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1.
Bioinformatics ; 40(5)2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38662583

RESUMO

MOTIVATION: The rapid expansion of Bioinformatics research has led to a proliferation of computational tools for scientific analysis pipelines. However, constructing these pipelines is a demanding task, requiring extensive domain knowledge and careful consideration. As the Bioinformatics landscape evolves, researchers, both novice and expert, may feel overwhelmed in unfamiliar fields, potentially leading to the selection of unsuitable tools during workflow development. RESULTS: In this article, we introduce the Bioinformatics Tool Recommendation system (BTR), a deep learning model designed to recommend suitable tools for a given workflow-in-progress. BTR leverages recent advances in graph neural network technology, representing the workflow as a graph to capture essential context. Natural language processing techniques enhance tool recommendations by analyzing associated tool descriptions. Experiments demonstrate that BTR outperforms the existing Galaxy tool recommendation system, showcasing its potential to streamline scientific workflow construction. AVAILABILITY AND IMPLEMENTATION: The Python source code is available at https://github.com/ryangreenj/bioinformatics_tool_recommendation.


Assuntos
Biologia Computacional , Software , Fluxo de Trabalho , Biologia Computacional/métodos , Aprendizado Profundo , Processamento de Linguagem Natural
2.
Environ Sci Technol ; 57(51): 21815-21822, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38085788

RESUMO

Per- and polyfluoroalkyl substances (PFAS), nicknamed "forever chemicals" due to the strength of their carbon-fluorine bonds, are a class of potent micropollutants that cause deleterious health effects in mammals. The current state-of-the-art detection method requires the collection and transport of water samples to a centralized facility where chromatography and mass spectrometry are performed for the separation, identification, and quantification of PFAS. However, for efficient remediation efforts to be properly informed, a more rapid in-field testing method is required. We previously demonstrated the development and use of dioxygen as the mediator molecule. The use of dioxygen is predicated on the assumption that there will be consistent ambient dioxygen levels in natural waters. This is not always the case in hypoxic groundwater and at high altitudes. To overcome this challenge and further advance the strategies that will enable in-field electroanalysis of PFAS, we demonstrate, as a proof of concept, that dioxygen can be generated in solution through the hydrolysis of water. The electrogenerated dioxygen can then be used as a mediator molecule for the indirect detection of PFOS via molecularly imprinted polymer (MIP)-based electroanalysis. We demonstrate that calibration curves can be constructed with high precision and sensitivity (LOD < 1 ppt or 1 ng/L). Our results provide a foundation for enabling in-field hypoxic PFAS electroanalysis.


Assuntos
Fluorocarbonos , Poluentes Químicos da Água , Animais , Rios , Oxigênio/análise , Fluorocarbonos/análise , Poluentes Químicos da Água/análise , Água , Mamíferos
3.
Infect Immun ; 90(5): e0062821, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35435726

RESUMO

Orientia tsutsugamushi is a genetically intractable obligate intracellular bacterium, causes scrub typhus, and has one of the largest known armamentariums of ankyrin repeat-containing effectors (Anks). Most have a C-terminal F-box presumed to interact with the SCF ubiquitin ligase complex primarily based on their ability to bind overexpressed Skp1. Whether all F-box-containing Anks bind endogenous SCF components and the F-box residues essential for such interactions has gone unexplored. Many O. tsutsugamushi Ank F-boxes occur as part of a PRANC (pox protein repeats of ankyrin-C-terminal) domain. Roles of the non-F-box portion of the PRANC and intervening sequence region (ISR) that links the ankyrin repeat and F-box/PRANC domains are unknown. The functional relevance of these effectors' non-ankyrin repeat domains was investigated. The F-box was necessary for Flag-tagged versions of most F-box-containing Anks to precipitate endogenous Skp1, Cul1, and/or Rbx1, while the ISR and PRANC were dispensable. Ank toxicity in yeast was predominantly F-box dependent. Interrogations of Ank1, Ank5, and Ank6 established that L1, P2, E4, I9, and D17 of the F-box consensus are key for binding native SCF components and for Ank1 and Ank6 to inhibit NF-κB. The ISR is also essential for Ank1 and Ank6 to impair NF-κB. Ectopically expressed Ank1 and Ank6 lacking the ISR or having a mutagenized F-box incapable of binding SCF components performed as dominant-negative inhibitors to block O. tsutsugamushi NF-κB modulation. This study advances knowledge of O. tsutsugamushi Ank functional domains and offers an approach for validating their roles in infection.


