are considered as promising porous materials with versatile functionality. Currently the designable synthesis of PAFs with the desired surface area and pore size is still a challenge, and instead kinetically irreversible coupling reactions for PAFs synthesis has resulted in the unpredictable connection of building units. Herein, a series of PAFs with highly porous and hierarchical structures were successfully synthesized through a multivariate inspired strategy, where multiple building units with various topologies and sizes were selected for PAFs synthesis. All the PAFs synthesized through this strategy possessed hierarchical structures and high specific surface areas at the same time. Encouraged by their high surface area and hierarchical structures, we loaded lipase onto one of the multivariate PAFs. The enzyme loading content of the obtained lipase@PAF-147 was as high as 1456 mg g-1, which surpassed any other currently reported enzyme loading materials. The lipase@PAF-147 also exhibited favorable catalytic activity and stability to a model reaction of p-nitrophenyl caprylate (p-NPC) hydrolysis. This multivariate strategy inspired synthetic method broadens the selection of building units for PAFs design and opens a new avenue for the design of functional porous materials.

Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors.

Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi.

MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer.

PURPOSE: Although 67% of high-grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Because MAPK activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses antiestrogen resistance. EXPERIMENTAL DESIGN: Effects of MEKi (selumetinib), antiestrogen (fulvestrant), or both were assayed in ER-positive HGSOC in vitro and in xenografts. Response biomarkers were investigated by gene expression microarray and reverse phase protein array (RPPA). Genes differentially expressed in two independent primary HGSOC datasets with high versus low pMAPK by RPPA were used to generate a "MAPK-activated gene signature." Gene signature components that were reversed by MEKi were then identified. RESULTS: High intratumor pMAPK independently predicts decreased survival (HR, 1.7; CI > 95%,1.3-2.2; P = 0.0009) in 408 HGSOC from The Cancer Genome Atlas. A differentially expressed "MAPK-activated" gene subset was also prognostic. "MAPK-activated genes" in HGSOC differ from those in breast cancer. Combined MEK and ER blockade showed greater antitumor effects in xenografts than monotherapy. Gene set enrichment analysis and RPPA showed that dual therapy downregulated DNA replication and cell-cycle drivers, and upregulated lysosomal gene sets. Selumetinib reversed expression of a subset of "MAPK-activated genes" in vitro and/or in xenografts. Three of these genes were prognostic for poor survival (P = 0.000265) and warrant testing as a signature predictive of MEKi response. CONCLUSIONS: High pMAPK is independently prognostic and may underlie antiestrogen failure. Data support further evaluation of fulvestrant and selumetinib in ER-positive HGSOC. The MAPK-activated HGSOC signature may help identify MEK inhibitor responsive tumors.

[Prophylactic antibiotics: a necessity in totally percutaneous thoracic endovascular aortic repair?].

OBJECTIVE: To study the benefit of prophylactic antibiotics (PA) in totally percutaneous aortic endovascular repair (PEVAR) in the catheterization laboratory for reducing stent-graft infection and postimplantation syndrome (PIS). METHODS: The clinical data were analyzed of patients undergoing thoracic endovascular aortic repairs. The patients were divided into non-PA group and PA group according to the use of prophylactic antibiotics before PEVAR. The diagnosis of infection was made by two senior physicians with reference to Hospital Acquired Infection Diagnostic Criteria Assessment released by the Ministry of Health of China. RESULTS: The 95 enrolled patients included 35 with PA and 60 without PA group, who were comparable for baseline characteristics. Infection-related deaths occurred in 1 case in non-PA group and retrograde Stanford type A dissection and death occurred in 1 case in PA group (1.67% vs 2.85%, P=1.00). The PA and non-PA groups showed no significant difference in the incidence of postoperative infection (5% vs 2.86%, P=1.000), hospital stay (9.30±7.21 vs 10.06±5.69, P=0.094), infection-related mortality (1.67% vs 0%, P=1.00), or postoperative fever (70.90% vs 91.43%, P=0.20). The body temperature showed significant variations at different time points after procedure (F=19.831, P<0.001) irrelevant to the use of prophylactic antibiotics (F=0.978, P=0.326). CONCLUSION: The current data do not support the benefit of PA in reducing postoperative infection and PIS in patients undergoing PEVAR, but the patients without PA may have worse clinical outcomes in the event of postoperative infections.

Preferential infection of human Ad5-specific CD4 T cells by HIV in Ad5 naturally exposed and recombinant Ad5-HIV vaccinated individuals.

Efficacy trials of adenovirus 5-vectored candidate HIV vaccines [recombinant Ad5 (rAd5)-HIV] were halted for futility due to lack of vaccine efficacy and unexpected excess HIV infections in the vaccine recipients. The potential immunologic basis for these observations is unclear. We comparatively evaluated the HIV susceptibility and phenotypes of human CD4 T cells specific to Ad5 and CMV, two viruses that have been used as HIV vaccine vectors. We show that Ad5-specific CD4 T cells, either induced by natural Ad5 exposure or expanded by rAd5 vaccination, are highly susceptible to HIV in vitro and are preferentially lost in HIV-infected individuals compared with CMV-specific CD4 T cells. Further investigation demonstrated that Ad5-specific CD4 T cells selectively display a proinflammatory Th17-like phenotype and express macrophage inflammatory protein 3α and α4ß7 integrin, suggestive of gut mucosa homing potential of these cells. Analysis of HIV p24 and cytokine coexpression using flow cytometry revealed preferential infection of IL-17- and IL-2-producing, Ad5-specific CD4 T cells by HIV in vitro. Our data suggest a potential mechanism explaining the excess HIV infections in vaccine recipients after rAd5-HIV vaccination and highlight the importance of testing the HIV susceptibility of vaccine-generated, vector and insert-specific CD4 T cells in future HIV vaccine studies.

