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1.
Cell Transplant ; 33: 9636897241259723, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38877676

RESUMO

Stem cells in vivo can transit between quiescence and activation, two metabolically distinct states. It is increasingly appreciated that cell metabolism assumes profound roles in stem cell maintenance and tissue homeostasis. However, the lack of suitable models greatly hinders our understanding of the metabolic control of stem cell quiescence and activation. In the present study, we have utilized classical signaling pathways and developed a cell culture system to model reversible NSC quiescence and activation. Unlike activated ones, quiescent NSCs manifested distinct morphology characteristics, cell proliferation, and cell cycle properties but retained the same cell proliferation and differentiation potentials once reactivated. Further transcriptomic analysis revealed that extensive metabolic differences existed between quiescent and activated NSCs. Subsequent experimentations confirmed that NSC quiescence and activation transition was accompanied by a dramatic yet coordinated and dynamic shift in RNA metabolism, protein synthesis, and mitochondrial and autophagy activity. The present work not only showcases the broad utilities of this powerful in vitro NSC quiescence and activation culture system but also provides timely insights for the field and warrants further investigations.


Assuntos
Diferenciação Celular , Proliferação de Células , Células-Tronco Neurais , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Animais , Camundongos , Técnicas de Cultura de Células/métodos , Células Cultivadas , Ciclo Celular/fisiologia , Autofagia
2.
Elife ; 132024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38921956

RESUMO

BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.


Assuntos
Neoplasias do Ceco , Quinase 1 de Adesão Focal , Proteínas Proto-Oncogênicas B-raf , Animais , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Fosforilação , Camundongos , Humanos , Neoplasias do Ceco/metabolismo , Neoplasias do Ceco/genética , Neoplasias do Ceco/patologia , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , Sistema de Sinalização das MAP Quinases , Receptores ErbB/metabolismo , Receptores ErbB/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Masculino
3.
Innovation (Camb) ; 5(3): 100620, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38706954

RESUMO

In the last decade, organoid research has entered a golden era, signifying a pivotal shift in the biomedical landscape. The year 2023 marked a milestone with the publication of thousands of papers in this arena, reflecting exponential growth. However, amid this burgeoning expansion, a comprehensive and accurate overview of the field has been conspicuously absent. Our review is intended to bridge this gap, providing a panoramic view of the rapidly evolving organoid landscape. We meticulously analyze the organoid field from eight distinctive vantage points, harnessing our rich experience in academic research, industrial application, and clinical practice. We present a deep exploration of the advances in organoid technology, underpinned by our long-standing involvement in this arena. Our narrative traverses the historical genesis of organoids and their transformative impact across various biomedical sectors, including oncology, toxicology, and drug development. We delve into the synergy between organoids and avant-garde technologies such as synthetic biology and single-cell omics and discuss their pivotal role in tailoring personalized medicine, enhancing high-throughput drug screening, and constructing physiologically pertinent disease models. Our comprehensive analysis and reflective discourse provide a deep dive into the existing landscape and emerging trends in organoid technology. We spotlight technological innovations, methodological evolution, and the broadening spectrum of applications, emphasizing the revolutionary influence of organoids in personalized medicine, oncology, drug discovery, and other fields. Looking ahead, we cautiously anticipate future developments in the field of organoid research, especially its potential implications for personalized patient care, new avenues of drug discovery, and clinical research. We trust that our comprehensive review will be an asset for researchers, clinicians, and patients with keen interest in personalized medical strategies. We offer a broad view of the present and prospective capabilities of organoid technology, encompassing a wide range of current and future applications. In summary, in this review we attempt a comprehensive exploration of the organoid field. We offer reflections, summaries, and projections that might be useful for current researchers and clinicians, and we hope to contribute to shaping the evolving trajectory of this dynamic and rapidly advancing field.

