RESUMO
To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.
Assuntos
Comunicação Celular/fisiologia , RNA/metabolismo , Adulto , Líquidos Corporais/química , Ácidos Nucleicos Livres/metabolismo , MicroRNA Circulante/metabolismo , Vesículas Extracelulares/metabolismo , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Análise de Sequência de RNA/métodos , SoftwareRESUMO
Bone infections caused by Staphylococcus aureus may lead to an inflammatory condition called osteomyelitis, which results in progressive bone loss. Biofilm formation, intracellular survival, and the ability of S. aureus to evade the immune response result in recurrent and persistent infections that present significant challenges in treating osteomyelitis. Moreover, people with diabetes are prone to osteomyelitis due to their compromised immune system, and in life-threatening cases, this may lead to amputation of the affected limbs. In most cases, bone infections are localized; thus, early detection and targeted therapy may prove fruitful in treating S. aureus-related bone infections and preventing the spread of the infection. Specific S. aureus components or overexpressed tissue biomarkers in bone infections could be targeted to deliver active therapeutics, thereby reducing drug dosage and systemic toxicity. Compounds like peptides and antibodies can specifically bind to S. aureus or overexpressed disease markers and combining these with therapeutics or imaging agents can facilitate targeted delivery to the site of infection. The effectiveness of photodynamic therapy and hyperthermia therapy can be increased by the addition of targeting molecules to these therapies enabling site-specific therapy delivery. Strategies like host-directed therapy focus on modulating the host immune mechanisms or signaling pathways utilized by S. aureus for therapeutic efficacy. Targeted therapeutic strategies in conjunction with standard surgical care could be potential treatment strategies for S. aureus-associated osteomyelitis to overcome antibiotic resistance and disease recurrence. This review paper presents information about the targeting strategies and agents for the therapy and diagnostic imaging of S. aureus bone infections.
Assuntos
Antibacterianos , Osteomielite , Infecções Estafilocócicas , Staphylococcus aureus , Osteomielite/microbiologia , Osteomielite/tratamento farmacológico , Humanos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , AnimaisRESUMO
BACKGROUND: Racial disparities among clinical trial participants present a challenge to assess whether trial results can be generalized into patients representing diverse races and ethnicities. The objective of this study was to evaluate the impact of race and ethnicity on treatment response in patients with advanced non-small cell lung cancer (aNSCLC) treated with programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitors through analysis of real-world data (RWD). MATERIALS AND METHODS: A retrospective cohort study of 11,138 patients with lung cancer treated at hospitals within the Mount Sinai Health System was performed. Patients with confirmed aNSCLC who received anti-PD-1/PD-L1 treatment were analyzed for clinical outcomes. Our cohort included 249 patients with aNSCLC who began nivolumab, pembrolizumab, or atezolizumab treatment between November 2014 and December 2018. Time-to-treatment discontinuation (TTD) and overall survival (OS) were the analyzed clinical endpoints. RESULTS: After a median follow-up of 14.8 months, median TTD was 7.8 months (95% confidence interval, 5.4-not estimable [NE]) in 75 African American patients versus 4.6 (2.4-7.2) in 110 White patients (hazard ratio [HR], 0.63). Median OS was not reached (18.4-NE) in African American patients versus 11.6 months (9.7-NE) in White patients (HR, 0.58). Multivariable Cox regression conducted with potential confounders confirmed longer TTD (adjusted HR, 0.65) and OS (adjusted HR, 0.60) in African American versus White patients. Similar real-world response rate (42.6% vs. 43.5%) and disease control rate (59.6% vs. 56.5%) were observed in the African American and White patient populations. Further investigation revealed the African American patient group had lower incidence (14.7%) of putative hyperprogressive diseases (HPD) upon anti-PD-1/PD-L1 treatment than the White patient group (24.5%). CONCLUSION: Analysis of RWD showed longer TTD and OS in African American patients with aNSCLC treated with anti-PD-1/PD-L1 inhibitors. Lower incidence of putative HPD is a