Assuntos
Orientia tsutsugamushi , Tifo por Ácaros , Repetição de Anquirina , Proteínas de Bactérias/metabolismo , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Orientia tsutsugamushi/genética
4.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361743

RESUMO

There is currently a growing interest in the use of cannabidiol (CBD) to alleviate the symptoms caused by cancer, including pain, sleep disruption, and anxiety. CBD is often self-administered as an over-the-counter supplement, and patients have reported benefits from its use. However, despite the progress made, the mechanisms underlying CBD's anti-cancer activity remain divergent and unclear. Herein, we provide a comprehensive review of molecular mechanisms to determine convergent anti-cancer actions of CBD from pre-clinical and clinical studies. In vitro studies have begun to elucidate the molecular targets of CBD and provide evidence of CBD's anti-tumor properties in cell and mouse models of cancer. Furthermore, several clinical trials have been completed testing CBD's efficacy in treating cancer-related pain. However, most use a mixture of CBD and the psychoactive, tetrahydrocannabinol (THC), and/or use variable dosing that is not consistent between individual patients. Despite these limitations, significant reductions in pain and opioid use have been reported in cancer patients using CBD or CBD+THC. Additionally, significant improvements in quality-of-life measures and patients' overall satisfaction with their treatment have been reported. Thus, there is growing evidence suggesting that CBD might be useful to improve the overall quality of life of cancer patients by both alleviating cancer symptoms and by synergizing with cancer therapies to improve their efficacy. However, many questions remain unanswered regarding the use of CBD in cancer treatment, including the optimal dose, effective combinations with other drugs, and which biomarkers/clinical presentation of symptoms may guide its use.


Assuntos
Canabidiol , Neoplasias , Animais , Camundongos , Canabidiol/uso terapêutico , Dronabinol/efeitos adversos , Qualidade de Vida , Neoplasias/tratamento farmacológico , Neoplasias/induzido quimicamente , Dor/tratamento farmacológico
5.
Surg Innov ; 28(5): 560-566, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33710930

RESUMO

Purpose. The primary aim of the study was to review the existing literature about patient-reported outcome measures (PROMs) in colorectal cancer and IBD. The secondary aim was to present a road map to develop a core outcome set via opinion gathering using social media. Method. This study is the first step of a three-step project aimed at constructing simple, applicable PROMs in colorectal surgery. This article was written in a collaborative manner with authors invited both through Twitter via the #OpenSourceResearch hashtag. The 5 most used PROMs were presented and discussed as slides/images on Twitter. Inputs from a wide spectrum of participants including researchers, surgeons, physicians, nurses, patients, and patients' organizations were collected and analyzed. The final draft was emailed to all contributors and 6 patients' representatives for proofreading and approval. Results. Five PROM sets were identified and discussed: EORTC QLQ-CR29, IBDQ short health questionnaire, EORTC QLQ-C30, ED-Q5-5L, and Short Form-36. There were 315 tweets posted by 50 tweeters with 1458 retweets. Awareness about PROMs was generally limited. The general psycho-physical well-being score (GPP) was suggested and discussed, and then a survey was conducted in which more than 2/3 of voters agreed that GPP covers the most important aspects in PROMs. Conclusion. Despite the limitations of this exploratory study, it offered a new method to conduct clinical research with opportunity to engage patients. The general psycho-physical well-being score suggested as simple, applicable PROMs to be eventually combined procedure-specific, disease-specific, or symptom-specific PROMs if needed.


Assuntos
Cirurgia Colorretal , Humanos , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Inquéritos e Questionários
6.
Infect Immun ; 88(10)2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32661123