4.
Adv Sci (Weinh) ; 11(26): e2309602, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38682481

RESUMO

Living organisms ranging from bacteria to animals have developed their own ways to accumulate and store phosphate during evolution, in particular as the polyphosphate (polyP) granules in bacteria. Degradation of polyP into phosphate is involved in phosphorus cycling, and exopolyphosphatase (PPX) is the key enzyme for polyP degradation in bacteria. Thus, understanding the structure basis of PPX is crucial to reveal the polyP degradation mechanism. Here, it is found that PPX structure varies in the length of ɑ-helical interdomain linker (ɑ-linker) across various bacteria, which is negatively correlated with their enzymatic activity and thermostability - those with shorter ɑ-linkers demonstrate higher polyP degradation ability. Moreover, the artificial DrPPX mutants with shorter ɑ-linker tend to have more compact pockets for polyP binding and stronger subunit interactions, as well as higher enzymatic efficiency (kcat/Km) than that of DrPPX wild type. In Deinococcus-Thermus, the PPXs from thermophilic species possess a shorter ɑ-linker and retain their catalytic ability at high temperatures (70 °C), which may facilitate the thermophilic species to utilize polyP in high-temperature environments. These findings provide insights into the interdomain linker length-dependent evolution of PPXs, which shed light on enzymatic adaption for phosphorus cycling during natural evolution and rational design of enzyme.


Assuntos
Hidrolases Anidrido Ácido , Fósforo , Polifosfatos , Polifosfatos/metabolismo , Hidrolases Anidrido Ácido/metabolismo , Hidrolases Anidrido Ácido/genética , Hidrolases Anidrido Ácido/química , Fósforo/metabolismo , Bactérias/genética , Bactérias/enzimologia , Bactérias/metabolismo , Evolução Molecular
5.
J Clin Oncol ; 42(13): 1520-1530, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38315963

RESUMO

PURPOSE: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects. METHODS: We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P) between the model prediction and the treatment effect. RESULTS: Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65). CONCLUSION: The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Colo , Fluoruracila , Leucovorina , Aprendizado de Máquina , Oxaliplatina , Humanos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias do Colo/mortalidade , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Quimioterapia Adjuvante , Adulto , Ensaios Clínicos Fase III como Assunto , Estadiamento de Neoplasias
6.
Res Sq ; 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36778401

RESUMO

BRAF V600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a "just-right" level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vill-Cre;BRAFV600E/+;Fakfl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a "just-right" ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.

7.
Nat Commun ; 14(1): 7699, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-38052788

RESUMO

Protocell fitness under extreme prebiotic conditions is critical in understanding the origin of life. However, little is known about protocell's survival and fitness under prebiotic radiations. Here we present a radioresistant protocell model based on assembly of two types of coacervate droplets, which are formed through interactions of inorganic polyphosphate (polyP) with divalent metal cation and cationic tripeptide, respectively. Among the coacervate droplets, only the polyP-Mn droplet is radiotolerant and provides strong protection for recruited proteins. The radiosensitive polyP-tripeptide droplet sequestered with both proteins and DNA could be encapsulated inside the polyP-Mn droplet, and form into a compartmentalized protocell. The protocell protects the inner nucleoid-like condensate through efficient reactive oxygen species' scavenging capacity of intracellular nonenzymic antioxidants including Mn-phosphate and Mn-peptide. Our results demonstrate a radioresistant protocell model with redox reaction system in response to ionizing radiation, which might enable the protocell fitness to prebiotic radiation on the primitive Earth preceding the emergence of enzyme-based fitness. This protocell might also provide applications in synthetic biology as bioreactor or drug delivery system.