possible reason for the favorable outcomes in this patient population. IMPLICATIONS FOR PRACTICE: There is a significant underrepresentation of minority patients in randomized clinical trials, and this study demonstrates that real-world data can be used to investigate the impact of race and ethnicity on treatment response. In retrospective analysis of patients with advanced non-small cell lung cancer treated with programmed cell death-1 or programmed cell death-ligand 1 inhibitors, African American patients had significantly longer time-to-treatment discontinuation and longer overall survival. Analysis of real-world data can yield clinical insights and establish a more complete picture of medical interventions in routine clinical practice.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Apoptose , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Etnicidade , Humanos , Inibidores de Checkpoint Imunológico , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Estudos RetrospectivosRESUMO
PURPOSE: We sought to 1) assess the association of radiomics features based on multiparametric magnetic resonance imaging with histopathological Gleason score, gene signatures and gene expression levels in prostate cancer and 2) build machine learning models based on radiomics features to predict adverse histopathological scores and the Decipher® genomics metastasis risk score. MATERIALS AND METHODS: We retrospectively analyzed the records of 64 patients with prostate cancer with a mean age of 64 years (range 41 to 76) who underwent magnetic resonance imaging between January 2016 and January 2017 before radical prostatectomy. A total of 226 magnetic resonance imaging radiomics features, including histogram and texture features in addition to lesion size and the PI-RADS™ (Prostate Imaging Reporting and Data System) score, were extracted from T2-weighted, apparent diffusion coefficient and diffusion kurtosis imaging maps. Radiomics features were correlated with the pathological Gleason score, 40 gene expression signatures, including Decipher, and 698 prostate cancer related gene expression levels. Cross-validated, lasso regularized, logistic regression machine learning models based on radiomics features were built and evaluated for the prediction of Gleason score 8 or greater and Decipher score 0.6 or greater. RESULTS: A total of 14 radiomics features significantly correlated with the Gleason score (highest correlation r = 0.39, p = 0.001). A total of 31 texture and histogram features significantly correlated with 19 gene signatures, particularly with the PORTOS (Post-Operative Radiation Therapy Outcomes Score) signature (strongest correlation r = -0.481, p = 0.002). A total of 40 diffusion-weighted imaging features correlated significantly with 132 gene expression levels. Machine learning prediction models showed fair performance to predict a Gleason score of 8 or greater (AUC 0.72) and excellent performance to predict a Decipher score of 0.6 or greater (AUC 0.84). CONCLUSIONS: Magnetic resonance imaging radiomics features are promising markers of prostate cancer aggressiveness on the histopathological and genomics levels.
Assuntos
Imageamento por Ressonância Magnética/métodos , Modelos Biológicos , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Adulto , Idoso , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Observacionais como Assunto , Valor Preditivo dos Testes , Próstata/diagnóstico por imagem , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estudos RetrospectivosRESUMO
Chronic inflammation resulting from infections, altered metabolism, inflammatory diseases or other environmental factors can be a major contributor to the development of several types of cancer. In fact around 20% of all cancers are linked to some form of inflammation. Evidence gathered from genetic, epidemiological and molecular pathological studies suggest that inflammation plays a crucial role at various stages of prostatic carcinogenesis and tumor progression. These include initiation, promotion, malignant conversion, invasion, and metastasis. Detailed basic and clinical research in these areas, focused towards understanding the etiology of prostatic inflammation, as well as the exact roles that various signaling pathways play in promoting tumor growth, is critical for understanding this complex process. The information gained would be useful in developing novel therapeutic strategies such as molecular targeting of inflammatory mediators and immunotherapy-based approaches.
