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1.
Nat Commun ; 15(1): 5597, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961064

RESUMO

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.


Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Fator de Transcrição Associado à Microftalmia , N-Acetilglucosaminiltransferases , Piperazinas , Piridinas , Humanos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fator de Transcrição Associado à Microftalmia/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Linhagem Celular Tumoral , N-Acetilglucosaminiltransferases/metabolismo , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/genética , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
ACS Omega ; 9(21): 22979-22989, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38826557

RESUMO

Liver diseases pose a significant global health burden, with limited therapeutic options for chronic cases. Zinc oxide (ZnO) nanomaterials have emerged as promising candidates for hepatoprotection due to their antioxidant, anti-inflammatory, and regenerative properties. However, their potential remains hampered by insufficient drug loading and controlled release. The current study explores the intercalation of Naproxen (Nx), a potent anti-inflammatory and analgesic drug, within ZnO stacked nanosheets (SNSs) to address these limitations. Herein, an easy and solution-based synthesis of novel Nx intercalated ZnO SNSs was established. The obtained Nx intercalated ZnO SNSs were encapsulated with poly(vinyl acetate) (PVA) to make them biocompatible. The synthesized biocomposite was characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR), which confirm the successful synthesis and intercalation of Nx within the ZnO SNSs. The obtained outcomes showed that the configuration of ZnO nanosheets was altered when Nx was introduced, resulting in a more organized stacking pattern. An in vivo investigation of mice liver cells unveiled that the Nx intercalated ZnO SNss had increased hepatoprotective properties. The study's results provide valuable insights into using Nx intercalated ZnO SNss for targeted drug delivery and improved treatment effectiveness, particularly for liver-related illnesses.

3.
BMC Pediatr ; 24(1): 389, 2024 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-38851708

RESUMO

BACKGROUND: There are limited data available, particularly in low- and middle-income countries (LMICs), on the long-term quality of life (QoL) and family functioning of primary caregivers of children and young people (CYPs) affected by primary brain tumors (PBTs). This study aimed to assess the factors associated with the mean change in QoL and family functioning scores of primary caregivers of CYP patients with PBTs 12 months posttreatment. METHODS: This prospective cohort study enrolled CYPs aged 5-21 years with newly diagnosed PBTs and their primary caregivers. The study was carried out between November 2020 and July 2023. The primary caregivers of CYPs were recruited from two major tertiary care centers in Karachi, Pakistan. The primary caregivers QoL were assessed by the Pediatric Quality of Life Inventory (PedsQL) Family Impact Module. The assessment was undertaken by a psychologist at the time of diagnosis and 12 months posttreatment. The data were analyzed with STATA version 12. RESULTS: Forty-eight CYPs with newly diagnosed PBTs and their primary caregivers (46 mothers and 2 fathers) were enrolled. At 12 months posttreatment, 25 (52%) CYPs and their primary caregivers (mothers) were reassessed, and 23 (48%) were lost to follow-up. On multivariable analysis, a significant decrease in mothers' mean 12-month posttreatment QoL and family functioning scores was associated with CYP having posttreatment seizures (beta= -10.2; 95% CI: -18.4 to -2.0) and with the financial burden associated with the CYP's illness (beta= -0.3; 95% CI: -0.4 to -0.1). However, in those cases where CYP had higher posttreatment quality of life scores (beta = 0.4; 95% CI = 0.1, 0.6) and posttreatment higher verbal intelligence scores (beta = 0.1; 95% CI = 0.01, 0.3), the mothers' QoL and family functioning scores were significantly greater. CONCLUSION: We found a significant decrease in QoL of mothers who had a high financial burden and whose CYP had posttreatment seizures. However, those whose CYPs had higher posttreatment verbal intelligence scores and quality of life scores had significantly greater QoL scores. Identification of the factors that influence primary caregivers QoL has the potential to aid in the development of targeted strategies to alleviate stressors and improve the overall quality of life for primary caregivers and their children who are at high risk.