Assuntos
Células Artificiais , Células Artificiais/metabolismo , Peptídeos , Proteínas , Minerais
8.
Cell Transplant ; 32: 9636897231187996, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37488947

RESUMO

Ovarian cancer (OC), particularly high-grade serous cancer (HGSC), is the leading cause of mortality among gynecological cancers owing to the treatment difficulty and high recurrence probability. As therapeutic drugs approved for OC, poly ADP-ribose polymerase inhibitors (PARPi) lead to synthetic lethality by inhibiting single-strand DNA repair, particularly in homologous recombination-deficient cancers. However, even PARPi have distinct efficacies and are prone to have drug resistance, the molecular mechanisms underlying the PARPi resistance in OC remain unclear. A patient-derived organoid platform was generated and treated with a PARPi to understand the factors associated with PARPi resistance. PARPi significantly inhibits organoid growth. After 72 h of treatment, both the size of organoids and the numbers of adherent cells decreased. Moreover, immunofluorescence results showed that the proportion of Ki67 positive cells significantly reduced. When the PARPi concentration reached 200 nM, the percentage of Ki67+/4',6-diamidino-2-phenylindole (DAPI) cells decreased approximately 50%. PARPi treatment also affected the expression of genes involved in base excision repair and cell cycle. Functional assays revealed that PARPi inhibits cell growth by upregulating early apoptosis. The expression levels of several key genes were validated. In addition to previously reported genes, some promising genes FEN1 and POLA2, were also be founded. The results demonstrate the complex effects of PARPi treatment on changes in potential genes relevant to PARPi resistance, and provide perspectives for further research on the PARPi resistance mechanisms.


Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Antígeno Ki-67/metabolismo , Neoplasias Ovarianas/metabolismo , Reparo do DNA , Apoptose , Organoides/metabolismo
9.
Cell Transplant ; 31: 9636897221134540, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324293

RESUMO

Wnts, bone morphogenetic protein (BMP), and fibroblast growth factor (FGF) are paracrine signaling pathways implicated in the niche control of stem cell fate decisions. BMP-on and Wnt-off are the dominant quiescent niche signaling pathways in many cell types, including neural stem cells (NSCs). However, among the multiple inhibitory family members of the Wnt pathway, those with direct action after BMP4 stimulation in NSCs remain unclear. We examined 11 Wnt inhibitors in NSCs after BMP4 treatment. Wnt inhibitory factor 1 (Wif1) has been identified as the main factor reacting to BMP4 stimuli. RNA sequencing confirmed that Wif1 was markedly upregulated after BMP4 treatment in different gene expression analyses. Similar to the functional role of BMP4, Wif1 significantly decreased the cell cycle of NSCs and significantly inhibited cell proliferation (P < 0.05). Combined treatment with BMP4 and Wif1 significantly enhanced the inhibition of cell growth compared with the single treatment (P < 0.05). Wif1 expression was clearly lower in glioblastoma and low-grade glioma samples than in normal samples (P < 0.05). A functional analysis revealed that both BMP4 and Wif1 could decrease glioma cell growth. These effects were abrogated by the BMP inhibitor Noggin. The collective findings demonstrate that Wif1 plays a key role in quiescent NSC homeostasis and glioma cell growth downstream of BMP-on signaling. The functional roles of Wif1/BMP4 in glioma cells may provide a technical basis for regenerative medicine, drug discovery, and personal molecular therapy in future clinical treatments.


Assuntos
Glioma , Células-Tronco Neurais , Humanos , Via de Sinalização Wnt , Proteínas Morfogenéticas Ósseas/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
10.
Cell Regen ; 11(1): 36, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36316503

RESUMO

Malignant glioma is a highly heterogeneous and invasive primary brain tumor characterized by high recurrence rates, resistance to combined therapy, and dismal prognosis. Glioma stem cells (GSCs) are likely responsible for tumor progression, resistance to therapy, recurrence, and poor prognosis owing to their high self-renewal and tumorigenic potential. As a family member of BMP signaling, bone morphogenetic protein4 (BMP4) has been reported to induce the differentiation of GSCs and neural stem cells (NSCs). However, the molecular mechanisms underlying the BMP4-mediated effects in these two cell types are unclear. In this study, we treated hGSCs and hNSCs with BMP4 and compared the phenotypic and transcriptional changes between these two cell types. Phenotypically, we found that the growth of hGSCs was greatly inhibited by BMP4, but the same treatment only increased the cell size of hNSCs. While the RNA sequencing results showed that BMP4 treatment evoked significantly transcriptional changes in both hGSCs and hNSCs, the profiles of differentially expressed genes were distinct between the two groups. A gene set that specifically targeted the proliferation and differentiation of hGSCs but not hNSCs was enriched and then validated in hGSC culture. Our results suggested that hGSCs and hNSCs responded differently to BMP4 stimulation. Understanding and investigating different responses between hGSCs and hNSCs will benefit finding partner factors working together with BMP4 to further suppress GSCs proliferation and stemness without disturbing NSCs.