Assuntos
Inflamação/fisiopatologia , Neoplasias da Próstata/fisiopatologia , Carcinogênese , Transformação Celular Neoplásica , Humanos , MasculinoRESUMO
Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
Assuntos
Síndrome de Noonan/genética , Proteína SOS1/genética , Animais , Células COS , Chlorocebus aethiops , Análise Mutacional de DNA/métodos , Testes Genéticos , Humanos , Modelos Moleculares , Mutação , Proteína SOS1/química , TransfecçãoRESUMO
Epigenetic regulation established during development to maintain patterns of transcriptional expression and silencing for metabolism and other fundamental cell processes can be reprogrammed in cancer, providing a molecular mechanism for persistent alterations in phenotype. Metabolic deregulation and reprogramming are thus an emerging hallmark of cancer with opportunities for molecular classification as a critical preliminary step for precision therapeutic intervention. Yet, acquisition of therapy resistance against most conventional treatment regimens coupled with tumor relapse, continue to pose unsolved problems for precision healthcare, as exemplified in breast cancer where existing data informs both cancer genotype and phenotype. Furthermore, epigenetic reprograming of the metabolic milieu of cancer cells is among the most crucial determinants of therapeutic resistance and cancer relapse. Importantly, subtype-specific epigenetic-metabolic interplay profoundly affects malignant transformation, resistance to chemotherapy, and response to targeted therapies. In this review, we therefore prismatically dissect interconnected epigenetic and metabolic regulatory pathways and then integrate them into an observable cancer metabolism-therapy-resistance axis that may inform clinical intervention. Optimally coupling genome-wide analysis with an understanding of metabolic elements, epigenetic reprogramming, and their integration by metabolic profiling may decode missing molecular mechanisms at the level of individual tumors. The proposed approach of linking metabolic biochemistry back to genotype, epigenetics, and phenotype for specific tumors and their microenvironment may thus enable successful mechanistic targeting of epigenetic modifiers and oncometabolites despite tumor metabolic heterogeneity.
Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes e Vias Metabólicas/genéticaRESUMO
The present study explores growth potential of two medicinal herbs, Withania somnifera (Ashwagandha or 'A') and Asparagus racemosus (Shatavari or 'S') after their dietary inclusion in fish, Channa punctatus (13.5 ± 2 g; 11.5 ± 1 cm). Three hundred well-acclimatized fish were distributed into 10 groups- C (Control), S1 (1% S), S2 (2% S), S3 (3% S), A1 (1% A), A2 (2% A), A3 (3% A), AS1 (1% A and S), AS2 (2% A and S), and AS3 (3% A and S), each having 10 specimens. Fish were fed with these diets for 60 days. The study was performed in triplicate. Growth indices- weight gain (WG), specific growth rate percentage (SGR%), feed intake (FI), and condition factor (CF), after 30 and 60 days, were found significantly (p < 0.05) up-regulated in all the groups, except S1, when compared to the C. A significant (p < 0.05) increase in final body weight (FBW) was noticed in all the groups, except S1, after 60 days. Relative to the control group, activities of lipase and amylase in the gut tissue were elevated in all groups, at both sampling times, with the exception of lipase in S1 at 60 days, and amylase in S1 at day 30 and day 60 and S2 at day 60. The mRNA expression of myogenic regulatory factors (MRFs) was also found to be significantly (p < 0.05) up-regulated with the highest fold changes recorded in AS3 for myoD (3.93 ± 0.91); myoG (6.71 ± 0.30); myf5 (4.40 ± 0.33); MRF4 (4.94 ± 0.21) in comparison to the C.
Assuntos
Channa punctatus , Fatores de Regulação Miogênica , Withania , Animais , Withania/genética , Dieta/veterinária , Peixes , Amilases , Lipase , Ração Animal/análiseRESUMO
Mimics of α-helices on protein surfaces have emerged as powerful reagents for antagonizing protein-protein interactions, which are difficult to target with small molecules. Here we describe the design of a cell-permeable synthetic α-helix, based on the guanine nucleotide exchange factor Sos, that interferes with Ras-Sos interaction and downregulates Ras signaling in response to receptor tyrosine kinase activation.
