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Brain Connectivity Oct 2018Alcohol misuse is associated with thalamic dysfunction. The thalamus comprises subnuclei that relay and integrate information between cortical and subcortical...
Alcohol misuse is associated with thalamic dysfunction. The thalamus comprises subnuclei that relay and integrate information between cortical and subcortical structures. However, it is unclear how the subnuclei contribute to thalamic dysfunctions in problem drinking. We investigated resting-state functional connectivity (rsFC) of thalamic subregions in 107 nondependent drinkers (57 women), using masks delineated by white matter tractography. Thalamus was parceled into motor, somatosensory, visual, premotor, frontal association, parietal association, and temporal association subregions. Whole-brain linear regression, each against Alcohol Use Disorders Identification Test (AUDIT) and positive alcohol expectancy (AE) score with age as a covariate, was performed for each seed, for men and women combined, and separately. Overall, problem drinking was associated with increased thalamic connectivities, whereas AE was associated with a mixed pattern of increased and decreased connectivities. Motor, premotor, somatosensory, and frontal association thalamic connectivity with bilateral caudate head was positively correlated with AUDIT score in men and women combined. Connectivity of the right caudate head with frontal association and premotor thalamus was also positively correlated with AE score in men and women combined. In contrast, motor and premotor thalamic connectivity with a number of cortical and subcortical structures showed sex differences in the correlation each with AUDIT and AE score. In mediation analyses, AE score completely mediated the correlation between thalamic caudate connectivity and AUDIT score, whereas the model where AE contributed to problem drinking and, in turn, altered thalamic caudate connectivity was not supported. To conclude, thalamic subregional rsFCs showed both shared and distinct changes and sex differences in association with problem drinking and AE. Increased thalamic caudate connectivity may contribute to problem drinking via enhanced AE. The findings suggest the importance of examining thalamic subdivisions and sex in investigating the functional roles of thalamus in problem drinking.
Topics: Adolescent; Adult; Alcohol Drinking; Correlation of Data; Diffusion Tensor Imaging; Drinking Behavior; Female; Frontal Lobe; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Neural Pathways; Oxygen; Rest; Sex Characteristics; Surveys and Questionnaires; Thalamus; Young Adult
PubMed: 30198312
DOI: 10.1089/brain.2018.0633 -
Drug and Alcohol Dependence May 2023Alcohol use disorder is a public health problem, especially among US veterans. This study examined the nature and predictors of 10-year trajectories of alcohol...
BACKGROUND
Alcohol use disorder is a public health problem, especially among US veterans. This study examined the nature and predictors of 10-year trajectories of alcohol consumption in US veterans.
METHODS
Data were analyzed from the 2011-2021 National Health and Resilience in Veterans Study, a nationally representative, longitudinal study of 2309 US veterans.
RESULTS
Latent growth mixture modeling analyses revealed four trajectories of alcohol consumption (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]) over a 10-year period: excessive (4.1%; mean [standard deviation] AUDIT-C baseline=8.6 [2.0], slope= -0.33 [0.07]); at-risk (22.1%; baseline=4.1 [1.6], slope=0.02 [0.07]); rare (71.7%; baseline=1.2 [1.3], slope= -0.01 [0.03]); and recovering alcohol consumption (2.1%; baseline=8.4 [1.9], slope= -0.70 [0.14]). The strongest predictors of excessive vs. rare alcohol consumption group were younger age (relative variance explained [RVE]=27.8%), and lower agreeableness (RVE=27.0%); at-risk vs. rare alcohol consumption group were fewer medical comorbidities (RVE=82.3%); recovering vs. rare alcohol consumption group were greater dysphoric arousal symptoms (RVE=46.1%) and current mental health treatment (RVE=26.5%); excessive vs. at-risk alcohol consumption group were younger age (RVE=25.9%), greater dysphoric arousal symptoms of posttraumatic stress disorder (RVE=22.0%), and lower conscientiousness (RVE=19.1%); and excessive vs. recovering alcohol consumption group were current mental health treatment (RVE=61.1%) and secure attachment style (RVE=12.4%).