11.
Cancers (Basel) ; 14(19)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36230748

RESUMO

Head and neck squamous cell cancer (HNSCC) is an aggressive cancer resulting from heterogeneous causes. To reveal the underlying drivers and signaling mechanisms of different HNSCC tumors, we developed a novel Bayesian framework to identify drivers of individual tumors and infer the states of driver proteins in cellular signaling system in HNSCC tumors. First, we systematically identify causal relationships between somatic genome alterations (SGAs) and differentially expressed genes (DEGs) for each TCGA HNSCC tumor using the tumor-specific causal inference (TCI) model. Then, we generalize the most statistically significant driver SGAs and their regulated DEGs in TCGA HNSCC cohort. Finally, we develop machine learning models that combine genomic and transcriptomic data to infer the protein functional activation states of driver SGAs in tumors, which enable us to represent a tumor in the space of cellular signaling systems. We discovered four mechanism-oriented subtypes of HNSCC, which show distinguished patterns of activation state of HNSCC driver proteins, and importantly, this subtyping is orthogonal to previously reported transcriptomic-based molecular subtyping of HNSCC. Further, our analysis revealed driver proteins that are likely involved in oncogenic processes induced by HPV infection, even though they are not perturbed by genomic alterations in HPV+ tumors.

12.
Cell Regen ; 11(1): 23, 2022 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-35778531

RESUMO

Malignant Glioma is characterized by strong self-renewal potential and immature differentiation potential. The main reason is that malignant glioma holds key cluster cells, glioma stem cells (GSCs). GSCs contribute to tumorigenesis, tumor progression, recurrence, and treatment resistance. Interferon-beta (IFN-ß) is well known for its anti-proliferative efficacy in diverse cancers. IFN-ß also displayed potent antitumor effects in malignant glioma. IFN-ß affect both GSCs and Neural stem cells (NSCs) in the treatment of gliomas. However, the functional comparison, similar or different effects of IFN-ß on GSCs and NSCs are rarely reported. Here, we studied the similarities and differences of the responses to IFN-ß between human GSCs and normal NSCs. We found that IFN-ß preferentially inhibited GSCs over NSCs. The cell body and nucleus size of GSCs increased after IFN-ß treatment, and the genomic analysis revealed the enrichment of the upregulated immune response, cell adhesion genes and down regulated cell cycle, ribosome pathways. Several typical cyclin genes, including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin B2 (CCNB2), and cyclin D1 (CCND1), were significantly downregulated in GSCs after IFN-ß stimulation. We also found that continuous IFN-ß stimulation after passage further enhanced the inhibitory effect. Our study revealed how genetic diversity resulted in differential effects in response to IFN-ß treatment. These results may contribute to improve the applications of IFN-ß in anti-cancer immunotherapy. In addition, these results may also help to design more effective pharmacological strategies to target cancer stem cells while protecting normal neural stem cells.

14.
J Clin Invest ; 131(16)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34228644
15.
Front Genet ; 12: 639858, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295351