Assuntos
Materiais Biomiméticos/química , Desenho de Fármacos , Oligopeptídeos/química , Proteína Son Of Sevenless de Drosófila/antagonistas & inibidores , Fatores ras de Troca de Nucleotídeo Guanina/antagonistas & inibidores , Sequência de Aminoácidos , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/farmacologia , Biomimética , Linhagem Celular , Regulação para Baixo , Humanos , Dados de Sequência Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Transdução de Sinais/efeitos dos fármacos , Proteína Son Of Sevenless de Drosófila/química , Fatores ras de Troca de Nucleotídeo Guanina/químicaRESUMO
Regulated activation of Ras by receptor tyrosine kinases (RTK) constitutes a key transduction step in signaling processes that control an array of fundamental cellular functions including proliferation, differentiation, and survival. The principle mechanism by which Ras is activated down stream of RTKs involves the stimulation of guanine nucleotide exchange by the ubiquitous guanine nucleotide exchange factor Son of sevenless (Sos). In resting conditions, Sos activity is constrained by intramolecular interactions that maintain the protein in an autoinhibited conformation. Structural, biochemical, and genetic studies have implicated the histone domain (Sos-H), which comprises the most N-terminal region of Sos, in the regulation of Sos autoinhibition. However, the molecular underpinnings of this regulatory function are not well understood. In the present study we demonstrate that Sos-H possesses in vitro and in vivo membrane binding activity that is mediated, in part, by the interactions between a cluster of basic residues and phosphatidic acid. This interaction is required for Sos-dependent activation of Ras following EGF stimulation. The inducible association of Sos-H with membranes contributes to the catalytic activity of Sos by forcing the domain to adopt a conformation that destabilizes the autoinhibitory state. Thus, Sos-H plays a critical role in governing the catalytic output of Sos through the coupling of membrane recruitment to the release of autoinhibition.
Assuntos
Histonas/metabolismo , Proteína SOS1/metabolismo , Regulação Alostérica , Sequência de Aminoácidos , Catálise , Cristalografia por Raios X , Humanos , Estrutura Terciária de Proteína , Proteína SOS1/antagonistas & inibidores , Proteína SOS1/químicaRESUMO
The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation pathway essential for maintaining cellular homeostasis. This system plays a critical role in several cellular processes, which include DNA damage repair, cell cycle checkpoint control, and immune response regulation. Recently, the UPS has emerged as a promising target for cancer therapeutics due to its involvement in oncogenesis and tumor progression. Here we aim to summarize the key aspects of the UPS and its significance in cancer therapeutics. We begin by elucidating the fundamental components of the UPS, highlighting the role of ubiquitin, E1-E3 ligases, and the proteasome in protein degradation. Furthermore, we discuss the intricate process of ubiquitination and proteasomal degradation, emphasizing the specificity and selectivity achieved through various signaling pathways. The dysregulation of the UPS has been implicated in cancer development and progression. Aberrant ubiquitin-mediated degradation of key regulatory proteins, such as tumor suppressors and oncoproteins, can lead to uncontrolled cell proliferation, evasion of apoptosis, and metastasis. We outline the pivotal role of the UPS in modulating crucial oncogenic pathways, including the regulation of cyclins, transcription factors, Replication stress components and DNA damage response. The increasing recognition of the UPS as a target for cancer therapeutics has spurred the development of small molecules, peptides, and proteasome inhibitors with the potential to restore cellular balance and disrupt tumor growth. We provide an overview of current therapeutic strategies aimed at exploiting the UPS, including the use of proteasome inhibitors, deubiquitinating enzyme inhibitors, and novel E3 ligase modulators. We further discuss novel emerging strategies for the development of next-generation drugs that target proteasome inhibitors. Exploiting the UPS for cancer therapeutics offers promising avenues for developing innovative and effective treatment strategies, providing hope for improved patient outcomes in the fight against cancer.