CONCLUSIONS
Over the past decade, more than 1 in 4 US veterans consumed alcohol at the at-risk-to-excessive level. Veterans who are younger, score lower on agreeableness and conscientiousness, endorse greater dysphoric arousal symptoms, and currently not engaged in mental health treatment may require close monitoring and prevention efforts to mitigate the risk of a chronic course of at-risk-to-excessive alcohol consumption.
Topics: Humans; Veterans; Alcoholism; Longitudinal Studies; Alcohol Drinking; Stress Disorders, Post-Traumatic
PubMed: 36963160
DOI: 10.1016/j.drugalcdep.2023.109833 -
Oncology Letters Jul 2015Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its...
Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated and . Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.
PubMed: 26170970
DOI: 10.3892/ol.2015.3184 -
Oncotarget Jul 2018Potent inhibitors of PI3K (GDC-0941) and Src (Saracatinib) exhibit as individual agents, excellent oral anticancer activity in preclinical models and have entered phase...
Potent inhibitors of PI3K (GDC-0941) and Src (Saracatinib) exhibit as individual agents, excellent oral anticancer activity in preclinical models and have entered phase II clinical trials in various cancers. We found that PI3K and Src kinases are dysregulated in clear cell renal carcinomas (ccRCCs), an aggressive disease without effective targeted therapies. In this study we addressed this challenge by testing GDC-0941 and Saracatinib as either single agents or in combination in ccRCC cell lines, as well as in mouse and PDX models. Our findings demonstrate that combined inhibition of PI3K and Src impedes cell growth and invasion and induces cell death of renal carcinoma cells providing preclinical evidence for a pairwise combination of these anticancer drugs as a rational strategy to improve renal cancer treatment.
PubMed: 30046388
DOI: 10.18632/oncotarget.25700 -
Briefings in Bioinformatics Nov 2021The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is undeniably the most severe global health emergency since the 1918 Influenza outbreak....
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is undeniably the most severe global health emergency since the 1918 Influenza outbreak. Depending on its evolutionary trajectory, the virus is expected to establish itself as an endemic infectious respiratory disease exhibiting seasonal flare-ups. Therefore, despite the unprecedented rally to reach a vaccine that can offer widespread immunization, it is equally important to reach effective prevention and treatment regimens for coronavirus disease 2019 (COVID-19). Contributing to this effort, we have curated and analyzed multi-source and multi-omics publicly available data from patients, cell lines and databases in order to fuel a multiplex computational drug repurposing approach. We devised a network-based integration of multi-omic data to prioritize the most important genes related to COVID-19 and subsequently re-rank the identified candidate drugs. Our approach resulted in a highly informed integrated drug shortlist by combining structural diversity filtering along with experts' curation and drug-target mapping on the depicted molecular pathways. In addition to the recently proposed drugs that are already generating promising results such as dexamethasone and remdesivir, our list includes inhibitors of Src tyrosine kinase (bosutinib, dasatinib, cytarabine and saracatinib), which appear to be involved in multiple COVID-19 pathophysiological mechanisms. In addition, we highlight specific immunomodulators and anti-inflammatory drugs like dactolisib and methotrexate and inhibitors of histone deacetylase like hydroquinone and vorinostat with potential beneficial effects in their mechanisms of action. Overall, this multiplex drug repurposing approach, developed and utilized herein specifically for SARS-CoV-2, can offer a rapid mapping and drug prioritization against any pathogen-related disease.
Topics: Antiviral Agents; COVID-19; Drug Repositioning; Humans; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34009288
DOI: 10.1093/bib/bbab114 -
International Journal of Molecular... Dec 2020Dasatinib is a multi-target kinase inhibitor, whose targets include BCR-ABL, SRC family kinases, and various cancer kinases. The elevated SRC activity in gastric cancer...