Assuntos
Neoplasias Encefálicas , Cuidadores , Qualidade de Vida , Humanos , Paquistão , Cuidadores/psicologia , Feminino , Criança , Estudos Prospectivos , Masculino , Adolescente , Neoplasias Encefálicas/psicologia , Neoplasias Encefálicas/terapia , Pré-Escolar , Adulto Jovem
4.
Scientifica (Cairo) ; 2024: 8144325, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38595942

RESUMO

Objective: To determine the final year pharmacy undergraduate students' attitudes toward research after completing a research project. Methods: A research project was introduced in the final year of the PharmD program in January 2022. After a period of one year, in Janurary 2023, students submitted their final research to the faculty members. The survey was conducted from 1st March to 30st April 2023 using a study tool that contained items asking students' demographic, their research perceptions, attitude and experience, and also motivation/barriers faced during the research project. Descriptive and t-test statistics were utilized to compare the means of subgroups at a level of significance, i.e., p < 0.05. The data were also analyzed using Goodman and Kruskal's gamma and Mann-Whitney U test. Results: Majority of the students (93.8%) agreed regarding the significance of research in the pharmacy profession. Students were found to have their projects a worthwhile learning opportunity (94.2%). Students' motivation to execute research project stems from mandatory curriculum courses, improving clinical or hospital pharmacist training and fulfilling research skills (90%). Barriers hindered include lack of training, time, and patient follow-up (approximately 70%). Conclusion: The current study's finding was concluded with the fact that research is a valuable component of a well-rounded education and can enhance a pharmacist's skills. However, they need a combination of formal education and practical experience to pursue a profession in pharmacy.

5.
Heliyon ; 10(7): e27177, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38601685

RESUMO

The Internet of Things (IoT) is a network of intelligent devices especially in healthcare-based systems. Internet of Medical Things (IoMT) uses wearable sensors to collect data and transmit to central repositories. The security and privacy of healthcare data is a challenging task. The aim of the study is to provide a secure data sharing mechanism. The existing studies provide secure data sharing schemes but still have limitations in terms of hiding the patient identify in the messages exchanged to upload the data on central repositories. This paper presents a Secure Aggregated Data Collection and Transmission (SADCT) that provides anonymity for the identities of patient's mobile device and the intermediate fog nodes. Our system involves an authenticated server for node registration and authentication by saving security credentials. The proposed scheme presents the novel data aggregation algorithm at the mobile device, and the data extraction algorithm at the fog node. The work is validated through extensive simulations in NS along with a security analysis. Results prove the supremacy of SADCT in terms of energy consumption, storage, communication, and computational costs.

6.
Res Sq ; 2023 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-37886470

RESUMO

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we found that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors; O-GlcNAcylation of MITF at Serine 49 enhanced its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppressed palbociclib-induced senescence; inhibition of MITF or its O-GlcNAcylation re-sensitized resistant cells to palbociclib. Remarkably, clinical studies confirmed the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on a novel mechanism regulating palbociclib-resistance, and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.

7.
J Public Health Res ; 12(3): 22799036231197185, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37700932

RESUMO

Background: Brain tumors are a common cause of morbidity, disability, cognitive deterioration and mortality in children, even after treatment. Little is know about the specific causes. The study aimed to assess potential socio-demographic and antenatal factors in primary brain tumor (PBTs) in children and young people (CYP) in Karachi, Pakistan. Designs and methods: A single center hospital based matched case control study in Karachi, Pakistan. Cases were defined as CYP aged between 5 and 21 years with any histological type and grade of primary brain tumor of any histology, stage or grade. Data were collected from parents of 244 patients at the selected center between 2017 and 2021 via telephonic interview. Controls were 5-21 years old CYP admitted with non-oncological diagnoses matched on age and sex. Matched Odds Ratios for predictors of brain tumor in children were derived. Those of statistical significance were included in a multivariable logistic regression model. Results: In the adjusted model, lower paternal education (matched adjusted odds ratio (maOR) 2.46; 95% CI 1.09-5.55), higher household monthly income (maOR 3.4; 95% CI 1.1-10.2), antenatal paternal use of addictive substances (maOR 19.5; 95% CI 2.1-179.8), and antenatal maternal use of analgesics during pregnancy (maOR 3.0; 95% CI 1.2-7.9) were all independently predictive of brain tumors. Conclusion: This matched case-control study found novel associations between maternal use of analgesics, paternal use of addictive substances, higher household income, and lower paternal education and Primary Brain Tumors in Children and Young People. Longitudinal multicenter studies will be required to test these associations prospectively.

