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1.
Syst Rev ; 13(1): 226, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39227940

RESUMEN

BACKGROUND: Lifestyle interventions are key to the control of diabetes and the prevention of complications, especially when used with pharmacological interventions. This protocol aims to review the effectiveness of lifestyle interventions in relation to nutrition and physical activity within the West African region. This systematic review and meta-analysis seeks to understand which interventions for lifestyle modification are implemented for the control of diabetes in West Africa at the individual and community level, what evidence is available on their effectiveness in improving glycaemic control and why these interventions were effective. METHODS: We will review randomised control trials and quasi-experimental designs on interventions relating to physical activity and nutrition in West Africa. Language will be restricted to English and French as these are the most widely spoken languages in the region. No other filters will be applied. Searching will involve four electronic databases - PubMed, Scopus, Africa Journals Online and Cairn.info using natural-language phrases plus reference/citation checking. Two reviewers will independently screen results according to titles and abstracts against the inclusion and exclusion criteria to identify eligible studies. Upon full-text review, all selected studies will be assessed using Cochrane's Collaboration tool for assessing the risk of bias of a study and the ROBINS-I tool before data extraction. Evidence will be synthesised narratively and statistically where appropriate. We will conduct a meta-analysis when the interventions and contexts are similar enough for pooling and compare the treatment effects of the interventions in rural to urban settings and short term to long term wherever possible. DISCUSSION: We anticipate finding a number of studies missed by previous reviews and providing evidence of the effectiveness of different nutrition and physical activity interventions within the context of West Africa. This knowledge will support practitioners and policymakers in the design of interventions that are fit for context and purpose within the West African region. SYSTEMATIC REVIEW REGISTRATION: This systematic review has been registered in the International Prospective Register for Systematic Reviews - PROSPERO, with registration number CRD42023435116. All amendments to this protocol during the process of the review will be explained accordingly.


Asunto(s)
Diabetes Mellitus Tipo 2 , Ejercicio Físico , Control Glucémico , Adulto , Humanos , África Occidental , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/terapia , Control Glucémico/métodos , Estilo de Vida , Metaanálisis como Asunto , Revisiones Sistemáticas como Asunto , Proyectos de Investigación
4.
Transl Anim Sci ; 8: txae117, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39192876

RESUMEN

This study investigated the potency of bird eye pepper (BEP) of varying proportion and sieve size on growth performance and meat quality of broiler chickens. Two hundred and forty-six 2-wk-old broiler chicks were randomly allotted to six treatment groups (basal diet (B) inclusive × 2) in a 2 × 3 factorial arrangement each replicated four times (10 × 10 × 10 × 11) in a completely randomized design. Diets containing BEP of varying proportion (0, 150, and 300 g) and sieve size (0.05 and 0.1 mm) were offered in two phases, starter (14 d) and finisher (17 d). Postfeeding, 48 birds (two per replicate) were sacrificed to further evaluate performance and assess the quality of meat produced. Result obtained indicates chicks fed 150 g BEP consumed less feed compared to 300 g BEP. Also, 0 and 150 g BEP groups had better (P < 0.05) feed conversion ratio (FCR) than 300 g BEP, while 0.05 mm BEP diet improved (P < 0.05) FCR as against 0.1 mm BEP. Interaction of proportion and sieve size effects of BEP increased (P < 0.05) the final weight of the birds and suppressed (P < 0.05) feed intake for all groups as against 300 g (0.1 mm) BEP (1,576.00 g/bird; 964.20 g/bird). Feeding 150 and 300 g BEP diets lowered (P < 0.05) superoxide dismutase (SOD) production compared to 0 g BEP, while 150 g BEP diet increased (P < 0.05) catalase production over 0 g BEP. Interactive effect of proportion and sieve size of BEP reduced (P < 0.05) SOD production in 150 g (0.05 and 0.1 mm) BEP and 300 g (0.05 mm) BEP groups, followed by 300 g (0.1 mm) BEP group that had lower (P < 0.05) SOD than both basal groups. Birds fed B + 150 g (0.05 mm) BEP diet produced more (P < 0.05) catalase compared to both basal groups. Meat pH for 150 and 300 g BEP groups was significantly (P < 0.05) reduced than 0 g BEP. The Hue angle corresponds with a high value (P < 0.05) to 0 g BEP, while 300 g BEP showed a low value. This study has shown BEP at low concentration (150 g) screened with 0.05 and 0.1 mm sieves enhanced chick welfare, while a higher concentration (300 g) screened at 0.05 mm improved overall growth performance (endogenous antioxidant profile) at finisher phase. Broiler chickens, farmers, and meat processors will benefit from diet containing BEP screened through 0.05 mm sieve.

