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1.
Laryngoscope ; 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-39323321

RESUMO

OBJECTIVE: To compare survival endpoints in patients with laryngeal carcinoma in situ (L-CIS) who received definitive radiotherapy (RT) versus other modalities as first-line treatment and after disease recurrence. METHODS: This is a retrospective study of patients with L-CIS treated between June 2001 and December 2021. Survival outcomes (recurrence-free (RFS), invasion-free (IFS), laryngectomy-free (LFS), and overall survival (OS)) were compared between patients who had first-line RT versus non-RT modalities and for patients with recurrent disease who underwent second-line RT. RESULTS: A total of 85 patients with L-CIS were included (73 men [85.9%] and 12 [14.1%] women, median age of 65 [IQR: 55-74] years). Of these, 42 had first-line RT (49.4%) and 43 (50.6%) had non-RT treatment. After median follow-up of 4.8 (IQR: 2.8-9) years, patients in the first-line RT group had improved 2-year (94.2% [95% confidence interval (CI): 86.7-100] versus 41.7% [CI: 29.3-59.5]) and 5-year (90.6% [CI: 80.9-100] versus 27.5% [CI: 16.4-48.2]) RFS relative to non-RT recipients (p < 0.001). OS and IFS were similar between groups. However, patients in the RT group had worse 2-year (94% [CI: 87-100] versus 98% [CI: 93-100]) and 5-year (82% [CI: 68-99] versus 98% [CI: 93-100]; p = 0.013) LFS. All 35 patients with recurrent L-CIS were successfully cured with second-line treatments (12 received RT [34.3%]), and no differences in any survival endpoints were seen in these patients based on first-line and second-line treatments. CONCLUSION: Although first-line RT for L-CIS led to improved recurrence-free survival compared with other modalities, second-line RT may be a particularly valuable option for recurrent CIS. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

2.
J Gerontol A Biol Sci Med Sci ; 79(11)2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39297494

RESUMO

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with early onset of chronic diseases and increased risk of chronic disorders. Chronic viral infections have been linked to accelerated biological aging based on epigenetic clocks. In this study, we aimed to investigate the association between HCV infection and clinical measures of biological aging among 8 306 adults participating in the 2015-2018 waves of the National Health and Nutrition Examination Survey (NHANES). METHODS: NHANES 2015-2018 participants aged 20 years and older who had complete data on clinical blood markers and HCV-related tests were included in the current study. We estimated biological age using 2 approaches including phenotypic age (PhenoAge) and allostatic load (AL) score based on 9 clinical biomarkers. RESULTS: After adjusting for demographic and other confounding factors, HCV antibody-positivity was associated with advanced PhenoAge (ß = 2.43, 95% confidence interval: 1.51-3.35), compared with HCV antibody-negativity. Additionally, both active HCV infection (HCV RNA (+)) and resolved infection were associated with greater PhenoAge acceleration. The positive association with the AL score was not statistically significant. We did not observe any significant interactions of potential effect modifiers, including smoking and use of drug/needle injection, with HCV infection on measures of biological aging. CONCLUSIONS: Our findings suggest that HCV infection is independently associated with biological aging measured by phenotypic age in the U.S. general population. Further studies are warranted to confirm the findings.


Assuntos
Hepatite C Crônica , Inquéritos Nutricionais , Fenótipo , Humanos , Masculino , Feminino , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Adulto , Hepatite C Crônica/epidemiologia , Idoso , Biomarcadores/sangue , Senilidade Prematura/epidemiologia , Adulto Jovem , Alostase/fisiologia , Anticorpos Anti-Hepatite C/sangue , Hepatite C/epidemiologia
3.
Gynecol Oncol ; 188: 44-51, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38936280

RESUMO

OBJECTIVE: Substantial lymphovascular space invasion (LVSI) is an important predictor of lymph node (LN) involvement in women with endometrial carcinoma. We studied the prognostic significance of substantial LVSI in patients with 2009-FIGO stage-I uterine endometrioid adenocarcinoma (EC) who all had pathologic negative nodal evaluation (PNNE). METHODS: Pathologic specimens were retrieved and LVSI was quantified (focal or substantial) in women with stage-I EC who had a hysterectomy and PNNE. In addition to multivariate analysis (MVA), recurrence-free (RFS), disease-specific (DSS), and overall (OS) survival was compared between women with focal vs. substantial LVSI. RESULTS: 1052 patients were identified with a median follow-up of 9.7 years. 358 women (34%) received adjuvant radiotherapy. 907 patients (86.2%) had no LVSI, 87 (8.3%) had focal, and 58 (5.5%) had substantial LVSI. Five-year RFS was 93.3% (95% CI: 91.5-95.1), 76.8% (95% CI: 67.2-87.7) and 79.1% (95% CI: 67.6-95.3) for no, focal, and substantial LVSI(p < 0.0001). There was no statistically significant difference in 5-year RFS, DSS, OS, and in the patterns of initial recurrence between women with focal vs substantial LVSI. On MVA with propensity score matching, substantial LVSI was not independently associated with any survival endpoint compared to focal LVSI, albeit both were detrimental when compared to no LVSI. Age ≥ 60 years and higher grade were predictors of worse RFS, DSS, and OS. Additionally, comorbidity burden was an independent predictor for OS. CONCLUSIONS: Our results suggest that substantial LVSI does not predict worse survival endpoints or different recurrence patterns in women with stage-I EC with PNNE when compared to focal LVSI.