8.
Sensors (Basel) ; 23(5)2023 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-36904577

RESUMO

Intelligent traffic management systems have become one of the main applications of Intelligent Transportation Systems (ITS). There is a growing interest in Reinforcement Learning (RL) based control methods in ITS applications such as autonomous driving and traffic management solutions. Deep learning helps in approximating substantially complex nonlinear functions from complicated data sets and tackling complex control issues. In this paper, we propose an approach based on Multi-Agent Reinforcement Learning (MARL) and smart routing to improve the flow of autonomous vehicles on road networks. We evaluate Multi-Agent Advantage Actor-Critic (MA2C) and Independent Advantage Actor-Critical (IA2C), recently suggested Multi-Agent Reinforcement Learning techniques with smart routing for traffic signal optimization to determine its potential. We investigate the framework offered by non-Markov decision processes, enabling a more in-depth understanding of the algorithms. We conduct a critical analysis to observe the robustness and effectiveness of the method. The method's efficacy and reliability are demonstrated by simulations using SUMO, a software modeling tool for traffic simulations. We used a road network that contains seven intersections. Our findings show that MA2C, when trained on pseudo-random vehicle flows, is a viable methodology that outperforms competing techniques.

9.
Nanotechnology ; 34(26)2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-36972572

RESUMO

Recently, there has been considerable interest in a new family of transition metal carbides, carbonitrides, and nitrides referred to as MXenes (Ti3C2Tx) due to the variety of their elemental compositions and surface terminations that exhibit many fascinating physical and chemical properties. As a result of their easy formability, MXenes may be combined with other materials, such as polymers, oxides, and carbon nanotubes, which can be used to tune their properties for various applications. As is widely known, MXenes and MXene-based composites have gained considerable prominence as electrode materials in the energy storage field. In addition to their high conductivity, reducibility, and biocompatibility, they have also demonstrated outstanding potential for applications related to the environment, including electro/photocatalytic water splitting, photocatalytic carbon dioxide reduction, water purification, and sensors. This review discusses MXene-based composite used in anode materials, while the electrochemical performance of MXene-based anodes for Li-based batteries (LiBs) is discussed in addition to key findings, operating processes, and factors influencing electrochemical performance.

10.
J Affect Disord ; 328: 191-199, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36773763

RESUMO

BACKGROUND: Maternal depressive symptoms are common in pregnancy and may extend to the perinatal period and beyond for some women. To date, few longitudinal studies have investigated maternal depressive symptoms from pregnancy to eleven years postpartum. Drawing data from a large population-based study cohort the aims of this study were to 1) identify distinct groups of mothers defined by their trajectories of depressive symptoms spanning from pregnancy to eleven years following the birth of the child, and 2) to identify psychosocial risk factors during pregnancy and in the first few postnatal years that are associated with these trajectories. METHODS: Data were analyzed from 14,170 mothers who participated in Avon Longitudinal Study of Parents and Children (ALSPAC). The Edinburgh Postnatal Depression Scale (EPDS) was used to capture maternal depressive symptoms across 10 time points including two prenatal (18 and 32 weeks), and eight postnatal (2, 8, 21, 33, 61, 73, 97 and 134 months) time points. The latent growth model was created to describe the course of maternal depressive symptoms across the preceding time points followed by a latent growth mixture modelling (LGMM) to identify distinct trajectories of depressive symptoms over time within the overall sample. The predictors of maternal depressive symptoms trajectories were categorized into sociodemographic, child, and psychosocial factors. The multinomial regression analyses were conducted to explore associations between the risk factors and depressive symptoms trajectories. RESULTS: LGMM identified four distinct trajectories of maternal depressive symptoms over time: minimal symptoms, increasing symptoms, persistent symptoms, and decreasing symptoms. Predictors of all patterns of depression - persistent, increasing and decreasing symptoms include smoking during pregnancy, and partner conflict. The strongest predictors of the persistent symptom trajectory included maternal history of depression and inadequate social support. LIMITATIONS: The use of self-reported maternal mental health symptoms and under representation of ethnic minorities are our study's limitations. CONCLUSIONS: The study findings highlight the importance of early identification and treatment for mothers experiencing depressive symptoms from pregnancy to the perinatal period and beyond.


