RESUMO
Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFß) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFß induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFß to activate fibrotic pathways, and FOXS1 mRNA was significantly increased. To study TGFß-FOXS1 signaling, we developed human LX2 FOXS1 CRISPR KO and scrambled control HSCs. To determine differentially expressed gene transcripts controlled by TGFß-FOXS1, we performed RNA-seq in the FOXS1 KO and control cells and over 400 gene responses were attenuated in the FOXS1 KO HSCs with TGFß-activation. To validate the RNA-seq findings, we used our state-of-the-art PamGene PamStation kinase activity technology that measures hundreds of signaling pathways nonselectively in real time. Using our RNA-seq data, kinase activity data, and descriptive measurements, we found that FOXS1 controls pathways mediating TGFß responsiveness, protein translation, and proliferation. Our study is the first to identify that FOXS1 may serve as a biomarker for liver fibrosis and HSC activation, which may help with early detection of hepatic fibrosis or treatment options for end-stage liver disease.
Assuntos
Fatores de Transcrição Forkhead , Expressão Gênica , Células Estreladas do Fígado , Cirrose Hepática , Fator de Crescimento Transformador beta , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Biomarcadores/metabolismo , Técnicas de Inativação de Genes , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais/genéticaRESUMO
The leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular disease (CVD). However, the mechanisms are unknown. Mice deficient in hepatocyte proliferator-activated receptor-α (PPARα) (PparaHepKO) exhibit hepatic steatosis on a regular chow diet, making them prone to manifesting NAFLD. We hypothesized that the PparaHepKO mice might be predisposed to poorer cardiovascular phenotypes due to increased liver fat content. Therefore, we used PparaHepKO and littermate control mice fed a regular chow diet to avoid complications with a high-fat diet, such as insulin resistance and increased adiposity. After 30 wk on a standard diet, male PparaHepKO mice exhibited elevated hepatic fat content compared with littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, P < 0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01 mM, P < 0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The PparaHepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, P < 0.05), impaired diastolic function, cardiac remodeling, and enhanced vascular stiffness. To determine mechanisms controlling the increase in stiffness in the aorta, we used state-of-the-art PamGene technology to measure kinase activity in this tissue. Our data suggest that the loss of hepatic PPARα induces alterations in the aortas that reduce the kinase activity of tropomyosin receptor kinases and p70S6K kinase, which might contribute to the pathogenesis of NAFLD-induced CVD. These data indicate that hepatic PPARα protects the cardiovascular system through some as-of-yet undefined mechanism.
Assuntos
Doenças Cardiovasculares , Hipertensão , Hepatopatia Gordurosa não Alcoólica , Animais , Masculino , Camundongos , Doenças Cardiovasculares/genética , Dieta Hiperlipídica , Hipertensão/patologia , Fígado/patologia , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genéticaRESUMO
BACKGROUND AND AIMS: Resolution of pathways that converge to induce deleterious effects in hepatic diseases, such as in the later stages, have potential antifibrotic effects that may improve outcomes. We aimed to explore whether humans and rodents display similar fibrotic signaling networks. APPROACH AND RESULTS: We assiduously mapped kinase pathways using 340 substrate targets, upstream bioinformatic analysis of kinase pathways, and over 2000 random sampling iterations using the PamGene PamStation kinome microarray chip technology. Using this technology, we characterized a large number of kinases with altered activity in liver fibrosis of both species. Gene expression and immunostaining analyses validated many of these kinases as bona fide signaling events. Surprisingly, the insulin receptor emerged as a considerable protein tyrosine kinase that is hyperactive in fibrotic liver disease in humans and rodents. Discoidin domain receptor tyrosine kinase, activated by collagen that increases during fibrosis, was another hyperactive protein tyrosine kinase in humans and rodents with fibrosis. The serine/threonine kinases found to be the most active in fibrosis were dystrophy type 1 protein kinase and members of the protein kinase family of kinases. We compared the fibrotic events over four models: humans with cirrhosis and three murine models with differing levels of fibrosis, including two models of fatty liver disease with emerging fibrosis. The data demonstrate a high concordance between human and rodent hepatic kinome signaling that focalizes, as shown by our network analysis of detrimental pathways. CONCLUSIONS: Our findings establish a comprehensive kinase atlas for liver fibrosis, which identifies analogous signaling events conserved among humans and rodents.