5.
Sci Rep ; 14(1): 18438, 2024 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-39117897

RESUMEN

Utilizing medicinal plants and other natural resources to prevent different types of human cancers is the prime focus of attention. Cervical cancer in women ranks as the fourth most common type of malignancy. The current study used gas chromatography-mass spectrometry (GC-MS) to identify the active phytochemical constituents from Caladium lindenii leaf extracts using ethanol (ECL) and n-hexane (HCL) solvents. Plant extracts were tested for potential cytotoxic effects on HeLa and HEK-293 T cells using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) and the crystal violet assays. SYBR Green-based real-time PCR was performed to assess the mRNA expression profile of the apoptosis biomarkers (BCL-2 and TP53). The molecular interaction of the compounds with the targeted proteins (TP53, BCL2, EGFR, and HER2) was determined using molecular docking. GC-MS analysis revealed a total of 93 compounds in both extracts. The ECL extract significantly reduced the proliferation of HeLa cervical cancer cells, with an IC50 value of 40 µg/mL, while HEK-293 T cells showed less effect (IC50 = 226 µg/mL). The quantitative RT-PCR gene expression analysis demonstrated the ethanol extract regulated TP53 and BCL2 mRNA expressions in treated cancer cell samples. Heptanediamide, N,N'-di-benzoyloxy-(- 10.1) is the best-docked ligand with a TP53 target found in the molecular docking study, whereas EGFR/Clionasterol had the second highest binding affinity (- 9.7), followed by EGFR/Cycloeucalenol (- 9.6). It is concluded that ECL extract has promising anti-cervical cancer potential and might be valued for developing new plant-derived anticancer agents after further investigations.


Asunto(s)
Apoptosis , Cromatografía de Gases y Espectrometría de Masas , Simulación del Acoplamiento Molecular , Extractos Vegetales , Neoplasias del Cuello Uterino , Humanos , Células HeLa , Extractos Vegetales/farmacología , Extractos Vegetales/química , Apoptosis/efectos de los fármacos , Femenino , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Células HEK293 , Proliferación Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética
7.
Int J Epidemiol ; 53(4)2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-39096096

RESUMEN

BACKGROUND: Biomass burning (BB) is a major source of air pollution and particulate matter (PM) in Southeast Asia. However, the health effects of PM smaller than 10 µm (PM10) originating from BB may differ from those of other sources. This study aimed to estimate the short-term association of PM10 from BB with respiratory and cardiovascular hospital admissions in Peninsular Malaysia, a region often exposed to BB events. METHODS: We obtained and analyzed daily data on hospital admissions, PM10 levels and BB days from five districts from 2005 to 2015. We identified BB days by evaluating the BB hotspots and backward wind trajectories. We estimated PM10 attributable to BB from the excess of the moving average of PM10 during days without BB hotspots. We fitted time-series quasi-Poisson regression models for each district and pooled them using meta-analyses. We adjusted for potential confounders and examined the lagged effects up to 3 days, and potential effect modification by age and sex. RESULTS: We analyzed 210 960 respiratory and 178 952 cardiovascular admissions. Almost 50% of days were identified as BB days, with a mean PM10 level of 53.1 µg/m3 during BB days and 40.1 µg/m3 during normal days. A 10 µg/m3 increment in PM10 from BB was associated with a 0.44% (95% CI: 0.06, 0.82%) increase in respiratory admissions at lag 0-1, with a stronger association in adults aged 15-64 years and females. We did not see any significant associations for cardiovascular admissions. CONCLUSIONS: Our findings suggest that short-term exposure to PM10 from BB increased the risk of respiratory hospitalizations in Peninsular Malaysia.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Biomasa , Enfermedades Cardiovasculares , Hospitalización , Material Particulado , Enfermedades Respiratorias , Humanos , Material Particulado/análisis , Material Particulado/efectos adversos , Malasia/epidemiología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Adolescente , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Adulto Joven , Hospitalización/estadística & datos numéricos , Enfermedades Cardiovasculares/epidemiología , Anciano , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/efectos adversos , Enfermedades Respiratorias/epidemiología , Niño , Preescolar , Lactante , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/estadística & datos numéricos , Recién Nacido
9.
SAGE Open Med Case Rep ; 12: 2050313X241266477, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39055671