Assuntos
Neoplasias , Inibidores de Proteassoma , Humanos , Inibidores de Proteassoma/uso terapêutico , Ubiquitinação , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
With the progression of aquaculture industry, there has been a spurt in dietary supplementation with economically viable medicinal herbs having enough immunostimulatory potential. This also aids in avoidance of environmentally undesirable therapeutics that are almost inevitable to safeguard fish against an array of diseases in aquaculture practices. The study aims to determine the optimal dose of herbs that can stimulate substantial immune response in fish for reclamation of aquaculture. Immunostimulatory potential of the two medicinal herbs- Asparagus racemosus (Shatavari), Withania somnifera (Ashwagandha), individually, and in combination, with a basal diet was screened up to 60 days in Channa punctatus. 300 laboratory acclimatized healthy fish (14 ± 1 g; 11 ± 1 cm) were divided into ten groups- C, S1, S2, S3, A1, A2, A3, AS1, AS2, and AS3, based on the composition of dietary supplementation, in triplicates, with 10 specimens per group. The hematological index, total protein and lysozyme enzyme activity were performed after 30 and 60 days, while qRT-PCR analysis of lysozyme expression was done after 60 days of the feeding trial. The significant (P < 0.05) increments in hematological indices- (TEC, TLC, DLC, Hb, Hct, MCV, MCH and MCHC), total protein content and serum lysozyme activity, after 30 and 60 days; whereas upregulation of lysozyme transcript levels, both in liver and muscle tissues after 60 days of the feeding trial were recorded in groups- AS1, AS2, and AS3. The maximal increment in lysozyme expression was recorded in AS3, both in liver and muscle tissues, with 3.75 ± 0.13 and 3.21 ± 0.18-folds, respectively. However, increments were non-significant (P > 0.05) for MCV in AS2 and AS3 after 30 days; and for MCHC in AS1 for both the durations; whereas in AS2 and AS3, after 60 days of the feeding trial. A positive correlation (P < 0.05) among lysozyme expression, MCH, lymphocytes, neutrophils, total protein content, and serum lysozyme activity in AS3, after 60 days, conclusively, evinces that a 3% dietary supplementation with both A. racemosus and W. somnifera enhances immunity and health profile of the fish, C. punctatus. The study, thus finds ample scope in augmentation of aquaculture production and also paves the way for more researches for biological screenings of potential immunostimulatory medicinal herbs that can be appropriately incorporated in the fish diet.
Assuntos
Doenças dos Peixes , Withania , Animais , Ração Animal/análise , Dieta/veterinária , Suplementos Nutricionais/análise , Peixes , MuramidaseRESUMO
Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic-metabolic interplay profoundly affects genomic stability of the cancer cells as well as their resistance to genotoxic therapies. These observations identify defining mechanisms of cancer epigenetics-metabolism-DNA repair axis that can be critical for devising novel, targeted therapeutic approaches that could sensitize cancer cells to conventional treatment strategies.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Reparo do DNA , Dano ao DNA , Epigênese GenéticaRESUMO
The drug-food interaction brings forth changes in the clinical effects of drugs. While favourable interactions bring positive clinical outcomes, unfavourable interactions may lead to toxicity. This article reviews the impact of food intake on drug-food interactions, the clinical effects of drugs, and the effect of drug-food in correlation with diet and precision medicine. Emerging areas in drug-food interactions are the food-genome interface (nutrigenomics) and nutrigenetics. Understanding the molecular basis of food ingredients, including genomic sequencing and pharmacological implications of food molecules, helps to reduce the impact of drug-food interactions. Various strategies are being leveraged to alleviate drug-food interactions; measures including patient engagement, digital health, approaches involving machine intelligence, and big data are a few of them. Furthermore, delineating the molecular communications across dietmicrobiome- drug-food-drug interactions in a pharmacomicrobiome framework may also play a vital role in personalized nutrition. Determining nutrient-gene interactions aids in making nutrition deeply personalized and helps mitigate unwanted drug-food interactions, chronic diseases, and adverse events from their onset. Translational bioinformatics approaches could play an essential role in the next generation of drug-food interaction research. In this landscape review, we discuss important tools, databases, and approaches along with key challenges and opportunities in drug-food interaction and its immediate impact on precision medicine.