RESUMO

Anaplasma phagocytophilum causes granulocytic anaplasmosis, a debilitating infection that can be fatal in the immunocompromised. It also afflicts animals, including dogs, horses, and sheep. No granulocytic anaplasmosis vaccine exists. Because A. phagocytophilum is an obligate intracellular bacterium, inhibiting microbe-host cell interactions that facilitate invasion can disrupt infection. The binding domains of A. phagocytophilum adhesins A. phagocytophilum invasion protein A (AipA), A. phagocytophilum surface protein (Asp14), and outer membrane protein A (OmpA) are essential for optimal bacterial entry into host cells, but their relevance to infection in vivo is undefined. In this study, C57BL/6 mice were immunized with a cocktail of keyhole limpet hemocyanin-conjugated peptides corresponding to the AipA, Asp14, and OmpA binding domains in alum followed by challenge with A. phagocytophilum The bacterial peripheral blood burden was pronouncedly reduced in immunized mice compared to controls. Examination of pre- and postchallenge sera from these mice revealed that immunization elicited antibodies against AipA and Asp14 peptides but not OmpA peptide. Nonetheless, pooled sera from pre- and postchallenge groups, but not from control groups, inhibited A. phagocytophilum infection of HL-60 cells. Adhesin domain immunization also elicited interferon gamma (IFN-γ)-producing CD8-positive (CD8+) T cells. A follow-up study confirmed that immunization against only the AipA or Asp14 binding domain was sufficient to reduce the bacterial peripheral blood load in mice following challenge and elicit antibodies that inhibit A. phagocytophilum cellular infection in vitro These data demonstrate that AipA and Asp14 are critical for A. phagocytophilum to productively infect mice, and immunization against their binding domains elicits a protective immune response.


Assuntos
Adesinas Bacterianas/imunologia , Anaplasma phagocytophilum/imunologia , Vacinas Bacterianas/imunologia , Ehrlichiose/prevenção & controle , Adesinas Bacterianas/química , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Anticorpos Bloqueadores/sangue , Anticorpos Bloqueadores/imunologia , Carga Bacteriana , Vacinas Bacterianas/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Células HL-60 , Humanos , Imunização , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Domínios Proteicos/imunologia , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia
7.
Nanomedicine ; 30: 102294, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32861031

RESUMO

The tumor microenvironment plays a critical role in tumor initiation, progression, metastasis, and drug resistance. However, models recapitulating the complex 3D structure, heterogeneous cell environment, and cell-cell interactions found in vivo are lacking. Herein, we report on a gravitational microfluidic platform (GMP) retrofitted with MEMS sensors, which is integrated with 3D nanofiber scaffold-aided tumoroid culture. The results showed that this GMP for tumoroid growth mimics the tumor microenvironment more precisely than static culture models of colon cancer, including higher drug resistance, enhanced cancer stem cell properties, and increased secretion of pro-tumor cytokines. In addition, the GMP includes an integrated surface acoustic wave-based biosensing to monitor cell growth and pH changes to assess drug efficacy. Thus, this simple-to-use perfused GMP tumoroid culture system for in vitro and ex vivo studies may accelerate the drug development process and be a tool in personalized cancer treatment.


Assuntos
Neoplasias Colorretais/patologia , Gravitação , Microfluídica/instrumentação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração de Íons de Hidrogênio , Medicina de Precisão , Microambiente Tumoral
8.
Sensors (Basel) ; 19(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013700

RESUMO

The most vital step in the development of novel and existing surface acoustic wave (SAW)-based sensors and transducers is their design and optimization. Demand for SAW devices has been steadily increasing due to their low cost, portability, and versatility in electronics, telecommunications, and biosensor applications. However, a full characterization of surface acoustic wave biosensors in a three-dimensional (3D) finite element model has not yet been developed. In this study, a novel approach is developed for analyzing shear horizontal Love wave resonator devices. The developed modeling methodology was verified using fabricated devices. A thorough analysis of the 3D model and the experimental device was performed in this study including scattering parameters (S-parameters), reflection coefficient parameters, transmission parameters, and phase velocity. The simulated results will be used as a design guideline for future device design and optimization, which has thus far resulted in close matching between prediction and experimental results. This manuscript is the first to demonstrate a 3D finite element model to correlate the sensitivity of the SAW device with the magnitude of the phase shift, the real and imaginary part of the response, insertion loss, and the frequency shift. The results show that the imaginary part of the response shift has a higher sensitivity compared to other parameters.

9.
Int J Mol Sci ; 20(21)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731424

RESUMO

Ashwagandha (Withania Somnifera, WS), belonging to the family Solanaceae, is an Ayurvedic herb known worldwide for its numerous beneficial health activities since ancient times. This medicinal plant provides benefits against many human illnesses such as epilepsy, depression, arthritis, diabetes, and palliative effects such as analgesic, rejuvenating, regenerating, and growth-promoting effects. Several clinical trials of the different parts of the herb have demonstrated safety in patients suffering from these diseases. In the last two decades, an active component of Withaferin A (WFA) has shown tremendous cytotoxic activity suggesting its potential as an anti-carcinogenic agent in treatment of several cancers. In spite of enormous progress, a thorough elaboration of the proposed mechanism and mode of action is absent. Herein, we provide a comprehensive review of the properties of WS extracts (WSE) containing complex mixtures of diverse components including WFA, which have shown inhibitory properties against many cancers, (breast, colon, prostate, colon, ovarian, lung, brain), along with their mechanism of actions and pathways involved.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias/tratamento farmacológico , Withania/química , Vitanolídeos/química , Vitanolídeos/uso terapêutico , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia
10.
Cell Microbiol ; 19(7)2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28103630

