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A mechanistic understanding of host-microbe interactions in the gut microbiome is hindered by poorly annotated bacterial genomes. While functional genomics can generate large gene-to-phenotype datasets to accelerate functional discovery, their applications to study gut anaerobes have been limited. For instance, most gain-of-function screens of gut-derived genes have been performed in Escherichia coli and assayed in a small number of conditions. To address these challenges, we develop Barcoded Overexpression BActerial shotgun library sequencing (Boba-seq). We demonstrate the power of this approach by assaying genes from diverse gut Bacteroidales overexpressed in Bacteroides thetaiotaomicron. From hundreds of experiments, we identify new functions and phenotypes for 29 genes important for carbohydrate metabolism or tolerance to antibiotics or bile salts. Highlights include the discovery of a D-glucosamine kinase, a raffinose transporter, and several routes that increase tolerance to ceftriaxone and bile salts through lipid biosynthesis. This approach can be readily applied to develop screens in other strains and additional phenotypic assays.
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Ácidos y Sales Biliares , Carbono , Microbioma Gastrointestinal , Carbono/metabolismo , Microbioma Gastrointestinal/genética , Ácidos y Sales Biliares/metabolismo , Antibacterianos/farmacología , Estrés Fisiológico/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Bacteroides thetaiotaomicron/genética , Bacteroides thetaiotaomicron/metabolismo , Regulación Bacteriana de la Expresión Génica , Bacteroidetes/genética , Bacteroidetes/metabolismo , Metabolismo de los Hidratos de Carbono/genética , Humanos , Genes Bacterianos/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Genoma BacterianoRESUMEN
Cystic fibrosis (CF) is a life-threatening genetic disorder caused by mutations in the CFTR gene. This leads to a defective protein that impairs chloride transport, resulting in thick mucus buildup and chronic inflammation in the airways. The review discusses current and future therapeutic approaches for CFTR dysfunction and airway dysbiosis in the era of personalized medicine. Personalized medicine has revolutionized CF treatment with the advent of CFTR modulator therapies that target specific genetic mutations. These therapies have significantly improved patient outcomes, slowing disease progression, and enhancing quality of life. It also highlights the growing recognition of the airway microbiome's role in CF pathogenesis and discusses strategies to modulate the microbiome to further improve patient outcomes. This review discusses various therapeutic approaches for cystic fibrosis (CFTR) mutations, including adenovirus gene treatments, nonviral vectors, CRISPR/cas9 methods, RNA replacement, antisense-oligonucleotide-mediated DNA-based therapies, and cell-based therapies. It also introduces airway dysbiosis with CF and how microbes influence the lungs. The review highlights the importance of understanding the cellular and molecular causes of CF and the development of personalized medicine to improve quality of life and health outcomes.
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INTRODUCTION: Pneumococcal diseases pose a significant public health concern in India, with substantial morbidity and mortality, with the elderly and those with coexisting medical conditions being most at risk. Pneumococcus was also seen to be one of the main reasons for co-infection, pneumonia and complications in COVID. Current guidelines recommend vaccination for specific adult populations, but there is a lack of uniformity and guidance on risk stratification, prioritisation and optimal timing. METHODS: Nation Against Pneumococcal Infections - Expert Panel Opinion (NAP-EXPO) is a panel convened to review and update recommendations for adult pneumococcal vaccination in India. The panel of 23 experts from various medical specialties engaged in discussions and evidence-based reviews, discussed appropriate age for vaccination, risk stratification for COPD and asthma patients, vaccination strategies for post-COVID patients, smokers and diabetics, as well as methods to improve vaccine awareness and uptake. OUTCOME: The NAP-EXPO recommends the following for adults: All healthy individuals 60 years of age and above should receive the pneumococcal vaccine; all COPD patients, regardless of severity, high-risk asthma patients, post-COVID cases with lung fibrosis or significant lung damage, should be vaccinated with the pneumococcal vaccine; all current smokers and passive smokers should be educated and offered the pneumococcal vaccine, regardless of their age or health condition; all diabetic individuals should receive the pneumococcal vaccine, irrespective of their diabetes control. Strategies to improve vaccine awareness and uptake should involve general practitioners (GPs), primary health physicians (PHPs) and physicians treating patients at high risk of pneumococcal disease. Advocacy campaigns should involve media, including social media platforms. CONCLUSION: These recommendations aim to enhance pneumococcal vaccination coverage among high-risk populations in India in order to ensure a reduction in the burden of pneumococcal diseases, in the post-COVID era. There is a need to create more evidence and data to support the recommendations that the vaccine will be useful to a wider range of populations, as suggested in our consensus.
