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1.
Oral Health Prev Dent ; 22: 373-380, 2024 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-39105314

RESUMEN

PURPOSE: The relationship between body mass index (BMI) and oral disorders remains unclear. This study examined the prevalence and types of dental abnormalities and oral mucosal lesions among female students with obesity attending a Taif University sports centre. MATERIALS AND METHODS: This non-interventional cross-sectional study enrolled female students with high BMI from a university sports facility using a convivence sampling method. The participants were divided into three BMI groups. Data were collected using an interview and by clinical oral examination. Prevalence and oral disorder types and possible mechanisms linking BMI and dental development were evaluated. RESULTS: Ultimately, 86 female students with obesity were analysed. The mean BMI was 42.8 kg/m2, indicating high obesity levels. A weak although statistically significant correlation was observed between age and BMI (r=0.27), indicating that older students had higher BMI. A statistically significant association was observed between BMI and dental abnormalities (p0.05). The dental abnormality prevalence increased with BMI, ranging from 37.5% to 40.7% in the ≤40 and >45 kg/m2 groups, respectively. Most participants (66.3%) had oral mucosal lesions, with the highest prevalence among participants in the 40-45 kg/m2 group (71.4%). CONCLUSION: A statistically significant relationship was observed between BMI and dental abnormalities; obesity may negatively affect oral health.


Asunto(s)
Índice de Masa Corporal , Obesidad , Humanos , Femenino , Estudios Transversales , Prevalencia , Adulto Joven , Obesidad/epidemiología , Obesidad/complicaciones , Adulto , Maloclusión/epidemiología , Anomalías Dentarias/epidemiología , Enfermedades de la Boca/epidemiología , Adolescente
2.
Int J Pharm ; 660: 124301, 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-38851411

RESUMEN

The application of gold nanoparticles (AuNPs) in cancer therapy, particularly targeted therapy of glioblastoma multiforme (GBM), is an up-and-coming field of research that has gained much interest in recent years. GBM is a life-threatening malignant tumour of the brain that currently has a 95 % death rate with an average of 15 months of survival. AuNPs have proven to have wide clinical implications and compelling therapeutic potential in many researches, specifically in GBM treatment. It was found that the reason why AuNPs were highly desired for GBM treatment was due to their unique properties that diversified the applications of AuNPs further to include imaging, diagnosis, and photothermal therapy. These properties include easy synthesis, biocompatibility, and surface functionalization. Various studies also underscored the ability of AuNPs to cross the blood-brain-barrier and selectively target tumour cells while displaying no major safety concerns which resulted in better therapy results. We attempt to bring together some of these studies in this review and provide a comprehensive overview of safety evaluations and current and potential applications of AuNPs in GBM therapy that may result in AuNP-mediated therapy to be the new gold standard for GBM treatment.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Oro , Nanopartículas del Metal , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Oro/química , Oro/administración & dosificación , Humanos , Nanopartículas del Metal/administración & dosificación , Nanopartículas del Metal/química , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos
3.
Biochim Biophys Acta Proteins Proteom ; 1872(5): 141027, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38796131

RESUMEN

Misfolding and aggregation of transthyretin (TTR) is associated with numerous ATTR amyloidosis. TTR aggregates extracted from ATTR patients consist of not only full-length TTR, but also N-terminally truncated TTR fragments that can be produced by proteolytic cleavage, suggesting the presence of multiple misfolding pathways. Here, we report mechanistic studies of an early stage of TTR aggregation to probe the oligomerization process for the full-length as well as N-terminally truncated TTR. Our kinetic analyses using size exclusion chromatography revealed that amyloidogenic monomers dissociated from wild-type (WT) as well as pathogenic variants (V30M and L55P) form misfolded dimers, which self-assemble into oligomers, precursors of fibril formation. Dimeric interfaces in the full-length misfolded oligomers were investigated by examining the effect of single-point mutations on the two ß-strands (F and H). The single-point mutations on the two ß-strands (E92P on strand F and T119W on strand H) inhibited the dimerization of misfolded monomers, while the TTR variants can still form native dimers through the same F and H strands. These results suggest that the two strands are involved in intermolecular associations for both native and misfolded dimers, but detailed intermolecular interactions are different in the two forms of dimers. In the presence of a proteolytic enzyme, TTR aggregation is greatly accelerated. The two mutations on the two ß-strands, however, inhibited TTR aggregation even in the presence of a proteolytic enzyme, trypsin. These results suggest that the two ß-strands (F and H) play a critical role in aggregation of the N-terminally truncated TTR as well.