RESUMEN

Accidental injuries in the pediatric population are common. The response to injury also differs owing to anatomical and physiological differences in children. While such injuries carry a risk of lifelong morbidity, some cases may follow a benign course despite their distressing appearance. We report two cases of accidentally incurred penetrating trauma in the pediatric population with unusual objects, including a pencil and a toy wheel. Despite their intracranial extension, neither of the patients exhibited any discernible neurological deficits. Penetrating brain injuries require early removal and meticulous perioperative care to minimize the risk of long-term adverse neurological events in children.

11.
Ann Card Anaesth ; 27(1): 76-78, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38722128

RESUMEN

ABSTRACT: Aneurysmal dilation of coronary arteries is a rare condition detected during coronary angiography. Due to their poorly elucidated underlying mechanisms, their variable presentations, and the lack of large-scale outcome data on their various treatment modalities, coronary artery aneurysms, and coronary ectasia pose a challenge to the managing clinician. This case presentation provides insight into the challenges regarding the management of the coronary artery aneurysm during the perioperative period.


Asunto(s)
Aneurisma Coronario , Angiografía Coronaria , Insuficiencia de la Válvula Tricúspide , Humanos , Aneurisma Coronario/diagnóstico por imagen , Aneurisma Coronario/complicaciones , Aneurisma Coronario/cirugía , Insuficiencia de la Válvula Tricúspide/complicaciones , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Insuficiencia de la Válvula Tricúspide/etiología , Insuficiencia de la Válvula Tricúspide/cirugía , Masculino , Ecocardiografía Transesofágica , Persona de Mediana Edad , Femenino
12.
Environ Sci Technol ; 58(23): 9945-9953, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38806168

RESUMEN

Background: understanding the effects of coexposure to compound extreme events, such as air pollution and extreme heat, is important for reducing current and future health burdens. This study investigated the independent and synergistic effects of exposure to air pollution from vegetation fires and extreme heat on all-cause mortality in Upper Northern Thailand. Methods: we used a time-stratified case-crossover study design with a conditional quasi-Poisson model to examine the association between mortality and coexposure to air pollution due to vegetation fire events (fire-PM2.5) and extreme heat. Extreme heat days were defined using the 90th and 99th percentile thresholds for daily maximum temperature. Results: we observed a significant positive excess risk of mortality due to independent exposure to fire-PM2.5 and extreme heat, but not an interactive effect. All-cause mortality risk increased by 0.9% (95% confidence interval (CI): 0.1, 1.8) for each 10 µg/m3 increase in fire-PM2.5 on the same day and by 12.8% (95% CI: 10.5, 15.1) on extreme heat days (90th percentile) relative to nonextreme heat days. Conclusion: this study showed that exposure to PM2.5 from vegetation fires and extreme heat independently increased all-cause mortality risk in UNT. However, there was no evidence of a synergistic effect of these events.


Asunto(s)
Contaminación del Aire , Incendios , Tailandia , Humanos , Calor Extremo/efectos adversos , Contaminantes Atmosféricos , Material Particulado
13.
Lab Chip ; 24(11): 3015-3026, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38745471

RESUMEN

The paper demonstrates an adaptation of a 3D printer (Prusa Mini+) with novel modules to develop a droplet generation system that generates combinatorial droplets from a standard 96 well plate. The calibration methodology developed would allow any fused deposition modeling (FDM) printer to generate monodisperse droplets (coefficient of variance (CV%) < 5%) from well plates or vials of any geometry. The system maintains precision across various volumes while maintaining a C.V. range of 0.81% to 3.61%, with an increased precision for larger volumes. The cost of the system developed is 70% less than commercially available droplet generation packages. Successful droplet library storage is accomplished via 3D printed cartridge connectors. The implemented system has been calibrated for Tygon® and PTFE at different velocities and volumetric configurations.