Assuntos
Depressão Pós-Parto , Depressão , Gravidez , Criança , Feminino , Humanos , Depressão/psicologia , Estudos Longitudinais , Depressão Pós-Parto/psicologia , Pais , Período Pós-Parto
11.
Int J Public Health ; 68: 1605038, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36816832

RESUMO

Objective: This study assessed the feasibility of implementing screening, brief intervention and referral (SBIR) intervention in hospital settings. Methods: This cross-sectional study evaluated the implementation of the SBIR intervention in a hospital in Alberta for tobacco use, alcohol intake, physical inactivity, and insufficient vegetable and fruit consumption. Patients were interviewed approximately 4-month later to collect data on the acceptability and effectiveness of the intervention received (n = 108). The data were primarily analyzed using descriptive statistics. Results: Of 108 patients, >80% agreed that "they were ok with being screened" for the risk factors during their hospital visit. Up to 68% of patients recalled the provider's brief education. At the follow-up, 20% of patients quit tobacco, 50% reduced alcohol use, 30% increased physical activity, and 25% increased vegetable and fruit intake. Conclusion: Risk factor screening was acceptable for patients. Patients recalled the brief education they received from healthcare providers. Patients reported risk-reducing changes in their risk factors. Our future work will integrate the SBIR approach within the Electronic Clinical Information System and use robust research methods to investigate the impact of SBIR on patients' behavior change.


Assuntos
Intervenção em Crise , Promoção da Saúde , Humanos , Projetos Piloto , Alberta , Estudos Transversais , Promoção da Saúde/métodos , Verduras , Hospitais , Encaminhamento e Consulta , Programas de Rastreamento
12.
Molecules ; 28(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36677548

RESUMO

All nutrient-rich feed and food environments, as well as animal and human mucosae, include lactic acid bacteria known as Lactobacillus plantarum. This study reveals an advanced analysis to study the interaction of probiotics with the gastrointestinal environment, irritable bowel disease, and immune responses along with the analysis of the secondary metabolites' characteristics of Lp YW11. Whole genome sequencing of Lp YW11 revealed 2297 genes and 1078 functional categories of which 223 relate to carbohydrate metabolism, 21 against stress response, and the remaining 834 are involved in different cellular and metabolic pathways. Moreover, it was found that Lp YW11 consists of carbohydrate-active enzymes, which mainly contribute to 37 glycoside hydrolase and 28 glycosyltransferase enzyme coding genes. The probiotics obtained from the BACTIBASE database (streptin and Ruminococcin-A bacteriocins) were docked with virulent proteins (cdt, spvB, stxB, and ymt) of Salmonella, Shigella, Campylobacter, and Yersinia, respectively. These bacteria are the main pathogenic gut microbes that play a key role in causing various gastrointestinal diseases. The molecular docking, dynamics, and immune simulation analysis in this study predicted streptin and Ruminococcin-A as potent nutritive bacteriocins against gut symbiotic pathogens.


Assuntos
Bacteriocinas , Lactobacillus plantarum , Probióticos , Animais , Humanos , Simulação de Acoplamento Molecular , Bacteriocinas/genética , Bacteriocinas/farmacologia , Bacteriocinas/metabolismo , Bactérias/metabolismo , Probióticos/farmacologia , Lactobacillus plantarum/metabolismo
13.
Semin Cancer Biol ; 88: 106-122, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36565895

RESUMO

Deregulation of the cell cycle machinery, which has been linked to dysregulation of cyclin-dependent kinases (CDKs), is a defining characteristic of cancer, eventually promoting abnormal proliferation that feeds tumorigenesis and disease development. In this regard, several CDK inhibitors (CDKIs) have been developed during the last few decades (1st, 2nd, and 3rd generation CDKIs) to inhibit cancer cell proliferation. 1st and 2nd generation CDKIs have not received much clinical attention for the treatment of cancer patients because of their limited specificity and high toxicity. However, the recent development of combination strategies allowed us to reduce the toxicity and side effects of these CDKIs, paving the way for their potential application in clinical settings. The 3rd generation CDKIs have yielded the most promising results at the preclinical and clinical levels, propelling them into the advanced stages of clinical trials against multiple malignancies, especially breast cancer, and revolutionizing traditional treatment strategies. In this review, we discuss the most-investigated candidates from the 1st, 2nd, and 3rd generations of CDKIs, their basic mechanisms of action, the reasons for their failure in the past, and their current clinical development for the treatment of different malignancies. Additionally, we briefly highlighted the most recent clinical trial results and advances in the development of 3rd generation FDA-approved selective CDK4/6 inhibitors that combat the most prevalent cancer. Overall, this review will provide a thorough knowledge of CDKIs from the past to the present, allowing researchers to rethink and develop innovative cancer therapeutic regimens.