RESUMO

Glioma is the most common and malignant primary brain tumor. Patients with malignant glioma usually have a poor prognosis due to drug resistance and disease relapse. Cancer stem cells contribute to glioma initiation, progression, resistance, and relapse. Hence, quick identification and efficient understanding of glioma stem cells (GSCs) are of profound importance for therapeutic strategies and outcomes. Ideally, therapeutic approaches will only kill cancer stem cells without harming normal neural stem cells (NSCs) that can inhibit GSCs and are often beneficial. It is key to identify the differences between cancer stem cells and normal NSCs. However, reports detailing an efficient and uniform protocol are scarce, as are comparisons between normal neural and cancer stem cells. Here, we compared different protocols and developed a fast and efficient approach to obtaining high-purity glioma stem cell by tracking observation and optimizing culture conditions. We examined the proliferative and differentiative properties confirming the identities of the GSCs with relevant markers such as Ki67, SRY-box containing gene 2, an intermediate filament protein member nestin, glial fibrillary acidic protein, and s100 calcium-binding protein (s100-beta). Finally, we identified distinct expression differences between GSCs and normal NSCs including cyclin-dependent kinase 4 and tumor protein p53. This study comprehensively describes the features of GSCs, their properties, and regulatory genes with expression differences between them and normal stem cells. Effective approaches to quickly obtaining high-quality GSCs from patients should have the potential to not only help understand the diseases and the resistances but also enable target drug screening and personalized medicine for brain tumor treatment.

16.
Biomed Res Int ; 2020: 1308526, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32509845

RESUMO

The mammalian central nervous system (CNS) has a limited ability to renew the damaged cells after a brain or spinal cord injury whether it is nonhuman primates like monkeys or humans. Transplantation of neural stem cells (NSCs) is a potential therapy for CNS injuries due to their pluripotency and differentiation abilities. Cytokines play an important role in CNS development and repair of CNS injuries. However, the detailed cytokine signaling response in monkey neural stem cells is rarely studied. In our previous research, we isolated NSCs from the adult monkey brain and found the effects of cytokines on monkey NSCs. Now, we further analyzed the regulation mechanisms of cytokines to the proliferation of monkey NSCs such as bone morphogenic protein 4 (BMP4), BMP4/leukaemia inhibitory factor (LIF), or retinoic acid (RA)/Forskolin. The data showed that BMP4 inhibited cell proliferation to arrest, but it did not affect the stemness of NSCs. BMP4/LIF promoted the astrocyte-like differentiation of monkey NSCs, and RA/forskolin induced the neuronal differentiation of monkey NSCs. BMP4/LIF and RA/forskolin induced monkey NSC differentiation by regulating Notch signaling. These results provide some theoretical evidence for NSC therapy to brain or spinal cord injury in regenerative medicine.


Assuntos
Citocinas/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína Morfogenética Óssea 4/farmacologia , Encéfalo/citologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colforsina/farmacologia , Fator Inibidor de Leucemia/farmacologia , Macaca fascicularis , Masculino , Tretinoína/farmacologia
17.
J Mater Chem B ; 8(6): 1310-1315, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31970363

RESUMO

Intracellular viscosity can be measured to reflect the state of living cells. Fluorescent probes are powerful tools for viscosity detection in vivo. Herein, we report on a novel red-emitting viscosity-sensitive probe DJH with a large Stokes shift of 165 nm, showing a 400-fold fluorescence enhancement from PBS solution to 90% glycerol. The probe was suitable for the visualization of the changes in viscosity within living cells and also in zebrafish treated with microplastics for the first time. Furthermore, the viscosity of fresh blood from diabetic mice and hypertensive and diabetic patients was first evaluated by using DJH. These results showed that the probe has a wide range of potential applications in basic research on environmental pollution and in the pre-diagnosis of patients.


Assuntos
Diabetes Mellitus Experimental/diagnóstico , Corantes Fluorescentes/química , Imagem Óptica , Animais , Diabetes Mellitus Experimental/sangue , Corantes Fluorescentes/síntese química , Humanos , Camundongos , Estrutura Molecular , Teoria Quântica , Células Tumorais Cultivadas , Viscosidade , Peixe-Zebra
18.
Pac Symp Biocomput ; 25: 79-90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31797588