RESUMO

Orientia tsutsugamushi causes scrub typhus, a potentially fatal infection that afflicts 1 million people annually. This obligate intracellular bacterium boasts one of the largest microbial arsenals of ankyrin repeat-containing protein (Ank) effectors, most of which target the endoplasmic reticulum (ER) by undefined mechanisms. Ank9 is the only one proven to function during infection. Here, we demonstrate that Ank9 bears a motif that mimics the GRIP domain of eukaryotic golgins and is necessary and sufficient for its Golgi localization. Ank9 reaches the ER exclusively by retrograde trafficking from the Golgi. Consistent with this observation, it binds COPB2, a host protein that mediates Golgi-to-ER transport. Ank9 destabilizes the Golgi and ER in a Golgi localization domain-dependent manner and induces the activating transcription factor 4-dependent unfolded protein response. The Golgi is also destabilized in cells infected with O. tsutsugamushi or treated with COPB2 small interfering RNA. COPB2 reduction and/or the cellular events that it invokes, such as Golgi destabilization, benefit Orientia replication. Thus, Ank9 or bacterial negative modulation of COPB2 might contribute to the bacterium's intracellular replication. This report identifies a novel microbial Golgi localization domain, links Ank9 to the ability of O. tsutsugamushi to perturb Golgi structure, and describes the first mechanism by which any Orientia effector targets the secretory pathway.


Assuntos
Anquirinas/metabolismo , Proteínas de Bactérias/metabolismo , Proteína Coatomer/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Orientia tsutsugamushi/patogenicidade , Fator 4 Ativador da Transcrição/metabolismo , Linhagem Celular Tumoral , Células HeLa , Humanos , Ligação Proteica/fisiologia , Domínios Proteicos/fisiologia , Transporte Proteico/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética , Tifo por Ácaros/microbiologia , Resposta a Proteínas não Dobradas/fisiologia
11.
Nucleic Acids Res ; 42(1): 307-14, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24049082

RESUMO

Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUS(R521G), harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Dano ao DNA , Poli(ADP-Ribose) Polimerases/fisiologia , Proteína FUS de Ligação a RNA/metabolismo , Animais , Células Cultivadas , Humanos , Camundongos , Mutação , Oxirredução , Poli(ADP-Ribose) Polimerase-1 , Poli Adenosina Difosfato Ribose/biossíntese , Poli Adenosina Difosfato Ribose/metabolismo , Proteína FUS de Ligação a RNA/genética
13.
Sensors (Basel) ; 15(12): 32045-55, 2015 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-26703604

RESUMO

Detection and quantification of cell viability and growth in two-dimensional (2D) and three-dimensional (3D) cell cultures commonly involve harvesting of cells and therefore requires a parallel set-up of several replicates for time-lapse or dose-response studies. Thus, developing a non-invasive and touch-free detection of cell growth in longitudinal studies of 3D tumor spheroid cultures or of stem cell regeneration remains a major unmet need. Since surface acoustic waves (SAWs) permit mass loading-based biosensing and have been touted due to their many advantages including low cost, small size and ease of assembly, we examined the potential of SAW-biosensing to detect and quantify cell growth. Herein, we demonstrate that a shear horizontal-surface acoustic waves (SH-SAW) device comprising two pairs of resonators consisting of interdigital transducers and reflecting fingers can be used to quantify mass loading by the cells in suspension as well as within a 3D cell culture platform. A 3D COMSOL model was built to simulate the mass loading response of increasing concentrations of cells in suspension in the polydimethylsiloxane (PDMS) well in order to predict the characteristics and optimize the design of the SH-SAW biosensor. The simulated relative frequency shift from the two oscillatory circuit systems (one of which functions as control) were found to be concordant to experimental data generated with RAW264.7 macrophage and A549 cancer cells. In addition, results showed that SAW measurements per se did not affect viability of cells. Further, SH-SAW biosensing was applied to A549 cells cultured on a 3D electrospun nanofiber scaffold that generate tumor spheroids (tumoroids) and the results showed the device's ability to detect changes in tumor spheroid growth over the course of eight days. Taken together, these results demonstrate the use of SH-SAW device for detection and quantification of cell growth changes over time in 2D suspension cultures and in 3D cell culture models, which may have potential applications in both longitudinal 3D cell cultures in cancer biology and in regenerative medicine.