Assuntos
Hepatopatias , Receptor de Insulina , Humanos , Camundongos , Animais , Receptor de Insulina/metabolismo , Roedores , Cirrose Hepática/patologia , Fígado/patologia , Hepatopatias/patologia , Fibrose , Proteínas Quinases/metabolismo , Colágeno/metabolismo , Serina/metabolismo , Receptores com Domínio Discoidina/metabolismo , Treonina/metabolismoRESUMO
BACKGROUND: This study examines trends in racial and gender diversity of trainees within Complex General Surgical Oncology Fellowships, and compares the racial and gender proportions of trainees across different fields to assess potential barriers to increasing diversity within surgical oncology training programs. METHODS: Accredited Council for Graduate Medical Education (ACGME) data were queried to identify surgical trainees between 2013 and 2021. Trainees were identified based on self-reported race and gender and were stratified based on residency type and fellowship program type if applicable. Chi-square tests were used to assess differences between groups and trends. RESULTS: A significantly lower proportion of individuals who are underrepresented in medicine (URMs) trained in surgical oncology fellowships (8.9%) compared with both the overall trainee pool (12.8%) and general surgery residency programs (13.1%) [p < 0.05]. There was no significant increase in URM representation in surgical oncology fellowships across the study period. Furthermore, there was a significantly lower proportion of females training in surgical oncology fellowships (38.6%) compared with the overall trainee pool (45.6%) [p < 0.05]. Despite a significant increase in female representation in general surgery residency and other surgical fellowships, there was no significant increase in female representation in surgical oncology fellowships across the study period. CONCLUSIONS: This study identifies disparities in gender and racial minority representation within ACGME-accredited Complex General Surgical Oncology Fellowship training programs. While steps have been taken to expand diversity, more needs to be done to combat the systemic barriers that both racial minorities and women face during their training.
Assuntos
Internato e Residência , Oncologia Cirúrgica , Humanos , Feminino , Estados Unidos , Bolsas de Estudo , Educação de Pós-Graduação em MedicinaRESUMO
Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have been investigated as potentially viable therapeutic and diagnostic modalities in the management of carcinoid tumors. Classic treatment options for carcinoid tumors rely upon surgical resection or non-immune pharmacology. Though surgical intervention can be curative, tumor characteristics, such as size, location, and spread, heavily limit success. Non-immune pharmacologic treatments can be similarly limited, and many demonstrate problematic side effects. Immunotherapy may be able to overcome these limitations and further improve clinical outcomes. Similarly, emerging immunologic carcinoid biomarkers may improve diagnostic capabilities. Recent developments in immunotherapeutic and diagnostic modalities of carcinoid management are summarized here.
Assuntos
Tumor Carcinoide , Humanos , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/patologia , Tumor Carcinoide/terapia , Biomarcadores , Fatores ImunológicosRESUMO
Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as "hypobilirubinemia," are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly seen in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for patients with hypobilirubinemia, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.
Assuntos
Bilirrubina/sangue , Bilirrubina/fisiologia , Metabolismo Energético , Hormônios/fisiologia , Animais , Bilirrubina/deficiência , Metabolismo Energético/genética , Regulação da Expressão Gênica , Doença de Gilbert/sangue , Doença de Gilbert/genética , Doença de Gilbert/metabolismo , Heme/metabolismo , Humanos , Hiperbilirrubinemia/complicações , Hiperbilirrubinemia/genética , Hiperbilirrubinemia/metabolismo , Redes e Vias Metabólicas/genética , PPAR alfa/metabolismo , PPAR alfa/fisiologiaRESUMO
Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing. This manuscript will review BRCA1/2 function and homologous recombination proficiency in respect to breast and ovarian cancer. The current standard testing methods for HRD will be discussed as well as trials leading to approval of PARPi's. Finally, standard of care treatment and synthetic lethality will be reviewed.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Recombinação Homóloga/fisiologia , Neoplasias Ovarianas/genética , Reparo de DNA por Recombinação/fisiologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Variação Genética , Humanos , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/fisiologiaRESUMO
Patients who have mutations of the genes BRCA1 or BRCA2 are at an increased risk for developing breast and ovarian cancer. BRCA1/2 function as tumor suppressor genes, responsible for regulating DNA repair, and play an essential role in homologous recombination. Mutation of BRCA1/2 results in homologous recombination deficiency and genomic instability which drives oncogenesis and cancer proliferation. Recently, BRCA1/2 gene expression has been implicated in regulating immune response. Here we discuss the signaling pathway of BRCA1/2 in relation to breast and ovarian cancer, with emphasis on how dysregulation facilitates the path to malignancy and current treatment options.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinogênese/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Instabilidade Genômica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Reparo de DNA por Recombinação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1ß and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin's transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.
Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Perfilação da Expressão Gênica , Ocitocina/análogos & derivados , Pneumonia Viral/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Imunidade Adaptativa/genética , Betacoronavirus/imunologia , COVID-19 , Linhagem Celular , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Bases de Dados Genéticas , Interações Hospedeiro-Patógeno , Humanos , Ocitocina/farmacologia , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Linfócitos T/imunologia , Linfócitos T/virologia , Transcriptoma , Tratamento Farmacológico da COVID-19RESUMO
Given recent advances in cancer immune therapy, specifically use of checkpoint inhibitors, understanding the link between autoimmunity and cancer is essential. Rheumatoid arthritis (RA) affects about 1% of the population, and early diagnosis is key to prevent joint damage. Management consists of disease-modifying antirheumatic drugs that alter normal immunologic pathways, which could affect malignancy growth and survival. Prolonged immune dysregulation and the resulting inflammatory response associated with development of RA may also lead to increased cancer development risk. RA has long been associated with increased risk of non-Hodgkin's lymphoma [1] and further evidence supports relationship to lung cancer [2]. This review will address the mechanisms behind cancer development and progression in RA patients, biomarkers and assess cancer risk and early detection.
Assuntos
Artrite Reumatoide/etiologia , Neoplasias/patologia , Neoplasias/terapia , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Humanos , Imunoterapia/efeitos adversos , Inflamação , Neoplasias/imunologia , RiscoRESUMO
Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.
Assuntos
Adenocarcinoma/genética , Tumor Desmoplásico de Pequenas Células Redondas/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Receptor com Domínio Discoidina 1/genética , Progressão da Doença , Humanos , Neoplasias Pancreáticas/patologia , Proteínas Tirosina Quinases/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-hck/genética , Transdução de Sinais , Quinases da Família src/genéticaRESUMO
Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.
Assuntos
Carcinoma Ductal Pancreático/enzimologia , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Neoplasias Pancreáticas/enzimologia , Proteínas Tirosina Quinases/biossíntese , Carcinoma Ductal Pancreático/genética , Humanos , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Proteínas Tirosina Quinases/genética , Proto-Oncogene MasRESUMO
The attribution of incentive-motivational value to drug-related cues underlies relapse and craving in drug addiction. One method of addiction treatment, cue-exposure therapy, utilizes repeated presentations of drug-related cues in the absence of drug (i.e., extinction learning); however, its efficacy has been limited due to an incomplete understanding of extinction and relapse processes after cues have been imbued with incentive-motivational value. To investigate this, we used a Pavlovian conditioned approach procedure to screen for rats that attribute incentive-motivational value to reward-related cues (sign-trackers; STs) or those that do not (goal-trackers; GTs). In Experiment 1, rats underwent Pavlovian extinction followed by reinstatement and spontaneous recovery tests. For comparison, a separate group of rats underwent PCA training followed by operant conditioning, extinction, and tests of reinstatement and spontaneous recovery. In Experiment 2, three cognitive enhancers (sodium butyrate, D-cycloserine, and fibroblast growth factor 2) were administered following extinction training to facilitate extinction learning. STs but not GTs displayed enduring resistance to Pavlovian, but not operant, extinction and were more susceptible to spontaneous recovery. In addition, none of the cognitive enhancers tested affected extinction learning. These results expand our understanding of extinction learning by demonstrating that there is individual variation in extinction and relapse processes and highlight potential difficulties in applying extinction-based therapies to drug addiction treatment in the clinic.
Assuntos
Ácido Butírico/farmacologia , Condicionamento Clássico , Sinais (Psicologia) , Ciclosserina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Nootrópicos/farmacologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Masculino , Motivação , Ratos , Ratos Sprague-DawleyRESUMO
Selective delivery of therapeutic agents into solid tumors has been a major challenge impeding the achievement of long-term disease remission and cure. The need to develop alternative drug delivery routes to achieve higher drug concentration in tumor tissue, reduce unwanted off-target side effects and thus achieve greater therapeutic efficacy, has resulted in an explosive body of research. Bifidobacterium spp. are anaerobic, nonpathogenic, Gram-positive bacteria, commensal to the human gut that are a possible anticancer drug-delivery vehicle. In this review, we describe Bifidobacterium's microbiology, current clinical applications, overview of the preclinical work investigating Bifidobacterium's potential to deliver anticancer therapy, and review the different strategies used up to date. Finally, we discuss both current challenges and future prospects.