Assuntos
Neoplasias da Mama , Inibidores de Proteínas Quinases , Humanos , Feminino , Inibidores de Proteínas Quinases/efeitos adversos , Quinases Ciclina-Dependentes/metabolismo , Quinases Ciclina-Dependentes/farmacologia , Quinases Ciclina-Dependentes/uso terapêutico , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células
14.
J Parasit Dis ; 46(4): 1164-1175, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36457787

RESUMO

Avian coccidiosis is caused by genus Eimeria (E.) i.e. E. maxima, E. necatrix, E. tenella, E. acervulina, E. brunette and E. mitis and lead to three billion US dollar per year economic loss in poultry industry and reduces the growth performance of birds. To purge undesirable foreign agents, immune system produces a variety of molecules and cells that ultimately neutralize target particles in healthy organisms. However; when this particular system compromises, infection develops and the load of pathogens along with their virulence factors overcome both; innate and adaptive immune systems. Livestock and poultry sectors are important part of agriculture industry worldwide. Due to excessive use of chemotherapeutic agents, pathogens have developed resistance against these agents leading to the great economic losses. Numerous therapeutic approaches are in routine process for the treatment and prevention of various ailments but irrational use of antibiotics/chemicals has raised alarming concerns, like the development of drug resistant strains, residual effects in ultimate users and environmental pollution. These problems have led to the development of alternatives. In this regard, anticoccidial vaccine can be used as an alternative but due to high cost of production, plant derived biological response modifiers and antioxidants compounds are considered as a promising alternative. This review summarizes the immunotherapeutic effects of different compounds particularly with reference to avian coccidiosis.

15.
Front Microbiol ; 13: 960285, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36329838

RESUMO

Serratia marcescens, a Gram-negative bacterium, is one of the known disease-causing pathogens. It is resistant to ampicillin, macrolides, cephalosporins, cefotaxime, and ceftazidime. The only antibiotic that has been proven to be effective against S. marcescens is gentamicin. By causing epigenetic alterations, bacteria can also become resistant to all antibiotics. Many epigenetically related proteins were studied, and four proteins were selected in this regard for epitope evaluation and their subsequent use in the development of a messenger ribonucleic acid (mRNA) vaccine. A series of immune-informatics tools used to build this mRNA vaccine elicited cellular and humoral immunity. Molecular docking between epitopes and alleles of the major histocompatibility complex (MHC) was performed. The vaccine was developed using 37 epitopes, an adjuvant that is a TLR-4 agonist known as resuscitation-promoting factor E (RpfE), subcellular trafficking structures, secretion boosters, and linkers. This proposed architecture was found to cover 99.6% of the population during testing. During testing, it was proven that it was both effective and safe. To confirm our idea, we performed an in silico immunological simulation of vaccination. The codon was also optimized to ensure that the mRNA reached the cytoplasm of a human host and underwent efficient translation. TLR-4 and TLR-3 were also docked against the secondary and tertiary structures of the vaccine peptide. Furthermore, the vaccine's stability was confirmed by molecular dynamics simulation. In summary, this vaccine construct can be a potential candidate against S. marcescens and is suitable for in vitro analyses to validate its effectiveness.

17.
Sci Rep ; 12(1): 20258, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36424413

RESUMO

Lung cancer progression is often driven by metastasis, which has resulted in a considerable increase in lung cancer-related deaths. Cell-derived extracellular vesicles (EVs), particularly exosomes, serve key roles in cellular signal transmission via microenvironment, however, their biological relevance in cancer development and metastasis still needs to be clear. Here, we demonstrate that extracellular vesicles (EVs) derived from lung cancer bone metastatic patients exhibited a great capacity to promote the progression of lung cancer cells. We carried out a comprehensive meta-analysis to identify the gene expression profile of bone metastases using publicly available microarray datasets. Furthermore, mRNA expression of six identified genes was quantified by real time PCR in lung cancer with and without bone metastasis and healthy individual derived EVs. In addition, we utilized a very novel approach by to study how lung cancer cells uptake EVs by co-culturing EVs with lung cells. We observed that EVs obtained from bone metastases patients were efficiently ingested by lung cancer cells. Morevore, integration and uptake of these EVs lead to increased lung cancer cell proliferation, migration, invasion, and sphere formation. We discovered that EV uptake increase the expression of SPP1, CD44, and POSTN genes in lung cancer cells. The data obtained from this study, support to the possibility that circulating EVs play a significant role in the formation of the pre-metastatic niche, eventually leading to metastasis.