Dasatinib is a multi-target kinase inhibitor, whose targets include BCR-ABL, SRC family kinases, and various cancer kinases. The elevated SRC activity in gastric cancer (GC) has prompted the need for the therapeutic application of dasatinib in GC. We observed that the efficacy of dasatinib varied with the GC cell lines. The differential effect of dasatinib was not correlated with the basal SRC activity of each cell line. Moreover, the GC cell lines showing the strong antitumor effects of dasatinib were refractory to other SRC inhibitors, i.e., bosutinib and saracatinib, suggesting that unexpected dasatinib's targets could exist. To profile the targets of dasatinib in GC, we performed activity-based protein profiling (ABPP) via mass spectrometry using a desthiobiotin-ATP probe. We identified 29 and 18 kinases as potential targets in dasatinib-sensitive (SNU-216, MKN-1) and -resistant (SNU-484, SNU-601) cell lines, respectively. The protein-protein interaction mapping of the differential drug targets in dasatinib-sensitive and -resistant GC using the STRING database suggested that dasatinib could target cellular energy homeostasis in the drug-sensitive GC. RNAi screening for identified targets indicated p90RSK could be a novel dasatinib target, which is important for maintaining the viability and motility of GC cells. Further functional validation of dasatinib off-target actions will provide more effective therapeutic options for GC.
Topics: Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Chromatography, Liquid; Dasatinib; Humans; Molecular Targeted Therapy; Phenotype; Protein Kinase Inhibitors; Proteome; Proteomics; Stomach Neoplasms; Tandem Mass Spectrometry
PubMed: 33291786
DOI: 10.3390/ijms21239276 -
Scientific Reports Oct 2018Excessive neutrophil degranulation is a common feature of many inflammatory disorders, including alpha-1 antitrypsin (AAT) deficiency. Our group has demonstrated that...
Excessive neutrophil degranulation is a common feature of many inflammatory disorders, including alpha-1 antitrypsin (AAT) deficiency. Our group has demonstrated that phospholipid transfer protein (PLTP) prevents neutrophil degranulation but serine proteases, which AAT inhibits, cleave PLTP in diseased airways. We propose to identify if airway PLTP activity can be restored by AAT augmentation therapy and how PLTP subdues degranulation of neutrophils in AAT deficient subjects. Airway PLTP activity was lower in AAT deficient patients but elevated in the airways of patients on augmentation therapy. Functional AAT protein (from PiMM homozygotes) prevented PLTP cleavage unlike its mutated ZZ variant (PiZZ). PLTP lowered leukotriene B4 induced degranulation of primary, secondary and tertiary granules from neutrophils from both groups (n = 14/group). Neutrophils isolated from Pltp knockout mice have enhance neutrophil degranulation. Both AAT and PLTP reduced neutrophil degranulation and superoxide production, possibly though their inhibition of the Src tyrosine kinase, Hck. Src kinase inhibitors saracatinib and dasatinib reduced neutrophil degranulation and superoxide production. Therefore, AAT protects PLTP from proteolytic cleavage and both AAT and PLTP mediate degranulation, possibly via Hck tyrosine kinase inhibition. Deficiency of AAT could contribute to reduced lung PLTP activity and elevated neutrophil signaling associated with lung disease.
Topics: Aged; Animals; Cell Degranulation; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Neutrophil Activation; Neutrophils; Phospholipid Transfer Proteins; Proto-Oncogene Proteins c-hck; Signal Transduction; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency
PubMed: 30337619
DOI: 10.1038/s41598-018-33851-8 -
Oncotarget Feb 2018Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15-20% of all kidney neoplasms and may require...
Papillary renal cell carcinomas (PRCC) are a histologically and genetically heterogeneous group of tumors that represent 15-20% of all kidney neoplasms and may require diverse therapeutic approaches. Alteration of the tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC. The Hippo signaling pathway controls cell proliferation by regulating the transcriptional activity of Yes-Associated Protein, YAP1. Loss of results in aberrant YAP1 activation. The Src family kinase member Yes also regulates YAP1 transcriptional activity. This study investigated the importance of YAP and Yes activity in three -deficient PRCC cell lines. -deficency correlated with increased expression of YAP1 transcriptional targets and siRNA-based knockdown of YAP1 and Yes1 downregulated this pathway and dramatically reduced cell viability. Dasatinib and saracatinib have potent inhibitory effects on Yes and treatment with either resulted in downregulation of YAP1 transcription targets, reduced cell viability, and G0-G1 cell cycle arrest. Xenograft models for -deficient PRCC also demonstrated reduced tumor growth in response to dasatinib. Thus, inhibiting Yes and the subsequent transcriptional activity of YAP1 had a substantial anti-tumor cell effect both and and may provide a viable therapeutic approach for patients with -deficient PRCC.
