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Journal of Cancer 2024Skin cutaneous melanoma (SKCM) is a highly malignant tumor that is prone to immune escape and distant metastasis. Immunotherapy is considered to be the best treatment...
Skin cutaneous melanoma (SKCM) is a highly malignant tumor that is prone to immune escape and distant metastasis. Immunotherapy is considered to be the best treatment for patients with SKCM. However, not all patients benefit from it. We observed a significant differential expression of the lncRNA CYTOR in patients with SKCM based on single-cell and bulk RNA sequencing data mining results. The results showed that compared to normal tissue lncRNA CYTOR expression was significantly upregulated in SKCM tissue. Subsequently, we validated this finding in clinical samples, and we also found that the expression of lncRNA CYTOR in SKCM was higher as it progressed. lncRNA CYTOR was differentially expressed in patients who responded to immunotherapy, suggesting that it may serve as a biomarker to predict the efficacy of SKCM immunotherapy. In-depth analysis revealed that lncRNA CYTOR expression was strongly correlated with immune cell infiltration, immune response, and immune checkpoint expression. Meanwhile, our experiments revealed that CYTOR affects SKCM cell invasion and clone formation and is associated with the activation of the EMT pathway. In summary, our findings illustrate, for the first time, the value of CYTOR as a potential prognostic and immunotherapeutic response marker in SKCM.
PubMed: 38911384
DOI: 10.7150/jca.94823 -
Microsystems & Nanoengineering 2024Assays mimicking in vitro the concentration gradients triggering biological responses like those involved in fighting infections and blood clotting are essential for...
Assays mimicking in vitro the concentration gradients triggering biological responses like those involved in fighting infections and blood clotting are essential for biomedical research. Microfluidic assays prove especially attractive as they allow precise control of gradient shape allied to a reduction in scale. Conventional microfluidic devices are fabricated using solid plastics that prevent direct access to responding cells. Fluid-walled microfluidics allows the manufacture of circuits on standard Petri dishes in seconds, coupled to simple operating methods; cell-culture medium sitting in a standard dish is confined to circuits by fluid walls made of an immiscible fluorocarbon. We develop and experimentally validate an analytical model of diffusion between two or more aqueous streams flowing at different rates into a fluid-walled conduit with the cross-section of a circular segment. Unlike solid walls, fluid walls morph during flows as pressures fall, with wall shape changing down the conduit. The model is validated experimentally for Fourier numbers < 0.1 using fluorescein diffusing between laminar streams. It enables a priori prediction of concentration gradients throughout a conduit, so allowing rapid circuit design as well as providing bio-scientists with an accurate way of predicting local concentrations of bioactive molecules around responsive and non-responsive cells.
PubMed: 38911344
DOI: 10.1038/s41378-024-00698-1 -
Clinical, Cosmetic and Investigational... 2024High levels of UV exposure are a significant factor that can trigger the onset and progression of SKCM. Moreover, this exposure is closely linked to the malignancy of...
BACKGROUND
High levels of UV exposure are a significant factor that can trigger the onset and progression of SKCM. Moreover, this exposure is closely linked to the malignancy of the tumor and the prognosis of patients. Our objective is to identify a tumor biomarker database associated with UV exposure, which can be utilized for prognostic analysis and diagnosis and treatment of SKCM.
METHODS
This study used the weighted gene co-expression network analyses (WGCNA) and gene mutation frequency analyses to screen for UV-related target genes using the GSE59455 and the cancer genome atlas databases (TCGA). The prognostic model was created using Cox regression and least absolute shrinkage and selection operator analyses (LASSCO). Furthermore, in vitro experiments further validated that the overexpression or knockdown of COL4A3 could regulate the proliferation and migration abilities of SKMEL28 and A357 melanoma cells.
RESULTS
A prognostic model was created that included six genes with a high UV-related mutation in SKCM: COL4A3, CHRM2, DSC3, GIMAP5, LAMC2, and PSG7. The model had a strong patient survival correlation (˂0.001, hazard ratio (HR) = 1.57) and significant predictor (˂0.001, HR = 3.050). Furthermore, the model negatively correlated with immune cells, including CD8 T cells (Cor=-0.408, ˂0.001), and M1-type macrophages (Cor=-0.385, ˂0.001), and immune checkpoints, including programmed cell death ligand-1. Moreover, we identified COL4A3 as a molecule with significant predictive functionality. Overexpression of COL4A3 significantly inhibited the proliferation, migration, and invasion abilities of SKMEL28 and A357 melanoma cells, while knockdown of COL4A3 yielded the opposite results. And overexpression of COL4A3 enhanced the inhibitory effects of imatinib on the proliferation, migration, and invasion abilities of SKMEL28 and A357 cells.
CONCLUSION
The efficacy of the prognostic model was validated by analyzing the prognosis, immune infiltration, and immune checkpoint profiles. COL4A3 stands out as a novel diagnostic and therapeutic target for SKCM, offering new strategies for small-molecule targeted drug therapies.
