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The function of CD5 protein in T cells is well documented, but regulation of its surface-level expression has yet to be fully understood. However, variation in its surface expression is associated with various immunopathological conditions and haematological malignancies. Briefly, expression of an alternate exon E1B of a human endogenous retroviruses (HERV) origin directly downregulates the conventional transcript variant (E1A), as its expression leads to the retention of the resultant protein at the intracellular level (cCD5). A separate promoter governs the expression of E1B and may be influenced by different transcription factors. Hence, we performed in silico transcription factor binding site (TFBS) analysis of the 3 kb upstream region from TSS of exon E1B and found five putative DREs (Dioxin Response elements) with good similarity scores. Further, we observed the upregulation in E1B expression after the exposure of BaP (a dioxin) and the reduction of E1A expression and their respective protein, i.e. sCD5 and cCD5. The binding of AHR at the predicted DRE sites was confirmed by ChIP qPCR and AHR specific inhibitor and gene silencing studies suggested the involvement of AHR in exonal switch. This study indicates that the polycyclic aromatic hydrocarbon decreases the sCD5 expression by upregulating alternative exon expression, which may adversely affect the overall T cell functions.
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Benzo(a)pireno , Antígenos CD5 , Éxons , Regulação da Expressão Gênica , Receptores de Hidrocarboneto Arílico , Humanos , Antígenos CD5/metabolismo , Antígenos CD5/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Éxons/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Ligação Proteica , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Sítios de Ligação , Células JurkatRESUMO
The unrestricted release of various toxic substances into the environment is a critical global issue, gaining increased attention in modern society. Many of these substances are pristine to various environmental compartments known as contaminants/emerging contaminants (ECs). Nanoparticles and emerging sorbents enhanced remediation is a compelling methodology exhibiting great potential in addressing EC-related issues and facilitating their elimination from the environment, particularly those compounds that demonstrate eco-toxicity and pose considerable challenges in terms of removal. It provides a novel technique enabling the secure and sustainable removal of various ECs, including persistent organic compounds, microplastics, phthalate, etc. This extensive review presents a critical perspective on the current advancements and potential outcomes of nano-enhanced remediation techniques such as photocatalysis, nano-sensing, nano-enhanced sorbents, bio/phyto-remediation, which are applied to clean-up the natural environment. In addition, when dealing with residual contaminants, special attention is paid to both health and environmental implications; therefore, an evaluation of the long-term sustainability of nano-enhanced remediation methods has been considered. The integrated mechanical approaches were thoroughly discussed and presented in graphical forms. Thus, the critical evaluation of the integrated use of most emerging remediation technologies will open a new dimension in environmental safety and clean-up program.
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Recuperação e Remediação Ambiental , Nanopartículas , Nanoestruturas , Plásticos , Carvão VegetalRESUMO
Recent multi-omics studies, including proteomics, transcriptomics, genomics, and metabolomics have revealed the critical role of post-translational modifications (PTMs) in the progression and pathogenesis of Glioblastoma multiforme (GBM). Further, PTMs alter the oncogenic signaling events and offer a novel avenue in GBM therapeutics research through PTM enzymes as potential biomarkers for drug targeting. In addition, PTMs are critical regulators of chromatin architecture, gene expression, and tumor microenvironment (TME), that play a crucial function in tumorigenesis. Moreover, the implementation of artificial intelligence and machine learning algorithms enhances GBM therapeutics research through the identification of novel PTM enzymes and residues. Herein, we briefly explain the mechanism of protein modifications in GBM etiology, and in altering the biologics of GBM cells through chromatin remodeling, modulation of the TME, and signaling pathways. In addition, we highlighted the importance of PTM enzymes as therapeutic biomarkers and the role of artificial intelligence and machine learning in protein PTM prediction.