Assuntos
Carcinoma Endometrioide , Invasividade Neoplásica , Estadiamento de Neoplasias , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Prognóstico , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/terapia , Metástase Linfática , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/terapia , Linfonodos/patologia , Adulto , Idoso de 80 Anos ou mais , Neoplasias Uterinas/patologia , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/terapia , Estudos Retrospectivos , Histerectomia
4.
Sci Rep ; 12(1): 16176, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36171201

RESUMO

Patients with SARS-CoV-2 infection are at an increased risk of cardiovascular and thrombotic complications conferring an extremely poor prognosis. COVID-19 infection is known to be an independent risk factor for acute ischemic stroke and myocardial infarction (MI). We developed a risk assessment model (RAM) to stratify hospitalized COVID-19 patients for arterial thromboembolism (ATE). This multicenter, retrospective study included adult COVID-19 patients admitted between 3/1/2020 and 9/5/2021. Among 3531 patients from the training cohort, 15.5% developed acute in-hospital ATE, including stroke, MI, and other ATE, compared to 13.4% in the validation cohort. The 16-item final score was named SARS-COV-ATE (Sex: male = 1, Age [40-59 = 2, > 60 = 4], Race: non-African American = 1, Smoking = 1 and Systolic blood pressure elevation = 1, Creatinine elevation = 1; Over the range: leukocytes/lactate dehydrogenase/interleukin-6, B-type natriuretic peptide = 1, Vascular disease (cardiovascular/cerebrovascular = 1), Aspartate aminotransferase = 1, Troponin-I [> 0.04 ng/mL = 1, troponin-I > 0.09 ng/mL = 3], Electrolytes derangement [magnesium/potassium = 1]). RAM had a good discrimination (training AUC 0.777, 0.756-0.797; validation AUC 0.766, 0.741-0.790). The validation cohort was stratified as low-risk (score 0-8), intermediate-risk (score 9-13), and high-risk groups (score ≥ 14), with the incidence of ATE 2.4%, 12.8%, and 33.8%, respectively. Our novel prediction model based on 16 standardized, commonly available parameters showed good performance in identifying COVID-19 patients at risk for ATE on admission.


Assuntos
COVID-19 , AVC Isquêmico , Tromboembolia , Adulto , Aspartato Aminotransferases , COVID-19/complicações , Creatinina , Humanos , Interleucina-6 , AVC Isquêmico/etiologia , Lactato Desidrogenases , Magnésio , Masculino , Peptídeo Natriurético Encefálico , Potássio , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , SARS-CoV-2 , Tromboembolia/epidemiologia , Tromboembolia/etiologia , Troponina I
5.
Autophagy ; 16(7): 1296-1313, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31612776

RESUMO

BIRC5/Survivin is known as a dual cellular functions protein that directly regulates both apoptosis and mitosis in embryonic cells during embryogenesis and in cancer cells during tumorigenesis and tumor metastasis. However, BIRC5 has seldom been demonstrated as a direct macroautophagy/autophagy regulator in cells. ATG7 expression and ATG12-ATG5-ATG16L1 complex formation are crucial for the phagophore elongation during autophagy in mammalian cells. In this study, we observed that the protein expression levels of BIRC5 and ATG7 were inversely correlated, whereas the expression levels of BIRC5 and SQSTM1/p62 were positively correlated in normal breast tissues and tumor tissues. Mechanistically, we found that BIRC5 negatively modulates the protein stability of ATG7 and physically binds to the ATG12-ATG5 conjugate, preventing the formation of the ATG12-ATG5-ATG16L1 protein complex in human cancer (MDA-MB-231, MCF7, and A549) and mouse embryonic fibroblast (MEF) cells. We also observed a concurrent physical dissociation between BIRC5 and ATG12-ATG5 (but not CASP3/caspase-3) and upregulation of autophagy in MDA-MB-231 and A549 cells under serum-deprived conditions. Importantly, despite the fact that upregulation of autophagy is widely thought to promote DNA repair in cells under genotoxic stress, we found that BIRC5 maintains DNA integrity through autophagy negative-modulations in both human cancer and MEF cells under non-stressed conditions. In conclusion, our study reveals a novel role of BIRC5 in cancer cells as a direct regulator of autophagy. BIRC5 may act as a "bridging molecule", which regulates the interplay between mitosis, apoptosis, and autophagy in embryonic and cancer cells. ABBREVIATIONS: ACTA1: actin; ATG: autophagy related; BIRC: baculoviral inhibitor of apoptosis repeat-containing; BAF: bafilomycin A1; CQ: chloroquine; CASP3: caspase 3; HSPB1/Hsp27: heat shock protein family B (small) member 1/heat shock protein 27; IAPs: inhibitors of apoptosis proteins; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PLA: proximity ligation assay; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA.