Assuntos
Big Data , Interações Alimento-Droga , Humanos , Nutrigenômica , Dieta , Inteligência ArtificialRESUMO
Organ-on-a-chip (OOAC) is an emerging technology based on microfluid platforms and in vitro cell culture that has a promising future in the healthcare industry. The numerous advantages of OOAC over conventional systems make it highly popular. The chip is an innovative combination of novel technologies, including lab-on-a-chip, microfluidics, biomaterials, and tissue engineering. This paper begins by analyzing the need for the development of OOAC followed by a brief introduction to the technology. Later sections discuss and review the various types of OOACs and the fabrication materials used. The implementation of artificial intelligence in the system makes it more advanced, thereby helping to provide a more accurate diagnosis as well as convenient data management. We introduce selected OOAC projects, including applications to organ/disease modelling, pharmacology, personalized medicine, and dentistry. Finally, we point out certain challenges that need to be surmounted in order to further develop and upgrade the current systems.
Assuntos
Inteligência Artificial , Dispositivos Lab-On-A-Chip , Materiais Biocompatíveis , Microfluídica , Engenharia TecidualRESUMO
The impact of pelvic inflammation on prostate cancer (PCa) biology and aggressive phenotype has never been studied. Our study objective was to evaluate the role of pelvic inflammation on PCa aggressiveness and its association with clinical outcomes in patients following radical prostatectomy (RP). This study has been conducted on a retrospective single-institutional consecutive cohort of 2278 patients who underwent robot-assisted laparoscopic prostatectomy (RALP) between 01/2013 and 10/2019. Data from 2085 patients were analyzed to study the association between pelvic inflammation and adverse pathology (AP), defined as Gleason Grade Group (GGG) > 2 and ≥ pT3 stage, at resection. In a subset of 1997 patients, the association between pelvic inflammation and biochemical recurrence (BCR) was studied. Alteration in tumor transcriptome and inflammatory markers in patients with and without pelvic inflammation were studied using microarray analysis, immunohistochemistry, and culture supernatants derived from inflamed sites used in functional assays. Changes in blood inflammatory markers in the study cohort were analyzed by O-link. In univariate analyses, pelvic inflammation emerged as a significant predictor of AP. Multivariate cox proportional-hazards regression analyses showed that high pelvic inflammation with pT3 stage and positive surgical margins significantly affected the time to BCR (p ≤ 0.05). PCa patients with high inflammation had elevated levels of pro-inflammatory cytokines in their tissues and in blood. Genes involved in epithelial-to-mesenchymal transition (EMT) and DNA damage response were upregulated in patients with pelvic inflammation. Attenuation of STAT and IL-6 signaling decreased tumor driving properties of conditioned medium from inflamed sites. Pelvic inflammation exacerbates the progression of prostate cancer and drives an aggressive phenotype.
