Evaluation of the protective efficacy of four newly identified surface proteins of Erysipelothrix rhusiopathiae

Erysipelothrix rhusiopathiae is the causative agent of animal erysipelas and human erysipeloid. Bacterial surface proteins are promising vaccine candidates. We recently identified 3 E. rhusiopathiae surface proteins (GAPDH, HP0728, and HP1472) and characterized their roles as virulence factors. However, their efficacy as protective antigens is still unknown. The N-terminal region of a previously identified surface protein, CbpB (CbpB-N), is speculated to be a protective antigen, but this needs to be verified. The aim of this study was to evaluate the protective efficacy of GAPDH, HP0728, HP1472, and CbpB-N. Immunization with recombinant GAPDH provided complete protection in a mouse model, recombinant CbpB-N provided partial protection, while recombinant HP0728 and HP1472 provided no protection. Recombinant GAPDH also provided good protection in a pig model. GAPDH antiserum exhibited significant blood bactericidal activity against E. rhusiopathiae. In conclusion, GAPDH and CbpB-N were found to be protective antigens of E. rhusiopathiae, and GAPDH is a promising vaccine candidate.     

Dissecting the role of AMP-activated protein kinase in human diseases

AMP-activated protein kinase (AMPK), known as a sensor and a master of cellular energy balance, integrates various regulatory signals including anabolic and catabolic metabolic processes. Accompanying the application of genetic methods and a plethora of AMPK agonists, rapid progress has identified AMPK as an attractive therapeutic target for several human diseases, such as cancer, type 2 diabetes, atherosclerosis, myocardial ischemia/reperfusion injury and neurodegenerative disease. The role of AMPK in metabolic and energetic modulation both at the intracellular and whole body levels has been reviewed elsewhere. In the present review, we summarize and update the paradoxical role of AMPK implicated in the diseases mentioned above and put forward the challenge encountered. Thus it will be expected to provide important clues for exploring rational methods of intervention in human diseases.     

Structure–Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors

We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.     

Aggressive resection of craniopharyngioma achieved by drilling the tuberculum sellae/planum sphenoidale using a frontal basal interhemispheric approach: A review of 55 cases

ObjectiveThe frontal basal interhemispheric approach (FBIA) is preferable for resection of craniopharyngioma (CP), achieving desirable total resection rates in early reports of lesions located in the suprasellar region to the third ventricle. For tumours that have created a larger obstruction of the tuberculum sellae and planum sphenoidale, aggressive resection in the intrasellar region and medial wall of the cavernous sinus is not feasible compared to improving tumour visualization by drilling the tuberculum sellae and planum sphenoidale. In a report of drilling the sellar tuberculum and sphenoid planum, drilling allowed the direct visualization of tumours invading the intrasellar region and medial wall of the cavernous sinus. Reconstructing the opening of the sellar-sphenoid cavity is achieved by microsuturing a piece of the pericranium/dura around the dural edge of the defective dura of the open sphenoid sinus and sellar cavity to prevent cerebrospinal fluid (CSF) leakage.Patients and methodsThe FBIA with drilling of the tuberculum sellae and planum sphenoidale was performed to remove the tumours that invaded the intrasellar region and cavernous sinus in 55 patients from January 2014 to October 2019 at our institution. The pre- and postoperative pituitary hormone levels and vision were evaluated as effective standards after surgery and compared using paired t-tests. The different rates of CSF leakage between the packing and microsuture groups were compared by χ² test, p < 0.05.ResultsIn all patients with a mean 37-month follow-up (range, 3–2 months), 43 (78.2%) patients returned to their normal life or school independently, 7 (12.7%) patients were able to perform normal activities with minor complaints or effort, and 4 (7.3%) patients could care for themselves or only required occasional assistance. One (1.8%) death occurred, attributed to CSF leak-related meningitis at 5 months after surgery. Postoperative CSF leakage occurred in eight (19.0%) of 42 patients with packed bone wax or pieces of muscle to the sphenoid sinus. Of 13 patients with a piece of the periosteum/dura microsutured around the defective dura of the sellar region and open sphenoid sinus, one (7.7%) of 13 patients experienced CSF leakage in the perioperative period. With statistical analysis, there was a potential risk for postoperative CSF leakage in the bone wax and muscle piece in the open sphenoid sinus, whereas microsuture manoeuvres were effective for avoiding the risk of postoperative CSF leakage (χ² = 8.865, p < 0.005). The microsutures closed the open sphenoid sinus such that it was water-tight. Postoperative visual acuity and the visual field were not affected by the increased intrasellar exposure or the open sphenoid sinus achieved by drilling the tuberculum sellae and planum sphenoidale.ConclusionTuberculum sellae/planum sphenoidale drilling via FBIA is feasible to enhance the direct visualization of CP resection, which expands the intrasellar region with a direct resection of recurrent tumours in the sellar cavity and adhering to the medial wall of the cavernous sinus. The potential risk of a CSF leakage seemed to be mitigated when using water-tight microsutures on a piece of the pericranium/dura around the edge of the defective dura in the sellar region and the open sphenoid sinus cavity.     