Asunto(s)
Prealbúmina , Pliegue de Proteína , Multimerización de Proteína , Prealbúmina/química , Prealbúmina/genética , Prealbúmina/metabolismo , Humanos , Mutación Puntual , Cinética , Neuropatías Amiloides Familiares/metabolismo , Neuropatías Amiloides Familiares/genética , Amiloide/química , Amiloide/metabolismo
4.
Brain Res Bull ; 213: 110973, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38723694

RESUMEN

Epilepsy is a common neurological disease characterized by the recurrent, paroxysmal, and unprovoked seizures. It has been shown that hyperuricemia enhances and associated with the development and progression of epilepsy through induction of inflammation and oxidative stress. In addition, uric acid is released within the brain and contributes in the development of neuronal hyperexcitability and epileptic seizure. Brain uric acid acts as damage associated molecular pattern (DAMP) activates the immune response and induce the development of neuroinflammation. Therefore, inhibition of xanthine oxidase by allopurinol may reduce hyperuricemia-induced epileptic seizure and associated oxidative stress and inflammation. However, the underlying mechanism of allopurinol in the epilepsy was not fully elucidated. Therefore, this review aims to revise from published articles the link between hyperuricemia and epilepsy, and how allopurinol inhibits the development of epileptic seizure.


Asunto(s)
Alopurinol , Epilepsia , Hiperuricemia , Hiperuricemia/tratamiento farmacológico , Alopurinol/farmacología , Alopurinol/uso terapéutico , Humanos , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Animales , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ácido Úrico/metabolismo , Xantina Oxidasa/metabolismo , Xantina Oxidasa/antagonistas & inhibidores , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos
6.
J Biomol Struct Dyn ; : 1-10, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38669200

RESUMEN

The discovery of novel therapeutic agents with potent anticancer activity remains a critical challenge in drug development. Natural products, particularly bioactive phytoconstituents derived from plants, have emerged as promising sources for anticancer drug discovery. In this study, we used virtual screening techniques to explore the potential of bioactive phytoconstituents as inhibitors of fibroblast growth factor receptor 1 (FGFR1), a key signaling protein implicated in cancer progression. We used virtual screening techniques to analyze phytoconstituents extracted from the IMPPAT 2.0 database. Our primary objective was to discover promising inhibitors of FGFR1. To ensure the selection of promising candidates, we initially filtered the molecules based on their physicochemical properties. Subsequently, we performed binding affinity calculations, PAINS, ADMET, and PASS filters to identify nontoxic and highly effective hits. Through this screening process, one phytocompound, namely Mundulone, emerged as a potential lead. This compound demonstrated an appreciable affinity for FGFR1 and exhibited specific interactions with the ATP-binding site residues. To gain further insights into the conformational dynamics of Mundulone and the reference FGFR1 inhibitor, Lenvatinib, we conducted time-evolution analyses employing 200 ns molecular dynamics simulations (MDS) and essential dynamics. These analyses provided valuable information regarding the dynamic behavior and stability of the compounds in complexes with FGFR1. Overall, the findings indicate that Mundulone exhibits promising binding affinity, specific interactions, and favorable drug profiles, making it a promising lead candidate. Further experimental analysis will be necessary to confirm its effectiveness and safety profiles for therapeutic advancement in the cancer field.Communicated by Ramaswamy H. Sarma.

7.
Cancers (Basel) ; 16(7)2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38611120

RESUMEN

Metastatic cancer is a leading cause of death in cancer patients worldwide. While circulating hybrid cells (CHCs) are implicated in metastatic spread, studies documenting their tissue origin remain sparse, with limited candidate approaches using one-two markers. Utilizing high-throughput single-cell and spatial transcriptomics, we identified tumor hybrid cells (THCs) co-expressing epithelial and macrophage markers and expressing a distinct transcriptome. Rarely, normal tissue showed these cells (NHCs), but their transcriptome was easily distinguishable from THCs. THCs with unique transcriptomes were observed in breast and colon cancers, suggesting this to be a generalizable phenomenon across cancer types. This study establishes a framework for HC identification in large datasets, providing compelling evidence for their tissue residence and offering comprehensive transcriptomic characterization. Furthermore, it sheds light on their differential function and identifies pathways that could explain their newly acquired invasive capabilities. THCs should be considered as potential therapeutic targets.