RESUMO
Epitranscriptomic analysis has recently led to the profiling of modified nucleosides in cancer cell biological matrices, helping to elucidate their functional roles in cancer and reigniting interest in exploring their use as potential markers of cancer development and progression. Pseudouridine, one of the most well-known and the most abundant of the RNA nucleotide modifications, is the C5-glycoside isomer of uridine and its distinctive physiochemical properties allows it to perform many essential functions. Pseudouridine functionally (a) confers rigidity to local RNA structure by enhancing RNA stacking, engaging in a cooperative effect on neighboring nucleosides that overall contributes to RNA stabilization (b) refines the structure of tRNAs, which influences their decoding activity (c) facilitates the accuracy of decoding and proofreading during translation and efficiency of peptide bond formation, thus collectively improving the fidelity of protein biosynthesis and (e) dynamically regulates mRNA coding and translation. Biochemical synthesis of pseudouridine is carried out by pseudouridine synthases. In this review we discuss the evidence supporting an association between elevated pseudouridine levels with the incidence and progression of human prostate cancer and the translational significance of the value of this modified nucleotide as a novel biomarker in prostate cancer progression to advanced disease.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Próstata/química , Neoplasias da Próstata/metabolismo , Pseudouridina/análise , Previsões , Humanos , Masculino , Pseudouridina/biossíntese , Pseudouridina/química , Pseudouridina/fisiologiaRESUMO
Lipid droplets store neutral lipids, primarily triacylglycerol and steryl esters. Seipin plays a role in lipid droplet biogenesis and is thought to determine the site of lipid droplet biogenesis and the size of newly formed lipid droplets. Here we show a seipin-independent pathway of lipid droplet biogenesis. In silico and in vitro experiments reveal that retinyl esters have the intrinsic propensity to sequester and nucleate in lipid bilayers. Production of retinyl esters in mammalian and yeast cells that do not normally produce retinyl esters causes the formation of lipid droplets, even in a yeast strain that produces only retinyl esters and no other neutral lipids. Seipin does not determine the size or biogenesis site of lipid droplets composed of only retinyl esters or steryl esters. These findings indicate that the role of seipin in lipid droplet biogenesis depends on the type of neutral lipid stored in forming droplets.
Assuntos
Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Gotículas Lipídicas/metabolismo , Ésteres de Retinil/metabolismo , Triglicerídeos/metabolismo , Animais , Células Cultivadas , Cricetulus , Subunidades gama da Proteína de Ligação ao GTP/deficiência , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.
Assuntos
Negro ou Afro-Americano/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Neoplasias da Próstata/genética , População Branca/genética , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Disparidades nos Níveis de Saúde , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/imunologia , Estudos Retrospectivos , Estados Unidos , População Branca/estatística & dados numéricosRESUMO
The studies were designed to assess the extent of chromosomal aberrations (CA) under the exposure of three common heavy metalic compounds, viz. mercuric chloride, arsenic trioxide and copper sulphate pentahydrate, in vivo using fish, Channa punctata (2n=32), as a test model. Prior acclimatized fishes were divided into five groups. Group I and II served as negative and positive control, respectively. An intramuscular injection of Mitomycin-C (@ 1mg/kg body wt.) was administered to group II only. Fishes of groups III, IV and V were subjected to sublethal concentrations (10% of 96h LC(50)), of HgCl(2) (0.081mg/L), As(2)O(3) (6.936mg/L) and CuSO(4)x5H(2)O (0.407mg/L). Fishes of all the groups were exposed uninterrupted for 24, 48, 72, 96 and 168h. Observations of kidney cells of exposed fishes revealed chromatid and chromosome breaks, chromatid and chromosome gaps along with ring and di-centric chromosomes. A significant increase over negative control in the frequency of chromosomal aberrations (CA) was observed in fish exposed to Mitomycin-C, Hg(II), As(III) and Cu(II). As the average + or - SE total number of CA, average number of CA per metaphase and %incidence of aberrant cells in Hg(II) was 104.40 + or - 8.189, 0.347 + or - 0.027 and 10.220 + or - 0.842, respectively; in As(III) 109.20 + or - 8.309, 0.363 + or - 0.027 and 10.820 + or - 2.347, respectively and in Cu(II) 89.00 + or - 19.066, 0.297 + or - 0.028 and 8.900 + or - 0.853, respectively. Hence, it reveals that the order of induction of frequency of CA was CuAssuntos
Aberrações Cromossômicas
, Peixes/genética
, Metais Pesados/toxicidade
, Poluentes Químicos da Água/toxicidade
, Animais
, Trióxido de Arsênio
, Arsenicais
, Carcinógenos/toxicidade
, Sulfato de Cobre/toxicidade
, Cloreto de Mercúrio/toxicidade
, Testes de Mutagenicidade/métodos
, Óxidos/toxicidade