Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the ...development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Previous studies comparing outcomes of hepatocellular carcinoma (HCC) patients after living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) showed ...conflicting results, and most studies measured survival outcomes from the time of liver transplantation (LT).
Method
This retrospective study was aimed to evaluate the long-term outcomes of HCC patients listed for LT using intention-to-treat (ITT) and propensity score matching (PSM) analyses. Clinicopathological data were retrieved from a prospectively collected database.
Results
From 1995 to 2014, 375 HCC patients were listed for LT. ITT-LDLT group had 188 patients, whereas ITT-DDLT group had 187 patients. Twenty-seven patients (14.4%) and 122 patients (65.2%) were delisted from LDLT and DDLT waitlist, respectively. The 1-, 3- and 5-year overall survival rates were significantly better in ITT-LDLT group than ITT-DDLT group (94.1 vs. 77.5%, 81.4 vs. 48.7% and 75.9 vs. 40.8%). High alphafetoprotein (AFP) and ITT-DDLT treatment arm were independent poor prognostic factors affecting overall survival. LDLT group (
n
= 161) had more young patients, poorer liver function, higher AFP, more tumors outside Milan/UCSF criteria, when compared with DDLT group (
n
= 85). After PSM, the 1-, 3- and 5-year overall (95.4 vs. 98.5%, 80.0 vs. 92.3% and 73.4 vs. 84.4%) and recurrence-free (87.7% vs. 90.8%, 76.9% vs. 83.1% and 72.2% vs. 81.5%) survival rates were comparable between the matched LDLT and the matched DDLT group, respectively.
Conclusion
Survival benefit of LDLT was observed for HCC patients with ITT analysis. Despite a more advanced tumor stage, overall and recurrence-free survival rates were comparable between LDLT and DDLT using PSM analysis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cryptococcus gattii recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in ...tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these C. gattii genomes with each other and with the genomes of representative strains of the two varieties of Cryptococcus neoformans that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative C. gattii strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the C. gattii complex. More extensive chromosome rearrangements were observed upon comparison of the C. gattii and the C. neoformans genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in C. gattii isolates displaying fluconazole heteroresistance.
Tropical mountains are hot spots of biodiversity and endemism, but the evolutionary origins of their unique biotas are poorly understood. In varying degrees, local and regional extinction, ...long-distance colonization, and local recruitment may all contribute to the exceptional character of these communities. Also, it is debated whether mountain endemics mostly originate from local lowland taxa, or from lineages that reach the mountain by long-range dispersal from cool localities elsewhere. Here we investigate the evolutionary routes to endemism by sampling an entire tropical mountain biota on the 4,095-metre-high Mount Kinabalu in Sabah, East Malaysia. We discover that most of its unique biodiversity is younger than the mountain itself (6 million years), and comprises a mix of immigrant pre-adapted lineages and descendants from local lowland ancestors, although substantial shifts from lower to higher vegetation zones in this latter group were rare. These insights could improve forecasts of the likelihood of extinction and 'evolutionary rescue' in montane biodiversity hot spots under climate change scenarios.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply ...energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune‐driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence‐related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Arterial stiffness predicts cardiovascular events beyond traditional risk factors. However, the relationship with aging of novel noninvasive measures of aortic function by MRI and their ...interrelationship with established markers of vascular stiffness remain unclear and currently limit their potential impact. Our aim was to compare age-related changes of central measures of aortic function with carotid distensibility, global carotid–femoral pulse wave velocity, and wave reflections. We determined aortic strain, distensibility, and aortic arch pulse wave velocity by MRI, carotid distensibility by ultrasound, and carotid–femoral pulse wave velocity by tonometry in 111 asymptomatic subjects (54 men, age range20 to 84 years). Central pressures were used to calculate aortic distensibility. Peripheral and central pulse pressure, augmentation index, and carotid–femoral pulse wave velocity increased with age, but aortic strain and aortic arch PWV were most closely and specifically related to aging. Ascending aortic (AA) strain and distensibility decreased, respectively, by 5.3±0.5% (R=0.54, P<0.0001) and 13.6±1 kPa×10 (R=0.62, P<0.0001), and aortic arch pulse wave velocity increased by 1.6±0.13 m/sec (R=0.60, P<0.0001) for each decade of age after adjustment for gender, body size, and heart rate. We demonstrate in this study a dramatic decrease in AA distensibility before the fifth decade of life in individuals with diverse prevalence of risk factors free of overt cardiovascular disease. In particular, compared with other measures of aortic function, the best markers of subclinical large artery stiffening, were AA distensibility in younger and aortic arch pulse wave velocity in older individuals.
