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BACKGROUND: Rotational atherectomy (RA) remains an integral tool for the treatment of severe coronary calcified lesions despite emergence of newer techniques. We aimed to evaluate the contemporary clinical practices and outcomes of RA in China. METHODS: The Rota China Registry (NCT03806621) was an investigator-initiated, prospective, multicenter registry based on China Rota Elite Group. Consecutive patients treated with RA were recruited. A pre-designed, standardized protocol was recommended for the RA procedure. The primary safety endpoint was major adverse cardiovascular events (MACE: composite of cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) at 30 days. The primary efficacy endpoint was procedural success. RESULTS: Between July 2018 and December 2020, 980 patients were enrolled at 19 sites in China. Mean patient age was 68.4 years, and 61.4% were men. Radial access was used in 79.1% patients, and 32.7% procedures were guided by intravascular imaging. A total of 22.6% procedures used more than 1 burr, and the maximal burr size was ≥1.75 mm in 24.4% cases, with burr upsizing in 19.3% cases, achieving a final burr-to-artery ratio of 0.52. Procedural success was achieved in 91.1% of patients, and the rate of 30-day and 1-year MACE was 4.9% and 8.2%, respectively. Multivariable analysis identified the total lesion length (HR 1.014, 95% CI: 1.002-1.027; p = 0.021) as predictor of 30-day MACE, and renal insufficiency (HR 1.916, 95% CI: 1.073-3.420; p = 0.028) as predictor of 1-year MACE. CONCLUSIONS: In this contemporary prospective registry in China, the use of RA was effective in achieving high procedural success rate with good short- and long-term outcomes in patients with severely calcified lesions.
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Cardiovascular disease is a leading cause of disability and death worldwide. Although the survival rate of patients with heart diseases can be improved with contemporary pharmacological treatments and surgical procedures, none of these therapies provide a significant improvement in cardiac repair and regeneration. Stem cell-based therapies are a promising approach for functional recovery of damaged myocardium. However, the available stem cells are difficult to differentiate into cardiomyocytes, which result in the extremely low transplantation efficiency. Nanomaterials are widely used to regulate the myocardial differentiation of stem cells, and play a very important role in cardiac tissue engineering. This study discusses the current status and limitations of stem cells and cell-derived exosomes/micro RNAs based cardiac therapy, describes the cardiac repair mechanism of nanomaterials, summarizes the recent advances in nanomaterials used in cardiac repair and regeneration, and evaluates the advantages and disadvantages of the relevant nanomaterials. Besides discussing the potential clinical applications of nanomaterials in cardiac therapy, the perspectives and challenges of nanomaterials used in stem cell-based cardiac repair and regeneration are also considered. Finally, new research directions in this field are proposed, and future research trends are highlighted.
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Miocárdio , Nanoestruturas , Humanos , Miócitos Cardíacos , Células-Tronco , RegeneraçãoAssuntos
Atrofia Óptica Hereditária de Leber , Deficiência de Vitamina B 12 , Humanos , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/genética , Mutação , Mitocôndrias/genética , DNA Mitocondrial/genéticaRESUMO
Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3' untranslated regions (3'UTRs) and/or coding sequences. How core cleavage/polyadenylation (C/P) factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3'UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A) sites (pAs), CFI-25/68, PABPN1 and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI-25/68 or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly inhibiting C/P events in introns near the 5' end of gene and U2 suppressing those in introns with features for efficient splicing. Furthermore, PABPN1 inhibits expression of transcripts with pAs near the transcription start site (TSS), a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results support an APA code where an APA event in a given cellular context is regulated by a number of parameters, including relative location to the TSS, splicing context, distance between competing pAs, surrounding cis elements and concentrations of core C/P factors.
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Diferenciação Celular/genética , Proteína I de Ligação a Poli(A)/genética , Poliadenilação/genética , Splicing de RNA/genética , Regiões 3' não Traduzidas/genética , Éxons , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons/genética , Proteína I de Ligação a Poli(A)/biossíntese , Estabilidade de RNA/genética , RNA Mensageiro/genéticaRESUMO
Alternative cleavage and polyadenylation (APA) generates diverse mRNA isoforms. We developed 3' region extraction and deep sequencing (3'READS) to address mispriming issues that commonly plague poly(A) site (pA) identification, and we used the method to comprehensively map pAs in the mouse genome. Thorough annotation of gene 3' ends revealed over 5,000 previously overlooked pAs (â¼8% of total) flanked by A-rich sequences, underscoring the necessity of using an accurate tool for pA mapping. About 79% of mRNA genes and 66% of long noncoding RNA genes undergo APA, but these two gene types have distinct usage patterns for pAs in introns and upstream exons. Quantitative analysis of APA isoforms by 3'READS indicated that promoter-distal pAs, regardless of intron or exon locations, become more abundant during embryonic development and cell differentiation and that upregulated isoforms have stronger pAs, suggesting global modulation of the 3' end-processing activity in development and differentiation.
