Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 86
Filtrar
1.
Nucleic Acids Res ; 52(11): e50, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38797520

RESUMO

Whole-genome bisulfite sequencing (BS-Seq) measures cytosine methylation changes at single-base resolution and can be used to profile cell-free DNA (cfDNA). In plasma, ultrashort single-stranded cfDNA (uscfDNA, ∼50 nt) has been identified together with 167 bp double-stranded mononucleosomal cell-free DNA (mncfDNA). However, the methylation profile of uscfDNA has not been described. Conventional BS-Seq workflows may not be helpful because bisulfite conversion degrades larger DNA into smaller fragments, leading to erroneous categorization as uscfDNA. We describe the '5mCAdpBS-Seq' workflow in which pre-methylated 5mC (5-methylcytosine) single-stranded adapters are ligated to heat-denatured cfDNA before bisulfite conversion. This method retains only DNA fragments that are unaltered by bisulfite treatment, resulting in less biased uscfDNA methylation analysis. Using 5mCAdpBS-Seq, uscfDNA had lower levels of DNA methylation (∼15%) compared to mncfDNA and was enriched in promoters and CpG islands. Hypomethylated uscfDNA fragments were enriched in upstream transcription start sites (TSSs), and the intensity of enrichment was correlated with expressed genes of hemopoietic cells. Using tissue-of-origin deconvolution, we inferred that uscfDNA is derived primarily from eosinophils, neutrophils, and monocytes. As proof-of-principle, we show that characteristics of the methylation profile of uscfDNA can distinguish non-small cell lung carcinoma from non-cancer samples. The 5mCAdpBS-Seq workflow is recommended for any cfDNA methylation-based investigations.


Assuntos
5-Metilcitosina , Ácidos Nucleicos Livres , Ilhas de CpG , Metilação de DNA , DNA de Cadeia Simples , Humanos , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , DNA de Cadeia Simples/metabolismo , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/sangue , 5-Metilcitosina/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangue , Sulfitos/química , Regiões Promotoras Genéticas , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos
2.
Artigo em Inglês | MEDLINE | ID: mdl-38761231

RESUMO

Cellular plasticity refers to the ability of cells to change their identity or behavior, which can be advantageous in some cases (e.g., tissue regeneration) but detrimental in others (e.g., cancer metastasis). With a better understanding of cellular plasticity, the complexity of cancer cells, their heterogeneity, and their role in metastasis is being unraveled. The plasticity of the cells could also prove as a nemesis to their characterization. In this review, we have attempted to highlight the possibilities and benefits of using multiomics approach in characterizing the plastic nature of cancer cells. There is a need to integrate fragmented evidence at different levels of cellular organization (DNA, RNA, protein, metabolite, epigenetics, etc.) to facilitate the characterization of different forms of plasticity and cell types. We have discussed the role of cellular plasticity in generating intra-tumor heterogeneity. Different omics level evidence is being provided to highlight the variety of molecular determinants discovered using different techniques. Attempts have been made to integrate some of this information to provide a quantitative assessment and scoring of the plastic nature of the cells. However, there is a huge gap in our understanding of mechanisms that lead to the observed heterogeneity. Understanding of these mechanism(s) is necessary for finding targets for early detection and effective therapeutic interventions in metastasis. Targeting cellular plasticity is akin to neutralizing a moving target. Along with the advancements in precision and personalized medicine, these efforts may translate into better clinical outcomes for cancer patients, especially in metastatic stages.

3.
BMC Bioinformatics ; 25(1): 12, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195379

RESUMO

The integration of biology, computer science, and statistics has given rise to the interdisciplinary field of bioinformatics, which aims to decode biological intricacies. It produces extensive and diverse features, presenting an enormous challenge in classifying bioinformatic problems. Therefore, an intelligent bioinformatics classification system must select the most relevant features to enhance machine learning performance. This paper proposes a feature selection model based on the fractal concept to improve the performance of intelligent systems in classifying high-dimensional biological problems. The proposed fractal feature selection (FFS) model divides features into blocks, measures the similarity between blocks using root mean square error (RMSE), and determines the importance of features based on low RMSE. The proposed FFS is tested and evaluated over ten high-dimensional bioinformatics datasets. The experiment results showed that the model significantly improved machine learning accuracy. The average accuracy rate was 79% with full features in machine learning algorithms, while FFS delivered promising results with an accuracy rate of 94%.