Coronary CTA enhanced with CTA based FFR analysis provides higher diagnostic value than invasive coronary angiography in patients with intermediate coronary stenosis

BackgroundCTA based FFR, a software based application, enhances diagnostic value of coronary computed tomography angiography (CTA) examination. However it remains unknown whether it improves accuracy over the gold standard of invasive coronary angiography (ICA) in predicting functionally significant coronary stenosis. The aim of our study was to compare diagnostic accuracies of coronary CTA, CTA based FFR, and ICA, with invasive FFR as the reference standard in patients with intermediate stenosis on CTA.Methods96 intermediate stenoses (50–90%) from 90 subjects, with intermediate pre-test probability of CAD, who underwent coronary CTA were analyzed. Each patient had subsequent ICA with FFR. CTA based FFR (cFFR v2.1, Siemens) analysis was performed on-site. The stenoses with invasive FFR≤0.8 were considered hemodynamically significant.Results41/96 stenoses were hemodynamically significant (FFR≤0.8). While the area under ROC curves (AUC) for identification of significant stenosis evaluated on QCA (0.653), visual ICA (0.652), qCTA (0.690) and visual CTA (0.660) did not significantly differ, the AUC for CTA based FFR (0.835) was significantly higher (p = 0.004, p = 0.004, p = 0.010, p = 0.007, respectively). The accuracies of CTA based FFR, qCTA and QCA were 76%, 63% and 58% respectively.ConclusionOur results suggest that diagnostic potential of routine coronary CTA, augmented with CTA based FFR analysis, is superior to ICA in patients with intermediate stenosis.     

Reactive oxygen at the heart of metabolism

During heart development, the progression from a pluripotent, undifferentiated embryonic stem cell to a functional cardiomyocyte in the adult mammalian heart is characterised by profound changes in gene expression, cell structure, proliferative capacity and metabolism. Whilst the precise causal relationships between these processes are not fully understood, it is clear that the availability and cellular ability to utilise oxygen are critical effectors of cardiomyocyte differentiation and function during development. In particular, cardiomyocytes switch from a largely glycolytic-based production of ATP to predominantly β-oxidation of long-chain fatty acids to generate the cellular energy requirements. Whilst this transition occurs progressively during embryonic and foetal development, it is particularly abrupt over the period of birth. In the adult heart, many cardiopathologies are accompanied by a reversal to a more foetal-like metabolic profile. Understanding the mechanistic causes and consequences of the normal metabolic changes that occur during heart development and those in the pathological heart setting is crucial to inform future potential therapeutic interventions. It is becoming clear that reactive oxygen species (ROS) play critical roles in the regulation of redox-mediated molecular mechanisms that control cellular homoeostasis and function. ROS are generated as a consequence of metabolic processes in aerobic organisms. An overproduction of ROS, when not balanced by the cell's antioxidant defence mechanisms (termed “oxidative stress”), results in non-specific oxidation of proteins, lipids and DNA and is cytotoxic. However, the tightly regulated temporal and spatial production of ROS such as H₂O₂ acts to control the activity of proteins through specific post-translational oxidative modifications and is crucial to cellular function. We describe here the metabolic changes that occur in the developing heart and how they can revert in cardiopathologies. They are discussed in the light of what is currently known about the regulation of these processes by changes in the cellular redox state and levels of ROS production.