- Immune checkpoint pathways, including programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) signaling pathway, which are important in mediating self-tolerance and controlling ...self-damage, can sometimes be manipulated by cancer cells to evade immune surveillance. Recent clinical trials further demonstrate the efficacy of PD-1/PD-L1-targeted therapy in various cancers and reveal a new era of cancer immunotherapy.
- To review the mechanism of the PD-1/PD-L1 signaling pathway, the regulation of this pathway, PD-1/PD-L1 as a predictive and/or prognostic marker in various cancers, and strategies of measuring PD-L1 expression.
- Representative medical literature regarding PD-L1 expression in various cancers, including the preliminary results of the Blue Proposal, which compares different immunohistochemical stains for PD-L1 reported in the recent American Association of Cancer Research (AACR) Annual Meeting (April 16-20, 2016).
- Either PD-1/PD-L1-targeted therapy alone or in combination with other treatment modalities provides benefit for patients with advanced cancers. Because of the complexity of cancer immunity, we still do not have a reliable biomarker to predict the response of PD-1/PD-L1-targeted therapy. Future studies, including methods beyond immunohistochemical stains, are needed to develop reliable biomarker/biomarkers for pathology laboratories to aid in selecting patients who will benefit most from PD-1/PD-L1-targeted therapy.
Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of ...this study is to assess whether a widely used probiotic
can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of
on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of
or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes,
or
, according to the reduction of caspase-1 activation and IL-1β maturation. Mechanistically,
attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments,
can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand,
cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic,
, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.
The advancement of unmanned aerial vehicles (UAVs) enables early detection of numerous disasters. Efforts have been made to automate the monitoring of data from UAVs, with machine learning methods ...recently attracting significant interest. These solutions often face challenges with high computational costs and energy usage. Conventionally, data from UAVs are processed using cloud computing, where they are sent to the cloud for analysis. However, this method might not meet the real-time needs of disaster relief scenarios. In contrast, edge computing provides real-time processing at the site but still struggles with computational and energy efficiency issues. To overcome these obstacles and enhance resource utilization, this paper presents a convolutional neural network (CNN) model with an early exit mechanism designed for fire detection in UAVs. This model is implemented using TSMC 40 nm CMOS technology, which aids in hardware acceleration. Notably, the neural network has a modest parameter count of 11.2 k. In the hardware computation part, the CNN circuit completes fire detection in approximately 230,000 cycles. Power-gating techniques are also used to turn off inactive memory, contributing to reduced power consumption. The experimental results show that this neural network reaches a maximum accuracy of 81.49% in the hardware implementation stage. After automatic layout and routing, the CNN hardware accelerator can operate at 300 MHz, consuming 117 mW of power.
Traumatic brain injury (TBI) is a progressive and complex pathological condition that results in multiple adverse consequences, including impaired learning and memory. Transplantation of mesenchymal ...stem cells (MSCs) has produced limited benefits in experimental TBI models. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has neuroprotective effects, promotes remyelination, enhances angiogenesis, and elongates astrocytic processes. In this study, MSCs were genetically engineered to overexpress FGF21 in order to improve their efficacy in TBI. MSCs overexpressing FGF21 (MSC-FGF21) were transplanted to mouse brain by intracerebroventricular injection 24 h after TBI was induced by controlled cortical impact (CCI). Hippocampus-dependent spatial learning and memory, assessed by the Morris water maze test, was markedly decreased 3-4 weeks after TBI, a deficit that was robustly recovered by treatment with MSC-FGF21, but not MSC-mCherry control. Hippocampus-independent learning and memory, assessed by the novel object recognition test, was also impaired; these effects were blocked by treatment with both MSC-FGF21 and MSC-mCherry control. FGF21 protein levels in the ipsilateral hippocampus were drastically reduced 4 weeks post-TBI, a loss that was restored by treatment with MSC-FGF21, but not MSC-mCherry. MSC-FGF21 treatment also partially restored TBI-induced deficits in neurogenesis and maturation of immature hippocampal neurons, whereas MSC-mCherry was less effective. Finally, MSC-FGF21 treatment also normalized TBI-induced impairments in dendritic arborization of hippocampal neurons. Taken together, the results indicate that MSC-FGF21 treatment significantly improved TBI-induced spatial memory deficits, impaired hippocampal neurogenesis, and abnormal dendritic morphology. Future clinical investigations using MSC-FGF21 to improve post-TBI outcomes are warranted.
Cancer stem cells (CSCs) comprise a minor cell population in a tumor; however, they possess self-renewal capacity and are responsible for tumor recurrence and the emerging issue of tumor resistance. ...Despite recent advances in the study of pathogenesis and mechanisms of CSC-mediated disease recurrence and multidrug resistance, many questions remain unanswered.
To provide an overview of CSC theory and to describe major methods of CSC detection and isolation, with the emphasis on those techniques that are potentially relevant in clinical laboratory practice. Particular attention is given to CSC markers, such as cancer testis antigens, which could become promising targets in the development of immunotherapy in settings of minimal residual disease.
The review is based on analysis of peer-reviewed literature cited in PubMed, as well as preliminary results of studies conducted in our laboratory.
Despite a lack of consensus in the scientific community on research methodology, CSCs have demonstrated significant potential as therapeutic targets in the treatment of cancer. Further research of CSC biology and markers will eventually lead to the development of novel therapeutic approaches for targeting these cells to treat resistant and recurrent tumors and minimal residual disease.
Polychromatic flow cytometry is a popular technique that has wide usage in the medical sciences, especially for studying phenotypic properties of cells. The high-dimensionality of data generated by ...flow cytometry usually makes it difficult to visualize. The naive solution of simply plotting two-dimensional graphs for every combination of observables becomes impractical as the number of dimensions increases. A natural solution is to project the data from the original high dimensional space to a lower dimensional space while approximately preserving the overall relationship between the data points. The expert can then easily visualize and analyze this low-dimensional embedding of the original dataset.