Assuntos
Algoritmos , Fractais , Biologia Computacional , Aprendizado de Máquina
4.
Saudi Pharm J ; 32(3): 101942, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38318319

RESUMO

The protein kinase TAOK3, belongs to the MAP kinase family, is one of three closely related members, namely TAOK1, TAOK2, and TAOK3. We performed a pan-cancer investigation of TAOK3 across different cancer types, including uterine carcinosarcoma, adenocarcinoma of the stomach and pancreas, and endometrial carcinoma of the uterus, to better understand TAOK3's role in cancer. In at least 16 types of cancer, our findings indicate that TAOK3 expression levels differ considerably between normal and tumor tissues. In addition, our study is the first to identify the oncogenic role of TAOK3 locus S331 and S471 in renal clear cell carcinoma, Glioblastoma Multiforme, hepatocellular carcinoma, Lung adenocarcinoma, and Pancreatic adenocarcinoma, indicating their involvement in cancer progression. In addition, our data analysis indicates that copy number variation is the most prevalent form of mutation in the TAOK3 gene, and that there is a negative correlation between TAOK3 mRNA and DNA promoter methylation. Moreover, our analysis suggests that TAOK3 may serve as a prognostic marker for several kinds of cancer, including Colon adenocarcinoma, renal clear cell carcinoma, Lower Grade Glioma, Lung adenocarcinoma, Mesothelioma, and hepatocellular carcinoma. In addition, our research on signature cancer genes has uncovered a positive association between TAOK3 and SMAD2, SMAD4, and RNF168 in most of the malignancies we have examined. TAOK3 is also correlated with the frequency of mutations and microsatellite instability in four types of cancer. Numerous immune-related genes are closely associated with TAOK3 levels in numerous malignancies. TAOK3 expression is positively correlated with immune infiltrates, which include activated CD4 T cells, CD8 T cells, and type 2T helper cells. Our pan-cancer analysis of TAOK3 provides vital insight into its potential role across a variety of cancer types.

5.
Ann Surg ; 278(6): 1018-1023, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37010512

RESUMO

BACKGROUND AND OBJECTIVES: A high systemic immune-inflammation index (SIII) at diagnosis of various cancers, including pancreatic cancer, is associated with poor prognosis. The impact of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) chemotherapy or stereotactic body radiotherapy on this index is unknown. In addition, the prognostic value of changes in the SIII during treatment is unclear. In this retrospective analysis, we aimed to find answers regarding patients with advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer treated with FOLFIRINOX chemotherapy alone or with FOLFIRINOX chemotherapy followed by stereotactic body radiotherapy between 2015 and 2021 in 2 tertiary referral centers were included. Baseline characteristics, laboratory values at 3 time points during treatment, and survival outcomes were collected. The patient-specific evolutions of SIII and their association with mortality were assessed with joint models for longitudinal and time-to-event data. RESULTS: Data of 141 patients were analyzed. At a median follow-up time of 23.0 months (95% CI: 14.6-31.3), 97 (69%) patients had died. Median overall survival was 13.2 months (95% CI: 11.0-15.5). During treatment with FOLFIRINOX, the log (SIII) was reduced by -0.588 (95% CI: -0.0978, -0.197; P = 0.003). One unit increase in log (SIII) increased the hazard ratio of dying by 1.604 (95% CI: 1.068-2.409; P = 0.023). CONCLUSIONS: In addition to carbohydrate antigen 19-9, the SIII is a reliable biomarker in patients with advanced pancreatic cancer.