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Regiões 3' não Traduzidas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Poliadenilação , Animais , Camundongos , RNA Longo não Codificante , RNA Mensageiro/genéticaRESUMO
The human gene encoding the cleavage/polyadenylation (C/P) factor CstF-77 contains 21 exons. However, intron 3 (In3) accounts for nearly half of the gene region, and contains a C/P site (pA) with medium strength, leading to short mRNA isoforms with no apparent protein products. This intron contains a weak 5' splice site (5'SS), opposite to the general trend for large introns in the human genome. Importantly, the intron size and strengths of 5'SS and pA are all highly conserved across vertebrates, and perturbation of these parameters drastically alters intronic C/P. We found that the usage of In3 pA is responsive to the expression level of CstF-77 as well as several other C/P factors, indicating it attenuates the expression of CstF-77 via a negative feedback mechanism. Significantly, intronic C/P of CstF-77 pre-mRNA correlates with global 3'UTR length across cells and tissues. In addition, inhibition of U1 snRNP also leads to regulation of the usage of In3 pA, suggesting that the C/P activity in the cell can be cross-regulated by splicing, leading to coordination between these two processes. Importantly, perturbation of CstF-77 expression leads to widespread alternative cleavage and polyadenylation (APA) and disturbance of cell proliferation and differentiation. Thus, the conserved intronic pA of the CstF-77 gene may function as a sensor for cellular C/P and splicing activities, controlling the homeostasis of CstF-77 and C/P activity and impacting cell proliferation and differentiation.
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Diferenciação Celular/genética , Fator Estimulador de Clivagem/genética , Íntrons/genética , Poliadenilação/genética , Ribonucleoproteína Nuclear Pequena U1/genética , Regiões 3' não Traduzidas/genética , Proliferação de Células , Fator Estimulador de Clivagem/metabolismo , Éxons/genética , Genoma Humano , Células HeLa , Humanos , Sítios de Splice de RNA/genética , RNA Mensageiro/genética , Ribonucleoproteína Nuclear Pequena U1/antagonistas & inibidoresRESUMO
The aim of this work is to study cytoskeletal impairment during the development of ouabain-induced ventricular hypertrophy. Male Sprague-Dawley rats were treated with either ouabain or saline. Systolic blood pressure (SBP) was recorded weekly. At the end of the 3rd and 6th week, the rats were killed and cardiac mass index were measured. Hematoxylin-eosin and Sirius red staining were carried out and cardiac ultrastructure were studied using transmission electron microscopy. The mRNA level of Profilin-1, Desmin, PCNA, TGF-ß(1) and ET-1 in the left ventricle were measured using real-time quantitative PCR while their protein levels were examined by Western blot or immunohistochemistry. After 3 weeks, there was no significant difference in the mean SBP, cardiac mass index, mRNA and protein expression of PCNA, TGF-ß(1) and ET-1 between the two groups. However, ouabain-treated rats showed disorganized cardiac cytoskeleton with abnormal expression of Profilin-1 and Desmin. After 6 weeks, the cardiac mass index remained the same in the two groups while PCNA, TGF-ß(1), and ET-1 have been upregulated in ouabain-treated rats. The cardiac cytoskeletal impairment was more severe in ouabain-treated rats with further changes of Profilin-1 and Desmin. Cytoskeletal abnormality is an ultra-early change during ouabain-induced ventricular hypertrophy, before the release of hypertrophic factors. Therapy for prevention of ouabain-induced hypertrophy should start at the early stage by preventing the cytoskeleton from disorganization.
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Citoesqueleto/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/patologia , Miocárdio/ultraestrutura , Ouabaína/toxicidade , Animais , Pressão Sanguínea , Citoesqueleto/ultraestrutura , Desmina/biossíntese , Desmina/genética , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Microscopia Eletrônica de Transmissão , Miocárdio/metabolismo , Profilinas/biossíntese , Profilinas/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Synovial sarcomas are high-grade soft tissue sarcomas of primitive mesenchymal origin which are defined by a pathognomonic t(X;18)(p11,q11) translocation, and which occur in pediatric and adult populations. Herein we report a case of a 33-year-old female with a history of nasopharyngeal carcinoma status post radiotherapy, presenting with a poorly differentiated synovial sarcoma of the nasal cavity arising in the radiation field. While the development of radiation-associated sarcoma is a known complication of radiotherapy, to date only 10 cases of synovial sarcoma have been reported to occur in previously irradiated tissues. Moreover, only 1 case of poorly differentiated synovial sarcoma involving the nasopharynx has been described.
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Sarcoma Sinovial , Neoplasias de Tecidos Moles , Adulto , Feminino , Humanos , Criança , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/patologia , Cavidade Nasal/patologia , Proteínas de Fusão OncogênicaRESUMO
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.
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Accretion of material onto a black hole drags any magnetic fields present inwards, increasing their strength. Theory predicts that sufficiently strong magnetic fields can halt the accretion flow, producing a magnetically arrested disk (MAD). We analyzed archival multiwavelength observations of an outburst from the black hole x-ray binary MAXI J1820+070 in 2018. The radio and optical fluxes were delayed compared with the x-ray flux by about 8 and 17 days, respectively. We interpret this as evidence for the formation of a MAD. In this scenario, the magnetic field is amplified by an expanding corona, forming a MAD around the time of the radio peak. We propose that the optical delay is due to thermal viscous instability in the outer disk.
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OBJECTIVES: Fluorescence in situ hybridization (FISH) is a quick and reliable test to detect the reciprocal t(15;17)(q22;q21) translocation in acute promyeloid leukemia (APL). The typical signal pattern for positive t(15;17) is one red, one green, and two fusion when using a PML/RARA dual fusion translocation probe. However, for variant translocations leading to the fusion of a RARA gene with an alternate gene partner, a RARA break-apart probe should be used to verify the RARA rearrangement. The typical signal pattern for a positive RARA break-apart probe is one red, one green, and one fusion. In this study, we report a rare APL case with a PRKAR1A-RARA fusion gene with a signal pattern distinct from that of t(15;17) and its other variants.
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Endothelial inflammation plays a critical role in the development and progression of cardiovascular disease, albeit the mechanisms need to be fully elucidated. Nur77 is highly expressed in vascular endothelial cells (ECs) and plays a role in the regulation of cell proliferation and angiogenesis; its role in vascular inflammation, however, remains unknown. Treatment of human umbilical vein ECs (HUVECs) with tumor necrosis factor (TNF)-alpha substantially increased the transcription and protein expression of Nur77 in a dose and time-dependent manner, as determined by Northern blot and Western blot analysis. Adenovirus mediated overexpression of Nur77 markedly increased the intracellular levels of IkappaBalpha by approximately 4-fold, whereas overexpression of dominant negative Nur77 (DN-Nur77), which lacks its transactivation domain, had no effect on IkappaBalpha expression, suggesting that Nur77 is an important transcriptional factor in controlling IkappaBalpha expression in ECs. Furthermore, overexpression of Nur77 significantly increased IkappaBalpha promoter activity via directly binding to a Nur77 response element in the IkappaBalpha promoter. Importantly, overexpression of Nur77, but not DN-Nur77, protected ECs against the TNF-alpha- and interleukin-1beta-induced endothelial activation, as characterized by attenuation in the nuclear factor kappaB activation, expression of adhesion molecules ICAM-1 and VCAM-1, and monocytic adherence to ECs. These results indicate that Nur77 negatively regulates the TNF-alpha- and interleukin-1beta-induced vascular EC activation by transcriptionally upregulation of IkappaBalpha expression.
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Proteínas de Ligação a DNA/biossíntese , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Proteínas I-kappa B/biossíntese , Receptores de Esteroides/biossíntese , Adenoviridae , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Humanos , Proteínas I-kappa B/genética , Inflamação/genética , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Interleucina-1beta/farmacologia , Monócitos/metabolismo , Mutação , Inibidor de NF-kappaB alfa , Neovascularização Fisiológica/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Receptores de Esteroides/genética , Elementos de Resposta/genética , Fatores de Tempo , Fator de Necrose Tumoral alfa/farmacologia , Células U937 , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
OBJECTIVE: To elucidate the roles of monocyte chemotactic factors (MCP-1, RANTES and Fractalkine) on the vulnerability of atherosclerotic plaques in patients with stable (SAP) and unstable angina pectoris (UAP). METHODS: Patients with SAP (n = 50) and UAP (n = 50) underwent coronary angiography (CAG) and intravenous ultrasound (IVUS) were included in the study. Monocyte chemotaxis was assayed by the transwell chamber. Concentrations of hs-CRP, MCP-1, RANTES and Fractalkine were measured by Enzyme-linked-immunosorbent assay (ELISA). mRNA expression of MCP-1, RANTES and Fractalkine in the monocytes was detected by RT-PCR. RESULTS: IVUS evidenced soft lipid plaques in 48% UAP patients and in 16% SAP patients (P < 0.05). SAP patients had mainly fibrous and mixed plaques. Plaque burden and vascular remodeling index were significantly higher in UAP patients than in SAP patients (P < 0.01). The averaged number of migrated monocytes in the UAP patients were higher than that in patients with SAP (P < 0.01). Concentration of hs-CRP, MCP-1, RANTES and Fractalkine were significantly higher in UAP patients than those of SAP patients (P < 0.05 or P < 0.01). mRNA expression of MCP-1, RANTES and Fractalkine in patients with UAP was significantly higher than those of SAP patients (P < 0.05). CONCLUSION: Upregulated monocyte chemotactic factors (MCP-1, RANTES and Fractalkine) might promote coronary plaque vulnerability in UAP patients.
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Angina Pectoris/metabolismo , Angina Instável/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CX3CL1/metabolismo , Placa Aterosclerótica/patologia , Angina Pectoris/patologia , Angina Instável/patologia , Angiografia Coronária , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genéticaRESUMO
A black hole X-ray binary produces hard X-ray radiation from its corona and disk when the accreting matter heats up. During an outburst, the disk and corona co-evolves with each other. However, such an evolution is still unclear in both its geometry and dynamics. Here we report the unusual decrease of the reflection fraction in MAXI J1820+070, which is the ratio of the coronal intensity illuminating the disk to the coronal intensity reaching the observer, as the corona is observed to contrast during the decay phase. We postulate a jet-like corona model, in which the corona can be understood as a standing shock where the material flowing through. In this dynamical scenario, the decrease of the reflection fraction is a signature of the corona's bulk velocity. Our findings suggest that as the corona is observed to get closer to the black hole, the coronal material might be outflowing faster.
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Endothelium-derived nitric oxide (NO) is an important regulator of vascular function. NO is produced by endothelial NO synthase (eNOS), whose expression is downregulated by tumor necrosis factor (TNF)-alpha at the posttranscriptional level. To elucidate the molecular basis of TNF-alpha-mediated eNOS mRNA instability, eNOS 3' untranslated region (3'-UTR) binding proteins were purified by RNA affinity chromatography from cytosolic fractions of TNF-alpha-stimulated human umbilical vein endothelial cells (HUVECs). The formation of 3'-UTR ribonucleoprotein complexes, with molecular weight of 52 and 57 kDa, was increased by TNF-alpha. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis of the 52-kDa protein identified 3 peptides that comprise the peptide sequence of translation elongation factor 1-alpha 1 (eEF1A1). In HUVECs, TNF-alpha rapidly increased eEF1A1 expression, which is maximal after 1 hour and persists for up to 48 hours. RNA gel mobility-shift and UV cross-linking assays indicated that recombinant glutathione S-transferase-eEF1A1 fusion protein specifically binds to a UC-rich sequence in the 3'-UTR of eNOS mRNA. In addition, the domain III of eEF1A1 mediates the binding of eNOS 3'-UTR in eEF1A1. Overexpression of eEF1A1 markedly attenuated the expression of eNOS and luciferase gene fused with eNOS 3'-UTR in both COS-7 cells and bovine aortic endothelial cells (BAECs). Furthermore, adenovirus-mediated overexpression of eEF1A1 increased eNOS mRNA instability, whereas knockdown of eEF1A1 substantially attenuated TNF-alpha-induced destabilization of eNOS mRNA and downregulation of eNOS expression in HUVECs. These results indicate that eEF1A1 is a novel eNOS 3'-UTR binding protein that plays a critical role in mediating TNF-alpha-induced decrease in eNOS mRNA stability.
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Regulação para Baixo/fisiologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/genética , Fator 1 de Elongação de Peptídeos/fisiologia , Estabilidade de RNA/genética , Fator de Necrose Tumoral alfa/fisiologia , Sequência de Aminoácidos , Animais , Células COS , Bovinos , Células Cultivadas , Chlorocebus aethiops , Humanos , Dados de Sequência Molecular , Óxido Nítrico Sintase Tipo III/metabolismo , Fator 1 de Elongação de Peptídeos/genética , Biossíntese de Proteínas/fisiologiaRESUMO
Mst1 (mammalian sterile 20-like kinase 1) is a ubiquitously expressed serine/threonine kinase and its activation in the heart causes cardiomyocyte apoptosis and dilated cardiomyopathy. Its myocardial substrates, however, remain unknown. In a yeast two-hybrid screen of a human heart cDNA library with a dominant-negative Mst1 (K59R) mutant used as bait, cTn [cardiac Tn (troponin)] I was identified as an Mst1-interacting protein. The interaction of cTnI with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK-293 cells (human embryonic kidney cells) and native cardiomyocytes, in which cTnI interacted with full-length Mst1, but not with its N-terminal kinase fragment. in vitro phosphorylation assays demonstrated that cTnI is a sensitive substrate for Mst1. In contrast, cTnT was phosphorylated by Mst1 only when it was incorporated into the Tn complex. MS analysis indicated that Mst1 phosphorylates cTnI at Thr(31), Thr(51), Thr(129) and Thr(143). Substitution of Thr(31) with an alanine residue reduced Mst1-mediated cTnI phosphorylation by 90%, whereas replacement of Thr(51), Thr(129) or Thr(143) with alanine residues reduced Mst1-catalysed cTnI phosphorylation by approx. 60%, suggesting that Thr(31) is a preferential phosphorylation site for Mst1. Furthermore, treatment of cardiomyocytes with hydrogen peroxide rapidly induced Mst1-dependent phosphorylation of cTnI at Thr(31). Protein epitope analysis and binding assays showed that Mst1-mediated phosphorylation modulates the molecular conformation of cTnI and its binding affinity to TnT and TnC, thus indicating functional significances. The results of the present study suggest that Mst1 is a novel mediator of cTnI phosphorylation in the heart and may contribute to the modulation of myofilament function under a variety of physiological and pathophysiological conditions.
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Miocárdio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Troponina I/metabolismo , Sequência de Aminoácidos , Animais , Biocatálise , Linhagem Celular , Sequência Conservada , Ativação Enzimática/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Dados de Sequência Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Alinhamento de Sequência , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Troponina C/metabolismo , Troponina I/química , Troponina I/genética , Troponina T/metabolismoRESUMO
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic neoplasm that exhibits myelodysplastic and myeloproliferative characteristics with heterogeneous clinical and pathological features. There are limited publications on the ethnic and racial disparity of cytogenetics and genomics in CMML patients. This study aims to define the cytogenetic and molecular landscape in Hispanic CMML patients from Puerto Rico and explore its possible clinical significance. One hundred and eleven (111) Hispanic CMML patients from Puerto Rico were diagnosed in our institute from 2009 to 2018. Karyotypes were available in one hundred and seven (107) patients. Seventeen (17) patients had abnormal karyotypes (17/107, 16%). Compared to previously published data, Hispanic CMML patients in this study had significantly lower rates of overall cytogenetic abnormalities (16% vs 27-28%, p < 0.05) and trisomy 8 (2% vs 7%, p < 0.05). Among one hundred and eleven (111) Hispanic CMML patients, 40-gene myeloid molecular profile tests were performed in fifty-six (56) CMML patients. Gene mutations were identified in fifty-four (54) patients (96%). The most frequent mutated genes were: TET2, SRSF2, ASXL1, ZRSR2, DNMT3A, NRAS, CBL, and RUNX1. Twenty-nine (29) out of fifty-six (56) patients (29/56, 52%) had mutated TET2/wild type ASXL1 (muTET2/wtASXL1). Previous studies indicated that mutated ASXL1, DNMT3A, NRAS, RUNX1, and SETBP1 may associate with an unfavorable prognosis and muTET2/wtASXL1 may associate with a favorable prognosis in CMML patients. Compared to previously published data, Hispanic CMML patients from Puerto Rico in this study had significantly lower mutation rates in ASXL1 and SETBP1, and a higher rate of muTET2/wtASXL1. The findings raise the possibility of a favorable prognosis in Hispanic CMML patients.
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Targeted therapy has changed the paradigm of advanced NSCLC management by improving the survival rate of patients carrying actionable gene alterations using specific inhibitors. The epidemiologic features of these alterations vary among races. Understanding the racial differences benefits drug development, clinical trial design, and health resource allocation. Compared to Caucasian and Asian populations, current knowledge on Hispanic patients is less and no data of Hispanic patients from Puerto Rico have been reported. We retrieved and analyzed the demographic, clinical, and molecular data of Hispanic NSCLC patients from Puerto Rico with molecular tests performed in the Genoptix Medical Laboratory in Carlsbad, CA, USA between 2011 and 2018. The majority of the NSCLC patients in our study had either adenocarcinoma (75.4%) or squamous cell carcinoma (15.1%). The incidence of EGFR mutations was 24%. They were more common in female and younger patients (<60 years). The deletion of Exon 19 and Exon 21 L858R comprised 55.1% and 31.0% of all EGFR mutations, respectively. The frequency of the T790M mutation was lower compared to that of Hispanic patients reported in the literature (0.5% vs. 2.1%). In addition, 18.7% of the patients were positive for KRAS mutations, which was at the high end of that reported in Hispanic patients. Other driver gene alterations, ALK, MET, RET, ROS1, KRAS, ERBB2, etc., demonstrated similar incidences, as well as gender and age distributions to those previously reported. The KRAS/TP53 and KRAS/STK11 co-mutations were of very low frequencies (3.6%), which could potentially affect the responsiveness to PD1/PD-L1 immunotherapy. Our study demonstrated that the prevalence of NSCLC gene alterations in Hispanic patients from Puerto Rico was comparable to the reported average prevalence in Latin American countries, supporting the intermediate NSCLC gene alteration rate of Hispanic patients between Asian and Caucasian patients. Novel information of the frequencies of KRAS mutation subtypes, driver gene alterations in ROS1, BRAF, and ERBB2, and passenger gene alterations including a rare case with the FGFR2-TACC2 translocation in Hispanic NSCLC patients from Puerto Rico were also described.
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This study investigated the value of arterial elasticity measurement in the early diagnosis of angiographic coronary artery atherosclerosis in 105 consecutive elderly patients. They were divided into two groups according to the results of selective coronary angiography: 55 with coronary atherosclerosis and 50 with a normal coronary angiogram. The Gensini score of the coronary artery was acquired and capacitive arterial compliance (C1) and oscillatory arterial compliance (C2) were measured. An independent-sample t-test was used to evaluate the difference in C1 and C2 between the two groups. Bivariate analyses were performed to study the association between the Gensini score and C1 and C2. A significant difference between the two groups in C2 was found and the Gensini score of the coronary artery was significantly correlated with C2. Identification of early coronary atherosclerosis in geriatrics may be aided by the prognostic value of C2.
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Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/patologia , Resistência Vascular/fisiologia , Idoso , Doença da Artéria Coronariana/sangue , Elasticidade , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
AIMS: Recent evidence suggests that the epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess mitogenic and angiogenic effects in vascular endothelial cells. However, the mechanisms underlying these effects are not fully elucidated. Because sphingosine kinase (SK) and its product S1P play essential roles in cell growth, survival and migration, we hypothesized that SK activation by EETs may mediate some of its angiogenic effects. METHODS AND RESULTS: We studied the effects of EETs on SK activity in human umbilical vein endothelial cells (HUVECs). Treatment with EETs, particularly 11,12-EET, markedly augmented SK activity in HUVECs. At the concentration of 1 micromol/L, 11,12-EET increased SK activity by 110% and the maximal effect on SK activation was observed at 20 min after 11,12-EET addition. Furthermore, inhibition of SK by a specific inhibitor, SKI-II, markedly attenuated 11,12-EET-induced EC proliferation. Importantly, 11,12-EET-induced activation of Akt kinase and transactivation of the epidermal growth factor (EGF) receptor was also inhibited by SKI-II. To investigate the isoform-specific role of SK in EET-induced angiogenesis, inhibition of SK1 by expression of dominant-negative SK1(G82D) substantially attenuated 11,12-EET-induced EC proliferation, migration, and tube formation in vitro and Matrigel plug angiogenesis in vivo. Furthermore, knockdown of SK1 expression by specific siRNA also inhibited 11,12-EET-induced EC proliferation and migration, whereas SK2 siRNA knockdown was without effect. CONCLUSION: These results suggest that SK1 is an important mediator of the 11,12-EET-induced angiogenic effects in human ECs. Thus, SK1 may represent a novel therapeutic modality for the treatment of angiogenesis-related diseases such as cancer and ischaemia.