This paper describes a new method, SANJAY, for visualizing high-dimensional flow cytometry datasets. This technique uses a decision procedure to automatically synthesize two-dimensional and three-dimensional projections of the original high-dimensional data while trying to minimize distortion. We compare SANJAY to the popular multidimensional scaling (MDS) approach for visualization of small data sets drawn from a representative set of benchmarks, and our experiments show that SANJAY produces distortions that are 1.44 to 4.15 times smaller than those caused due to MDS. Our experimental results show that SANJAY also outperforms the Random Projections technique in terms of the distortions in the projections.
We describe a new algorithmic technique that uses a symbolic decision procedure to automatically synthesize low-dimensional projections of flow cytometry data that typically have a high number of dimensions. Our algorithm is the first application, to our knowledge, of using automated theorem proving for automatically generating highly-accurate, low-dimensional visualizations of high-dimensional data.
Activation of the nod-like receptor 3 (NLRP3) inflammasomes is crucial for immune defense, but improper and excessive activation causes inflammatory diseases. We previously reported that Cbl plays a ...pivotal role in suppressing NLRP3 inflammasome activation by inhibiting Pyk2-mediated apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. Here, we showed that Cbl dampened NLRP3 inflammasome activation by inhibiting glycolysis, as demonstrated with Cbl knockout cells and treatment with the Cbl inhibitor hydrocotarnine. We revealed that the inhibition of Cbl promoted caspase-1 cleavage and interleukin (IL)-1β secretion through a glycolysis-dependent mechanism. Inhibiting Cbl increased cellular glucose uptake, glycolytic capacity, and mitochondrial oxidative phosphorylation capacity. Upon NLRP3 inflammasome activation, inhibiting Cbl increased glycolysis-dependent activation of mitochondrial respiration and increased the production of reactive oxygen species, which contributes to NLRP3 inflammasome activation and IL-1β secretion. Mechanistically, inhibiting Cbl increased surface expression of glucose transporter 1 (GLUT1) protein through post-transcriptional regulation, which increased cellular glucose uptake and consequently raised glycolytic capacity, and in turn enhanced NLRP3 inflammasome activation. Together, our findings provide new insights into the role of Cbl in NLRP3 inflammasome regulation through GLUT1 downregulation. We also show that a novel Cbl inhibitor, hydrocortanine, increased NLRP3 inflammasome activity via its effect on glycolysis.
Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often ...limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo.
PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated.
Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway.
Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.
Aims
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm with leukaemic features and frequent skin involvement. Translocations involving the MYC locus have been recently ...identified as recurrent cytogenetic abnormalities in this entity. The aim of this study was to assess the clinicopathological, immunophenotypic and genetic features in MYC‐rearranged BPDCN cases.
Methods and results
Pathology archives from six major institutes were queried for cases of BPDCN with 8q24 MYC translocations, and two cases were identified. A literature review identified 14 cases. Clinicopathological features, immunophenotype and cytogenetic and molecular data were reviewed. In these 16 MYC‐rearranged cases, the median age at diagnosis was 70.5 years, and there was a male predominance. Whereas all cases showed marrow involvement, skin lesions (62.5%) and lymphadenopathy (50%) were variably seen. The median survival was 11 months. The median percentage of blasts in peripheral blood was 9%. All cases showed expression of CD4, with 10 of 16 being positive for CD56. HLA‐DR, CD123, TCL1 and CD303 were positive in all cases tested. Cytogenetic analysis revealed a single recurrent translocation partner of MYC at 6p21 in 11 cases (69%), whereas four cases showed different MYC translocation partners (2p12, Xq24, 3p25, and 14q32). Interestingly, the group of patients with t(6;8)(p21;q24) showed an older median age at diagnosis (74 years) and a remarkably shorter median survival (3 months).
Conclusions
Translocations involving the 8q24 MYC locus more frequently manifest as t(6;8)(p21;q24), and, given its association with specific clinicopathological features suggesting even more aggressive behaviour, t(6;8)(p21;q24) indicate a genetically defined subgroup within BPDCN.
Parkinson's disease (PD) is typically characterized by impairment of motor function. Gait disturbances similar to those observed in patients with PD can be observed in animals after injection of ...neurotoxin 6-hydroxydopamine (6-OHDA) to induce unilateral nigrostriatal dopamine depletion. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegenerative disease.
In this study, we investigated the long-term effects of voluntary running wheel exercise on gait phenotypes, depression, cognitive, rotational behaviors as well as histology in a 6-OHDA-lesioned rat model of PD.
We observed that, when compared with the non-exercise controls, five-week voluntary exercise alleviated and postponed the 6-OHDA-induced gait deficits, including a significantly improved walking speed, step/stride length, base of support and print length. In addition, we found that the non-motor functions, such as novel object recognition and forced swim test, were also ameliorated by voluntary exercise. However, the rotational behavior of the exercise group did not show significant differences when compared with the non-exercise group.
We first analyzed the detailed spatiotemporal changes of gait pattern to investigate the potential benefits after long-term exercise in the rat model of PD, which could be useful for future objective assessment of locomotor function in PD or other neurological animal models. Furthermore, these results suggest that short-term voluntary exercise is sufficient to alleviate cognition deficits and depressive behavior in 6-OHDA lesioned rats and long-term treatment reduces the progression of motor symptoms and elevates tyrosine hydroxylase (TH), Brain-derived neurotrophic factor (BDNF), bone marrow tyrosine kinase in chromosome X (BMX) protein expression level without affecting dopaminergic (DA) neuron loss in this PD rat model.
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