8.
J Appl Genet ; 65(3): 541-548, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38438717

RESUMEN

Oral tongue squamous cell carcinoma (OTSCC) is the most common malignancy type among males across the world. However, analysis of molecular markers could be useful in detecting the early-stage OTSCC, which would allow optimal clinical treatments and prolong the survival rate of patients consequently. The study has the objective of detecting the role of salivary biomarkers based on gene promoter hypermethylation. Sample data from 45 OTSCC and normal groups were analyzed to exhibit the methylation levels of salivary biomarkers (TRH, FHIT, MGMT, p16, and RASSF1A). The specificity and sensitivity analysis of methylation biomarkers was conducted in addition to the receiver operating characteristic (ROC) curve for both early-stage and advanced OTSCC stages. Quantitative data findings showed the perfect sensitivity and specificity for TRH, MGMT, p16, and RASSF1A with 100%, and > 90%, respectively. In addition, the results indicated an inefficient area under curves (> 0.7) for these biomarkers to detect the OTSCC. There were no significant differences observed between TRH and FHIT and p16 and MGMT based on the Wilcoxon signed-rank test. The methylation statuses of genes TRH, RASSF1A, p16, and MGMT might become utilized as predictive biomarkers for clinical application in early diagnosis of OTSCC and noninvasive oral cancer screening.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Escamosas , Metilación de ADN , Enzimas Reparadoras del ADN , Detección Precoz del Cáncer , Neoplasias de la Lengua , Proteínas Supresoras de Tumor , Humanos , Metilación de ADN/genética , Biomarcadores de Tumor/genética , Masculino , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/diagnóstico , Proteínas Supresoras de Tumor/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/diagnóstico , Persona de Mediana Edad , Femenino , Enzimas Reparadoras del ADN/genética , Metilasas de Modificación del ADN/genética , Adulto , Anciano , Regiones Promotoras Genéticas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Sensibilidad y Especificidad , Curva ROC , Proteínas de Neoplasias/genética , Ácido Anhídrido Hidrolasas/genética , Saliva/química
9.
J Biomol Struct Dyn ; : 1-11, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38529911

RESUMEN

Hematopoietic cell kinase (HCK) has emerged as a potential target for therapeutic intervention in cancer and HIV infection because of its critical role in critical signaling pathways. Repurposing FDA-approved drugs offers an efficient strategy to identify new treatment options. Here, we address the need for novel therapies in cancer and HIV by investigating the potential of repurposed drugs against HCK. Our goal was to identify promising drug candidates with high binding affinities and specific interactions within the HCK binding pocket. We employed an integrated computational approach combining molecular docking and extensive molecular dynamics (MD) simulations. Initially, we analyzed the binding affinities and interaction patterns of a library of FDA-approved drugs sourced from DrugBank. After careful analysis, we focused on two compounds, Nilotinib and Radotinib, which exhibit exceptional binding affinities and specificity to the HCK binding pocket, including the active site. Additionally, we assessed the pharmacological properties of Nilotinib and Radotinib, making them attractive candidates for further drug development. Extensive all-atom MD simulations spanning 200 nanoseconds (ns) elucidated the conformational dynamics and stability of the HCK-Nilotinib and HCK-Radotinib complexes. These simulations demonstrate the robustness of these complexes over extended timescales. Our findings highlighted the potential of Nilotinib and Radotinib as promising candidates against HCK that offer valuable insights into their binding mechanisms. This computational approach provides a comprehensive understanding of drug interactions with HCK and sets the stage for future experimental validation and drug development endeavors.Communicated by Ramaswamy H. Sarma.

10.
Cell Biochem Funct ; 42(2): e3962, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38491792

RESUMEN

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.


Asunto(s)
Neoplasias Colorrectales , Exosomas , Vesículas Extracelulares , Células Madre Mesenquimatosas , Humanos , Comunicación Celular , Microambiente Tumoral
11.
J Mol Model ; 30(4): 106, 2024 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-38491151