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Inteligência Artificial , Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/metabolismo , Processamento de Proteína Pós-Traducional , Genômica , Biomarcadores/metabolismo , Microambiente TumoralRESUMO
CD5, a T-cell receptor (TCR) negative regulator, is reduced on the surface of CD8+ lymphocytes in the tumor microenvironment (TME). Reduced surface CD5 expression (sCD5) occurs due to the preferential transcription of HERV-E derived exon E1B, i.e., anon-conventional formofthe cd5gene instead of its conventional exon E1A. A tumor employs several mechanisms to evade anti-tumor response, and hypoxia is one such mechanism that prevails in the TME and modulates the infiltrated T lymphocytes. We identified hypoxia response elements (HREs) upstream of E1B. We showed binding of HIF-1α onto these HREs and increased E1B mRNA expression in hypoxic T cells. This results in decreased sCD5 expression and increased cytoplasmic accumulation in T cells. We also validated our study in a solid tumor, i.e., colorectal cancer (CRC) patient samples. This hypoxia-driven mechanism reduces the surface CD5 expression on infiltrated T-cells in solid tumors.
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Neoplasias , Humanos , Neoplasias/genética , Hipóxia/genética , Isoformas de Proteínas/genética , Éxons , Fenótipo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia Celular/genética , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Non-cellular secretory components, including chemokines, cytokines, and growth factors in the tumor microenvironment, are often dysregulated, impacting tumorigenesis in Glioblastoma multiforme (GBM) microenvironment, where the prognostic significance of the current treatment remains unsatisfactory. Recent studies have demonstrated the potential of post-translational modifications (PTM) and their respective enzymes, such as acetylation and ubiquitination in GBM etiology through modulating signaling events. However, the relationship between non-cellular secretory components and post-translational modifications will create a research void in GBM therapeutics. Therefore, we aim to bridge the gap between non-cellular secretory components and PTM modifications through machine learning and computational biology approaches. Herein, we highlighted the importance of BMP1, CTSB, LOX, LOXL1, PLOD1, MMP9, SERPINE1, and SERPING1 in GBM etiology. Further, we demonstrated the positive relationship between the E2 conjugating enzymes (Ube2E1, Ube2H, Ube2J2, Ube2C, Ube2J2, and Ube2S), E3 ligases (VHL and GNB2L1) and substrate (HIF1A). Additionally, we reported the novel HAT1-induced acetylation sites of Ube2S (K211) and Ube2H (K8, K52). Structural and functional characterization of Ube2S (8) and Ube2H (1) have identified their association with protein kinases. Lastly, our results found a putative therapeutic axis HAT1-Ube2S(K211)-GNB2L1-HIF1A and potential predictive biomarkers (CTSB, HAT1, Ube2H, VHL, and GNB2L1) that play a critical role in GBM pathogenesis.
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Parkinson's disease (PD) is characterized by the loss of neuronal cells, which leads to synaptic dysfunction and cognitive defects. Despite the advancements in treatment strategies, the management of PD is still a challenging event. Early prediction and diagnosis of PD are of utmost importance for effective management of PD. In addition, the classification of patients with PD as compared to normal healthy individuals also imposes drawbacks in the early diagnosis of PD. To address these challenges, artificial intelligence (AI) and machine learning (ML) models have been implicated in the diagnosis, prediction, and treatment of PD. Recent times have also demonstrated the implication of AI and ML models in the classification of PD based on neuroimaging methods, speech recording, gait abnormalities, and others. Herein, we have briefly discussed the role of AI and ML in the diagnosis, treatment, and identification of novel biomarkers in the progression of PD. We have also highlighted the role of AI and ML in PD management through altered lipidomics and gut-brain axis. We briefly explain the role of early PD detection through AI and ML algorithms based on speech recordings, handwriting patterns, gait abnormalities, and neuroimaging techniques. Further, the review discuss the potential role of the metaverse, the Internet of Things, and electronic health records in the effective management of PD to improve the quality of life. Lastly, we also focused on the implementation of AI and ML-algorithms in neurosurgical process and drug discovery.