RESUMO

Cancers are mainly caused by somatic genomic alterations (SGAs) that perturb cellular signaling systems and eventually activate oncogenic processes. Therefore, understanding the functional impact of SGAs is a fundamental task in cancer biology and precision oncology. Here, we present a deep neural network model with encoder-decoder architecture, referred to as genomic impact transformer (GIT), to infer the functional impact of SGAs on cellular signaling systems through modeling the statistical relationships between SGA events and differentially expressed genes (DEGs) in tumors. The model utilizes a multi-head self-attention mechanism to identify SGAs that likely cause DEGs, or in other words, differentiating potential driver SGAs from passenger ones in a tumor. GIT model learns a vector (gene embedding) as an abstract representation of functional impact for each SGA-affected gene. Given SGAs of a tumor, the model can instantiate the states of the hidden layer, providing an abstract representation (tumor embedding) reflecting characteristics of perturbed molecular/cellular processes in the tumor, which in turn can be used to predict multiple phenotypes. We apply the GIT model to 4,468 tumors profiled by The Cancer Genome Atlas (TCGA) project. The attention mechanism enables the model to better capture the statistical relationship between SGAs and DEGs than conventional methods, and distinguishes cancer drivers from passengers. The learned gene embeddings capture the functional similarity of SGAs perturbing common pathways. The tumor embeddings are shown to be useful for tumor status representation, and phenotype prediction including patient survival time and drug response of cancer cell lines.


Assuntos
Neoplasias , Biologia Computacional , Genômica , Humanos , Neoplasias/genética , Fenótipo , Medicina de Precisão
19.
Sci Rep ; 9(1): 13225, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519988

RESUMO

Cancer is a disease mainly caused by somatic genome alterations (SGAs) that perturb cellular signalling systems. Furthermore, the combination of pathway aberrations in a tumour defines its disease mechanism, and distinct disease mechanisms underlie the inter-tumour heterogeneity in terms of disease progression and responses to therapies. Discovering common disease mechanisms shared by tumours would provide guidance for precision oncology but remains a challenge. Here, we present a novel computational framework for revealing distinct combinations of aberrant signalling pathways in tumours. Specifically, we applied the tumour-specific causal inference algorithm (TCI) to identify causal relationships between SGAs and differentially expressed genes (DEGs) within tumours from the Cancer Genome Atlas (TCGA) study. Based on these causal inferences, we adopted a network-based method to identify modules of DEGs, such that the member DEGs within a module tend to be co-regulated by a common pathway. Using the expression status of genes in a module as a surrogate measure of the activation status of the corresponding pathways, we divided breast cancers (BRCAs) into five subgroups and glioblastoma multiformes (GBMs) into six subgroups with distinct combinations of pathway aberrations. The patient groups exhibited significantly different survival patterns, indicating that our approach can identify clinically relevant disease subtypes.


Assuntos
Algoritmos , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Feminino , Glioblastoma/classificação , Glioblastoma/genética , Humanos , Medicina de Precisão
20.
PLoS Comput Biol ; 15(7): e1007088, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31276486

RESUMO

Cancer is mainly caused by somatic genome alterations (SGAs). Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. We developed a novel tumor-specific computational framework that finds the likely causative SGAs in an individual tumor and estimates their impact on oncogenic processes, which suggests the disease mechanisms that are acting in that tumor. This information can be used to guide precision oncology. We report a tumor-specific causal inference (TCI) framework, which estimates causative SGAs by modeling causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and estimated for each tumor the SGAs that causally regulate the differentially expressed genes (DEGs) in that tumor. Overall, TCI identified 634 SGAs that are predicted to cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both the well-known and the novel candidate drivers that are predicted by TCI. TCI provides a unified framework that integrates multiple types of SGAs and molecular phenotypes to estimate which genome perturbations are causally influencing one or more molecular/cellular phenotypes in an individual tumor. By identifying major candidate drivers and revealing their functional impact in an individual tumor, TCI sheds light on the disease mechanisms of that tumor, which can serve to advance our basic knowledge of cancer biology and to support precision oncology that provides tailored treatment of individual tumors.


Assuntos
Neoplasias/genética , Algoritmos , Teorema de Bayes , Biologia Computacional , Genoma Humano , Humanos , Modelos Genéticos , Mutação , Neoplasias/etiologia , Oncogenes , Fenótipo , Medicina de Precisão
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