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Exosomes have been the hidden treasure of the cell in terms of cellular interactions, transportation and therapy. The native exosomes (NEx) secreted by the parent cells hold promising aspects in cancer diagnosis and therapy. NEx has low immunogenicity, high biocompatibility, low toxicity and high stability which enables them to be an ideal prognostic biomarker in cancer diagnosis. However, due to heterogeneity, NEx lacks specificity and accuracy to be used as therapeutic drug delivery vehicle in cancer therapy. Transforming these NEx with their innate structure and multiple receptors to engineered exosomes (EEx) can provide better opportunities in the field of cancer theranostics. The surface of the NEx exhibits numeric receptors which can be modified to pave the direction of its therapeutic drug delivery in cancer therapy. Through surface membrane, EEx can be modified with increased drug loading potentiality and higher target specificity to act as a therapeutic nanocarrier for drug delivery. This review provides insights into promising aspects of NEx as a prognostic biomarker and drug delivery tool along with its need for the transformation to EEx in cancer theranostics. We have also highlighted different methods associated with NEx transformations, their nano-bio interaction with recipient cells and major challenges of EEx for clinical application in cancer theranostics.
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Exosomas , Neoplasias , Humanos , Exosomas/química , Medicina de Precisión , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Biomarcadores/metabolismoRESUMEN
Phytocompounds have shown hopeful results in cancer therapy. Piperlongumine (PIP), a naturally derived bioactive alkaloid found in our dietary spice, exhibits promising pharmacological relevance including anticancer activity. This study reconnoitred the anti-lung cancer effect of PIP and the allied mechanisms, in vitro and ex vivo. The cytotoxic, anti-proliferative, and apoptotic effects of PIP on lung cancer cells (LCC) were checked via cell viability, colony formation, cell migration, invasion, comet assay, and various staining techniques. Further, multicellular spheroids assay explored the anti-lung cancer potential of PIP, ex vivo. Preliminary results explored that PIP exerts selective cytotoxic and anti-proliferative effects on LCC by DNA damage and cell cycle arrest. PIP remarkably escalated the cellular and mitochondrial reactive oxygen species (ROS) generation and promoted dissipation of mitochondrial membrane potential (MMP), which triggers activation of caspase-dependent apoptotic pathway in LCC. Mechanistically, PIP showed F-actin deformation mediated significant anti-migratory and anti-invasive activity against LCC. Herein, we also found that F-actin dis-organization modulates the expression of epithelial to mesenchymal transition (EMT) markers and inhibits the expression of stemness marker proteins, like SOX9, CD-133, and CD-44. Moreover, PIP effectively reduced the size of spheroids with strong apoptotic and cytotoxic effects, ex vivo. This has been the first study to discover the high expression of SOX9 supporting the survival of LCC, whereas its inhibition induces higher sensitivity to PIP treatment. This study concludes a newer therapeutic agent (PIP) with promising anticancer activity against LCC by escalating ROS and attenuating MMP, stemness, and EMT.
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Apoptosis , Movimiento Celular , Dioxolanos , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Células Madre Neoplásicas , Especies Reactivas de Oxígeno , Factor de Transcripción SOX9 , Humanos , Dioxolanos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Células A549 , Supervivencia Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Fenotipo , PiperidonasRESUMEN
Randomly barcoded transposon mutant libraries are powerful tools for studying gene function and organization, assessing gene essentiality and pathways, discovering potential therapeutic targets, and understanding the physiology of gut bacteria and their interactions with the host. However, construction of high-quality libraries with uniform representation can be challenging. In this review, we survey various strategies for barcoded library construction, including transposition systems, methods of transposon delivery, optimal library size, and transconjugant selection schemes. We discuss the advantages and limitations of each approach, as well as factors to consider when selecting a strategy. In addition, we highlight experimental and computational advances in arraying condensed libraries from mutant pools. We focus on examples of successful library construction in gut bacteria and their application to gene function studies and drug discovery. Given the need for understanding gene function and organization in gut bacteria, we provide a comprehensive guide for researchers to construct randomly barcoded transposon mutant libraries.