Assuntos
Bifidobacterium/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Imunoterapia/métodos , Oncologia/métodos , Neoplasias/terapia , Medicina de Precisão/métodos , Animais , Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Genes Reporter/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Oncologia/tendências , Neoplasias/genética , Neoplasias/imunologia , Plasmídeos/genética , Medicina de Precisão/tendências , Probióticos/administração & dosagem , Resultado do TratamentoRESUMO
Individual variation in the attribution of motivational salience to reward-related cues is believed to underlie addiction vulnerability. Pavlovian conditioned approach measures individual variation in motivational salience by identifying rats that are attracted to and motivated by reward cues (sign-trackers) or motivationally fixed on the reward itself (goal-trackers). Previously, it has been demonstrated that sign-trackers are more vulnerable to addiction-like behavior. Moreover, sign-trackers release more dopamine in the nucleus accumbens than goal-trackers in response to reward-related cues, and sign- but not goal-tracking behavior is dopamine-dependent. In the present study, we investigated whether the ventral hippocampus, a potent driver of dopaminergic activity in the nucleus accumbens, modulates the acquisition and expression of Pavlovian conditioned approach behavior. In Experiment 1, lesions of the ventral, but not dorsal or total hippocampus, decreased sign-tracking behavior. In Experiment 2, lesions of the ventral hippocampus did not affect the expression of sign- or goal-tracking behaviors nor conditioned reinforcement. In addition, temporary inactivation of the ventral subiculum, the main output pathway of the ventral hippocampus, did not affect the expression of sign- or goal-tracking behaviors. High-pressure liquid chromatography of nucleus accumbens tissue punches revealed that ventral hippocampal lesions decreased levels of homovanillic acid and the homovanillic acid/dopamine ratio (a marker of dopamine release and metabolism) in only sign-trackers, and decreased accumbal norepinephrine levels in both sign- and goal-trackers. These results suggest that the ventral hippocampus is important for the acquisition but not expression of sign-tracking behavior, possibly as a result of altered dopamine and norepinephrine in the nucleus accumbens. © 2016 Wiley Periodicals, Inc.
Assuntos
Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Condicionamento Clássico/fisiologia , Hipocampo/lesões , Motivação/fisiologia , Detecção de Sinal Psicológico/fisiologia , Animais , Cromatografia Líquida de Alta Pressão , Sinais (Psicologia) , Dopamina/metabolismo , Agonistas de Aminoácidos Excitatórios/toxicidade , Masculino , N-Metilaspartato/toxicidade , Núcleo Accumbens/fisiologia , Probabilidade , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Reforço PsicológicoRESUMO
Adverse childhood experiences (ACEs) are an established independent risk factor for chronic disease including obesity and hypertension; however, only women exposed to multiple ACEs show a positive relationship with BMI. Our lab has reported that maternal separation and early weaning (MSEW), a mouse model of early life stress, induces sex-specific mechanisms underlying greater blood pressure response to a chronic high fat diet (HF). Specifically, female MSEW mice fed a HF display exacerbated perigonadal white adipose tissue (pgWAT) expansion and a metabolic syndrome-like phenotype compared to control counterparts, whereas hypertension is caused by sympathoactivation in male MSEW mice. Thus, this study aimed to determine whether there is a sex-specific serine/threonine kinase (STKA) activity in pgWAT adipose tissue associated with early life stress. Frozen pgWAT was collected from MSEW and control, male and female mice fed a HF to assess STKA activity using the Pamstation12 instrument. Overall, MSEW induces significant reduction of 7 phosphokinases (|Z| >=1.5) in females (QIK, MLK, PKCH, MST, STE7, PEK, FRAY) and 5 in males (AKT, SGK, P38, MARK, CDK), while 15 were downregulated in both sexes (DMPK, PKA, PKG, RSK, PLK, DYRK, NMO, CAMK1, JNK, PAKA, RAD53, ERK, PAKB, PKD, PIM, AMPK). This data provides new insights into the sex-specific dysregulation of the molecular network controlling cellular phosphorylation signals in visceral adipose tissue and identifies possible target phosphokinases implicated in adipocyte hypertrophy as a result of exposure to early life stress. Identifying functional metabolic signatures is critical to elucidate the underlying molecular mechanisms behind the sex-specific obesity risk associated with early life stress.