Procalcitonin could be a reliable marker in differential diagnosis of post-implantation syndrome and infection after percutaneous endovascular aortic repair.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is an emerging treatment modality, which has been rapidly embraced by clinicians treating thoracic aortic disease. However, the clinical manifestations of systemic inflammatory response after TEVAR as post-implantation syndrome (PIS) resemble the perioperative infection. This study aimed to evaluate changes and diagnostic value of procalcitonin (PCT) and other traditional inflammatory markers for infections after TEVAR. METHODS: We conducted a prospective clinical study that enrolled 162 consecutive aortic dissection cases, who underwent TEVAR in our institution between July 2011 and November 2012. The PCT, C-response protein (CRP), erythrocyte sedimentation rate (ESR) and blood routine examination were monitored before the operation and on days 1, 2, 3 and 5 after the operation. The diagnosis of infection was confirmed by the infection control committee with reference to Hospital Acquired Infection Diagnostic Criteria Assessment, released by the Ministry of Health of the People's Republic of China. RESULTS: Post endovascular repair of thoracic aorta, PCT changes significantly at different time points (χ(2) = 13.225, P = 0.021), without significant difference between the PIS group and the control group (0.24 ± 0.04 vs.0.26 ± 0.10, P = 0.804). PCT values were significantly higher in the first day after TEVAR than the preoperative levels (0.18 ± 0.03 vs. 0.11 ± 0.02, P < 0.001). Compared with PIS patients, the level of PCT, CRP, White blood cell (WBC) and neutrophil (NEU) in the infection patients elevated significantly (relatively χ(2) = 6.062, P = 0.048; χ(2) = 6.081, P = 0.048; χ(2) = 11.030, P = 0.004; χ(2) = 14.632, P = 0.001). According to the ROC analysis, the PCT levels in the first day after TEVAR (AUC = 0.785, P = 0.012) had better predictive values of infection than WBC, NEU CRP and ESR (AUC = 0.720, P = 0.040; AUC = 0.715, P = 0.045; AUC = 0.663, P = 0.274; AUC = 0.502, P = 0.991). The best predictive index was the changes of PCT between preoperative and postoperative (PCT), which possess AUC as 0.803 (P = 0.014). And PCT = 0.055 could be considered as an infection diagnosis cutoff value with a sensitivity of 83.3% and specificity 69.0%. CONCLUSIONS: PCT provides better diagnostic value of infection compared with other inflammatory markers. The potential applications of PCT in differential diagnosis of PIS and infection after percutaneous TEVAR deserve further studies.

Transcriptome profiling of human ulcerative colitis mucosa reveals altered expression of pathways enriched in genetic susceptibility loci.

Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently-generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate <0.05). The upregulated pathways were dominated by gene sets involved in immune function and signaling, as well as the control of mitosis. We applied pathway analysis to genotype data derived from genome-wide association studies (GWAS) of UC, consisting of 5,584 cases and 11,587 controls assembled from eight European-ancestry cohorts. The upregulated pathways derived from the gene expression data showed a highly significant overlap with pathways derived from the genotype data (33 of 56 gene sets, hypergeometric P = 1.49 × 10(-19)). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process.

Perioperative aortic dissection rupture after endovascular stent graft placement for treatment of type B dissection.

BACKGROUND: The perioperative aortic dissection (AD) rupture is a severe event after endovascular stent graft placement for treatment of type B AD. However, this life-threatening complication has not undergone systematic investigation. The aim of the study is to discuss the reasons of AD rupture after the procedure. METHODS: The medical record data of 563 Stanford type B AD patients who received thoracic endovascular repair from 2004 to December 2011 at our institution were collected and analyzed. Double entry and consistency checking were performed with Epidata software. RESULTS: Twelve patients died during the perioperation after thoracic endovascular repair, with an incidence of 2.1%, 66.6% were caused by aortic rupture and half of the aortic rupture deaths were caused by retrograde type A AD. In our study, 74% of the non-rupture surviving patients had the free-flow bare spring proximal stent implanted, compared with 100% of the aortic rupture patients (74% vs. 100%, P = 0.213). The aortic rupture patients are more likely to have ascending aortic diameters = 4 cm (62.5% vs. 9.0%, P = 0.032), involvement the aortic arch concavity (62% vs. 27%, P = 0.041) and have had multiple stents placed (P = 0.039). CONCLUSIONS: Thoracic AD endovascular repair is a safe and effective treatment option for AD with relative low in-hospital mortality. AD rupture may be more common in arch stent-graft patients with an ascending aortic diameter = 4 cm and with severe dissection that needs multi-stent placement. Attention should be paid to a proximal bare spring stent that has a higher probability of inducing an AD rupture. Post balloon dilation should be performed with serious caution, particularly for the migration during dilation.