RESUMEN

CONTEXT: Electronic durable behavior on the material surface was accompanied by a class of antipsychotic drugs (APD) to describe the surface modification in the designed adsorption model. Hierarchically Zn-MOF system was utilized for estimating its capacity for drug molecule removal. Geometrically optimized strategy on the studied systems was performed using DFT/GGA/PBE. FMOs analysis was depicted based on the same level of calculations, and molecular electrostatic potential surface (MEP) was generated for unadsorbed and adsorbed systems to illustrate the variation in the surface-active sites. By interpreting the electronic density of states (DOS), the atomic orbital can be identified as a major or minor electronic distribution by PDOS graph. Adsorption locating behavior was considered to detect the significant surface interaction mode between APD and Zn-MOF surface based on lower adsorption energy. The stability of the adsorbed model was best described through dynamic simulation analysis with time through elevated temperatures. The non-covalent interactions were described using RDG/NCI analysis to show the major favorable surface interaction predicting the highly stable adsorption system. METHODS: The most accurate geometrical computations were performed using the materials studio software followed by surface cleavage and vacuum slab generation. The first principle of DFT was used to apply CASTEP module with GGA/PBE method for band structure and DOS calculations. Three systems of antipsychotic drugs were computationally studied using CASTEP simulation package and adsorbed on an optimized Zn-MOF surface. Adsorption locator module predicted the preferred adsorption mechanistic models, in which the first model was arranged to be more stable, to confirm the occurrence of some interactions in the adsorption mechanism.

12.
J Biomol Struct Dyn ; : 1-15, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38165437

RESUMEN

Dihydrofolate reductase (DHFR) has gained significant attention in drug development, primarily due to marked distinctions in its active site among different species. DHFR plays a crucial role in both DNA and amino acid metabolism by facilitating the transfer of monocarbon residues through tetrahydrofolate, which is vital for nucleotide and amino acid synthesis. This considers its potential as a promising target for therapeutic interventions. In this study, our focus was on conducting a virtual screening of phytoconstituents from the IMPPAT2.0 database to identify potential inhibitors of DHFR. The initial criterion involved assessing the binding energy of molecules against DHFR and we screened top 20 compounds ranging energy -13.5 to -11.4 (kcal/Mol) while Pemetrexed disodium bound with less energy -10.2 (kcal/Mol), followed by an analysis of their interactions to identify more effective hits. We prioritized IMPHY007679 (Bismurrayaquinone-A), which displayed a high binding affinity and crucial interaction with DHFR. We also evaluated the drug-like properties and biological activity of IMPHY007679. Furthermore, MD simulation was done, RMSD, RMSF, Rg, SASA, PCA and FEL explore the time-evolution impact of IMPHY007679 comparing it with a reference drug, Pemetrexed disodium. Collectively, our findings suggest that IMPHY007679 recommend further investigation in both in vitro and in vivo settings for its potential in developing anticancer and antibacterial therapies. This compound holds promise as a valuable candidate for advancing drug research and treatment strategies.Communicated by Ramaswamy H. Sarma.

13.
J Biomol Struct Dyn ; : 1-12, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38240096

RESUMEN

Cancer is a significant global health concern that has a major impact on morbidity and mortality worldwide. Research has demonstrated the involvement of Interleukin-1 beta (IL1ß) in various aspects of cancer development and progression, including angiogenesis, tumor growth and metastasis. Consequently, targeting IL1ß activity represents a promising approach for cancer therapeutics. In this study, we utilized molecular docking and MD simulations to discover potent IL1ß inhibitors for the treatment of cancer. Five thousand compounds from ZINC15 database were screened against IL1ß target, and the top ten small molecules were selected based on their binding energy. The small molecule named 'ZINC08101049' was prioritized based on binding energy (-9.1 kcal/Mol) and residual interaction specifically forming seven hydrogen bonds with amino acid residues namely GLN81, GLY136, LEU134, LYS138, SER84, THR137 and TYR24 of IL1ß. Next, IL1ß alone and in complex with ZINC08101049 was subjected to MD simulations to determine their behavior at atomic level. The results of molecular docking and MD simulation revealed ZINC08101049 as a potential inhibitor of IL1ß, reflecting that ZINC08101049 can emerge as a promising small molecule paving for cancer therapeutics.Communicated by Ramaswamy H. Sarma.