Assuntos
Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Estudos de Coortes , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/efeitos adversos , Leucovorina , Inflamação/etiologia , Neoplasias Pancreáticas
6.
Clin Chem ; 69(11): 1270-1282, 2023 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-37725931

RESUMO

BACKGROUND: Using broad range cell-free DNA sequencing (BRcfDNA-Seq), a nontargeted next-generation sequencing (NGS) methodology, we previously identified a novel class of approximately 50 nt ultrashort single-stranded cell-free DNA (uscfDNA) in plasma that is distinctly different from 167 bp mononucleosomal cell-free DNA (mncfDNA). We hypothesize that uscfDNA possesses characteristics that are useful for disease detection. METHODS: Using BRcfDNA-Seq, we examined both cfDNA populations in the plasma of 18 noncancer controls and 14 patients with late-stage nonsmall cell lung carcinoma (NSCLC). In comparison to mncfDNA, we assessed whether functional element (FE) peaks, fragmentomics, end-motifs, and G-Quadruplex (G-Quad) signatures could be useful features of uscfDNA for NSCLC determination. RESULTS: In noncancer participants, compared to mncfDNA, uscfDNA fragments showed a 45.2-fold increased tendency to form FE peaks (enriched in promoter, intronic, and exonic regions), demonstrated a distinct end-motif-frequency profile, and presented with a 4.9-fold increase in G-Quad signatures. Within NSCLC participants, only the uscfDNA population had discoverable FE peak candidates. Additionally, uscfDNA showcased different end-motif-frequency candidates distinct from mncfDNA. Although both cfDNA populations showed increased fragmentation in NSCLC, the G-Quad signatures were more discriminatory in uscfDNA. Compilation of cfDNA features using principal component analysis revealed that the first 5 principal components of both cfDNA subtypes had a cumulative explained variance of >80%. CONCLUSIONS: These observations indicate that the distinct biological processes of uscfDNA and that FE peaks, fragmentomics, end-motifs, and G-Quad signatures are uscfDNA features with promising biomarker potential. These findings further justify its exploration as a distinct class of biomarker to augment pre-existing liquid biopsy approaches.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Pulmão/patologia , DNA de Cadeia Simples
7.
Dev World Bioeth ; 2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-37997006

RESUMO

Even though there is a significant amount of scholarly work examining the ethical issues surrounding human genomics research, little is known about its footing in Malaysia. This study aims to explore the experience of local researchers and research ethics committee (REC) members in developing it in Malaysia. In-depth interviews were conducted from April to May 2021, and the data were thematically analysed. In advancing this technology, both genomics researchers and REC members have concerns over how this research is being developed in the country especially the absence of a clear ethical and regulatory framework at the national level as a guidance. However, this study argues that it is not a salient issue as there are international guidelines in existence and both researchers and RECs will benefit from a training on the guidelines to ensure genomics research can be developed in an ethical manner.

8.
Dig Dis Sci ; 66(12): 4090-4098, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33433812

RESUMO

The etiology of most cases of liver diseases in pregnancy can be diagnosed with a thorough history, physical examination, laboratory values, serology, and noninvasive imaging. However, atypical clinical and laboratory presentations of liver diseases/chemistries require a liver biopsy to render an accurate diagnosis in cases where the biopsy results affect the timing of delivery or impact choice of medical therapy. According to the American College of Gastroenterology, liver biopsy can be effectively and safely conducted in pregnant women. Conventional routes of performing a liver biopsy include the percutaneous, transjugular route, and surgical methods. Endoscopic ultrasound-guided liver biopsy is a recent technique that has not yet gained widespread adoption but can potentially serve as an alternative route for obtaining the liver sample. Adverse events associated with liver biopsy include abdominal pain and hemorrhage. Maternal and fetal outcomes are limited to increased risk of preterm birth and small for gestational age neonate. However, very few studies have formally evaluated the safety of liver biopsy in pregnant women. In this review, we present two successful cases of liver biopsy performed during pregnancy and summarize the most recent evidence regarding the safety and outcomes of the procedure in pregnancy to assist clinicians in their decision to perform a liver biopsy during pregnancy or postpone it until after delivery.