14.
PLoS One ; 19(5): e0294917, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38768121

RESUMEN

BACKGROUND: The prevalence of diabetes in West Africa is increasing, posing a major public health threat. An estimated 24 million Africans have diabetes, with rates in West Africa around 2-6% and projected to rise 129% by 2045 according to the WHO. Over 90% of cases are Type 2 diabetes (IDF, World Bank). As diabetes is ambulatory care sensitive, good primary care is crucial to reduce complications and mortality. However, research on factors influencing diabetes primary care access, utilisation and quality in West Africa remains limited despite growing disease burden. While research has emphasised diabetes prevalence and risk factors in West Africa, there remains limited evidence on contextual influences on primary care. This scoping review aims to address these evidence gaps. METHODS AND ANALYSIS: Using the established methodology by Arksey and O'Malley, this scoping review will undergo six stages. The review will adopt the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Review (PRISMA-ScR) guidelines to ensure methodological rigour. We will search four electronic databases and search through grey literature sources to thoroughly explore the topic. The identified articles will undergo thorough screening. We will collect data using a standardised data extraction form that covers study characteristics, population demographics, and study methods. The study will identify key themes and sub-themes related to primary healthcare access, utilisation, and quality. We will then analyse and summarise the data using a narrative synthesis approach. RESULTS: The findings and conclusive report will be finished and sent to a peer-reviewed publication within six months. CONCLUSION: This review protocol aims to systematically examine and assess the factors that impact the access, utilisation, and standard of primary healthcare services for diabetes in West Africa.


Asunto(s)
Accesibilidad a los Servicios de Salud , Atención Primaria de Salud , Humanos , África Occidental/epidemiología , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Calidad de la Atención de Salud , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus/terapia , Diabetes Mellitus/epidemiología
15.
Front Mol Biosci ; 11: 1346242, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38567100

RESUMEN

Esophageal cancer (EC) remains a significant health challenge globally, with increasing incidence and high mortality rates. Despite advances in treatment, there remains a need for improved diagnostic methods and understanding of disease progression. This study addresses the significant challenges in the automatic classification of EC, particularly in distinguishing its primary subtypes: adenocarcinoma and squamous cell carcinoma, using histopathology images. Traditional histopathological diagnosis, while being the gold standard, is subject to subjectivity and human error and imposes a substantial burden on pathologists. This study proposes a binary class classification system for detecting EC subtypes in response to these challenges. The system leverages deep learning techniques and tissue-level labels for enhanced accuracy. We utilized 59 high-resolution histopathological images from The Cancer Genome Atlas (TCGA) Esophageal Carcinoma dataset (TCGA-ESCA). These images were preprocessed, segmented into patches, and analyzed using a pre-trained ResNet101 model for feature extraction. For classification, we employed five machine learning classifiers: Support Vector Classifier (SVC), Logistic Regression (LR), Decision Tree (DT), AdaBoost (AD), Random Forest (RF), and a Feed-Forward Neural Network (FFNN). The classifiers were evaluated based on their prediction accuracy on the test dataset, yielding results of 0.88 (SVC and LR), 0.64 (DT and AD), 0.82 (RF), and 0.94 (FFNN). Notably, the FFNN classifier achieved the highest Area Under the Curve (AUC) score of 0.92, indicating its superior performance, followed closely by SVC and LR, with a score of 0.87. This suggested approach holds promising potential as a decision-support tool for pathologists, particularly in regions with limited resources and expertise. The timely and precise detection of EC subtypes through this system can substantially enhance the likelihood of successful treatment, ultimately leading to reduced mortality rates in patients with this aggressive cancer.