14.
Pathol Res Pract ; 253: 154999, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38118218

RESUMEN

It is becoming more and more apparent that many of the genetic alterations associated with cancer are located in areas that do not encode proteins. lncRNAs are a class of RNAs that do not code for proteins but play a crucial role in maintaining cell function and regulating various cellular processes. By doing this, they have recently introduced what may be a brand-new and essential layer of biological control. These have more than 200 nucleotides and are linked to several diseases; as a result, they have become potential tools for therapeutic intervention. Emerging technologies suggest the presence of mutations on genomic loci that give rise to lncRNAs rather than proteins in a disease as complex as cancer. These lncRNAs play essential parts in gene regulation, which impacts several cellular homeostasis processes, including proliferation, survival, migration, and genomic stability. The leading cause of death in the world today is cancer. Delays in diagnosis and a lack of standard and efficient treatments are the leading causes of the high death rate. Clinically, surgery is frequently used successfully to remove cancers that have not spread, but it is less successful in treating metastatic cancer, which has a drastically lower chance of survival. Chemotherapeutic drugs are a typical therapy to treat the cancer that has spread to other organs. Drug resistance to chemotherapy, however, presents a significant challenge to achieving positive outcomes and is frequently the cause of treatment failure. A substantial barrier to progress in medical oncology is cancer drug resistance. Resistance can develop clinically either before or after cancer treatment. According to this study, lncRNAs influence drug resistance through several different methods. LncRNAs often impact drug resistance by controlling the expression of a few intermediary regulatory variables rather than by directly affecting drug resistance. Additionally, lncRNAs have a variety of roles in cancer medication resistance. Most lncRNAs induce drug resistance when overexpressed; however, other lncRNAs have inhibitory effects. This study provides an overview of the current understanding of lncRNAs, relevance to cancer, and potential therapeutic applications.


Asunto(s)
Neoplasias , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Resistencia a Antineoplásicos/genética , Transducción de Señal/genética
15.
J Mol Model ; 30(1): 14, 2023 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-38148383

RESUMEN

CONTEXT: Electronic sustainable behavior on the material surface and in situ metal configuration were accompted with some metal atoms like Li, Na, and K elements. Metal-doped ZrO2 crystal exported modified characteristics related to electronic conduction and exhibited some dynamic modification around the surface of the metal oxide. Computational perturbations were considered to discuss the modification behavior in addition to the studied Li, Na, and K metals. Optimization of the three doping systems was achieved followed by generating DOS and electronic band structure maps. A dynamic simulation was performed with temperature over 2000 k: the presence of the metal on the surface and prediction of its ZrO2 inclusion leading to access adsorption behavior, besides generating predictive designed models described the adsorption affinity on the solid-state surface. It cannot be neglected the importance of various metals as a main role in chemotherapy. Molecular docking investigation was considered to predict the binding behavior of the studied metal ZrO2 carrier system as an anticancer agent. Also, docking affinity was helpful in comparing the active sites binding for the studied metals, resulting in a notable binding affinity for both Li- and Na-zirconia incorporation. METHODS: The program PWSCF, which is a component of the quantum ESPRESSO suite for quantum simulation of materials, was used to construct geometric systems. The generalized gradient approximation in the Perdew-Burke-Ernzerhof (GGA/PBE) function with D3 correction (Becke-Jonson damping) was applied to the exchange-correlation energy. As the last step in the DFT postulation and design, adsorption locator annealing was carried out on the convergent models using the Materials Studio simulation package. The main roles played by metal atoms are in protein binding and the suppression of bio-active regions. For the docking process, the protein was produced using AutoDock 4.2 and Discovery Studio software in accordance with the usual methodology. Chimera and Discovery Studio were used to examine the docking data that was processed after generating specific grid box dimensions for 7BTN.

16.
J Biomol Struct Dyn ; : 1-12, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38116764

RESUMEN

Within the realm of soluble factors that have emerged as potential targets for therapeutic intervention, the chemokine interleukin-8 (IL-8) has garnered attention as a potential contributor to treatment responses in various cancer types. The utilization of naturally occurring anticancer compounds for treating cancer patients has shown substantial advancements in survival rates across early and advanced stages of the disease. In silico research findings provide support for the application of phytochemicals as potential inhibitors of IL-8, and phytochemicals exhibiting a high binding free energy and crucial interactions display promising anticancer properties, positioning them as candidates for future drug development. Noteworthy phytochemicals such as IMPHY006634 (Isohydnocarpin), IMPHY007957 (Chitranone) and IMPHY013015 (1-Hydroxyrutaecarpine) were predicted to possess inhibitory activity against IL-8, with calculated energies ranging from -9.9 to -9.1 kcal/mol, respectively. Several hydrogen bonds, including common amino acid residues Lys9 and CYS48, were identified. Molecular dynamics calculations conducted on these potent inhibitors demonstrated their stability throughout a 200 ns simulation, as indicated by metrics such as RMSD, RMSF, Rg, SASA, H-bonds, PCA and FEL analysis. Moreover, PASS analysis and adherence of these natural compounds to drug-likeness rules like Lipinski's further strengthen their candidacy. Considering these calculations and various parameters, these three prominent natural compounds emerge as promising candidates for anti-IL-8 therapy in the management of cancer.Communicated by Ramaswamy H. Sarma.