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Elementos Transponibles de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Elementos Transponibles de ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Clonación Molecular , Biblioteca de Genes , Bacterias/genética , Mutagénesis Insercional/genéticaRESUMEN
The critical role of the intestinal microbiota in human health and disease is well recognized. Nevertheless, there are still large gaps in our understanding of the functions and mechanisms encoded in the genomes of most members of the gut microbiota. Genome-scale libraries of transposon mutants are a powerful tool to help us address this gap. Recent advances in barcoded transposon mutagenesis have dramatically lowered the cost of mutant fitness determination in hundreds of in vitro and in vivo experimental conditions. In an accompanying review, we discuss recent advances and caveats for the construction of pooled and arrayed barcoded transposon mutant libraries in human gut commensals. In this review, we discuss how these libraries can be used across a wide range of applications, the technical aspects involved, and expectations for such screens.
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Elementos Transponibles de ADN , Humanos , Mutagénesis Insercional/genética , Elementos Transponibles de ADN/genética , Biblioteca de GenesRESUMEN
The gut microbiome modulates immune and metabolic health. Human microbiome data are biased toward industrialized populations, limiting our understanding of non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing on 351 fecal samples from the Hadza hunter-gatherers of Tanzania and comparative populations in Nepal and California. We recovered 91,662 genomes of bacteria, archaea, bacteriophages, and eukaryotes, 44% of which are absent from existing unified datasets. We identified 124 gut-resident species vanishing in industrialized populations and highlighted distinct aspects of the Hadza gut microbiome related to in situ replication rates, signatures of selection, and strain sharing. Industrialized gut microbes were found to be enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource, expands our understanding of microbes capable of colonizing the human gut, and clarifies the extensive perturbation induced by the industrialized lifestyle.
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Microbioma Gastrointestinal , Microbiota , Humanos , Microbioma Gastrointestinal/genética , Metagenoma , Eucariontes , Secuenciación de Nucleótidos de Alto Rendimiento , MetagenómicaRESUMEN
OBJECTIVE: Oral cancer is the sixteenth most prevalent cancer in the world and the third-most in India. Despite of several treatment modalities, the cure rate of oral cancer is still low due to drug resistance mechanisms, which are caused by many reasons. It is necessary to improve the existing treatment strategies and discover neoteric therapy to kill cancer cells, which will give oral cancer's cure rate more success. So this review aims to delineate the molecular mechanisms behind cisplatin resistance, specifically the role of the tumor microenvironment, extracellular vesicles, and altered signaling pathways and its overcoming strategies in oral cancer. DESIGN: This review was designed by searching words like cancer, oral cancer, cisplatin-resistance, tumor microenvironment, aberrant signalings, and extracellular vesicles, overcoming strategies for cisplatin resistance in databases like PubMed, Google Scholar, web science, and Scopus. Data available in this review is from 2017 to 2021. RESULTS: After searching too much data, we found these 98 data appropriate for our review. From these data, we found that tumor microenvironment, extracellular vesicles, and altered signaling pathways like PI3K/AKT, EGFR, NOTCH, Ras, PTEN, Nf-κß, and Wnt signaling have a crucial role in resistance development towards cisplatin in oral cancer. CONCLUSIONS: Lastly, this review explores the alternative strategies to overcome cisplatin resistance likely, the combination therapy and targeted therapy by combining more than one chemotherapeutic drug or inhibitors of signaling pathways and also by using nanoparticle loaded drugs that will reduce the drug efflux, which gives new treatment strategies.
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Antineoplásicos , Neoplasias de la Boca , Humanos , Cisplatino/farmacología , Microambiente Tumoral , Fosfatidilinositol 3-Quinasas/metabolismo , Resistencia a Antineoplásicos , Vía de Señalización Wnt , Neoplasias de la Boca/tratamiento farmacológico , Antineoplásicos/farmacología , Línea Celular TumoralRESUMEN
Apoptosis is the elimination of functionally non-essential, neoplastic, and infected cells via the mitochondrial pathway or death receptor pathway. The process of apoptosis is highly regulated through membrane channels and apoptogenic proteins. Apoptosis maintains cellular balance within the human body through cell cycle progression. Loss of apoptosis control prolongs cancer cell survival and allows the accumulation of mutations that can promote angiogenesis, promote cell proliferation, disrupt differentiation, and increase invasiveness during tumor progression. The apoptotic pathway has been extensively studied as a potential drug target in cancer treatment. However, the off-target activities of drugs and negative implications have been a matter of concern over the years. Phytochemicals (PCs) have been studied for their efficacy in various cancer cell lines individually and synergistically. The development of nanoparticles (NPs) through green synthesis has added a new dimension to the advancement of plant-based nanomaterials for effective cancer treatment. This review provides a detailed insight into the fundamental molecular pathways of programmed cell death and highlights the role of PCs along with the existing drugs and plant-based NPs in treating cancer by targeting its programmed cell death (PCD) network.
