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The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure
No full textThis review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions
Improve the precise pathological diagnosis of intrahepatic cholangiocarcinoma: introduction to 2022 expert consensus on pathological diagnosis of intrahepatic cholangiocarcinoma in China
No full textThe role of tumor microenvironment in cholangiocarcinoma
No full textCholangiocarcinoma (CCA) is an extremely aggressive neoplasia, mostly because of diagnostic delay and lack of effective therapies. CCA is typically surrounded by a peculiar microenvironment that includes abundant desmoplastic stroma and various cell types, which support and enhance CCA development. Among the tumor microenvironment (TME) cells, there are tumor infiltrating lymphocytes (TILs), such as CD8+ and CD4+ cells, Tregs, natural killers (NKs) and B lymphocytes. TILs contribute to an immunosuppressive microenvironment that leads to tumor immune escape. Dendritic cells (DCs) may lead to immunotolerance by maturation or antigen-presentation deficiency. Hepatic stellate cells (HSCs) are one of the major precursors of cancer-associated fibroblast (CAFs), which are distinguished in various subpopulations, each with different functions and interactions with other TME cells. CAFs can promote lymphangiogenesis, early lymph-node metastasis and proinflammatory environment, but they can also provide a physical and chemical barrier to protect CCA. Tumor-associated macrophages (TAMs) could be differentiated between two phenotypes, pro- and anti-inflammatory, and they may sustain invasiveness and immunosuppression. Myeloid-derived suppressor cells (MDSCs) impair cytotoxic T lymphocytes (CTLs) function, stimulating tumor proliferation and angiogenesis. Tumor-associated neutrophils (TANs) function is influenced by the TME, leading to tumor-suppressing or tumor-promoting functions. This paper aims to provide an overview of the CCA microenvironment cells, their role in tumor progression and possible correlated diagnostic, therapeutic and prognostic implications
The why, when and how of small bowel and panenteric capsule endoscopy in Crohn’s disease
No full textSmall bowel capsule endoscopy (SBCE) is a tool used for Crohn’s disease (CD) diagnosis and monitorization, which aids in appropriate clinical decision-making, especially in the switch of treatment or withdrawal and influencing reclassification of unclassified inflammatory bowel disease. Compared to cross-sectional imaging, namely intestinal ultrasound and magnetic resonance enterography, SBCE has a superior diagnostic yield in proximal small bowel inflammatory activity, which has been associated with greater morbidity. The risk of capsule retention is higher in patients with established CD with suspected stenosis and those with suspected CD with obstructive symptoms, known stenosis or previous small bowel resection. In these situations, SBCE should be administered only after small bowel patency has been evaluated. There is evidence that the pan-enteric capsule (PEC) has a higher diagnostic yield than ileocolonoscopy in detecting terminal ileum mucosal defects. Future research should evaluate the PEC place in CD algorithms as it offers a non-invasive approach, which is especially important in a long-term follow-up, likely diminishing the disease burden
Minimally-invasive anatomical liver resection for hepatocellular carcinoma: a literature overview with technical and anatomical tips and tricks
No full textSince its introduction in 1985, anatomical liver resection (AR) has been performed to treat early-stage hepatocellular carcinoma. The minimally-invasive AR (MIALR) approach can be safely performed at high-volume tertiary referral centers. The resection techniques can vary among surgeons, depending on the center’s experience, patient characteristics, hepatic segment involvement, and tumor characteristics. Profound knowledge of the liver’s surgical anatomy and a standardized inflow control approach is fundamental to performing MIALR safely. This article aims to summarize the applications of the MIALR and its outcomes, focusing on the techniques for vascular inflow control and the essential tips and tricks to standardize these techniques for laparoscopic and robotic approaches
Immunomodulatory role of EV-derived non-coding RNA in lung cancer
No full textLung cancer is the deadliest cancer worldwide, primarily because of its metastatic spread. Extracellular vesicles (EVs) are small lipid-bilayer particles released by almost all types of cells. EVs play fundamental roles in cell-cell communication and cell-environment interactions by carrying proteins, nucleic acids such as DNA and RNA (mRNAs, lncRNAs, and miRNAs), and other bioactive molecules that are able to influence the behaviour of recipient cells. EVs have been described as key players in the modulation of tumour progression and the anticancer immune response. In this review, we highlight current knowledge on the role of non-coding RNAs in the modulation of the immune response, focusing on lung cancer. Since EVs are fundamental cell-to-cell mediators, we discuss the current knowledge on the immunomodulatory properties of tumour-derived EVs and, in particular, their ncRNA cargo during the different phases of lung cancer development and progression
Synaptic proteins in neuron-derived extracellular vesicles as biomarkers for Alzheimer’s disease: novel methodology and clinical proof of concept
No full textAims: Blood biomarkers can improve drug development for Alzheimer’s disease (AD) and its treatment. Neuron-derived extracellular vesicles (NDEVs) in plasma offer a minimally invasive platform for developing novel biomarkers that may be used to monitor the diverse pathogenic processes involved in AD. However, NDEVs comprise only a minor fraction of circulating extracellular vesicles (EVs). Most published studies have leveraged the L1 cell adhesion molecule (L1CAM) for NDEV immunocapture. We aimed to develop and optimize an alternative, highly specific immunoaffinity method to enrich blood NDEVs for biomarker development.Methods: After screening multiple neuronal antigens, we achieved NDEV capture with high affinity and specificity using antibodies against Growth-Associated Protein (GAP) 43 and Neuroligin 3 (NLGN3). The EV identity of the captured material was confirmed by electron microscopy, western blotting, and proteomics. The specificity for neuronal origin was