Assuntos
Técnicas Biossensoriais/métodos , Contagem de Células/métodos , Técnicas de Cultura de Células/métodos , Som , Animais , Proliferação de Células , Sobrevivência Celular , Camundongos , Células RAW 264.7 , Óxido de Zinco
14.
Neurobiol Dis ; 69: 76-92, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24878508

RESUMO

Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and multiple system atrophy are characterized by the deposition of disease-associated α-synuclein. In the present study we 1) examined the molecular specificity of the novel anti-α-synuclein 5G4 antibody; 2) evaluated immunoreactivity patterns and their correlation in human brain tissue with micro- and astrogliosis in 57 cases with PD or DLB; and 3) performed a systematic immunoelectron microscopical mapping of subcellular localizations. 5G4 strongly binds to the high molecular weight fraction of ß-sheet rich oligomers, while no binding to primarily disordered oligomers or monomers was observed. We show novel localizations of disease-associated α-synuclein including perivascular macrophages, ependyma and cranial nerves. α-Synuclein immunoreactive neuropil dots and thin threads associate more with glial reaction than Lewy bodies alone. Astrocytic α-synuclein is an important component of the pathology. Furthermore, we document ultrastructurally the pathway of processing of disease-associated α-synuclein within neurons and astroglial cells. Interaction of mitochondria and disease-associated α-synuclein plays a key role in the molecular-structural cytopathogenesis of disorders with Lewy bodies. We conclude that 1) the 5G4 antibody has strong selectivity for ß-sheet rich α-synuclein oligomers; 2) Lewy bodies themselves are not the most relevant morphological substrate that evokes tissue lesioning; 3) both neurons and astrocytes internalize disease-associated α-synuclein in the human brain, suggesting prion-like cell-to-cell spread of α-synuclein by uptake from surrounding structures, as shown previously in experimental observations.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Espaço Intracelular/metabolismo , Neurônios/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anticorpos/metabolismo , Espaço Extracelular/metabolismo , Feminino , Gliose/metabolismo , Humanos , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/metabolismo , Masculino , Microglia/metabolismo , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Estrutura Secundária de Proteína , alfa-Sinucleína/genética , alfa-Sinucleína/imunologia
15.
Viruses ; 15(7)2023 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-37515117

RESUMO

Emergent Coronaviridae viruses, such as SARS-CoV-1 in 2003, MERS-CoV in 2012, and SARS-CoV-2 (CoV-2) in 2019, have caused millions of deaths. These viruses have added to the existing respiratory infection burden along with respiratory syncytial virus (RSV) and influenza. There are limited therapies for respiratory viruses, with broad-spectrum treatment remaining an unmet need. Since gut fermentation of fiber produces short-chain fatty acids (SCFA) with antiviral potential, developing a fatty acid-based broad-spectrum antiviral was investigated. Molecular docking of fatty acids showed α-linolenic acid (ALA) is likely to interact with CoV-2-S, NL63-CoV-S, and RSV-F, and an ALA-containing liposome interacted with CoV-2 directly, degrading the particle. Furthermore, a combination of ALA and a SCFA-acetate synergistically inhibited CoV2-N expression and significantly reduced viral plaque formation and IL-6 and IL-1ß transcript expression in Calu-3 cells, while increasing the expression of IFN-ß. A similar effect was also observed in RSV-infected A549 cells. Moreover, mice infected with a murine-adapted SARS-CoV-2 (MA10) and treated with an ALA-liposome encapsulating acetate showed significant reductions in plaque-forming units present in lung tissue and in infection-associated lung inflammation and cytokines. Taken together, these results demonstrate that the ALA liposome-encapsulating acetate can be a promising broad antiviral therapy against respiratory infections.


Assuntos
COVID-19 , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Animais , Camundongos , SARS-CoV-2 , Lipossomos , Ácido alfa-Linolênico/uso terapêutico , Simulação de Acoplamento Molecular , Antivirais/farmacologia , Antivirais/uso terapêutico , Acetatos
16.
Cancers (Basel) ; 15(12)2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-37370701

RESUMO

Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)-a herbal compound-and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.