Assuntos
Colestase Intra-Hepática/patologia , Fígado Gorduroso/patologia , Fígado/patologia , Complicações na Gravidez/patologia , Adulto , Biópsia com Agulha de Grande Calibre/efeitos adversos , Feminino , Humanos , Biópsia Guiada por Imagem/efeitos adversos , Laparoscopia/efeitos adversos , Valor Preditivo dos Testes , Gravidez , Medição de Risco , Ultrassonografia/efeitos adversos , Adulto Jovem
9.
Ann Surg ; 270(1): 139-146, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29334554

RESUMO

OBJECTIVE: Our aim was to determine the prognostic significance of the systemic-immune-inflammation index (SIII) in patients with resectable pancreatic cancer, using cancer-specific survival as the primary outcome. BACKGROUND: Pancreatic cancer is associated with a dysfunctional immune system and poor prognosis. We examined the prognostic significance of the SIII in patients with resectable pancreatic ductal adenocarcinoma (PDAC) and the effects of bilirubin on this index. METHODS: We retrospectively assessed all pancreatic resections performed between 2004 and 2015 at 4 tertiary referral centers to identify pathologically confirmed PDAC patients. Baseline clinicopathologic characteristics, preoperative laboratory values such as absolute neutrophil, lymphocyte, and platelet counts, C-reactive protein, albumin, bilirubin, and CA19-9 levels, and also follow-up information, were collected. The associations of the calculated inflammatory indices with outcome were both internally and externally validated. RESULTS: In all, 590 patients with resectable PDAC were included. The discovery and validation cohort included 170 and 420 patients, respectively. SIII >900 [hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.55-3.48], lymph node ratio (HR 3.75, 95% CI 2.08-6.76), and CA19.9 >200 kU/L (HR 1.62, 95% CI 1.07-2.46) were identified as independent predictors of cancer-specific survival. Separate model analysis confirmed that preoperative SIII contributed significantly to prognostication. However, SIII appeared to lose its prognostic significance in patients with bilirubin levels above 200 µmol/L. CONCLUSIONS: SIII is an independent predictor of cancer-specific survival and recurrence in patients with resectable PDAC. SIII may lose its prognostic significance in patients with high bilirubin levels. Properly designed prospective studies are needed to further confirm this hypothesis.


Assuntos
Bilirrubina/sangue , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/cirurgia , Inflamação/diagnóstico , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/imunologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos
10.
Dermatol Ther ; 32(6): e13094, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31580005

RESUMO

Pulsed-dye laser (PDL) is the treatment of choice for port wine stain (PWS), and the development of purpura is considered a therapeutic endpoint. Changes in PWS vasculature observed by dermoscopy immediately after laser irradiation have been suggested to predict the minimal effective fluence. The current study aimed at comparing these changes with purpura as a therapeutic endpoint. Fifty-six PWS patients, randomized into two groups, received five monthly PDL sessions (595 nm and 10 mm spot size). At the first visit, patients received multiple gradually increasing test irradiations. Patients in the first group were treated with the lowest dose that resulted in 24-hr-lasting purpura, while patients in the second group were treated with the lowest dose that resulted in vessel disappearance observed by dermoscope. No statistically significant differences were observed between the two groups (the dermoscopic and the purpuric) regarding mean average improvement (42.4 and 37.32%, respectively, p = .32), grade of improvement (p = .44), and the rate of side effects (0 and 13.79%, respectively, p = .13). In conclusion, the immediate post-irradiation vessel disappearance (detected by dermoscope) is comparable, in safety and efficacy, to purpura as a therapeutic endpoint and maybe more time-saving and more accepted cosmetically.


Assuntos
Dermoscopia , Lasers de Corante/uso terapêutico , Mancha Vinho do Porto/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Lasers de Corante/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mancha Vinho do Porto/patologia , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
11.
Mol Cancer ; 17(1): 97, 2018 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-30008265