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Inteligência Artificial , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Qualidade de Vida , Aprendizado de Máquina , AlgoritmosRESUMO
The present study investigated the concerted effort of Eisenia fetida and rhamnolipid JBR-425 in combination with a five-member bacterial consortium exhibiting elevated degradation levels of low and high molecular weight polycyclic aromatic hydrocarbons (PAH) from soil contaminated with Digboi crude oil. Application of bacterial consortium (G2) degraded 30-89% of selected PAH from the artificial soil after a 45-day post-exposure, in which chrysene showed the highest level of degradation with 89% and benzo(a)pyrene is the lowest with 30%, respectively. Moreover, an acute exposure study observed that earthworm biomass decreased, and mortality rates increased with increasing crude oil concentrations (0.25 to 2%). Earthworms with a 100% survival rate at 1% crude oil exposure suggest the tolerance potential and its mutual involvement in the bioremediation of crude oil with selected bacterial consortia. Bacterial consortium assisted with E. fetida (G3) showed 98% chrysene degradation with a slight change in benzo(a)pyrene degradation (35%) in crude oil spiked soil. Besides, the most dominant PAH in crude oil found in the current work, fluoranthene, undergoes 93% and 70% degradation in G3 and G5 groups, respectively. However, rhamnolipid JBR-425 coupled with the bacterial consortium (G5) has resulted in 97% degradation of chrysene and 33% for benzo(a)pyrene. Overall, bacterial consortium assisted with earthworm group has shown better degradation of selected PAH than bacterial consortium with biosurfactant. Catalase (CAT), glutathione reductase (GST) activity and MDA content was found to be reduced in earthworms after sub-lethal exposure, suggesting oxidative stress prevalence via reactive oxygen species (ROS). Hence, the findings of the present work suggest that the application of a bacterial consortium, along with earthworm E. fetida, has huge potential for field restoration of contaminated soil with PAH and ecosystem sustainability.
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Oligoquetos , Petróleo , Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Animais , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Oligoquetos/metabolismo , Crisenos , Ecossistema , Biodegradação Ambiental , Solo , Petróleo/metabolismo , Benzo(a)pireno/metabolismo , Poluentes do Solo/análise , Bactérias/metabolismoRESUMO
Glioblastoma multiforme (GBM) is an aggressive brain cancer showing poor prognosis. Currently, treatment methods of GBM are limited with adverse outcomes and low survival rate. Thus, advancements in the treatment of GBM are of utmost importance, which can be achieved in recent decades. However, despite aggressive initial treatment, most patients develop recurrent diseases, and the overall survival rate of patients is impossible to achieve. Currently, researchers across the globe target signaling events along with tumor microenvironment (TME) through different drug molecules to inhibit the progression of GBM, but clinically they failed to demonstrate much success. Herein, we discuss the therapeutic targets and signaling cascades along with the role of the organoids model in GBM research. Moreover, we systematically review the traditional and emerging therapeutic strategies in GBM. In addition, we discuss the implications of nanotechnologies, AI, and combinatorial approach to enhance GBM therapeutics.