PubMed: 38911338
DOI: 10.2147/CCID.S461959 -
RSC Advances Jun 2024High entropy alloys (HEAs) exhibit superior mechanical properties. However, the nanoscratching properties and deformation behaviour of FeCoCrNiAl0.5 HEAs remain unknown...
High entropy alloys (HEAs) exhibit superior mechanical properties. However, the nanoscratching properties and deformation behaviour of FeCoCrNiAl0.5 HEAs remain unknown at the nanoscale. Here, we investigate the effect of scratching depth on the microstructural and tribological characteristics of an FeCoCrNiAl0.5 HEA using molecular dynamics simulations combined with a physical model. The scratching force increases significantly as the scratching depth increases. In the lower part of the scratching region, there is a clear atomic movement process, with the load generated in the normal direction causing the atoms to shift downwards. Noticeable shear bands are formed in the subsurface area, and they are both small and narrow compared with the pure Ni. The plastic deformation mechanism of the compressed surface is mainly governed by the formation and expansion of stacking faults during the subsurface evolution process. The evolution process of screw dislocations is similar to that of edge dislocations. In addition, the high strength and deformation resistance of FeCoCrNiAl0.5 HEAs are further evaluated by establishing a microstructure-based physical model. The combined effect of the lattice distortion strengthening and dislocation strengthening promotes the high strength of the FeCoCrNiAl0.5 HEA, which is significantly better than the single strengthening mechanism of pure metals. These results accelerate the understanding of the mechanical properties and deformation mechanisms of HEAs.
PubMed: 38911269
DOI: 10.1039/d4ra02422b -
Frontiers in Human Neuroscience 2024Repetitive somatosensory stimulation (RSS) is a conventional approach to modulate the neural states of both the primary somatosensory cortex (S1) and the primary motor...
INTRODUCTION
Repetitive somatosensory stimulation (RSS) is a conventional approach to modulate the neural states of both the primary somatosensory cortex (S1) and the primary motor cortex (M1). However, the impact of RSS on skill acquisition and retention in sensorimotor adaptation remains debated. This study aimed to investigate whether whole-hand water flow (WF), a unique RSS-induced M1 disinhibition, influences sensorimotor adaptation by examining the hypothesis that whole-hand WF leads to M1 disinhibition; thereby, enhancing motor memory retention.
METHODS
Sixty-eight young healthy participants were randomly allocated to three groups based on the preconditioning received before motor learning: control, whole-hand water immersion (WI), and whole-hand WF. The experimental protocol for all the participants spanned two consecutive days. On the initial day (day 1), baseline transcranial magnetic stimulation (TMS) assessments (T0) were executed before any preconditioning. Subsequently, each group underwent their respective 30 min preconditioning protocol. To ascertain the influence of each preconditioning on the excitability of the M1, subsequent TMS assessments were conducted (T1). Following this, all participants engaged in the motor learning (ML) of a visuomotor tracking task, wherein they were instructed to align a cursor with a target trajectory by modulating the pinch force. Upon completion of the ML session, final TMS assessments (T2) were conducted. All participants were required to perform the same motor learning 24 h later on day 2.
RESULTS
The results revealed that whole-hand WF did not significantly influence skill acquisition during sensorimotor adaptation, although it did reduce intracortical inhibition. This phenomenon is consistent with the idea that S1, rather than M1, is involved in skill acquisition during the early stages of sensorimotor adaptation. Moreover, memory retention 24 h after skill acquisition did not differ significantly across the three groups, challenging our initial hypothesis that whole-hand WF enhances memory retention throughout sensorimotor adaptation. This could be due to the inability of whole-hand WF to alter sensorimotor connectivity and integration, as well as the nature of the plastic response elicited by the preconditioning.
DISCUSSION
In conclusion, these findings suggest that although whole-hand WF attenuates intracortical inhibition, it does not modulate skill acquisition or motor memory retention during sensorimotor adaptation.
PubMed: 38911224
DOI: 10.3389/fnhum.2024.1398164 -
Journal of Experimental Orthopaedics Jul 2024To investigate the level of cellular senescence in stem cells derived from microfragmented abdominal adipose tissue harvested from patients with knee osteoarthritis (OA).
Microfragmented abdominal adipose tissue-derived stem cells from knee osteoarthritis patients aged 29-65 years demonstrate in vitro stemness and low levels of cellular senescence.
PURPOSE
To investigate the level of cellular senescence in stem cells derived from microfragmented abdominal adipose tissue harvested from patients with knee osteoarthritis (OA).
METHODS
Stem cells harvested from microfragmented abdominal adipose tissue from 20 patients with knee OA, aged 29-65 years (mean = 49.8, SD = 9.58), were analysed as a function of patient age and compared with control cells exhibiting signs of cellular senescence. Steady-state mRNA levels of a panel of genes associated with senescence were measured by qPCR. Intracellular senescence-associated proteins p16 and p21, and senescence-associated β-galactosidase activity were measured by flow cytometry. Cellular proliferation was assessed using a 5-ethynyl-2'-deoxyuridine proliferation assay. Stemness was assessed by stem cell surface markers using flow cytometry and the capacity to undergo adipogenic and osteogenic differentiation in vitro.