17.
Haematologica ; 2023 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-37916386

RESUMEN

Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.

18.
Life Sci ; 335: 122244, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37949208

RESUMEN

High blood sugar and insulin insensitivity causes the lifelong chronic metabolic disease called Type 2 diabetes (T2D) which has a higher chance of developing different malignancies. T2D with comorbidities like Cancers can make normal medications for those disorders more difficult. There may be a significant correlation between comorbidities and have an impact on one another's health. These associations may be due to a number of direct and indirect mechanisms. Such molecular mechanisms that underpin T2D and cancer are yet unknown. However, the large volumes of data available on these diseases allowed us to use analytical tools for uncovering their interrelated pathways. Here, we tried to present a system for investigating potential comorbidity relationships between T2D and Cancer disease by looking at the molecular processes involved, analyzing a huge number of freely accessible transcriptomic datasets of various disorders using bioinformatics. Using semantic similarity and gene set enrichment analysis, we created an informatics pipeline that evaluates and integrates Gene Ontology (GO), expression of genes, and biological process data. We discovered genes that are common in T2D and Cancer along with molecular pathways and GOs. We compared the top 200 Differentially Expressed Genes (DEGs) from each selected T2D and cancer dataset and found the most significant common genes. Among all the common genes 13 genes were found most frequent. We also found 4 common GO terms: GO:0000003, GO:0000122, GO:0000165, and GO:0000278 among all the common GO terms between T2d and different cancers. Using these genes and GO term semantic similarity, we calculated the distance between these two diseases. The semantic similarity results of our study showed a higher association of Liver Cancer (LiC), Breast Cancer (BreC), Colorectal Cancer (CC), and Bladder Cancer (BlaC) with T2D. Furthermore we found KIF4A, NUSAP1, CENPF, CCNB1, TOP2A, CCNB2, RRM2, HMMR, NDC80, NCAPG, and IGFBP5 common hub proteins among different cancers correlated to T2D. AGE-RAGE signaling pathway in diabetic complications, Osteoclast differentiation, TNF signaling pathway, IL-17 signaling pathway, p53 signaling pathway, MAPK signaling pathway, Human T-cell leukemia virus 1 infection, and Non-alcoholic fatty liver disease are the 8 most significant pathways found among 18 common pathways between T2D and selected cancers. As a result of our technique, we now know more about disease pathways that are critical between T2D and cancer.


Asunto(s)
Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Humanos , Diabetes Mellitus Tipo 2/genética , Neoplasias Hepáticas/patología , Perfilación de la Expresión Génica/métodos , Transcriptoma , Comorbilidad , Biología Computacional/métodos , Cinesinas/genética
19.
BMC Surg ; 23(1): 342, 2023 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-37950198

RESUMEN

BACKGROUND: Appendicitis is the most common abdominal surgical emergency and up to our knowledge no previous studies have been conducted in Saudi Arabia particularly at Qassim region and this study aimed to determine a total and direct bilirubin as a predictor of acute complicated appendicitis. METHODS: Observational retrospective study that included patients admitted under the general surgery department with a diagnosis of acute appendicitis at King Saud Hospital, Unaizah, Saudi Arabia. Data on age, gender, BMI, diabetes mellitus, total and direct bilirubin, AST, ALT, sodium, and WBCs levels were obtained. RESULT: Among the overall study population of 158 patients, the age median [IQR] was 24.5 [19-31], males were 99 (62.7%), and complicated appendicitis was 33 (20.9%). The multivariable analysis revealed that both elevated total and direct bilirubin are associated with complicated appendicitis (aOR = 3.79, 95% CI: 1.67-8.48, P = 0.001) and (aOR = 4.74, 95% CI: 2.07-10.86, P < 0.001) respectively. A receiver operating characteristic curve showed the best cutoff value of total and direct bilirubin as ≥ 15 µmol/L and ≥ 5 µmol/L respectively, with a sensitivity of 57.6%, and specificity of 73.6% for elevated total bilirubin, and a sensitivity of 54.6%, and specificity of 80% for elevated direct bilirubin. CONCLUSION: Elevated total and direct bilirubin are associated with acute complicated appendicitis in this setting. However, it should be supportive factor for acute complicated appendicitis and not considered as standalone diagnostic test.


Asunto(s)
Apendicitis , Masculino , Humanos , Apendicitis/complicaciones , Apendicitis/diagnóstico , Apendicitis/cirugía , Estudios Retrospectivos , Arabia Saudita/epidemiología , Bilirrubina , Curva ROC , Enfermedad Aguda
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