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Glioblastoma , Humanos , Glioblastoma/patologia , Transdução de Sinais , Microambiente TumoralRESUMO
The main therapeutic difficulties in treating hypoxia-induced glioblastoma multiforme (GBM) are toxicity of current treatments and the resistance brought on by the microenvironment. More effective therapeutic alternatives are urgently needed to reduce tumor lethality. Hence, we screened plant-based natural product panels intending to identify novel drugs without elevating drug resistance. We explored GEO for the hypoxia GBM model and compared hypoxic genes to non-neoplastic brain cells. A total of 2429 differentially expressed genes expressed exclusively in hypoxia were identified. The functional enrichment analysis demonstrated genes associated with GBM, further PPI network was constructed, and biological pathways associated with them were explored. Seven webtools, including GEPIA2.0, TIMER2.0, TCGA-GBM, and GlioVis, were used to validate 32 hub genes discovered using Cytoscape tool in GBM patient samples. Four GBM-specific hypoxic hub genes, LYN, MMP9, PSMB9, and TIMP1, were connected to the tumor microenvironment using TIMER analysis. 11 promising hits demonstrated positive drug-likeness with nontoxic characteristics and successfully crossed blood-brain barrier and ADMET analyses. Top-ranking hits have stable intermolecular interactions with the MMP9 protein according to molecular docking, MD simulation, MM-PBSA, PCA, and DCCM analyses. Herein, we have reported flavonoids, 7,4'-dihydroxyflavan, (3R)-3-(4-hydroxybenzyl)-6-hydroxy-8-methoxy-3,4-dihydro-2H-1-benzopyran, and 4'-hydroxy-7-methoxyflavan, to inhibit MMP9, a novel hypoxia gene signature that could serve as a promising predictor in various clinical applications, including GBM diagnosis, prognosis, and targeted therapy.
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Necroptosis, a regulated form of cell death, is involved in the genesis and development of various life-threatening diseases, including cancer, neurological disorders, cardiac myopathy, and diabetes. Necroptosis initiates with the formation and activation of a necrosome complex, which consists of RIPK1, RIPK2, RIPK3, and MLKL. Emerging studies has demonstrated the regulation of the necroptosis cell death pathway through the implication of numerous post-translational modifications, namely ubiquitination, acetylation, methylation, SUMOylation, hydroxylation, and others. In addition, the negative regulation of the necroptosis pathway has been shown to interfere with brain homeostasis through the regulation of axonal degeneration, mitochondrial dynamics, lysosomal defects, and inflammatory response. Necroptosis is controlled by the activity and expression of signaling molecules, namely VEGF/VEGFR, PI3K/Akt/GSK-3ß, c-Jun N-terminal kinases (JNK), ERK/MAPK, and Wnt/ß-catenin. Herein, we briefly discussed the implication and potential of necrosome activation in the pathogenesis and progression of neurological manifestations, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, and others. Further, we present a detailed picture of natural compounds, micro-RNAs, and chemical compounds as therapeutic agents for treating neurological manifestations.
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Doenças do Sistema Nervoso , Proteínas Quinases , Humanos , Proteínas Quinases/metabolismo , Necroptose/fisiologia , Glicogênio Sintase Quinase 3 beta , Fosfatidilinositol 3-Quinases , ApoptoseRESUMO
Worldwide industrialization and other human activities have led to a frightening stage of release of hazardous, highly persistent, toxic, insoluble, strongly adsorbed to the soil and high molecular weight ubiquitous polycyclic aromatic hydrocarbons (PAHs) in soils and sediments. The various conventional remediation methods are being used to remediate PAHs with certain drawbacks. Time taking process, high expenditure, excessive quantities of sludge generation, and various chemical requirements do not only make these methods outdated but produce yet much resistant and toxic intermediate metabolites. These disadvantages may be overcome by using a microbial electrochemical system (MES), a booming technology in the field of bioremediation. MES is a green remediation approach that is regulated by electrochemically active microorganisms at the electrode in the system. The key advantage of the system over the conventional methods is it does not involve any additional chemicals, takes less time, and generates minimal sludge or waste during the remediation of PAHs in soils. However, a comprehensive review of the MES towards bioremediation of PAHs adsorbed in soil and sediment is still lacking. Therefore, the present review intended to summarize the recent information on PAHs bioremediation, application, risks, benefits, and challenges based on sediment microbial fuel cell and microbial fuel cell to remediate mount-up industrial sludge, soil, and sediment rich in PAHs. Additionally, bio-electrochemically active microbes, mechanisms, and future perspectives of MES have been discussed.