17.
J Biomol Struct Dyn ; 41(19): 9808-9827, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-36524419

RESUMO

Epidermal Growth Factor Receptor (EGFR) signaling and EGFR mutations play key roles in cancer pathogenesis, particularly in the development of drug resistance. For the ∼20% of all non-small cell lung cancer (NSCLC) patients that harbor an activating mutation, EGFR tyrosine kinase inhibitors (TKIs) provide initial clinical responses. However, long-term efficacy is not possible due to acquired drug resistance. Despite a gradually increasing knowledge of the mechanisms underpinning the development of resistance in tumors, there has been very little success in overcoming it and it is probable that many additional mechanisms are still unknown. Herein, publicly available RNASeq (RNA sequencing) datasets comparing lung cancer cell lines treated with EGFR TKIs until resistance developed with their corresponding parental cells and protein array data from our own EGFR TKI treated xenograft tumors, were analyzed for differential gene expression, with the intent to investigate the potential mechanisms of drug resistance to EGFR TKIs. Pathway analysis, as well as structural disorder analysis of proteins in these pathways, revealed several key proteins, including DUSP1, DUSP6, GAB2, and FOS, that could be targeted using novel combination therapies to overcome EGFR TKI resistance in lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Receptores ErbB/genética , Análise de Sequência de RNA , Linhagem Celular Tumoral
18.
J Oral Maxillofac Surg ; 70(9): 2085-91, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22326173

RESUMO

Cavernous sinus thrombosis represents a rare but devastating disease process that may be associated with significant long-term patient morbidity or mortality. The prompt recognition and management of this problem is critical. However, most of the literature involves case-specific discussions. The purpose of this article was to review the literature and present current recommendations for the treatment of cavernous sinus thrombosis.


Assuntos
Trombose do Corpo Cavernoso/terapia , Adulto , Antibacterianos/uso terapêutico , Anticoagulantes/uso terapêutico , Trombose do Corpo Cavernoso/diagnóstico , Drenagem , Feminino , Humanos , Esteroides/uso terapêutico
19.
Sci Rep ; 12(1): 11935, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831374

RESUMO

Ultraviolet (UV) irradiation-based methods used for viral inactivation have provided an important avenue targeting severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) virus. A major problem with state-of-the-art UV inactivation technology is that it is based on UV lamps, which have limited efficiency, require high power, large doses, and long irradiation times. These drawbacks limit the use of UV lamps in air filtering systems and other applications. To address these limitations, herein we report on the fabrication of a device comprising a pulsed nanosecond 266 nm UV laser coupled to an integrating cavity (LIC) composed of a UV reflective material, polytetrafluoroethylene. Previous UV lamp inactivation cavities were based on polished walls with specular reflections, but the diffuse reflective UV ICs were not thoroughly explored for virus inactivation. Our results show that LIC device can inactivate several respiratory viruses including SARS-CoV-2, at ~ 1 ms effective irradiation time, with > 2 orders of magnitude higher efficiency compared to UV lamps. The demonstrated 3 orders of magnitude cavity enhancement relative to direct exposure is crucial for the development of efficient real-time UV air and water purification systems. To the best of our knowledge this is the first demonstration of LIC application for broad viral inactivation with high efficiency.


Assuntos
COVID-19 , Vírus , Desinfecção/métodos , Humanos , Lasers , SARS-CoV-2 , Raios Ultravioleta , Inativação de Vírus/efeitos da radiação
20.
Mol Ther Methods Clin Dev ; 27: 217-229, 2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36187720

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has caused over 600,000,000 infections globally thus far. Up to 30% of individuals with mild to severe disease develop long COVID, exhibiting diverse neurologic symptoms including dementias. However, there is a paucity of knowledge of molecular brain markers and whether these can precipitate the onset of Alzheimer's disease (AD). Herein, we report the brain gene expression profiles of severe COVID-19 patients showing increased expression of innate immune response genes and genes implicated in AD pathogenesis. The use of a mouse-adapted strain of SARS-CoV-2 (MA10) in an aged mouse model shows evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferon-inducible gene Ifi204, and complement genes C4 and C5AR1. Brain histopathology shows AD signatures including increased tau-phosphorylation, tau-oligomerization, and α-synuclein expression in aged MA10 infected mice. The results of gene expression profiling of SARS-CoV-2-infected and AD brains and studies in the MA10 aged mouse model taken together, for the first time provide evidence suggesting that SARS-CoV-2 infection alters expression of genes in the brain associated with the development of AD. Future studies of common molecular markers in SARS-CoV-2 infection and AD could be useful for developing novel therapies targeting AD.

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