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Nanoestructuras , Neoplasias , Humanos , Apoptosis , Neoplasias/tratamiento farmacológico , Mitocondrias/metabolismo , Plantas , Fitoquímicos/farmacologíaRESUMEN
Evodiamine is a major alkaloid component found in the fruit of Evodia rutaecarpa. It shows the anti-proliferative potential against a wide range of cancers by suppressing cell growth, invasion, and metastasis and inducing apoptosis both in vitro and in vivo. Evodiamine shows its anticancer potential by modulating aberrant signaling pathways. Additionally, the review focuses on several therapeutic implications of evodiamine, such as epigenetic modification, cancer stem cells, and epithelial to mesenchymal transition. Moreover, combinatory drug therapeutics along with evodiamine enhances the anticancer efficacy of chemotherapeutic drugs in various cancers by overcoming the chemo resistance and radio resistance shown by cancer cells. It has been widely used in preclinical trials in animal models, exhibiting very negligible side effects against normal cells and effective against cancer cells. The pharmacokinetic and pharmacodynamics-based collaborations of evodiamine are also included. Due to its poor bioavailability, synthetic analogs of evodiamine and its nano capsule have been formulated to enhance its bioavailability and reduce toxicity. In addition, this review summarizes the ongoing research on the mechanisms behind the antitumor potential of evodiamine, which proposes an exciting future for such interests in cancer biology.
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Alcaloides , Antineoplásicos , Neoplasias , Animales , Transición Epitelial-Mesenquimal , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Alcaloides/farmacología , Extractos Vegetales/farmacología , Neoplasias/tratamiento farmacológicoRESUMEN
In this work, the structural, mechanical, and electronic properties of Janus zirconium halide monolayers have been systematically investigated using the first-principles calculations. After verifying the mechanical and dynamical stability of these monolayers, their electronic band structures have been predicted. These Janus monolayers have band gaps of 1.51-1.96 eV, which indicates their suitability for visible light absorption. The relaxation time and mobility of charge carriers are estimated using deformation potential theory, and the mobility of these monolayers has been predicted to be of the order â¼102 cm2 V-1 s-1. The lattice thermal conductivity has been calculated by solving the phonon Boltzmann transport equation using ShengBTE software. At 300 K, the in-plane lattice thermal conductivity has values of 76.94, 54.18, and 95.87 W m-1 K-1 for ZrBrCl, ZrBrF, and ZrClF monolayers, respectively. The higher group velocity and small anharmonic three-phonon scattering rate are the main reasons for the high lattice thermal conductivity of the ZrClF monolayer. The real and imaginary parts of the dielectric function are calculated to find the absorption coefficients and these monolayers have a high absorption coefficient of the order â¼106 cm-1 in the visible light range. Our results show that Janus zirconium halide monolayers are potential candidates for optoelectronic and photocatalytic applications.
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BACKGROUND: Identifying risk factors for poor outcomes can help with risk stratification and targeting of treatment. Risk factors for mortality and exacerbations have been identified in bronchiectasis but have been almost exclusively studied in European and North American populations. This study investigated the risk factors for poor outcome in a large population of bronchiectasis patients enrolled in India. METHODS: The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India (EMBARC-India) registry is a prospective observational study of adults with computed tomography-confirmed bronchiectasis enrolled at 31 sites across India. Baseline characteristics of patients were used to investigate associations with key clinical outcomes: mortality, severe exacerbations requiring hospital admission, overall exacerbation frequency and decline in forced expiratory volume in 1â s. RESULTS: 1018 patients with at least 12-month follow-up data were enrolled in the follow-up study. Frequent exacerbations (≥3 per year) at baseline were associated with an increased risk of mortality (hazard ratio (HR) 3.23, 95% CI 1.39-7.50), severe exacerbations (HR 2.71, 95% CI 1.92-3.83), future exacerbations (incidence rate ratio (IRR) 3.08, 95% CI 2.36-4.01) and lung function decline. Coexisting COPD, dyspnoea and current cigarette smoking were similarly associated with a worse outcome across all end-points studied. Additional predictors of mortality and severe exacerbations were increasing age and cardiovascular comorbidity. Infection with Gram-negative pathogens (predominantly Klebsiella pneumoniae) was independently associated with increased mortality (HR 3.13, 95% CI 1.62-6.06), while Pseudomonas aeruginosa infection was associated with severe exacerbations (HR 1.41, 95% CI 1.01-1.97) and overall exacerbation rate (IRR 1.47, 95% CI 1.13-1.91). CONCLUSIONS: This study identifies risk factors for morbidity and mortality among bronchiectasis patients in India. Identification of these risk factors may support treatment approaches optimised to an Asian setting.