demonstrated by showing enrichment for neuronal markers (proteins, mRNA) and recovery of spiked neuronal EVs. We performed NDEV isolation retrospectively from plasma samples from two cohorts of early AD patients (N = 19 and N = 40) and controls (N = 20 and N = 19) and measured p181-Tau, amyloid-beta (Aβ) 42, brain-derived neurotrophic factor (BDNF), precursor brain-derived neurotrophic factor (proBDNF), glutamate receptor 2 (GluR2), postsynaptic density protein (PSD) 95, GAP43, and syntaxin-1.Results: p181-Tau, Aβ42, and NRGN were elevated in AD samples, whereas proBDNF, GluR2, PSD95, GAP43, and Syntaxin-1 were reduced. Differences for p181-Tau, proBDNF, and GluR2 survived multiple-comparison correction and were correlated with cognitive scores. A model incorporating biomarkers correctly classified 94.7% of AD participants and 61.5% of control participants. The observed differences in NDEVs-associated biomarkers are consistent with previous findings.Conclusion: NDEV isolation by GAP43 and NLGN3 immunocapture offers a robust novel platform for biomarker development in AD, suitable for large-scale validation
Host-guest assemblies for improved photothermal cancer therapy
No full textPhotothermal cancer therapy has attracted plenty of attention in the last decades due to its promising efficacy, spatiotemporal control, negligible drug resistance, etc. However, to achieve widespread clinical application, studies in the field of photothermal therapy still need to focus on the improvement of efficacy and the minimization of side effects. Host-guest assemblies, constructed by the inclusion of small molecular guests into macrocyclic hosts through non-covalent interactions, are featured with unique microenvironments and flexible, dynamic nature. Based on the abovementioned advantages, host-guest assemblies show great potential in photothermal therapy. However, presumably, the endeavors of host-guest assemblies-based photothermal therapy have not been systematically discussed. Hence, to benefit the design of advanced host-guest assembly-based photothermal agents and promote the development of photothermal therapy, in this review, the major achievements of host-guest assemblies in photothermal cancer therapy, including the enhancement of photothermal conversion efficiency, the improvement of targeted distribution at tumor sites, and the superiority of constructing photothermal therapy-derived multimodal synergistic therapy, are discussed. In addition, the future perspectives on host-guest assemblies-based photothermal therapy are outlined
Mechanobiology in the development and progression of non-alcoholic fatty liver disease: an updated review
No full textMechanobiology is a rapidly emerging field focused on the biological impact of physical forces at the molecular, cellular, and tissue level. Living cells perceive mechanical cues and transform them into biochemical signals through mechanotransduction. Mechanotransduction is a complex process that involves mechanosensors (which are located in the plasma membrane or within the cell) and mechanotransmission to the nucleus (which occurs either by physical connection between the mechanosensor and the nucleus or by mechanosignaling through biochemical pathways). Essential biological functions, including development, growth, motility, and metabolism, depend on the mechanoresponses generated by these events. Multiple lines of evidence indicate that disruption of mechanical homeostasis may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a highly prevalent metabolic disorder characterized by abnormal accumulation of lipid droplets in hepatocytes (steatosis) and often associated with inflammation and liver cell injury (steatohepatitis). While predicting individual predisposition to adverse outcomes in NAFLD remains a challenge, there is increasing evidence that steatosis and steatohepatitis trigger mechanoresponses that contribute to the early stages of pathogenesis in NAFLD and critically impact disease progression. Lipid accumulation and lipotoxicity modify liver viscoelasticity, alter the biomechanics of liver sinusoids, and initiate aberrant pathways of mechanotransduction in hepatocytes and non-parenchymal liver cells, such as sinusoidal endothelial cells and hepatic stellate cells. Interactions of these cells at mechanical interfaces with each other, with extracellular matrix, and with sinusoidal blood flow are profoundly altered by steatosis and steatohepatitis; such changes may promote a pro-angiogenic and pro-fibrotic milieu. A better understanding of liver mechanobiology may facilitate the identification of novel molecular and cellular targets in the management of NAFLD.Highlights● Cellular and molecular behavior is regulated by a variety of physical forces;● Viscoelastic properties of the liver are altered in non-alcoholic fatty liver disease (NAFLD);● Sinusoidal hemostasis is disrupted by early functional and structural changes in NAFLD;● Mechanical cues are likely to contribute to all aspects of NAFLD pathogenesis
Parameters optimization of electro-hydraulic power steering system based on multi-objective collaborative method
No full textElectro-hydraulic power steering (EHPS) systems are widely used in commercial vehicles due to their adjustable power assist and energy-saving advantages. In this paper, a dynamic model of the EHPS system is developed, and quantitative expressions for three evaluation indexes, steering road feel, steering sensibility and steering energy loss, are derived for the first time. A multi-objective collaborative optimization model of the EHPS system is then established, which consists of one total system and three parallel subsystems, based on collaborative optimization theory. Considering the coupled variables of each subsystem, the total system is optimized by a multi-objective algorithm, while the subsystems are optimized by a single-objective algorithm. The optimization results demonstrate that the average frequency domain energy of the steering road feel is increased by 69.1%, the average frequency domain energy of steering sensitivity is reduced by 19.2%, and steering energy consumption is reduced by 10.8% compared to the initial value. The non-dominated sorting genetic algorithm-II (NSGA-II) shows superior comprehensive performance compared to the other two multi-objective algorithms, and the optimization performance can be further improved by setting appropriate algorithm parameters
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