RESUMO

BACKGROUND: Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Cancer exosomes have been shown to regulate organ-specific metastasis. However, little is known about the functional differences and molecular consequences of normal cells responding to exosomes derived from normal cells compared to those derived from cancer cells. METHODS: Here, we characterised and compared the transcriptome profiles of primary human normal oral keratinocytes (HNOK) in response to exosomes isolated from either primary HNOK or head and neck squamous cell carcinoma (HNSCC) cell lines. RESULTS: In recipient HNOK cells, we found that regardless of normal or cancer derived, exosomes altered molecular programmes involved in matrix modulation (MMP9), cytoskeletal remodelling (TUBB6, FEZ1, CCT6A), viral/dsRNA-induced interferon (OAS1, IFI6), anti-inflammatory (TSC22D3), deubiquitin (OTUD1), lipid metabolism and membrane trafficking (BBOX1, LRP11, RAB6A). Interestingly, cancer exosomes, but not normal exosomes, modulated expression of matrix remodelling (EFEMP1, DDK3, SPARC), cell cycle (EEF2K), membrane remodelling (LAMP2, SRPX), differentiation (SPRR2E), apoptosis (CTSC), transcription/translation (KLF6, PUS7). We have also identified CEP55 as a potential cancer exosomal marker. CONCLUSIONS: In conclusion, both normal and cancer exosomes modulated unique gene expression pathways in normal recipient cells. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Molecular pathways and biomarkers identified in this study may be clinically exploitable for developing novel liquid-biopsy based diagnostics and immunotherapies.


Assuntos
Proteínas de Ciclo Celular/genética , Exossomos/genética , Perfilação da Expressão Gênica/métodos , Neoplasias de Cabeça e Pescoço/genética , Proteínas Nucleares/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Exossomos/patologia , Proteína Forkhead Box M1/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
12.
Apoptosis ; 21(7): 873-86, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27154302

RESUMO

Natural and chemically synthesized heterocyclic compounds have been explored for their potential use as anticancer agents. We had synthesized non-natural heterocyclic analogs and evaluated their anti-tumor activity by measuring effect on cell proliferation and induction of apoptosis in different cell lines. Previously, we identified a pyrazole-containing compound (G-11) showing cytotoxic effect towards leukemia and lymphoma cell lines. In this study, we further investigated the mechanistic aspects of anticancer properties of G-11 in HL-60 cell line. We demonstrated that cytotoxic effect of G-11 is mediated by caspase-dependent apoptosis. However, the involvement of mitochondrial dysfunction induced by G-11 was independent of caspases. G-11 triggered generation of ROS, caused disruption of mitochondrial transmembrane potential, increased release of cytochrome c to the cytosol, and altered the expression of Bcl-2 and Bax proteins. These results suggest significant involvement of intrinsic apoptotic pathway. This study comprehensively details the possible mechanisms of action of a novel heterocyclic compound which could find its potential use as an anticancer agent.


Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Compostos Heterocíclicos/toxicidade , Caspases/genética , Citocromos c/metabolismo , Células HL-60 , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Cell Physiol Biochem ; 35(5): 1943-57, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25870953

RESUMO

BACKGROUND/AIMS: The antileukemic potential of isoindigos make them desired candidates for understanding their mechanism of action. We have recently synthesized a novel group of pyridone-annelated isoindigos and identified the derivative 5'-Cl that is cytotoxic to various cancer cell lines. In the present study, we analyzed the effect of this compound on cell cycle of the promyelocytic leukemia cell line HL-60. METHODS: HL-60 cells were treated with 5'-Cl and its effect on cell cycle stages were determined by flow cytometry. Expression of cyclins, cyclin dependent kinases (CDKs) and cyclin kinase inhibitors (CKIs) were determined by Western blotting, and activation of CDKs was studied using kinase assays. RESULTS: 5'-Cl remarkably arrested cell cycle in HL-60 cells at the G0/G1 phase in a dose and time-dependent manner. Furthermore, 5'-Cl treatment significantly inhibited expression of D-cyclins, CDK2 and CDK4 and suppressed phosphorylation of the retinoblastoma protein Rb, whereas it increased the level of CKI p21. Molecular modelling experiments show that 5'-Cl may compete with ATP for binding to the catalytic subunit of CDK2 and CDK4 that could lead to inhibition of these enzymes. Indeed, 5'-Cl inhibited the kinase activity of CDK2 and CDK4 both in cell free systems and in treated cells. 5'-Cl also inhibited cell cycle progression in several other tumor cell lines. CONCLUSION: We demonstrate the potent inhibitory effects of 5'-Cl on HL-60 cells could be mediated by arresting cells in the G0/G1 phase.


Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Piridonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Indóis/química , Indóis/farmacologia , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Simulação de Acoplamento Molecular , Fosforilação , Piridonas/farmacologia , Proteína do Retinoblastoma/metabolismo
14.
Cell Physiol Biochem ; 35(5): 1958-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25871324

RESUMO

BACKGROUND/AIMS: In our quest to develop an isoindigo with improved efficacy and bioavailability, we recently synthesized a series of novel substituted pyridone-annelated isoindigo and evaluated their antiproliferative effects. We identified the compound [(E)-1-(5'-Chloro-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f] quinoline-8-carboxylic acid], abbreviated as 5'-Cl, which shows selective antiproliferative activities against various cancer cell lines mediated through apoptosis. Here we have investigated the molecular mechanisms underlying the apoptotic activity of 5'-Cl in the human promyelocytic leukemia HL-60 cells. METHODS: We employed different methods to determine the apoptotic pathways triggered by 5'-Cl in HL-60 cells, using flow cytometry, nuclear staining, caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and Western blotting techniques. RESULTS: Low concentrations (1-8 µM) of 5'-Cl inhibited the growth of HL-60 cells in a dose and time-dependent manner. Cytotoxicity of this compound is found to be mediated by a caspase-dependent apoptosis. Also, there were indications of caspase independent apoptosis as z-VAD-FMK failed to fully rescue the cells from 5'-Cl-induced apoptosis. In addition, the compound triggered generation of Reactive Oxygen Species (ROS), caused depolarization of the mitochondrial inner membrane, decreased the level of cellular ATP, modulated the expression and phosphorylation of Bcl-2 leading to loss of its association with Bax and increased the release of cytochrome c to the cytosol of treated cells. The effects of 5'-Cl on mitochondria and apoptosis were substantially blocked in the presence of a combination between z-VAD-FMK and either of the ROS scavenger N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC). CONCLUSION: We demonstrated that the growth inhibitory effects of 5'-Cl in HL-60 cells involve multiple pathways of apoptosis and dysregulation of mitochondrial functions.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Mitocôndrias/metabolismo , Piridonas/química , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Caspases/metabolismo , Linhagem Celular Tumoral , Citocromos c/metabolismo , Células HL-60 , Humanos , Indóis/química , Indóis/farmacologia , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridonas/farmacologia , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Proteína X Associada a bcl-2/metabolismo
15.
J Spinal Cord Med ; 37(1): 54-71, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24090088

RESUMO

OBJECTIVE: To investigate the effect of bridging defects in chronic spinal cord injury using peripheral nerve grafts combined with a chitosan-laminin scaffold and enhancing regeneration through them by co-transplantation with bone-marrow-derived mesenchymal stem cells. METHODS: In 14 patients with chronic paraplegia caused by spinal cord injury, cord defects were grafted and stem cells injected into the whole construct and contained using a chitosan-laminin paste. Patients were evaluated using the International Standards for Classification of Spinal Cord Injuries. RESULTS: Chitosan disintegration leading to post-operative seroma formation was a complication. Motor level improved four levels in 2 cases and two levels in 12 cases. Sensory-level improved six levels in two cases, five levels in five cases, four levels in three cases, and three levels in four cases. A four-level neurological improvement was recorded in 2 cases and a two-level neurological improvement occurred in 12 cases. The American Spinal Impairment Association (ASIA) impairment scale improved from A to C in 12 cases and from A to B in 2 cases. Although motor power improvement was recorded in the abdominal muscles (2 grades), hip flexors (3 grades), hip adductors (3 grades), knee extensors (2-3 grades), ankle dorsiflexors (1-2 grades), long toe extensors (1-2 grades), and plantar flexors (0-2 grades), this improvement was too low to enable them to stand erect and hold their knees extended while walking unaided. CONCLUSION: Mesenchymal stem cell-derived neural stem cell-like cell transplantation enhances recovery in chronic spinal cord injuries with defects bridged by sural nerve grafts combined with a chitosan-laminin scaffold.