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Bronquiectasia , Adulto , Humanos , Estudios de Seguimiento , Bronquiectasia/terapia , Bronquiectasia/tratamiento farmacológico , Pulmón , Sistema de Registros , Progresión de la EnfermedadRESUMEN
BACKGROUND: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. METHODS: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. RESULTS AND CONCLUSION: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events.
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Productos Biológicos , Medios de Comunicación Sociales , HumanosRESUMEN
The gut microbiome is a key modulator of immune and metabolic health. Human microbiome data is biased towards industrialized populations, providing limited understanding of the distinct and diverse non-industrialized microbiomes. Here, we performed ultra-deep metagenomic sequencing and strain cultivation on 351 fecal samples from the Hadza, hunter-gatherers in Tanzania, and comparative populations in Nepal and California. We recover 94,971 total genomes of bacteria, archaea, bacteriophages, and eukaryotes, 43% of which are absent from existing unified datasets. Analysis of in situ growth rates, genetic pN/pS signatures, high-resolution strain tracking, and 124 gut-resident species vanishing in industrialized populations reveals differentiating dynamics of the Hadza gut microbiome. Industrialized gut microbes are enriched in genes associated with oxidative stress, possibly a result of microbiome adaptation to inflammatory processes. This unparalleled view of the Hadza gut microbiome provides a valuable resource that expands our understanding of microbes capable of colonizing the human gut and clarifies the extensive perturbation brought on by the industrialized lifestyle.
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Since December 2019 SARS-CoV-2 infections have affected millions of people worldwide. Along with the increasing number of COVID-19 patients, the number of cases of opportunistic fungal infections among the COVID-19 patients is also increasing. There have been reports of the cases of aspergillosis and candidiasis in the COVID-19 patients. The COVID-19 patients have also been affected by rare fungal infections such as histoplasmosis, pneumocystosis, mucormycosis and cryptococcosis. These fungal infections are prolonging the stay of COVID-19 patients in hospital. In this study several published case reports, case series, prospective and retrospective studies were investigated to explore and report the updated information regarding candidiasis, crytptococcosis, aspergillosis, mucormycosis, histoplasmosis, and pneumocystosis infections in COVID-19 patients. In this review, the risk factors of these co-infections in COVID-19 patients have been reported. There have been reports that the comorbidities and the treatment with corticoids, monoclonal antibodies, use of mechanical ventilation, and use of antibiotics during COVID-19 management are associated with the emergence of fungal infections in the COVID-19 patients. Hence, this review analyses the role of these therapies and comorbidities in the emergence of these fungal infections among COVID-19 patients. This review will help to comprehend if these fungal infections are the result of the co-morbidities, and treatment protocol followed to manage COVID-19 patients or directly due to the SARS-CoV-2 infection. The analysis of all these factors will help to understand their role in fungal infections among COVID-19 patients which can be valuable to the scientific community.
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Infant microbiome assembly has been intensely studied in infants from industrialized nations, but little is known about this process in nonindustrialized populations. We deeply sequenced infant stool samples from the Hadza hunter-gatherers of Tanzania and analyzed them in a global meta-analysis. Infant microbiomes develop along lifestyle-associated trajectories, with more than 20% of genomes detected in the Hadza infant gut representing novel species. Industrialized infants-even those who are breastfed-have microbiomes characterized by a paucity of Bifidobacterium infantis and gene cassettes involved in human milk utilization. Strains within lifestyle-associated taxonomic groups are shared between mother-infant dyads, consistent with early life inheritance of lifestyle-shaped microbiomes. The population-specific differences in infant microbiome composition and function underscore the importance of studying microbiomes from people outside of wealthy, industrialized nations.