PubMed: 29535838
DOI: 10.18632/oncotarget.24112 -
Bioengineered Feb 2022The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can target cardiomyocytes (CMs) to directly invade the heart resulting in high mortality. This study...
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can target cardiomyocytes (CMs) to directly invade the heart resulting in high mortality. This study aims to explore the biological characteristics of SARS-CoV-2 infected myocardium based on omics by collecting transcriptome data and analyzing them with a series of bioinformatics tools. Totally, 86 differentially expressed genes (DEGs) were discovered in SARS-CoV-2 infected CMs, and 15 miRNAs were discovered to target 60 genes. Functional enrichment analysis indicated that these DEGs were mainly enriched in the inflammatory signaling pathway. After the protein-protein interaction (PPI) network was constructed, several genes including CCL2 and CXCL8 were regarded as the hub genes. SRC inhibitor saracatinib was predicted to potentially act against the cardiac dysfunction induced by SARS-CoV-2. Among the 86 DEGs, 28 were validated to be dysregulated in SARS-CoV-2 infected hearts. Gene Set Enrichment Analysis (GSEA) analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that malaria, IL-17 signaling pathway, and complement and coagulation cascades were significantly enriched. Immune infiltration analysis indicated that 'naive B cells' was significantly increased in the SARS-CoV-2 infected heart. The above results may help to improve the prognosis of patients with COVID-19.
Topics: Blood Coagulation; COVID-19; Chemokine CCL2; Complement System Proteins; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Viral; Genome, Human; Heart; Humans; Inflammation; Interleukin-17; Interleukin-8; MicroRNAs; Myocardium; Prognosis; Protein Interaction Mapping; SARS-CoV-2; Signal Transduction
PubMed: 35037831
DOI: 10.1080/21655979.2021.2014621 -
Journal of Nuclear Medicine : Official... Dec 2019C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted C-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD)...
C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted C-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD) and found a 41% decrease in specific binding in the hippocampus compared with healthy subjects. We hypothesized that C-UCB-J may have potential to be a general biomarker for evaluating AD treatment effects via monitoring of synaptic density changes. In this study, we performed longitudinal C-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Nine wild-type (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1ΔE9 [APP/PS1]) mice underwent 3 C-UCB-J PET measurements: at baseline, after treatment, and during drug washout. After baseline measurements, saracatinib, a Fyn kinase inhibitor currently in clinical development for AD treatment, was administered by oral gavage for 41 ± 11 d. Treatment-phase measurements were performed on the last day of treatment, and washout-phase measurements occurred more than 27 d after the end of treatment. SUVs from 30 to 60 min after injection of C-UCB-J were calculated and normalized by the whole-brain (WB) or brain stem (BS) average values as SUV ratio (SUVR or SUVR-1). Hippocampal SUVR at baseline was significantly lower in APP/PS1 than WT mice (APP/PS1: 1.11 ± 0.04, WT: 1.15 ± 0.02, = 0.033, unpaired test). Using SUVR-1 in the hippocampus, there was also a significant difference at baseline (APP/PS1: 0.48 ± 0.13, WT: 0.65 ± 0.10, = 0.017, unpaired test). After treatment with saracatinib, hippocampal SUVR in APP/PS1 mice was significantly increased ( = 0.037, paired test). A trend-level treatment effect was seen with hippocampal SUVR-1 Saracatinib treatment effects may persist, as there were no significant differences between WT and APP/PS1 mice after drug washout. On the basis of the C-UCB-J PET results, hippocampal synaptic density was lower in APP/PS1 mice than in WT mice at baseline, and this deficit was normalized by treatment with saracatinib. These results support the use of C-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD.
Topics: Alzheimer Disease; Animals; Benzodioxoles; Disease Models, Animal; Female; Kinetics; Male; Mice; Positron-Emission Tomography; Pyridines; Pyrrolidines; Pyrrolidinones; Quinazolines; Synapses
PubMed: 31101744
DOI: 10.2967/jnumed.118.223867