Assuntos
Células da Medula Óssea/fisiologia , Transplante de Células/métodos , Quitosana/uso terapêutico , Laminina/uso terapêutico , Células-Tronco Mesenquimais/fisiologia , Regeneração Nervosa , Nervos Periféricos/fisiologia , Traumatismos da Medula Espinal/cirurgia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Recuperação de Função Fisiológica , Adulto Jovem
16.
J Pers Med ; 13(1)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36675796

RESUMO

There is a pertinent need to develop prognostic biomarkers for practicing predictive, preventive and personalized medicine (PPPM) in colorectal cancer metastasis. The analysis of isoform expression data governed by alternative splicing provides a high-resolution picture of mRNAs in a defined condition. This information would not be available by studying gene expression changes alone. Hence, we utilized our prior data from an exon microarray and found ADAM12 and MUC4 to be strong biomarker candidates based on their alternative splicing scores and pattern. In this study, we characterized their isoform expression in a cell line model of metastatic colorectal cancer (SW480 & SW620). These two genes were found to be good prognostic indicators in two cohorts from The Cancer Genome Atlas database. We studied their exon structure using sequence information in the NCBI and ENSEMBL genome databases to amplify and validate six isoforms each for the ADAM12 and MUC4 genes. The differential expression of these isoforms was observed between normal, primary and metastatic colorectal cancer cell lines. RNA-Seq analysis further proved the differential expression of the gene isoforms. The isoforms of MUC4 and ADAM12 were found to change expression levels in response to 5-Fluorouracil (5-FU) treatment in a dose-, time- and cell line-dependent manner. Furthermore, we successfully detected the protein isoforms of ADAM12 and MUC4 in cell lysates, reflecting the differential expression at the protein level. The change in the mRNA and protein expression of MUC4 and ADAM12 in primary and metastatic cells and in response to 5-FU qualifies them to be studied as potential biomarkers. This comprehensive study underscores the importance of studying alternatively spliced isoforms and their potential use as prognostic and/or predictive biomarkers in the PPPM approach towards cancer.

17.
Artigo em Inglês | MEDLINE | ID: mdl-37468775

RESUMO

Present investigation demonstrates the development and characterization of strontium titanate (SrTiO3) doped biochar nanohybrid photocatalysts. Biochar nanohybrid was synthesized using an ultrasonic-assisted dispersion technique, which involved dispersing SrTiO3 nanoparticles into activated biochar at a weight ratio of 1:2 (w/w) under ambient conditions. The development of the biochar nanohybrid was verified through a comprehensive analysis of their spectral, microstructural, thermal, electrical, and electrochemical properties. The scanning electron microscopy analysis reveals a surface-associated multiphase morphology of the biochar nanohybrid, attributed to the uniform distribution of SrTiO3 within the activated biochar matrix. Biochar nanohybrid exhibited a reduced optical band gap of 2.77 eV, accompanied by a crystallite size of 32.45. Thermogravimetric analysis revealed the thermal stability of the biochar nanohybrid, as evidenced by a char residue of 70.83% at 1000 °C. The working electrodes derived from biochar nanohybrid have exhibited ohmic behavior and displayed a significantly enhanced DC conductivity (mS/cm) of 1.13, surpassing that of activated biochar (0.53) and SrTiO3 (0.62) at 100 V. The developed biochar nanohybrid were employed for the degradation of congo red dye by exposing the dye solution to photocatalytic plates. These photocatalytic plates were prepared by coating biochar nanohybrid onto glass plates using epoxy-based reactive binders for secure binding. The photodegradation of congo red was evaluated through cyclic voltammetric analysis in a 0.1 M KCl solution at pH 8.0, resulting in an impressive 99.95% photocatalytic efficiency in degrading a congo red solution (50 mg/L). This study presents a novel approach for the fabrication of biochar nanohybrid-derived photocatalytic plates, offering high photocatalytic efficiency for the degradation of congo red dye.