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Bifidobacterium longum subspecies infantis , Países en Desarrollo , Microbioma Gastrointestinal , Estilo de Vida , Bifidobacterium longum subspecies infantis/clasificación , Bifidobacterium longum subspecies infantis/genética , Bifidobacterium longum subspecies infantis/aislamiento & purificación , Heces/microbiología , Femenino , Microbioma Gastrointestinal/genética , Genoma Bacteriano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Leche Humana/microbiología , TanzaníaRESUMEN
The dysregulated expression of the transcription factor (TF) Sry-related HMG box 9 (SOX9) has been extensively correlated with various biological effects, including the initiation and progression of cancer. Differential expression of SOX9 has been positively correlated with cancer cell growth, invasion, migration, metastasis, and therapy resistance. Studies showed that expression of SOX9 affects the expression of various miRNAs and vice versa, resulting in the development of cancer drug resistance. However, modulating the expression of SOX9 reverses drug resistance by modulating the expression of miRNAs. Therefore, in this review, we summarize current research focusing on SOX9 as a cancer therapeutic target and a prognostic biomarker of cancer drug resistance.
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Antineoplásicos , MicroARNs , Neoplasias , Biomarcadores , Resistencia a Antineoplásicos , Pronóstico , Factor de Transcripción SOX9RESUMEN
BACKGROUND: Targeted therapy in adenocarcinoma is recommended. The use of immune check point inhibitors for the treatment of Non-small cell lung carcinoma (NSCLC) is used as both first-line and the second-line treatment strategy. The current study was undertaken to assess the frequency of programmed cell death ligand-1 (PD-L1) expression with anaplastic lymphoma kinase (ALK), proto-oncogene 1, receptor tyrosine kinase (ROS), epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and v-Raf murine sarcoma viral oncogene homolog B (BRAF)V600E driver gene mutations in NSCLC adenocarcinoma phenotype. It assesses the frequencies of all markers in the cases where both treatment strategies can be implemented. Expression of the all markers was further compared with demographic, clinical parameters, and overall survival rate. MATERIALS AND METHODS: The formalin-fixed paraffin-embedded (FFPE) tissue blocks were used in immunohistochemistry (IHC) staining and real-time polymerase chain reaction (RT-PCR) for determining the driver genes and PD-L1 expression in the 100 NSCLC-Adenocarcinoma cases. RESULTS: PD-L1 positivity was observed in 26.36% (n=29/110) cases in adenocarcinoma. No significant differences in PD-L1 expression were observed among patients harboring ALK, ROS1, EGFR, KRAS, and BRAF mutations EGFR mutations had significant association with smoking status. (p= 0.008), Thyroid transcription factor 1 (TTF1) (p=0.0005) and Napsin (p=0.002) expression. ALK gene re-arrangement was significantly related to age (p= 0.001), gender (p= 0.009) and smoking status (p= 0.043). The single versus multiple driver mutations were significantly correlated with smoking status (p=0.005). In the survival rate analysis, EGFR (p=0.058), KRAS (p=0.021), and PD-L1 (p=0.039) were significantly high with the positive versus negative group. CONCLUSIONS: The current study is a novel attempt to document the co-expression of multiple driver mutations in the NSCLC-adenocarcinoma phenotype. PD-L1 immunopositivity in NSCLC-adenocarcinoma was higher with EGFR mutation as compared to those of KRAS, ALK, ROS, and BRAF driver genes.
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Adenocarcinoma/genética , Quinasa de Linfoma Anaplásico/genética , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proto-Oncogenes/genética , Animales , Modelos Animales de Enfermedad , Receptores ErbB/genética , Inmunohistoquímica , Ratones , Mutación , Fenotipo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
The presence of small subpopulations of cells within tumor cells are known as cancer stem cells (CSCs). These cells have been the reason for metastasis, resistance with chemotherapy or radiotherapy, and tumor relapse in several types of cancers. CSCs underwent to epithelial-mesenchymal transition (EMT) and resulted in the development of aggressive tumors. CSCs have potential to modulate numerous signaling pathways including Wnt, Hh, and Notch, therefore increasing the stem-like characteristics of cancer cells. The raised expression of drug efflux pump and suppression of apoptosis has shown increased resistance with anti-cancer drugs. Among many agents which were shown to modulate these, the plant-derived bioactive agents appear to modulate these key regulators and were shown to remove CSCs. This review aims to comprehensively scrutinize the preclinical and clinical studies demonstrating the effects of phytocompounds on CSCs isolated from various tumors. Based on the available convincing literature from preclinical studies, with some clinical data, it is apparent that selective targeting of CSCs with plants, plant preparations, and plant-derived bioactive compounds, termed phytochemicals, may be a promising strategy for the treatment of relapsed cancers.