RESULTS
No correlation was found between cellular senescence levels of the microfragmented adipose tissue-derived stem cells and patient age for any of the standard assays used to quantify senescence. The level of cellular senescence was generally low across all senescence-associated assays compared to the positive senescence control. Stemness was verified for all samples. An increased capacity to undergo adipogenic differentiation was shown with increasing patient age ( = 0.02). No effect of patient age was found for osteogenic differentiation.
CONCLUSIONS
Autologous microfragmented adipose tissue-derived stem cells may be used in clinical trials of knee OA of patients aged 29-65 years, at least until passage 4, as they show stemness potential and negligible senescence in vitro.
LEVEL OF EVIDENCE
Not applicable.
PubMed: 38911188
DOI: 10.1002/jeo2.12056 -
Frontiers in Cellular Neuroscience 2024Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. However,...
Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) at layer 2/3 pyramidal neurons (PNs) of the mouse barrel cortex is favored or prevented by IGF-I (10 nM) or IGF-I (7 nM), respectively, when IGF-I is applied 1 h before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10 nM IGF-I generates LTP (LTP) of the post-synaptic potentials (PSPs) by inducing long-term depression (LTD) of the inhibitory post-synaptic currents (IPSCs), 7 nM IGF-I generates LTD of the PSPs (LTD) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain.
PubMed: 38910964
DOI: 10.3389/fncel.2024.1390663 -
Acta Oncologica (Stockholm, Sweden) Jun 2024
Topics: Humans; Neoplasms; Practice Guidelines as Topic; Cancer Survivors
PubMed: 38910334
DOI: 10.2340/1651-226X.2024.40787 -
Brain Research Jun 2024Non-invasive brain stimulation induces changes in spontaneous neural activity in the cerebral cortex through facilitatory or inhibitory mechanisms, relying on... (Review)
Review
BACKGROUND
Non-invasive brain stimulation induces changes in spontaneous neural activity in the cerebral cortex through facilitatory or inhibitory mechanisms, relying on neuromodulation of neural excitability to impact brain plasticity. This systematic review assesses the state-of-the art and existing evidence regarding the effectiveness of NIBS in cognitive recovery among patients with chronic stroke.
MATERIALS AND METHODS
We conducted a systematic search, following PRISMA guidelines, for articles published from January 2010 through September 2023. We searched the following databases: PubMed, Embase, Cochrane Database of Systematic Reviews, PEDro, Rehab Data, and Web of Science.
RESULTS
Our electronic searches identified 109 papers. We assessed and included 61 studies based on their pertinence and relevance to the topic. After reading the full text of the selected publications and applying predefined inclusion criteria, we excluded 32 articles, leaving 28 articles for our qualitative analysis. We categorized our results into two sections as follows: (1) Cognitive and emotional domains (11 studies), (2) language and speech functions (16 studies).
CONCLUSION
Our findings highlight the potential of NIBS, such as tDCS and rTMS, in the cognitive, linguistic, and emotional recovery of post-stroke patients. Although it seems that NIBS may work as a complementary tool to enhance cognitive and communication abilities in patients with stroke -also in the chronic phase- evidence on behavioural outcomes is still poor. Future studies should focus on this important issue to confirm the effectiveness of neuromodulation in chronic neurological diseases. PROSPERO Registration: CRD42023458370.
PubMed: 38909976
DOI: 10.1016/j.brainres.2024.149093 -
European Journal of Pharmacology Jun 2024Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively... (Review)
Review
Cysteinyl leukotrienes (CysLTs) are central to the pathophysiology of asthma and various inflammatory disorders. Leukotriene receptor antagonists (LTRAs) effectively treat respiratory conditions by targeting cysteinyl leukotriene receptors, CysLT and CysLT subtypes. This review explores the multifaceted effects of LTs, extending beyond bronchoconstriction. CysLT receptors are not only present in the respiratory system but are also crucial in neuronal signaling pathways. LTRAs modulate these receptors, influencing downstream signaling, calcium levels, inflammation, and oxidative stress (OS) within neurons hinting at broader implications. Recent studies identify novel molecular targets, sparking interest in repurposing LTRAs for therapeutic use. Clinical trials are investigating their potential in neuroinflammation control, particularly in Alzheimer's disease (AD) and Parkinson's diseases (PD). However, montelukast, a long-standing LTRA since 1998, raises concerns due to neuropsychiatric adverse drug reactions (ADRs). Despite widespread use, understanding montelukast's metabolism and underlying ADR mechanisms remains limited. This review comprehensively examines LTRAs' diverse biological effects, emphasizing non-bronchoconstrictive activities. It also analyses plausible mechanisms behind LTRAs' neuronal effects, offering insights into their potential as neurodegenerative disease modulators. The aim is to inform clinicians, researchers, and pharmaceutical developers about LTRAs' expanding roles, particularly in neuroinflammation control and their promising repurposing for neurodegenerative disease management.
PubMed: 38909933
DOI: 10.1016/j.ejphar.2024.176755