Assuntos
Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/metabolismo , Autofagia , Dano ao DNA , Embrião de Mamíferos/citologia , Fibroblastos/metabolismo , Neoplasias/metabolismo , Survivina/metabolismo , Animais , Linhagem Celular Tumoral , Meios de Cultura Livres de Soro , Regulação para Baixo , Humanos , Camundongos , Neoplasias/patologia , Ligação Proteica , Processamento de Proteína Pós-Traducional , Estabilidade Proteica
6.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28853218

RESUMO

BACKGROUND: We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians. PROCEDURE: Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346). RESULTS: The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02). CONCLUSIONS: Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B-precursor ALL.


Assuntos
GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Taxa de Sobrevida , Taiwan
7.
Front Pharmacol ; 8: 902, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29326587

RESUMO

Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

8.
Onco Targets Ther ; 9: 2601-13, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27217778

RESUMO

Survivin is a member of the inhibitor-of-apoptosis proteins family. It is overexpressed in many different cancer types but not in the differentiated normal tissue. In addition, overexpression of survivin promotes cancer cell survival and induces chemotherapeutic drug resistance, making it an attractive target for new anticancer interventions. Despite survivin being a promising molecular target for anticancer treatment, it is widely accepted that survivin is only a "semi-druggable" target. Therefore, it is important to develop a new strategy to target survivin for anticancer treatment. In this study, we constructed a novel survivin promoter-driven full-length antisense survivin (pSur/AS-Sur) expression plasmid DNA. Promoter activity assay revealed that the activity of the survivin promoter of pSur/AS-Sur correlated with the endogenous expression of survivin at the transcriptional level in the transfected A549, MDA-MB-231, and PANC-1 cancer cells. Western blot analysis showed that liposomal delivery of pSur/AS-Sur successfully downregulated the expression of survivin in A549, MBA-MB-231, and PANC-1 cells in vitro. In addition, delivery of pSur/AS-Sur induced autophagy, caspase-dependent apoptosis, and caspase-independent apoptosis as indicated by the increased LC3B-II conversion, autophagosome formation, caspase-9/-3 and poly(ADP-ribose) polymerase-1 cleavage, and apoptosis-inducing factor nuclear translocation in A549, MBA-MB-231, and PANC-1 cells. Importantly, liposomal delivery of pSur/AS-Sur was also capable of decreasing the proliferation of the survivin/MDR1 coexpressing multidrug-resistant KB-TAX50 cancer cells and the estrogen receptor-positive tamoxifen-resistant MCF7-TamC3 cancer cells in vitro. In conclusion, the results of this study suggest that delivery of a survivin promoter-driven antisense survivin-expressing plasmid DNA is a promising way to target survivin and to treat survivin-expressing cancers in the future.

9.
Front Pharmacol ; 7: 81, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27065869

RESUMO

SAHA is a class I HDAC/HDAC6 co-inhibitor and an autophagy inducer currently undergoing clinical investigations in breast cancer patients. However, the molecular mechanism of action of SAHA in breast cancer cells remains unclear. In this study, we found that SAHA is equally effective in targeting cells of different breast cancer subtypes and tamoxifen sensitivity. Importantly, we found that down-regulation of survivin plays an important role in SAHA-induced autophagy and cell viability reduction in human breast cancer cells. SAHA decreased survivin and XIAP gene transcription, induced survivin protein acetylation and early nuclear translocation in MCF7 and MDA-MB-231 breast cancer cells. It also reduced survivin and XIAP protein stability in part through modulating the expression and activation of the 26S proteasome and heat-shock protein 90. Interestingly, targeting HDAC3 and HDAC6, but not other HDAC isoforms, by siRNA/pharmacological inhibitors mimicked the effects of SAHA in modulating the acetylation, expression, and nuclear translocation of survivin and induced autophagy in MCF7 and MDA-MB-231 cancer cells. Targeting HDAC3 also mimicked the effect of SAHA in up-regulating the expression and activity of proteasome, which might lead to the reduced protein stability of survivin in breast cancer cells. In conclusion, this study provides new insights into SAHA's molecular mechanism of actions in breast cancer cells. Our findings emphasize the complexity of the regulatory roles in different HDAC isoforms and potentially assist in predicting the mechanism of novel HDAC inhibitors in targeted or combinational therapies in the future.

10.
Oncotarget ; 6(32): 33217-25, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26375248

RESUMO

The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Duplicação Gênica , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , DNA Metiltransferase 3A , Feminino , Frequência do Gene , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Análise de Sobrevida , Sequências de Repetição em Tandem , Adulto Jovem
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