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Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Humanos , Hidrocarbonetos Policíclicos Aromáticos/análise , Solo/química , Esgotos , Poluentes do Solo/análise , Biodegradação AmbientalRESUMO
AIM: To evaluate the changes in the intraoral dynamic space with myofunctional therapy in skeletal class II division 1 malocclusion using three-dimensional digital volume tomography (3D-DVT). MATERIALS AND METHODS: The study type is observational and the duration of intervention was 3 years. Dental casts obtained from 20 samples of 11-14 years age-group were collected and 3D-DVT scans were performed prior to and after the myofunctional therapy. The parameters depicting the arch perimeter, arch width, arch length, arch shape, and arch volume on dental cast were used in the study using several linear and volumetric measurements. All parameters were compared before and after myofunctional therapy using t-test. RESULTS: The Intraoral volume before myofunctional therapy (T0) was 5.59 mL and after myofunctional therapy (T1), it was 7.22 mL. Significant changes were seen in intraoral volume, arch perimeter, arch length, and intercanine and intermolar arch width and the arch shape. Linear and volumetric measurements were increased after myofunctional therapy. CONCLUSION: Myofunctional appliances lead to an expansion in the anteroposterior and sagittal direction thus increasing the Donders space and leading to proper formation of dental arches and proper positioning of the teeth. CLINICAL SIGNIFICANCE: Myofunctional therapy is an effective method of increasing arch width, length, and volume. This therapy can be used in routine practices in young children with constricted arch and improvement in facial esthetic.
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Tomografia Computadorizada de Feixe Cônico , Má Oclusão Classe II de Angle , Criança , Pré-Escolar , Humanos , Má Oclusão Classe II de Angle/diagnóstico por imagem , Má Oclusão Classe II de Angle/terapia , Terapia Miofuncional , Projetos de PesquisaRESUMO
The 21st century has seen a spike in virus outbreaks. The Coronavirus infection in 2019, originating from Wuhan Province, China, spread across the world and was declared a pandemic. It led to the imposition of lockdowns in different parts of the world, as lockdowns were an effective and essential way to break down the cycle of infection. Physical distancing was the most significant measure to break the infection cycle. The Coronavirus infection outbreak has seen a concurrent spike in mental health risks worldwide. Mental health is considered to be one of the important components of overall health issues. A good mental health state is when people are stable with the environment and should not be effortlessly upset. They should know their requirements, difficulties, and goals properly; if they face problems, a trial should be done to solve them logically to cope with stress and anxiety. COVID-19 has set off a wide variation of mental issues, for example, anxiety, panic disorder, and depression. Most of the studies have reported negative impacts, including anger, stress indications, and confusion. Healthcare providers who have worked around the look after patients had also found a need for emphasis on mental health. Mental health awareness among the general population has gained importance since the high spike rise of mental health issues. This has garnered popularity in the general population and clinicians to pay due attention to mental health. Awareness and measures to keep mental health issues at bay need to be emphasized and undertaken. This organized review targets to highlight the psychological impact on the general population and associated risk factors that are components of aggravation.
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Human leukemic T cells show decreased surface CD5 (sCD5) and increased cytoplasmic CD5 (cCD5). When we examined their expressions in the Jurkat T cells, it showed increased sCD5 and decreased cCD5, which is in sharp contrast with the pattern of CD5 expression observed for human leukemic T cells. Furthermore, this opposite pattern was due to the absence of an exonal switch between E1A and E1B. This study suggests that Jurkat cell does not retain all characteristics of T-ALL cells; thus, we should carefully interpret the data obtained using Jurkat T cell as a model cell line of T-ALL.