16.
Front Chem ; 12: 1374739, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38601886

RESUMEN

The iron-based biomass-supported catalyst has been used for Fischer-Tropsch synthesis (FTS). However, there is no study regarding the life cycle assessment (LCA) of biomass-supported iron catalysts published in the literature. This study discusses a biomass-supported iron catalyst's LCA for the conversion of syngas into a liquid fuel product. The waste biomass is one of the source of activated carbon (AC), and it has been used as a support for the catalyst. The FTS reactions are carried out in the fixed-bed reactor at low or high temperatures. The use of promoters in the preparation of catalysts usually enhances C5+ production. In this study, the collection of precise data from on-site laboratory conditions is of utmost importance to ensure the credibility and validity of the study's outcomes. The environmental impact assessment modeling was carried out using the OpenLCA 1.10.3 software. The LCA results reveals that the synthesis process of iron-based biomass supported catalyst yields a total impact score in terms of global warming potential (GWP) of 1.235E + 01 kg CO2 equivalent. Within this process, the AC stage contributes 52% to the overall GWP, while the preparation stage for the catalyst precursor contributes 48%. The comprehensive evaluation of the iron-based biomass supported catalyst's impact score in terms of human toxicity reveals a total score of 1.98E-02 kg 1,4-dichlorobenzene (1,4-DB) equivalent.

17.
Artículo en Inglés | MEDLINE | ID: mdl-38561609

RESUMEN

BACKGROUND: Deregulated DNA damage response (DDR) network is implicated in cancer progression and therapy resistance. OBJECTIVE: The present study was designed to investigate whether nimbolide, an anticancer neem limonoid, targets key components of the DDR signalling pathway in cellular and animal models of oral squamous cell carcinoma (OSCC). METHODS: OSCC cells (SCC-4 and SCC-9), 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinoma model, chemoresistant OSCC patient-derived xenograft (PDX) model established in athymic nude mice, and tissue sections from patients with oral premalignant/malignant disease were used for the study. Key molecules that orchestrate the DDR, including the MRN complex, ATM, DNA-PKcs, H2AX, and p53, were analysed by qRT-PCR, immunoblotting, immunofluorescence, and immunohistochemistry. Cell proliferation and apoptosis indices were evaluated. RESULTS: Nimbolide significantly reduced 8-oxodG levels, expression of MRN, ATMS1891, and γ-H2AX, with an increase in p-p53S15 in OSCC cells as well as in the HBP model. Nimbolide potentiated the effect of KU-55933 in ATM inhibition. In the PDX model, nimbolide suppressed tumor formation, stimulated DDR and apoptosis, inhibited cell proliferation, and enhanced sensitivity to cisplatin. Analysis of p-ATM expression revealed a significant increase during the sequential progression of hamster and human OSCC. CONCLUSIONS: This study provides compelling evidence that nimbolide functions as a DDR inhibitor in cellular and hamster OSCC models and as a DDR activator in the PDX model primarily by targeting ATM. Small molecules like nimbolide that modulate DDR are of immense benefit in cancer therapy. The study has also unveiled p-ATM as a promising biomarker of tumour progression in human OSCCs.

18.
BMJ Open ; 14(4): e081881, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38658004

RESUMEN

INTRODUCTION: Telomeres are a measure of cellular ageing with potential links to diseases such as cardiovascular diseases and cancer. Studies have shown that some infections may be associated with telomere shortening, but whether an association exists across all types and severities of infections and in which populations is unclear. Therefore we aim to collate available evidence to enable comparison and to inform future research in this field. METHODS AND ANALYSIS: We will search for studies involving telomere length and infection in various databases including MEDLINE (Ovid interface), EMBASE (Ovid interface), Web of Science, Scopus, Global Health and the Cochrane Library. For grey literature, the British Library of electronic theses databases (ETHOS) will be explored. We will not limit by study type, geographical location, infection type or method of outcome measurement. Two researchers will independently carry out study selection, data extraction and risk of bias assessment using the ROB2 and ROBINS-E tools. The overall quality of the studies will be determined using the Grading of Recommendations Assessment, Development and Evaluation criteria. We will also evaluate study heterogeneity with respect to study design, exposure and outcome measurement and if there is sufficient homogeneity, a meta-analysis will be conducted. Otherwise, we will provide a narrative synthesis with results grouped by exposure category and study design. ETHICS AND DISSEMINATION: The present study does not require ethical approval. Results will be disseminated via publishing in a peer-reviewed journal and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023444854.