18.
Comput Intell Neurosci ; 2023: 2398121, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37383681

RESUMO

Automation in every part of life has become a frequent situation because of the rapid advancement of technology, mostly driven by AI technology, and has helped facilitate improved decision-making. Machine learning and the deep learning subset of AI provide machines with the capacity to make judgments on their own through a continuous learning process from vast amounts of data. To decrease human mistakes while making critical choices and to improve knowledge of the game, AI-based technologies are now being implemented in numerous sports, including cricket, football, basketball, and others. Out of the most globally popular games in the world, cricket has a stronghold on the hearts of its fans. A broad range of technologies are being discovered and employed in cricket by the grace of AI to make fair choices as a method of helping on-field umpires because cricket is an unpredictable game, anything may happen in an instant, and a bad judgment can dramatically shift the game. Hence, a smart system can end the controversy caused just because of this error and create a healthy playing environment. Regarding this problem, our proposed framework successfully provides an automatic no-ball detection with 0.98 accuracy which incorporates data collection, processing, augmentation, enhancement, modeling, and evaluation. This study starts with collecting data and later keeps only the main portion of bowlers' end by cropping it. Then, image enhancement technique are implied to make the image data more clear and noise free. After applying the image processing technique, we finally trained and tested the optimized CNN. Furthermore, we have increased the accuracy by using several modified pretrained model. Here, in this study, VGG16 and VGG19 achieved 0.98 accuracy and we considered VGG16 as the proposed model as it outperformed considering recall value.


Assuntos
Críquete , Futebol Americano , Humanos , , Extremidade Inferior , Aprendizado de Máquina
19.
Front Biosci (Landmark Ed) ; 28(6): 113, 2023 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-37395027

RESUMO

BACKGROUND: Lamins are the major component of nuclear lamina. Alternative splicing of the 12 exons comprising lamin A/C gene creates five known transcript variants, lamin A, lamin C, lamin AΔ10, lamin AΔ50, and lamin C2. The main objective for this study was to examine the association of critical pathways, networks, molecular and cellular functions regulated by each Lamin A/C transcript variants. METHODS: Ion AmpliSeq Transcriptome Human Gene Expression analysis was performed on MCF7 cells stably transfected with lamin A/C transcript variants. RESULTS: Lamin A or lamin AΔ50 upregulation was associated with activation of cell death and inactivation of carcinogenesis while both lamin C or lamin AΔ10 upregulation activated carcinogenesis and cell death. CONCLUSIONS: Data suggest anti-apoptotic and anti-senescence effects of lamin C and lamin AΔ10 as several functions, including apoptosis and necrosis functions are inactivated following lamin C or lamin AΔ10 upregulation. However, lamin AΔ10 upregulation is associated with a more carcinogenic and aggressive tumor phenotype. Lamin A or lamin AΔ50 upregulation is associated with a predicted activation of increased cell death and inactivation of carcinogenesis. Thus, different signaling pathways, networks, molecular and cellular functions are activated/inactivated by lamin A/C transcript variants resulting in a large number of laminopathies.


Assuntos
Lamina Tipo A , Transcriptoma , Humanos , Processamento Alternativo , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Células MCF-7 , Transdução de Sinais/genética
20.
J Adv Vet Anim Res ; 10(3): 522-537, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37969792

RESUMO

Probiotics are live bacteria beneficial to health when consumed adequately. Health professionals now recommend probiotics on regular diets due to their positive effects on human health. The probiotics that are usually consumed from the market through food products are mostly dairy-based. Fruit and vegetables are gaining popularity as preferred matrices for probiotic carriers to the human body, owing to their high cholesterol content and the lactose intolerance of dairy products. On the other hand, fruits and vegetable juices are rich in nutrient content such as vitamins, minerals, and antioxidants and do not contain a starter culture that can compete with the nutrients. The probiotication of fruit and vegetable juices (apple, carrot, citrus fruit, pome-granate, watermelon, tomato, and pineapple) are performing as efficient probiotic bacteria carriers. This review covers the previous works that highlighted the variety of probiotic fruit and vegetable juices as well as the viability of each probiotic in various products after proper fermentation and storage. In addition, physicochemical and sensory changes that occurred during the processing and storage period have been discussed. Furthermore, strategies (microencapsulation, adding prebiotics, antioxidant addition, maintaining optimum pH, temperature, adaptation with resistance, and good packaging) to improve the stability of probiotic bacteria are outlined, as it is difficult to maintain the stability of probiotic bacteria during storage. Finally, the manuscript discusses the effect of probiotic fruit and vegetable juices on human health.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA