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1.
Diagnostics (Basel) ; 13(19)2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37835821

RESUMO

Cervical cancer is a common and preventable disease that poses a significant threat to women's health and well-being. It is the fourth most prevalent cancer among women worldwide, with approximately 604,000 new cases and 342,000 deaths in 2020, according to the World Health Organization. Early detection and diagnosis of cervical cancer are crucial for reducing mortality and morbidity rates. The Papanicolaou smear test is a widely used screening method that involves the examination of cervical cells under a microscope to identify any abnormalities. However, this method is time-consuming, labor-intensive, subjective, and prone to human errors. Artificial intelligence techniques have emerged as a promising alternative to improve the accuracy and efficiency of Papanicolaou smear diagnosis. Artificial intelligence techniques can automatically analyze Papanicolaou smear images and classify them into normal or abnormal categories, as well as detect the severity and type of lesions. This paper provides a comprehensive review of the recent advances in artificial intelligence diagnostics of the Papanicolaou smear, focusing on the methods, datasets, performance metrics, and challenges. The paper also discusses the potential applications and future directions of artificial intelligence diagnostics of the Papanicolaou smear.

2.
Metabolites ; 13(7)2023 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-37512544

RESUMO

Breath volatile organic compound (VOC) analysis is a non-invasive tool for assessing health status; the compositional profile of these compounds in the breath of patients with chronic kidney disease is believed to change with decreasing renal function. We aimed to identify breath VOCs for recognizing patients with chronic kidney disease. Using thermal desorption-gas chromatography/mass spectrometry, untargeted analysis of breath markers was performed using breath samples of healthy controls (n = 18) versus non-dialysis (n = 21) and hemodialysis (n = 12) patients with chronic kidney disease in this cross-sectional study. A total of 303 VOCs alongside 12 clinical variables were used to determine the breath VOC profile. Metabolomic analysis revealed that age, systolic blood pressure, and fifty-eight breath VOCs differed significantly between the chronic kidney disease group (non-dialysis + hemodialysis) and healthy controls. Thirty-six VOCs and two clinical variables that showed significant associations with chronic kidney disease in the univariate analysis were further analyzed. Different spectra of breath volatile organic compounds between the control and chronic kidney disease groups were obtained. A multivariate model incorporating age, 2-methyl-pentane, and cyclohexanone showed high performance (accuracy, 86%) in identifying patients with chronic kidney disease with odds ratios of 0.18 (95% CI, 0.07-2.49, p = 0.013); 2.10 (0.94-2.24, p = 0.025); and 2.31 (0.88-2.64, p = 0.008), respectively. Hence, this study showed that renal dysfunction induces a characteristic profile of breath VOCs that can be used as non-invasive potential biomarkers in screening tests for CKD.

3.
Comput Methods Programs Biomed ; 240: 107718, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37451230

RESUMO

BACKGROUND AND OBJECTIVES: Cervical cancer affects around 0.5 million women per year, resulting in over 0.3 million fatalities. Therefore, repetitive screening for cervical cancer is of utmost importance. Computer-assisted diagnosis is key for scaling up cervical cancer screening. Current recognition algorithms, however, perform poorly on the whole-slide image (WSI) analysis, fail to generalize for different staining methods and on uneven distribution for subtype imaging, and provide sub-optimal clinical-level interpretations. Herein, we developed CervixFormer-an end-to-end, multi-scale swin transformer-based adversarial ensemble learning framework to assess pre-cancerous and cancer-specific cervical malignant lesions on WSIs. METHODS: The proposed framework consists of (1) a self-attention generative adversarial network (SAGAN) for generating synthetic images during patch-level training to address the class imbalanced problems; (2) a multi-scale transformer-based ensemble learning method for cell identification at various stages, including atypical squamous cells (ASC) and atypical squamous cells of undetermined significance (ASCUS), which have not been demonstrated in previous studies; and (3) a fusion model for concatenating ensemble-based results and producing final outcomes. RESULTS: In the evaluation, the proposed method is first evaluated on a private dataset of 717 annotated samples from six classes, obtaining a high recall and precision of 0.940 and 0.934, respectively, in roughly 1.2 minutes. To further examine the generalizability of CervixFormer, we evaluated it on four independent, publicly available datasets, namely, the CRIC cervix, Mendeley LBC, SIPaKMeD Pap Smear, and Cervix93 Extended Depth of Field image datasets. CervixFormer obtained a fairly better performance on two-, three-, four-, and six-class classification of smear- and cell-level datasets. For clinical interpretation, we used GradCAM to visualize a coarse localization map, highlighting important regions in the WSI. Notably, CervixFormer extracts feature mostly from the cell nucleus and partially from the cytoplasm. CONCLUSIONS: In comparison with the existing state-of-the-art benchmark methods, the CervixFormer outperforms them in terms of recall, accuracy, and computing time.


Assuntos
Teste de Papanicolaou , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Colo do Útero/diagnóstico por imagem , Colo do Útero/patologia , Diagnóstico por Computador
4.
J Korean Soc Radiol ; 84(3): 763-769, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37325001

RESUMO

Primary malignant melanoma in breast parenchyma (PMB) is an extremely rare disease, and the most common presentation is a palpable breast lump. To the best of our knowledge, a case of PMB presenting as a breast abscess has not been reported in English literatures. We present a case of PMB that manifested as a recurrent breast abscess in a 71-year-old woman. On MRI, an enhancing solid mass with a cystic or necrotic portion was revealed with some high signal intensities on precontrast-enhanced T1-weighted images and a dark rim on T2-weighed images. The MRI features played a pivotal role in identifying the underlying malignant condition and making an accurate diagnosis of this rare case of PMB with unusual clinical presentation.

5.
Diagnostics (Basel) ; 12(4)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35454046

RESUMO

BACKGROUND: POEMS syndrome (POEMS) is a rare plasma cell clonal paraneoplastic syndrome consisting of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes presenting with idiopathic multicentric Castleman disease (iMCD) histology, the treatment of which has not yet been well established. iMCD is also a distinctive rare non-clonal lymphoproliferative disorder, of which dramatic response to Siltuximab, a monoclonal anti-IL-6 antibody, has been reported recently. METHODS: the differential diagnosis between POEMS and iMCD can be very challenging because of the identical histology, overlapping similar symptoms such as polyneuropathy, and vital signs insidiously presented to diagnose POEMS. RESULTS: here, we report the case of a 53-year-old man with iMCD treated for 8 years developing sequential polyneuropathy, monoclonal gammopathy, and bone lytic lesions, all of which were confirmed after his iMCD achieved complete remission resulting from siltuximab administration and finally confirmed as POEMS. CONCLUSIONS: we describe the clinical ambiguity of disease presenting that we can face in the real world between iMCD and POEMS and emphasise careful, enduring observation lasting several years.

6.
Front Pharmacol ; 13: 843469, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35355724

RESUMO

This study aimed to evaluate skin health's functional improvement, such as wrinkles, elasticity, moisture, and whitening, and safety following the consumption of "edible bird's nest extract" for 12 weeks by women. This single-center, double-blinded, parallel-group, placebo-controlled study included women aged 40-60 years. Our primary purpose was to assess improvement in skin wrinkles, elasticity, and moisture after 12 weeks using an SV700, cutometer, and corneometer, respectively, compared to baseline measurements. Our secondary purpose was to evaluate skin wrinkle, elasticity, and moisture changes at 4 and 8 weeks from baseline using the aforementioned equipment, and measure transdermal water loss and melanin and erythema indexes using a tewameter and mexameter, respectively. Experts performed the visual evaluation of skin wrinkles at 4, 8, and 12 weeks from baseline. The participants were randomly allocated in a 1:1 ratio into the edible bird's nest extract or the placebo group with 43 participants each, where they consumed 100 mg of the extract or placebo, respectively, daily for 12 weeks. The outcomes were measured at every visit. In this study, upon comparing changes in the skin elasticity value between the two intake groups at 12 weeks of ingestion, skin elasticity in the edible bird's nest extract group decreased significantly compared with that in the placebo group. Adverse reactions were absent in both groups. In the case of laboratory test results, changes before and after the ingestion of the extract were within the normal range, thus indicating no clinically significant difference. The edible bird's nest extract was effective in improving skin wrinkles. Moreover, it is beneficial for skin health and can be used as a skin nutritional supplement. Compared with the placebo, the edible bird's nest extract was identified as safe. Clinical Trial Registration: https://cris.nih.go.kr/cris/search/detailSearch.do?search_lang=E&search_page=M&pageSize=10&page=undefined&seq=21007&status=5&seq_group=20330, identifier KCT0006558.

7.
Genes Genomics ; 44(5): 617-628, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35353341

RESUMO

BACKGROUND: Since COVID-19 was declared the pandemic by the WHO, it has continued to spread. There is a need for rapid, efficient, and accurate diagnostic kits and techniques to control its spread. OBJECTIVE: The diagnostic capability of the qRT-PCR-based Real-Q 2019-nCoV Detection Kit and dPCR-based Dr. PCR™ Di20K COVID-19 Detection Kit was compared and evaluated. METHODS: Diagnostic tests for COVID-19 were performed using two different COVID-19 kits and 301 individual specimens with confirmed COVID-19 positive/negative at the government-accredited medical institution. Assessment of diagnostic capability was measured through diagnostic sensitivity, specificity, Cohen's Kappa coefficient, and dilutional linearity tests. RESULTS: The COVID-19 diagnostic test results using two kits and 301 individual specimens perfectly matched the pre-diagnosis results of the medical institution. In addition, the measurement results of diagnostic sensitivity and specificity were "1", indicating high diagnostic capability. Cohen's Kappa coefficient value is "1", which means that the diagnosis concordance between the two kits is "Almost Perfect". As a result of dilutional linearity tests to evaluate their detection capability, both kits were measured with very high detection reliability. CONCLUSION: Here, we propose that the dPCR-based Dr. PCR™ Di20K COVID-19 Detection Kit has the advantages of the dPCR method reported in the previous study and is suitable for point-of-care testing (POCT) by overcoming the limitations of space, test time, cross-over contamination, and biosafety due to omitting RNA extraction process.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Humanos , Sistemas Automatizados de Assistência Junto ao Leito , Reação em Cadeia da Polimerase , RNA Viral/análise , RNA Viral/genética , Reprodutibilidade dos Testes , SARS-CoV-2/genética
8.
Curr Mol Pharmacol ; 15(3): 570-581, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34382511

RESUMO

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is the fourth leading cause of cancer- related death globally, with a high incidence rate in economically fast-growing countries. Sphingosine- 1-phosphate (S1P) is a bioactive lipid mediator that plays critical roles in cancer cell proliferation, migration, and angiogenesis converted by the isoforms of sphingosine kinase (SK1 and SK2). SK1 is highly expressed in colorectal cancer; its inhibitors suppress the formation of S1P and increase ceramide levels having a pro-apoptotic function. RB005 is a selective SK1 inhibitor and a structural analog of PP2A activator FTY720. The purpose of this study is to test whether RB005, an SK1 inhibitor, can be used as an anticancer agent by inhibiting the growth of colon cancer cells. METHODS: We performed MTT and colony-forming assay using colon cancer cell lines HT29 and HCT116 cells to examine the cell toxicity effect of RB005. To determine whether apoptosis of RB005 in colon cancer cell line is due to SK1 inhibition or other mechanisms due to its structural similarity with FTY720, we conducted LC/MS, siRNA knockdown, and PP2A activity experiments. RESULTS: RB005 notably inhibited CRC cell growth and proliferation compared to PF543 and ABC294640 by inducing the mitochondria-mediated intrinsic apoptotic pathway. Apoptotic cell death is caused by increased mitochondrial permeability Initiated by the activation of pro-apoptotic protein BAX, increased ceramides, and activation of PP2A. Also, RB005 treatment in HT29 cells did not change the expression level of SK1, but strikingly decreased SK1 activity and S1P levels. All these events of cell death and apoptosis were less effective when SK1 was knocked down by siRNA. CONCLUSION: This result indicates that RB005 shows the in-vitro anti-CRC effect by inhibiting SK1 activity and PP2A activation, increasing proapoptotic ceramide levels following the activation of the intrinsic apoptotic pathway.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Apoptose , Ceramidas/metabolismo , Ceramidas/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Cloridrato de Fingolimode/farmacologia , Humanos , RNA Interferente Pequeno/genética
9.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502095

RESUMO

Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P is linked to a pathological outcome with inflammation, cancer metastasis, or angiogenesis, etc. In this regard, SPHK/S1P axis regulation has been a specific issue in the anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhancing serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs, which eventually induced an unusual environment with a high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase), which contributes a partial increase in Cers. Collectively, a dansyl-modified DPF-543 relatively enhanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.


Assuntos
Ceramidas/biossíntese , Inibidores Enzimáticos/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Pirrolidinas/química , Sulfonas/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Compostos de Dansil/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Humanos , Metanol/química , Esfingosina/metabolismo , Especificidade por Substrato , Suínos
10.
Anal Methods ; 13(30): 3402-3409, 2021 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-34250988

RESUMO

A solvent-free headspace gas chromatography-mass spectrometry (SF-HS-GC/MS) method was developed and validated for screening N-nitrosodimethylamine (NDMA) in various active pharmaceutical ingredients (APIs) and drug products. Experimental parameters such as incubation temperature, incubation time, and sample volume in solvent-free headspace conditions were optimized. The developed SF-HS-GC/MS method was validated in terms of linearity, limit of quantification (LOQ), precision, and accuracy. The results indicated excellent linearity from 5 to 500 ng g-1 with correlation coefficients higher than 0.9999. The LOQ of this method was 5 ng g-1 and matrix effects ranged from 0.97 to 1.11. The accuracy ranged from 92.77 to 106.54% and the precision RSDs were below 5.94%. No significant matrix effect was observed for any of the drug products. Also, artefactual NDMA formation in ranitidine, nizatidine, and metformin was investigated under HS conditions. Adjusted (mild) SF-HS conditions were suggested for precise quantification of NDMA in positive drug products by GC/MS. The present SF-HS-GC/MS method is a promising tool for the screening and determination of toxic NDMA in APIs and drug products.


Assuntos
Dimetilnitrosamina , Preparações Farmacêuticas , Dimetilnitrosamina/análise , Cromatografia Gasosa-Espectrometria de Massas , Ranitidina , Solventes
11.
Genes Genomics ; 43(8): 961-973, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34129193

RESUMO

BACKGROUND: Recently, many researchers focus on the best way to produce high-quality meat, as the trend in food consumption today is to focus on quality. In general, consumers' preferences in beef differ depending on taste and meatiness. Therefore, researchers are interested in how the marbling score affects the flavors of meat or the various factors that make up the meatiness to captivate the consumers' tastes. OBJECTIVE: This study identifies single nucleotide polymorphisms (SNPs) or gene combinations that affect the carcass traits of Korean cattle (Hanwoo) by using the multifactor dimensionality reduction (MDR) method. METHODS: We collected the candidate SNPs to identify SNPs related to marbling scores from whole-exome sequencing and bovine SNP genotyping data. Using 96 Hanwoo samples, we performed PCR amplification to investigate the polymorphism status. In addition, we investigated genetic relationships between carcass traits and SNPs using 612 Hanwoo samples. Furthermore, each candidate SNP genotype and the combinations of SNP genotypes were verified to improve the accuracy of genetic relationships using MDR method. RESULTS: Twenty-four candidate SNPs associated with carcass trait and marbling scores were identified from SNP genotyping and whole-exome sequencing. Among them, three SNP markers (c.459 T > C of the PLCB1 gene, c.271 A > C of the C/EBPα gene, and g.17257 A > G of the TDRKH gene) were showed statistically significant differences between intramuscular fat and genotypes. Especially, two candidate SNPs, including c.459 T > C located in the PLCB1 gene and c.271 A > C located in the C/EBPα gene, could be highly associated with the intramuscular fat of Hanwoo quality grade. In addition, the combination of SNP genotypes is showed higher significant differences with carcass weight, backfat thickness, and longissimus dorsi muscle area. CONCLUSION: Three SNP genotypes and the combination of SNP genotypes in the PLCB1, C/EBPα, and TDRKH genes may be useful genetic markers for improving beef quality.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/genética , Análise de Alimentos , Carne/análise , Fosfolipase C beta/genética , Proteínas de Ligação a RNA/genética , Animais , Bovinos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Redução Dimensional com Múltiplos Fatores , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento do Exoma
12.
Diagnostics (Basel) ; 11(3)2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33801546

RESUMO

The spreading pattern of ovarian carcinoma is unique and unlike most other cancers, because exfoliated ovarian cancer cells primarily disseminate within the abdominal cavity, which are then transported throughout the peritoneum by physiological peritoneal fluid. An initial manifestation of a solitary peridiaphragmatic distant metastatic lymph node without peritoneal involvement is very rare. This study reports a case with an incidentally found single hypermetabolic mass in the peridiaphragmatic space without a pelvic lesion in the baseline staging 18 F-FDG PET/CT that histologically turned out to be metastatic serous papillary carcinoma due to ovarian cancer. 18F-FDG PET/CT may allow the identification of the initial manifestation of unexpected distant oligometastatic statuses of an unknown primary ovarian cancer.

13.
Molecules ; 26(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917070

RESUMO

Hair loss by excessive stress from work and lifestyle changes has become a growing concern, particularly among young individuals. However, most drugs for alopecia impose a plethora of side effects. We have found the powerful impact of Malva verticillata seed extracts on alleviating hair loss. This study further isolated effective chemicals in M. verticillata seed extracts by liquid silica gel column chromatography. Under the screening for the growth rate (%) of human follicles dermal papilla cells (HFDPCs), we identified linoleic acid (LA) and oleic acid in n-hexane of M. verticillate (MH)2 fraction. LA treatment activated Wnt/ß-catenin signaling and induced HFDPCs growth by increasing the expression of cell cycle proteins such as cyclin D1 and cyclin-dependent kinase 2. LA treatment also increased several growth factors, such as vascular endothelial growth factor, insulin-like growth factor-1, hepatocyte growth factor, and keratinocyte growth factor, in a dose-dependent manner. Besides, LA significantly inhibited Dickkopf-related protein expression (DKK-1), a primary alopecia signaling by dihydrotestosterone. Our findings suggest that LA treatment may alleviate a testosterone-induced signaling molecule and induces HFDPCs growth by activating Wnt/ß-catenin signaling.


Assuntos
Folículo Piloso/citologia , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Ácido Linoleico/farmacologia , Malva/química , Extratos Vegetais/farmacologia , Sementes/química , Biomarcadores , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fracionamento Químico , Expressão Gênica , Folículo Piloso/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ácido Linoleico/química , Ácido Linoleico/isolamento & purificação , Modelos Biológicos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Via de Sinalização Wnt/efeitos dos fármacos
14.
Int J Mol Sci ; 22(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535437

RESUMO

Sphingosine-1-phosphate (S1P) is a unique lipid ligand binding to S1P receptors to transduce various cell survival or proliferation signals via small G proteins. S1P lyase (S1PL) is the specific enzyme that degrades S1P to phosphoethanolamine and (2E)-hexadecenal and therefore regulates S1P levels. S1PL also degrades dihydrosphingosine-1-phosphate (Sa1P), with a higher affinity to produce hexadecanal. Here, we developed a newly designed assay using a C17-Sa1P substrate that degrades into pentadecanal and phosphoethanolamine. For higher sensitivity in pentadecanal analysis, we developed a quantitative protocol as well as a 5,5-dimethyl cyclohexanedione (5,5-dimethyl CHD) derivatization method. The derivatization conditions were optimized for the reaction time, temperature, and concentrations of the 5,5-dimethyl CHD reagent, acetic acid, and ammonium acetate. The S1PL reaction in the cell lysate after spiking 20 µM of C17-Sa1P for 20 min was linear to the total protein concentrations of 50 µg. The S1PL levels (4 pmol/mg/min) were readily detected in this HPLC with fluorescence detection (λex = 366 nm, λem = 455 nm). The S1PL-catalyzed reaction was linear over 30 min and yielded a Km value of 2.68 µM for C17-Sa1P. This new method was validated to measure the S1PL activity of mouse embryonal carcinoma cell lines of the standard cell (F9-0), S1PL knockdown cells (F9-2), and S1PL-overexpressed cells (F9-4). Furthermore, we treated F9-4 cells with different S1PL inhibitors such as FTY720, 4-deoxypyridoxine (DOP), and the deletion of pyridoxal-5-phosphate (P5P), an essential cofactor for S1PL activity, and observed a significant decrease in pentadecanal relative to the untreated cells. In conclusion, we developed a highly sensitive S1PL assay using a C17-Sa1P substrate for pentadecanal quantification for application in the characterization of S1PL activity in vitro.


Assuntos
Aldeído Liases/análise , Bioensaio/métodos , Aldeídos/química , Animais , Linhagem Celular Tumoral , Cromatografia/métodos , Cromatografia Líquida de Alta Pressão , Cicloexanonas/química , Etanolaminas/química , Corantes Fluorescentes/química , Ligantes , Limite de Detecção , Modelos Lineares , Camundongos , Mutação , Ligação Proteica
17.
Genes Genomics ; 42(12): 1381-1387, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33145728

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous entity that encompasses several subtypes with distinct molecular characteristics. The patients with TNBCs show unpredictable response to the chemotherapy, and further there is the lack of effective agents. Thus, many studies have been underway to discover targeted therapy suitable for patients with specific genetic alterations in each molecular subtypes. TNBCs are classified as four major molecular subtypes according to the gene expression patterns. These are luminal androgen receptor (LAR), mesenchymal-like, immunomodulatory (IM), and basal-like types. CONCLUSION: Here, we discuss the unique molecular features of each subtype as well as promising targets for anti-cancer therapy.


Assuntos
Patologia Molecular , Neoplasias de Mama Triplo Negativas/classificação , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Medicina de Precisão , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética
18.
Nat Metab ; 2(11): 1265-1283, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33199924

RESUMO

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.


Assuntos
ADP-Ribosil Ciclase 1/genética , Envelhecimento/metabolismo , Senescência Celular , Ativação de Macrófagos , Glicoproteínas de Membrana/genética , NAD/metabolismo , ADP-Ribosil Ciclase/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Antígenos CD/metabolismo , Citocinas/metabolismo , Feminino , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Glicólise/genética , Humanos , Fígado/metabolismo , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , NAD+ Nucleosidase/metabolismo
19.
Int J Mol Sci ; 21(15)2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751172

RESUMO

An in vitro cell transformation assay (CTA) is useful for the detection of non-genotoxic carcinogens (NGTXCs); however, it does not provide information on their modes of action. In this study, to pursue a mechanism-based approach in the risk assessment of NGTXCs, we aimed to develop an integrated strategy comprising an in vitro Bhas 42 CTA and global DNA methylation analysis. For this purpose, 10 NGTXCs, which were also predicted to be negative through Derek/Sarah structure-activity relationship analysis, were first tested for transforming activity in Bhas 42 cells. Methylation profiles using reduced representation bisulfite sequencing were generated for seven NGTXCs that were positive in CTAs. In general, the differentially methylated regions (DMRs) within promoter regions showed slightly more bias toward hypermethylation than the DMRs across the whole genome. We also identified 13 genes associated with overlapping DMRs within the promoter regions in four NGTXCs, of which seven were hypermethylated and six were hypomethylated. Using ingenuity pathway analysis, the genes with DMRs at the CpG sites were found to be enriched in cancer-related categories, including "cell-to-cell signaling and interaction" as well as "cell death and survival". Moreover, the networks related to "cell death and survival", which were considered to be associated with carcinogenesis, were identified in six NGTXCs. These results suggest that epigenetic changes supporting cell transformation processes occur during non-genotoxic carcinogenesis. Taken together, our combined system can become an attractive component for an integrated approach for the testing and assessment of NGTXCs.


Assuntos
Carcinógenos/toxicidade , Transformação Celular Neoplásica/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Animais , Linhagem Celular , Transformação Celular Neoplásica/genética , Ilhas de CpG/efeitos dos fármacos , Epigênese Genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Regiões Promotoras Genéticas , Transdução de Sinais , Relação Estrutura-Atividade
20.
Genes Genomics ; 42(10): 1207-1213, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32860627

RESUMO

BACKGROUND: Alu elements are most abundant retrotransposons with > 1.2 million copies in the primate genome. AluYb8 subfamily was diverged from AluY lineage, and has accumulated eight diagnostic mutations and 7-bp duplication during primate evolution. A total of 1851 AluYb copies are present in the human genome, and most of them are human-specific. On the other hand, only a few AluYb8 copies were identified in the chimpanzee genome by previous studies on AluYb8. The significantly different number of species-specific AluYb8 elements between human and chimpanzee might result from the incompletion of chimpanzee reference genome sequences at the time of the previous study. OBJECTIVE: AluYb8 elements could generate genomic structural variations in the chimpanzee genome. This study aimed to identify and characterize chimpanzee-specific AluYb elements using the most updated chimpanzee reference genome sequences (Jan. 2018, panTro6). METHODS: To identify chimpanzee-specific AluYb8, we carried out genomic comparison with non-chimpanzee primate genome using the UCSC table browser. In addition, chimpanzee-specific AluYb8 candidates were manually inspected and experimentally verified using PCR and Sanger sequencing. RESULTS: Among a total of 231 chimpanzee-specific AluYb8 candidates, 11 of the candidates are chimpanzee-specific AluYb8, and 29 elements are shared between the chimpanzee and non-chimpanzee primate genomes. Through the sequence analysis of AluYb8 and other Alu subfamilies, we were able to observe various diagnostic mutations and variable length duplications in 7-bp duplication region of AluYb8 element. In addition, we further validated two of the chimpanzee-specific AluYb8 elements (CS8 and CS20) that were not previously discovered by display PCR and Sanger sequencing. Interestingly, we identified a AluYb8 insertion-mediated deletion (CS8 locus) in the chimpanzee genome. CONCLUSION: Our study found that AluYb8 elements are much more abundant in the human genome than chimpanzee genome, and that it could be due to the absence of hyperactive "master" AluYb8 elements in the chimpanzee genome.


Assuntos
Elementos Alu/genética , Evolução Molecular , Pan troglodytes/genética , Retroelementos/genética , Animais , Genes Duplicados/genética , Genoma Humano/genética , Genômica , Humanos
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