The aims of this study were reviewing our experience regarding the pulmonary toxicity of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, discussing potential pathogenic mechanisms ...and proposing management strategies. Medical records and radiological reports of 22 patients treated with weekly doses of temsirolimus 25
mg were reviewed. Eight (36%) out of 22 patients developed pulmonary abnormalities compatible with drug-induced pneumonitis. Half were asymptomatic and in those with symptoms, dyspnea and dry cough were the most common. Radiologically two different patterns, ground glass opacities and lung parenchymal consolidation, were described. The management of this toxicity was variable, ranging from no intervention to discontinuation of the drug. In our experience temsirolimus may cause drug-induced pneumonitis at a higher incidence than that previously reported. The presentation and its severity are variable. The risk of developing this toxicity may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The phenotypic transformation of well-differentiated epithelial carcinoma into a mesenchymal-like state provides cancer cells with the ability to disseminate locally and to metastasise. Different ...degrees of epithelial-mesenchymal transition (EMT) have been found to occur in carcinomas from breast, colon and ovarian carcinoma (OC), among others. Numerous studies have focused on bona fide epithelial and mesenchymal states but rarely on intermediate states. In this study, we describe a model system for appraising the spectrum of EMT using 43 well-characterised OC cell lines. Phenotypic EMT characterisation reveals four subgroups: Epithelial, Intermediate E, Intermediate M and Mesenchymal, which represent different epithelial-mesenchymal compositions along the EMT spectrum. In cell-based EMT-related functional studies, OC cells harbouring an Intermediate M phenotype are characterised by high N-cadherin and ZEB1 expression and low E-cadherin and ERBB3/HER3 expression and are more anoikis-resistant and spheroidogenic. A specific Src-kinase inhibitor, Saracatinib (AZD0530), restores E-cadherin expression in Intermediate M cells in in vitro and in vivo models and abrogates spheroidogenesis. We show how a 33-gene EMT Signature can sub-classify an OC cohort into four EMT States correlating with progression-free survival (PFS). We conclude that the characterisation of intermediate EMT states provides a new approach to better define EMT. The concept of the EMT Spectrum allows the utilisation of EMT genes as predictive markers and the design and application of therapeutic targets for reversing EMT in a selective subgroup of patients.
The Filamenting temperature-sensitive mutant Z (FtsZ), an essential GTPase in bacterial cell division, is highly conserved among Gram-positive and Gram-negative bacteria and thus considered an ...attractive target to treat antibiotic-resistant bacterial infections. In this study, a new class of FtsZ inhibitors bearing the pyrimidine-quinuclidine scaffold was identified from structure-based virtual screening of natural product libraries. Iterative rounds of in silico studies and biological evaluation established the preliminary structure–activity relationships of the new compounds. Potent FtsZ inhibitors with low micromolar IC50 and antibacterial activity against S. aureus and E. coli were found. These findings support the use of virtual screening and structure-based design for the rational development of new antibacterial agents with innovative mechanisms of action.
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IJS, KILJ, NUK, PNG, UL, UM
•Enhancing total effective surface area can enhance alumina humidity sensing.•Reducing anodizing potential for the increased surface area benefits capacitance sensing.•The alumina humidity sensor ...formed at 20 V enhances 2–3 times capacitance than those at 40–50 V.•An enhanced linear-like relationship between the capacitance and humidity occurs.•The theoretic surface area enhancement mechanism is presented.
Total effective surface area is an important factor for environmentally sensing performance. The porous anodic aluminum oxide (AAO) film with a high density of nanopores leads to atremendous surface area for absorbing water molecules. But such an AAO humidity sensor formed in oxalic acid exhibits a low response of capacitance, especially under the low relative humidity (RH). Here, we demonstrate total effective surface area principle to greatly enhance the performance of AAO capacitive humidity sensor using small anodizing potential in oxalic acid. For pore-dependent surface area, the AAO pore wall would directly affect the absorbance of water molecules and the response of capacitive sensor. Decreasing the anodizing potential reduces both of the pore diameter and interpore distance proportionally but increases the surface area inversely. Therefore, the AAO sensor formed at small 20 V can greatly increase the amount of water molecules absorbed on the wall for enhancing 2–3 times response under low-to-high RH compared to those at 40 and 50 V. The good stability and reliable response/recovery time are also obtained for the AAO sensor synthesized at 20 V in oxalic acid.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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