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Leucemia-Linfoma de Células T do Adulto , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Linhagem Celular , Humanos , Células JurkatRESUMO
Visceral leishmaniasis (VL) is a fatal form among all forms of leishmaniasis and is caused by visceralization of the Leishmania donovani (Ld) parasite to the critical organs. Mild to severe malnutrition is common in VL patients and the deficiency of retinoic acid (RA), an important micronutrient, results in a compromised state of immune response in macrophages (mφ) leading to the increased parasite load. In the continuation of our earlier work, we observed loss of cellular cholesterol in infected mφ in the absence of RA i.e., upon inhibition of RALDH pathway. Moreover, the Leishmania utilizes host cholesterol for the establishment of infection and causes a decrease in the expressions of Niemann-Pick C2 (npc2) and Niemann-Pick C1 (npc1) genes involved in the uptake of extracellular cholesterol. This results in reduced levels of cellular cholesterol in infected mφ. Intrigued by this, as the first sign of our hypothesis, we investigated the presence of RA Response Element (RARE) sequences in the upstream of npc1 and npc2 genes. To functionally confirm this, we measured their expressions and the levels of cellular cholesterol in Ld infected mφ in the absence (i.e., using an inhibitor of RALDH pathway) and presence of RA. We found restoration of the levels of cellular cholesterol in infected mφ under the supplementation of RA resulting in the decreased parasite load. Hence, the supplementation of RA with the standard therapy and/or preventive use of RA could be potentially an advancement in the treatment and cure of VL patients.
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Leishmania donovani , Leishmaniose Visceral , Colesterol/metabolismo , Humanos , Macrófagos/metabolismo , Proteína C1 de Niemann-Pick , Tretinoína/metabolismo , Tretinoína/farmacologia , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
The etiology of the majority of human cancers is associated with a myriad of environmental causes, including physical, chemical, and biological factors. DNA damage induced by such mutagens is the initial step in the process of carcinogenesis resulting in the accumulation of mutations. Mutational events are considered the major triggers for introducing genetic and epigenetic insults such as DNA crosslinks, single- and double-strand DNA breaks, formation of DNA adducts, mismatched bases, modification in histones, DNA methylation, and microRNA alterations. However, DNA repair mechanisms are devoted to protect the DNA to ensure genetic stability, any aberrations in these calibrated mechanisms provoke cancer occurrence. Comprehensive knowledge of the type of mutagens and carcinogens and the influence of these agents in DNA damage and cancer induction is crucial to develop rational anticancer strategies. This review delineated the molecular mechanism of DNA damage and the repair pathways to provide a deep understanding of the molecular basis of mutagenicity and carcinogenicity. A relationship between DNA adduct formation and cancer incidence has also been summarized. The mechanistic basis of inflammatory response and oxidative damage triggered by mutagens in tumorigenesis has also been highlighted. We elucidated the interesting interplay between DNA damage response and immune system mechanisms. We addressed the current understanding of DNA repair targeted therapies and DNA damaging chemotherapeutic agents for cancer treatment and discussed how antiviral agents, anti-inflammatory drugs, and immunotherapeutic agents combined with traditional approaches lay the foundations for future cancer therapies.
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Mutagênicos , Neoplasias , Carcinógenos/metabolismo , Carcinógenos/toxicidade , DNA/metabolismo , Dano ao DNA , Reparo do DNA , Humanos , Mutagênicos/metabolismo , Mutagênicos/toxicidade , Neoplasias/epidemiologiaRESUMO
BACKGROUND: The global alliance for genomics and healthcare facilities provides innovative solutions to expedite research and clinical practices for complex and incurable health conditions. Precision oncology is an emerging field explicitly tailored to facilitate cancer diagnosis, prevention, and treatment based on patients' genetic profiles. Advancements in "omics" techniques, next-generation sequencing, artificial intelligence, and clinical trial designs provide a platform for assessing the efficacy and safety of combination therapies and diagnostic procedures. METHODS: Data were collected from PubMed and Google Scholar using keywords "Precision medicine," "precision medicine and cancer," "anticancer agents in precision medicine," and reviewed comprehensively. RESULTS: Personalized therapeutics, including immunotherapy and cancer vaccines, serve as a groundbreaking solution for cancer treatment. Herein, we take a measurable view of precision therapies and novel diagnostic approaches targeting cancer treatment. The contemporary applications of precision medicine have also been described, along with various hurdles identified in the successful establishment of precision therapeutics. CONCLUSION: This review highlights the key breakthroughs related to immunotherapies, targeted anticancer agents, and target interventions related to cancer signaling mechanisms. The success story of this field in context to drug resistance, safety, patient survival, and improving quality of life is yet to be elucidated. We conclude that, in the near future, the field of individualized treatments may truly revolutionize the nature of cancer patient care.