RESUMO
Exosomes continue to attract interest as a promising nanocarrier drug delivery technology. They are naturally derived nanoscale extracellular vesicles with innate properties well suited to shuttle proteins, lipids, and nucleic acids between cells. Nonetheless, their clinical utility is currently limited by several major challenges, such as their inability to target tumor cells and a high proportion of clearance by the mononuclear phagocyte system (MPS) of the liver and spleen. To overcome these limitations, we developed "Smart Exosomes" that co-display RGD and CD47p110-130 through CD9 engineering (ExoSmart). The resultant ExoSmart demonstrates enhanced binding capacity to αvß3 on pancreatic ductal adenocarcinoma (PDAC) cells, resulting in amplified cellular uptake in in vitro and in vivo models and increased chemotherapeutic efficacies. Simultaneously, ExoSmart significantly reduced liver and spleen clearance of exosomes by inhibiting macrophage phagocytosis via CD47p110-130 interaction with signal regulatory proteins (SIRPα) on macrophages. These studies demonstrate that an engineered exosome drug delivery system increases PDAC therapeutic efficacy by enhancing active PDAC targeting and prolonging circulation times, and their findings hold tremendous translational potential for cancer therapy while providing a concrete foundation for future work utilizing novel peptide-engineered exosome strategies.
Assuntos
Carcinoma Ductal Pancreático , Exossomos , Neoplasias Pancreáticas , Humanos , Exossomos/metabolismo , Antígeno CD47 , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologiaRESUMO
Folate is a B vitamin necessary for basic biological functions, including rapid cell turnover occurring in cancer cell proliferation. Though the role of folate as a causative versus protective agent in carcinogenesis is debated, several studies have indicated that the folate receptor (FR), notably subtype folate receptor alpha (FRα), could be a viable biomarker for diagnosis, progression, and prognosis. Several cancers, including gastrointestinal, gynecological, breast, lung, and squamous cell head and neck cancers overexpress FR and are currently under investigation to correlate receptor status to disease state. Traditional chemotherapies have included antifolate medications, such as methotrexate and pemetrexed, which generate anticancer activity during the synthesis phase of the cell cycle. Increasingly, the repertoire of pharmacotherapies is expanding to include FR as a target, with a heterogenous pool of directed therapies. Here we discuss the FR, expression and effect in cancer biology, and relevant pharmacologic inhibitors.
Assuntos
Carcinoma de Células Escamosas , Antagonistas do Ácido Fólico , Humanos , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Prognóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Ácido Fólico/uso terapêutico , Ácido Fólico/metabolismo , BiomarcadoresRESUMO
Introduction: Immunotherapy has revolutionized how cancer is treated. Many of these immunotherapies rely on ex vivo expansion of immune cells, classically T cells. Still, several immunological obstacles remain, including tumor impermeability by immune cells and the immunosuppressive nature of the tumor microenvironment (TME). Logistically, high costs of treatment and variable clinical responses have also plagued traditional T cell-based immunotherapies. Methods: To review the existing literature on cellular immunotherapy, the PubMed database was searched for publications using variations of the phrases "cancer immunotherapy", "ex vivo expansion", and "adoptive cell therapy". The Clinicaltrials.gov database was searched for clinical trials related to ex vivo cellular therapies using the same phrases. The National Comprehensive Cancer Network guidelines for cancer treatment were also referenced. Results: To circumvent the challenges of traditional T cell-based immunotherapies, researchers have developed newer therapies including tumor infiltrating lymphocyte (TIL), chimeric antigen receptor (CAR), T cell receptor (TCR) modified T cell, and antibody-armed T cell therapies. Additionally, newer immunotherapeutic strategies have used other immune cells, including natural killer (NK) and dendritic cells (DC), to modulate the T cell immune response to cancers. From a prognostic perspective, circulating tumor cells (CTC) have been used to predict cancer morbidity and mortality. Conclusion: This review highlights the mechanism and clinical utility of various types of ex vivo cellular therapies in the treatment of cancer. Comparing these therapies or using them in combination may lead to more individualized and less toxic chemotherapeutics.
RESUMO
Oxidative stress, a condition characterized by an imbalance between pro-oxidant molecules and antioxidant defense systems, is increasingly recognized as a key contributor to cancer development. This is because the reactive oxygen species (ROS) generated during oxidative stress can damage DNA, proteins, and lipids to facilitate mutations and other cellular changes that promote cancer growth. Antioxidant supplementation is a potential strategy for decreasing cancer incidence; by reducing oxidative stress, DNA damage and other deleterious cellular changes may be attenuated. Several clinical trials have been conducted to investigate the role of antioxidant supplements in cancer prevention. Some studies have found that antioxidant supplements, such as vitamin A, vitamin C, and vitamin E, can reduce the risk of certain types of cancer. On the other hand, some studies posit an increased risk of cancer with antioxidant supplement use. In this review, we will provide an overview of the current understanding of the role of oxidative stress in cancer formation, as well as the potential benefits of antioxidant supplementation in cancer prevention. Additionally, we will discuss both preclinical and clinical studies highlighting the potentials and limitations of preventive antioxidant strategies.