Asunto(s)
Proyectos de Investigación , Revisiones Sistemáticas como Asunto , Humanos , Acortamiento del Telómero , Telómero/genética , Infecciones
19.
Cureus ; 16(2): e53578, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38449967

RESUMEN

We present an interesting case of mediastinal small cell carcinoma (MSCC), an exceedingly rare entity, comorbid with idiopathic pulmonary fibrosis (IPF). A 66-year-old female was first seen in the pulmonology office for abnormal chest computed tomography (CT) findings of right apical bronchiectasis and subpleural fibrotic changes with focal pleural thickening along the fissures, along with a right lower lobe nodule. Pulmonary function testing (PFT) showed an obstructive pattern with modest bronchodilator response, although subsequent PFT showed a worsening restrictive pattern with a worsening DLCO. On a follow-up CT one year later, a soft tissue density with peripheral calcification was found in the anterior mediastinum, later found to be hypermetabolic on a PET scan. Radiographically, fibrosis worsened with the appearance of worsening diffuse bilateral coarse reticular interstitial changes with lower lobe predominance, honeycombing, and areas of ground-glass opacity. A biopsy of the mediastinal lesion showed a high-grade neuroendocrine tumor. Cam5.2, insulinoma-associated protein-1, synaptophysin, and thyroid transcription factor-1 immunostains were positive. She underwent four cycles of chemotherapy with cisplatin and etoposide with a total of 60 Gy of radiation. Mediastinal mass started to decrease in size. Her respiratory status, imaging, and PFTs continued to show evidence of IPF progression. Prednisone resulted in modest clinical and radiographic response. Steroid-sparing therapy with mycophenolate mofetil, although effective, had to be discontinued due to GI bleeding. Anti-fibrotic therapy was deferred due to evidence showing a lack of clinical improvement. We discuss the existing evidence available on IPF management and proceed to highlight the deficiencies in existing data available on the management of IPF and MSCC in these patients. Most of the cases of MSCC reported in the past have managed MSCC using guidance from treatment practices for small cell lung cancer. No reported cases discuss or describe the management of IPF and MSCC in the very rare cohort of patients our case represents.

20.
Int J Radiat Oncol Biol Phys ; 120(1): 162-177, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38493899

RESUMEN

PURPOSE: Glioblastoma (GBM) is a lethal brain tumor. Standard-of-care treatment comprising surgery, radiation, and chemotherapy results in median survival rates of 12 to 15 months. Molecular-targeted agents identified using conventional 2-dimensional (2D) in vitro models of GBM have failed to improve outcome in patients, rendering such models inadequate for therapeutic target identification. A previously developed 3D GBM in vitro model that recapitulates key GBM clinical features and responses to molecular therapies was investigated for utility for screening novel radiation-drug combinations using gold-standard clonogenic survival as readout. METHODS AND MATERIALS: Patient-derived GBM cell lines were optimized for inclusion in a 96-well plate 3D clonogenic screening platform, ClonoScreen3D. Radiation responses of GBM cells in this system were highly reproducible and comparable to those observed in low-throughout 3D assays. The screen methodology provided quantification of candidate drug single agent activity (half maximal effective concentration or EC50) and the interaction between drug and radiation (radiation interaction ratio). RESULTS: The poly(ADP-ribose) polymerase inhibitors talazoparib, rucaparib, and olaparib each showed a significant interaction with radiation by ClonoScreen3D and were subsequently confirmed as true radiosensitizers by full clonogenic assay. Screening a panel of DNA damage response inhibitors revealed the expected propensity of these compounds to interact significantly with radiation (13/15 compounds). A second screen assessed a panel of compounds targeting pathways identified by transcriptomic analysis and demonstrated single agent activity and a previously unreported interaction with radiation of dinaciclib and cytarabine (radiation interaction ratio 1.28 and 1.90, respectively). These compounds were validated as radiosensitizers in full clonogenic assays (sensitizer enhancement ratio 1.47 and 1.35, respectively). CONCLUSIONS: The ClonoScreen3D platform was demonstrated to be a robust method to screen for single agent and radiation-drug combination activity. Using gold-standard clonogenicity, this assay is a tool for identification of radiosensitizers. We anticipate this technology will accelerate identification of novel radiation-drug combinations with genuine translational value.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Ftalazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Fármacos Sensibilizantes a Radiaciones , Glioblastoma/radioterapia , Glioblastoma/patología , Humanos , Fármacos Sensibilizantes a Radiaciones/farmacología , Línea Celular Tumoral , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Indoles/farmacología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Reproducibilidad de los Resultados , Técnicas de Cultivo Tridimensional de Células/métodos
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