Assuntos
Neoplasias Ósseas , Exossomos , Vesículas Extracelulares , Neoplasias Pulmonares , Humanos , Solo , Vesículas Extracelulares/metabolismo , Neoplasias Pulmonares/patologia , Transdução de Sinais , Exossomos/metabolismo , Neoplasias Ósseas/patologia , Microambiente Tumoral/genética
19.
Medicina (Kaunas) ; 58(10)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36295517

RESUMO

Background and Objectives: Citrobacter freundii (C. freundii) is an emerging and opportunistic Gram-negative bacteria of the human gastrointestinal tract associated with nosocomial and severe respiratory tract infections. It has also been associated with pneumonia, bloodstream, and urinary tract infections. Intrinsic and adaptive virulence characteristics of C. freundii have become a significant source of diarrheal infections and food poisoning among immune-compromised patients and newborns. Impulsive usage of antibiotics and these adaptive virulence characteristics has modulated the C. freundii into multidrug-resistant (MDR) bacteria. Conventional approaches are futile against MDR C. freundii. Materials and Methods: The current study exploits the modern computational-based vaccine design approach to treat infections related to MDR C. freundii. A whole proteome of C. freundii (strain: CWH001) was retrieved to screen pathogenic and nonhomologous proteins. Six proteins were shortlisted for the selection of putative epitopes for vaccine construct. Highly antigenic, nonallergen, and nontoxic eleven B-cell, HTL, and TCL epitopes were selected for mRNA- and peptide-based multi-epitope vaccine construct. Secondary and tertiary structures of the multi-epitope vaccine (MEVC) were designed, refined, and validated. Results: Evaluation of population coverage of MHC-I and MHC-II alleles were 72% and 90%, respectively. Docking MEVC with TLR-3 receptor with the binding affinity of 21.46 (kcal/mol) occurred through the mmGBSA process. Further validations include codon optimization with an enhanced CAI value of 0.95 and GC content of about 51%. Immune stimulation and molecular dynamic simulation ensure the antibody production upon antigen interaction with the host and stability of the MEVC construct, respectively. Conclusions: These interpretations propose a new strategy to combat MDR C. freundii. Further, in vivo and in vitro trials of this vaccine will be valuable in combating MDR pathogens.


Assuntos
Citrobacter freundii , Proteômica , Recém-Nascido , Humanos , Proteoma , RNA Mensageiro , Receptor 3 Toll-Like , Vacinas de Subunidades Antigênicas/química , Epitopos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Peptídeos
20.
BMC Cancer ; 22(1): 990, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115941

RESUMO

BACKGROUND: A group of genetically altered cells that have not transformed into a clinical or histologically identifiable state of malignancy but contains a higher risk of transforming into one is known as the field of cancerization. Numerous molecules are being investigated for their significance in the development of this phenomenon. One such protein of this family is Kaiso also known as ZBTB33 (Zinc Finger and BTB Domain containing 33). This protein belongs to the POZ-ZF family of transcription factors and may have functional tasks similar to its other siblings such as the growth and development of vertebrates and the pathogenesis of neoplastic diseases. Nevertheless, its role in the pathogenesis, progression, epithelial mesenchyal transition and field cancerization in case of oral cancer still needs exploration. Hence, this study was designed to explore the expressional differences between the mucosa of controls and those diagnosed with oral squamous cell carcinoma (OSCC). METHODS: Soft tissue samples were obtained from the main tumor, tumor periphery and opposite buccal mucosa of 50 oral cancer patients, whereas normal mucosa was taken from 50 volunteers undergoing elective tooth removal. The acquired samples were subjected to Immunohistochemical exploration for expression of Kaiso and E-Cadherin. The expression was measured using Image-J IHC profiler and summed as Optical density. The Optical density values were then subjected to statistical analysis. RESULTS: Results revealed a significant differential expression of Kaiso between the mucosal tissues taken from oral cancer patients and controls (p-value: < 0.0001), showing almost 50% down-regulation of Kaiso in all three tissue samples taken from oral cancer patients as compared to normal mucosa. CONCLUSION: Kaiso has a significant difference of expression in the mucosa of oral cancer patients as compared to the mucosa of normal patients, making it a probable contributor to disease pathogenesis and field cancerization.


Assuntos
Transformação Celular Neoplásica , Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Transcrição , Caderinas/biossíntese , Caderinas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Mucosa Bucal/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
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