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Journal of Cancer Research and Clinical... Dec 2023FKBP1A, a gene encoding the FK506-binding protein 1A, has emerged as a significant player in cancer progression and prognosis. This study aimed to comprehensively...
BACKGROUND AND AIM
FKBP1A, a gene encoding the FK506-binding protein 1A, has emerged as a significant player in cancer progression and prognosis. This study aimed to comprehensively investigate the multifaceted role of FKBP1A in cancer, focusing on its differential expression patterns, prognostic implications, genetic alterations, and associations with the tumor microenvironment.
METHODS AND RESULTS
Using large-scale datasets, including GTEx, TCGA, HPA, and cBioPortal, we analyzed FKBP1A expression across normal tissues and various cancer types. Our findings revealed that FKBP1A exhibited aberrant upregulation in most human cancers, making it a potential biomarker for malignancy. Moreover, FKBP1A expression correlated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in several cancers, indicating its prognostic significance. Genetic alteration analysis showed that FKBP1A gene amplification was prevalent, particularly in ovarian cancer. Furthermore, FKBP1A expression was associated with tumor mutational burden and microsatellite instability, highlighting its potential involvement in tumor-immune response. Notably, FKBP1A expression positively correlated with stromal and immune cell scores, suggesting its role in shaping the tumor microenvironment. Additionally, according to the functional enrichment analysis, experimental validation in lung adenocarcinoma confirmed the role of FKBP1A through the regulation of EGFR signaling by apoptosis, which is consistent with drug sensitivity analysis to some extent.
CONCLUSION
In conclusion, FKBP1A exhibits differential expression in cancer, serves as a prognostic indicator, undergoes genetic alterations, and influences the tumor-immune microenvironment. These findings shed light on the multifaceted role of FKBP1A in cancer development and progression, suggesting its potential as a therapeutic target and guidance of clinical drugs selection, and provide valuable insights into patient prognosis for interventions based on pharmaceuticals.
Topics: Humans; Female; Lung Neoplasms; Prognosis; Adenocarcinoma of Lung; Ovarian Neoplasms; Apoptosis; Tumor Microenvironment; Tacrolimus Binding Proteins
PubMed: 37715833
DOI: 10.1007/s00432-023-05362-1 -
Shock (Augusta, Ga.) Aug 2023Alcohol use disorder is associated with increased mortality in septic patients. Murine studies demonstrate that ethanol/sepsis is associated with changes in gut...
Alcohol use disorder is associated with increased mortality in septic patients. Murine studies demonstrate that ethanol/sepsis is associated with changes in gut integrity. This study examined intestinal permeability after ethanol/sepsis and investigated mechanisms responsible for alterations in barrier function. Mice were randomized to drink either 20% ethanol or water for 12 weeks and then were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability was disproportionately increased in ethanol/septic mice via the pore, leak, and unrestricted pathways. Consistent with increased permeability in the leak pathway, jejunal myosin light chain (MLC) kinase (MLCK) expression and the ratio of phospho-MLC to total MLC were both increased in ethanol/CLP. Gut permeability was altered in MLCK -/- mice in water/CLP; however, permeability was not different between WT and MLCK -/- mice in ethanol/CLP. Similarly, jejunal IL-1β levels were decreased while systemic IL-6 levels were increased in MLCK -/- mice in water/CLP but no differences were identified in ethanol/CLP. While we have previously shown that mortality is improved in MLCK -/- mice after water/CLP, mortality was significantly worse in MLCK -/- mice after ethanol/CLP. Consistent with an increase in the pore pathway, claudin 4 levels were also selectively decreased in ethanol/CLP WT mice. Furthermore, mRNA expression of jejunal TNF and IFN-γ were both significantly increased in ethanol/CLP. The frequency of CD4 + cells expressing TNF and IL-17A and the frequency of CD8 + cells expressing IFN-γ in Peyer's Patches were also increased in ethanol/CLP. Thus, there is an ethanol-specific worsening of gut barrier function after CLP that impacts all pathways of intestinal permeability, mediated, in part, via changes to the tight junction. Differences in the host response in the setting of chronic alcohol use may play a role in future precision medicine approaches toward the treatment of sepsis.
Topics: Animals; Mice; Ethanol; Immunity; Intestinal Mucosa; Punctures; Sepsis; Tight Junctions
PubMed: 37405872
DOI: 10.1097/SHK.0000000000002162 -
Neuroscience and Biobehavioral Reviews Jun 2024Similar to addictive substances, addictive behaviours such as gambling and gaming are associated with maladaptive modulation of key brain areas and functional networks... (Review)
Review
Similar to addictive substances, addictive behaviours such as gambling and gaming are associated with maladaptive modulation of key brain areas and functional networks implicated in learning and memory. Therefore, this review sought to understand how different learning and memory processes relate to behavioural addictions and to unravel their underlying neural mechanisms. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched four databases - PsycINFO, PubMed, Scopus, and Web of Science using the agreed-upon search string. Findings suggest altered executive function-dependent learning processes and enhanced habit learning in behavioural addiction. Whereas the relationship between working memory and behavioural addiction is influenced by addiction type, working memory aspect, and task nature. Additionally, long-term memory is incoherent in individuals with addictive behaviours. Consistently, neurophysiological evidence indicates alterations in brain areas and networks implicated in learning and memory processes in behavioural addictions. Overall, the present review argues that, like substance use disorders, alteration in learning and memory processes may underlie the development and maintenance of behavioural addictions.
PubMed: 38870547
DOI: 10.1016/j.neubiorev.2024.105747 -
Medical Oncology (Northwood, London,... Jul 2023The Nuclear factor erythroid 2-related factor 2 (Nrf2) protein has garnered significant interest due to its crucial function in safeguarding cells and tissues. The Nrf2... (Review)
Review
The Nuclear factor erythroid 2-related factor 2 (Nrf2) protein has garnered significant interest due to its crucial function in safeguarding cells and tissues. The Nrf2 protein is crucial in preserving tissue integrity by safeguarding cells against metabolic, xenobiotic and oxidative stress. Due to its various functions, Nrf2 is a potential pharmacological target for reducing the incidence of diseases such as cancer. However, mutations in Keap1-Nrf2 are not consistently favored in all types of cancer. Instead, they seem to interact with specific driver mutations of tumors and their respective tissue origins. The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway mutations are a powerful cancer adaptation that utilizes inherent cytoprotective pathways, encompassing nutrient metabolism and ROS regulation. The augmentation of Nrf2 activity elicits significant alterations in the characteristics of neoplastic cells, such as resistance to radiotherapy and chemotherapy, safeguarding against apoptosis, heightened invasiveness, hindered senescence, impaired autophagy and increased angiogenesis. The altered activity of Nrf2 can arise from diverse genetic and epigenetic modifications that instantly impact Nrf2 regulation. The present study aims to showcase the correlation between the Keap1-Nrf2 pathway and the progression of cancers, emphasizing genetic mutations, metabolic processes, immune regulation, and potential therapeutic strategies. This article delves into the intricacies of Nrf2 pathway anomalies in cancer, the potential ramifications of uncontrolled Nrf2 activity, and therapeutic interventions to modulate the Keap1-Nrf2 pathway.
Topics: Humans; Kelch-Like ECH-Associated Protein 1; Antioxidants; NF-E2-Related Factor 2; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 37480500
DOI: 10.1007/s12032-023-02124-4 -
BMC Cancer Jul 2023Breast cancer (BC) with low human epidermal growth factor receptor 2 (HER2) expression is attracting much attention due to the breakthrough progress of novel anti-HER2...
BACKGROUND
Breast cancer (BC) with low human epidermal growth factor receptor 2 (HER2) expression is attracting much attention due to the breakthrough progress of novel anti-HER2 antibody-drug conjugates. HER2 expression is examined in patients with HER2-low BC and their distant metastases in this study, so as to further clarify the dynamic characteristics of HER2 low status in the process of disease progression.
METHODS
Patients diagnosed with HER2 low breast cancer (defined as IHC1+ or IHC2+/ISH-) between 2012 and 2021 were included in this study. We evaluated HER2 expression of primary sites and metastatic sites, compared the impact of different clinicopathological parameters on HER2 status of metastases and compared the overall survival and disease-free survival of patients with different HER2 status in metastases.
RESULTS
Ninety-eight patients were included. All HER2 IHC scores were confirmed and the consistent rate with the original pathological report was 81.1%. 27.6% of the patients showed different HER2 status in metastases. The HER2 discordance rate differed among different metastatic sites (p = 0.040). The higher the T stage of the primary BC, the higher the rate of HER2 discordance was observed (p = 0.042). For the specimen type of metastasis, HER2 discordant rate was higher in surgical specimen than biopsy (p = 0.050). No difference of HER2 discordance rate was found between HER2-1+ and HER2-2+ patients. But comparing HER2 IHC score, HER2-2+ patients were less likely to have consistent metastatic HER2 levels than HER2-1+ patients (p = 0.006). No difference in survival outcomes was observed between patients with different HER2 status in metastases.
CONCLUSIONS
There is a possibility of HER2 expression alteration in the metastases of HER2-low breast cancer. And the rate of altered HER2 low expression was different among different metastatic sites, different T stages of primary BC and specimen type of metastasis. No prognostic significance was observed.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Prognosis; Biopsy; Antineoplastic Agents; Disease Progression; Biomarkers, Tumor
PubMed: 37442945
DOI: 10.1186/s12885-023-11134-4 -
World Journal of Clinical Cases May 2024Despite the increasing scientific interest and expanding role of gut microbiota (GM) in human health, it is rarely reported in case reports and deployed in clinical...
Despite the increasing scientific interest and expanding role of gut microbiota (GM) in human health, it is rarely reported in case reports and deployed in clinical practice. Proteins and metabolites produced by microbiota contribute to immune system development, energy homeostasis and digestion. Exo- and endogenous factors can alter its composition. Disturbance of microbiota, also known as dysbiosis, is associated with various pathological conditions. Specific bacterial taxa and related metabolites are involved in disease pathogenesis and therefore can serve as a diagnostic tool. GM could also be a useful prognostic factor by predicting future disease onset and preventing hospital-associated infections. Additionally, it can influence response to treatments, including those for cancers, by altering drug bioavailability. A thorough understanding of its function has permitted significant development in therapeutics, such as probiotics and fecal transplantation. Hence, GM should be considered as a ground-breaking biological parameter, and it is advisable to be investigated and reported in literature in a more consistent and systematic way.
PubMed: 38765739
DOI: 10.12998/wjcc.v12.i14.2293 -
The Journal of Neuroscience : the... Nov 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Recently, genome-wide association studies identified KIF5A as a new...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Recently, genome-wide association studies identified KIF5A as a new ALS-causing gene. KIF5A encodes a protein of the kinesin-1 family, allowing the anterograde transport of cargos along the microtubule rails in neurons. In ALS patients, mutations in the KIF5A gene induce exon 27 skipping, resulting in a mutated protein with a new C-terminal region (KIF5A Δ27). To understand how KIF5A Δ27 underpins the disease, we developed an ALS-associated KIF5A model. When selectively expressed in motor neurons, KIF5A Δ27 alters larval locomotion as well as morphology and synaptic transmission at neuromuscular junctions in both males and females. We show that the distribution of mitochondria and synaptic vesicles is profoundly disturbed by KIF5A Δ27 expression. That is consistent with the numerous KIF5A Δ27-containing inclusions observed in motor neuron soma and axons. Moreover, KIF5A Δ27 expression leads to motor neuron death and reduces life expectancy. Our model reveals that a toxic gain of function underlies the pathogenicity of ALS-linked KIF5A mutant. Understanding how a mutation identified in patients with amyotrophic lateral sclerosis (ALS) causes the disease and the loss of motor neurons is crucial to fight against this disease. To this end, we have created a model based on the motor neuron expression of the KIF5A mutant gene, recently identified in ALS patients. KIF5A encodes a kinesin that allows the anterograde transport of cargos. This model recapitulates the main features of ALS, including alterations of locomotion, synaptic neurotransmission, and morphology at neuromuscular junctions, as well as motor neuron death. KIF5A mutant is found in cytoplasmic inclusions, and its pathogenicity is because of a toxic gain of function.
Topics: Male; Animals; Female; Humans; Amyotrophic Lateral Sclerosis; Kinesins; Genome-Wide Association Study; Neurodegenerative Diseases; Motor Neurons; Neuromuscular Junction; Mutation; Drosophila; Inclusion Bodies
PubMed: 37748861
DOI: 10.1523/JNEUROSCI.0562-23.2023 -
Frontiers in Cellular Neuroscience 2023Normal brain development, function, and aging critically depend on unique characteristics of the cerebrovascular system. Growing evidence indicated that cerebrovascular... (Review)
Review
Normal brain development, function, and aging critically depend on unique characteristics of the cerebrovascular system. Growing evidence indicated that cerebrovascular defects can have irreversible effects on the brain, and these defects have been implicated in various neurological disorders, including autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder with heterogeneous clinical manifestations and anatomical changes. While extensive research has focused on the neural abnormalities underlying ASD, the role of brain vasculature in this disorder remains poorly understood. Indeed, the significance of cerebrovascular contributions to ASD has been consistently underestimated. In this work, we discuss the neurovascular crosstalk during embryonic development and highlight recent findings on cerebrovascular alterations in individuals with ASD. We also discuss the potential of vascular-based therapy for ASD. Collectively, these investigations demonstrate that ASD can be considered a neurovascular disease.
PubMed: 37692552
DOI: 10.3389/fncel.2023.1226580 -
Cell Calcium Sep 2023Inositol 1,4,5-trisphosphate receptors (IPRs) are ER Ca-release channels that control a broad set of cellular processes. Animal models lacking IPRs in different...
Inositol 1,4,5-trisphosphate receptors (IPRs) are ER Ca-release channels that control a broad set of cellular processes. Animal models lacking IPRs in different combinations display severe developmental phenotypes. Given the importance of IPRs in human diseases, we investigated their role in human induced pluripotent stem cells (hiPSC) by developing single IPR and triple IPR knockouts (TKO). Genome edited TKO-hiPSC lacking all three IPR isoforms, IPR1, IPR2, IPR3, failed to generate Ca signals in response to agonists activating GPCRs, but retained stemness and pluripotency. Steady state metabolite profiling and flux analysis of TKO-hiPSC indicated distinct alterations in tricarboxylic acid cycle metabolites consistent with a deficiency in their pyruvate utilization via pyruvate dehydrogenase, shifting towards pyruvate carboxylase pathway. These results demonstrate that IPRs are not essential for hiPSC identity and pluripotency but regulate mitochondrial metabolism. This set of knockout hiPSC is a valuable resource for investigating IPRs in human cell types of interest.
PubMed: 37481871
DOI: 10.1016/j.ceca.2023.102782 -
Biological Psychology Oct 2023Posttraumatic stress disorder (PTSD) is characterized by alterations in emotional and cognitive processing. The current neurobiological model of PTSD posits that... (Review)
Review
INTRODUCTION
Posttraumatic stress disorder (PTSD) is characterized by alterations in emotional and cognitive processing. The current neurobiological model of PTSD posits that amygdala and prefrontal cortex functioning impairment underpins symptoms, such as altered emotional and cognitive processing. Additionally, these structures are key components of emotional and attention regulation.
AIM
This review sought to evaluate studies comparing PTSD group to non-PTSD controls performance in affective attention tasks during neuroimaging.
RESULTS
PTSD group behavioral performance when responding to affective stimuli differed from controls only in stroop-based tasks. However, neuroimaging techniques were able to identify brain activation differences even when behavioral differences were not present. Amygdala hyperactivation in PTSD patients was confirmed in most cases, but cortical networks results were not as consistent. More than a general reduction in activity, PTSD group data points out to impaired recruitment of ventral cortical structures and increased reliance on dorsal cortical structures during task performance.
CONCLUSION
Stroop-based tasks seem to be better at identifying differences in behavioral performance of PTSD individuals. PTSD individuals seems to present an altered brain activation pattern in affective attention tasks when compared to controls, where PTSD individuals seem to present enhanced amygdala activation and rely more on dorsal anterior cingulate cortex and posterior insula activation during tasks. The PROSPERO ID for this study is CRD42022355471.
PubMed: 37597766
DOI: 10.1016/j.biopsycho.2023.108660