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Antineoplásicos/farmacologia , Vacinas Anticâncer/imunologia , Neoplasias/terapia , Medicina de Precisão , Antineoplásicos/química , Humanos , Imunoterapia , Neoplasias/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The tumor microenvironment plays a pivotal role in tumor initiation and progression by creating a dynamic interaction with cancer cells. The tumor microenvironment consists of various cellular components, including endothelial cells, fibroblasts, pericytes, adipocytes, immune cells, cancer stem cells and vasculature, which provide a sustained environment for cancer cell proliferation. Currently, targeting tumor microenvironment is increasingly being explored as a novel approach to improve cancer therapeutics, as it influences the growth and expansion of malignant cells in various ways. Despite continuous advancements in targeted therapies for cancer treatment, drug resistance, toxicity and immune escape mechanisms are the basis of treatment failure and cancer escape. Targeting tumor microenvironment efficiently with approved drugs and combination therapy is the solution to this enduring challenge that involves combining more than one treatment modality such as chemotherapy, surgery, radiotherapy, immunotherapy and nanotherapy that can effectively and synergistically target the critical pathways associated with disease pathogenesis. This review shed light on the composition of the tumor microenvironment, interaction of different components within tumor microenvironment with tumor cells and associated hallmarks, the current status of combinatorial therapies being developed, and various growing advancements. Furthermore, computational tools can also be used to monitor the significance and outcome of therapies being developed. We addressed the perceived barriers and regulatory hurdles in developing a combinatorial regimen and evaluated the present status of these therapies in the clinic. The accumulating depth of knowledge about the tumor microenvironment in cancer may facilitate further development of effective treatment modalities. This review presents the tumor microenvironment as a sweeping landscape for developing novel cancer therapies.
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Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , HumanosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Infection with L. donovani affects mainly visceral organs. Importantly, the parasitic load differs in different visceral organs; therefore there is a need to understand the organ specific immune regulation, particularly in the spleen and liver. Comparative studies between these organs in Leishmania infected hamster (Mesocricetus auratus) are lacking. Our study highlights the importance of eicosanoids in the organ specific pathology of visceral leishmaniasis. Among other immune cells, macrophages (mφ) which harbor Leishmania parasite are major producers of eicosanoids. In this study, we intend to explore linkage between organ specific immune response and eicosanoids. We suggest that eicosanoids (early immune modulators) and their organ specific expressions, possibly tune the outcome of mφ differently at different sites. We have observed that liver showed better containment of parasitic load than spleen, where we have found higher expression of 5-lipoxygenase (5-LO) enzyme along with IL-12 and iNOS. However, in spleen, enzymes of the PGE2 pathway i.e. PGE2 synthases (cytosolic and microsomal) along with IL-10 were predominantly higher. To further corroborate our findings, in vitro assays were carried out using purified eicosanoids (LTB4 and PGE2) and the inhibitors of these pathways. Findings establish that the 5-lipoxygenase pathway (i.e. LTB4) is anti-parasitic and its inhibition increases the parasitic load (qPCR based kDNA detection). On the contrary, PGES pathway (i.e. PGE2) supports establishment of infection in mφ. Taken together, 5-LO pathway plays a protective role in liver during L. donovani infection. However, the PGES pathway favors the parasite growth, particularly in the spleen at a later stage.