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1.
Fish Shellfish Immunol ; 151: 109722, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38925447

RESUMO

Cytokine-like factor 1 (CYTL1) is a small cytokine and has diverse biological functions in mammals. However, whether CYTL1 exists in lower vertebrates is not clear. In this study, we identified cytl homologs in fish and characterized the immune functions in a teleost species, grass carp (Ctenopharyngodon idella). Fish CYTL1 homologs share conserved molecular features with their mammalian counterparts, including 6 cysteine residues in the mature peptide, genomic organization and synteny. Gene expression analysis revealed that cytl1 was constitutively expressed in tissues of grass carp, with the highest expression detected in the heart. Upon infection with Aeromonas hydrophila (A. hydrophila), cytl1 was downregulated in the hindgut, head kidney, skin, and spleen. In the primary head kidney leukocytes (HKLs), stimulation with inactivated A. hydrophila, LPS, poly(I:C), IL-22, IFN-a or IFN-γrel resulted in downregulation of cytl1 expression. Recombinant grass carp CYTL1 protein produced in the HEK293-F cells was potent to induce il-10 expression, but had little effect on the expression of il-1ß and il-6. In vivo experiments revealed that CYTL1 was effective to recruit macrophages to the muscle injected with cytl expression plasmids. Taken together, our results indicate that CYTL1 is a potent chemokine for recruitment of macrophages in fish.


Assuntos
Aeromonas hydrophila , Carpas , Doenças dos Peixes , Proteínas de Peixes , Infecções por Bactérias Gram-Negativas , Macrófagos , Carpas/imunologia , Carpas/genética , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Proteínas de Peixes/química , Doenças dos Peixes/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Aeromonas hydrophila/fisiologia , Macrófagos/imunologia , Filogenia , Regulação da Expressão Gênica/imunologia , Sequência de Aminoácidos , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Perfilação da Expressão Gênica/veterinária , Alinhamento de Sequência/veterinária , Imunidade Inata/genética , Fatores Quimiotáticos/genética , Fatores Quimiotáticos/imunologia
2.
J Natl Compr Canc Netw ; 21(10): 1039-1049.e10, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37856199

RESUMO

BACKGROUND: Although VEGFR tyrosine kinase inhibitors (TKIs) are a preferred systemic treatment approach for patients with advanced renal cell carcinoma (RCC) and thyroid carcinoma (TC), treatment-related cardiovascular (CV) toxicity is an important contributor to morbidity. However, the clinical risk assessment and impact of CV toxicities, including early significant hypertension, among real-world advanced cancer populations receiving VEGFR TKI therapies remain understudied. METHODS: In a multicenter, retrospective cohort study across 3 large and diverse US health systems, we characterized baseline hypertension and CV comorbidity in patients with RCC and those with TC who are newly initiating VEGFR TKI therapy. We also evaluated baseline patient-, treatment-, and disease-related factors associated with the risk for treatment-related early hypertension (within 6 weeks of TKI initiation) and major adverse CV events (MACE), accounting for the competing risk of death in an advanced cancer population, after VEGFR TKI initiation. RESULTS: Between 2008 and 2020, 987 patients (80.3% with RCC, 19.7% with TC) initiated VEGFR TKI therapy. The baseline prevalence of hypertension was high (61.5% and 53.6% in patients with RCC and TC, respectively). Adverse CV events, including heart failure and cerebrovascular accident, were common (occurring in 14.9% of patients) and frequently occurred early (46.3% occurred within 1 year of VEGFR TKI initiation). Baseline hypertension and Black race were the primary clinical factors associated with increased acute hypertensive risk within 6 weeks of VEGFR TKI initiation. However, early significant "on-treatment" hypertension was not associated with MACE. CONCLUSIONS: These multicenter, real-world findings indicate that hypertensive and CV morbidities are highly prevalent among patients initiating VEGFR TKI therapies, and baseline hypertension and Black race represent the primary clinical factors associated with VEGFR TKI-related early significant hypertension. However, early on-treatment hypertension was not associated with MACE, and cancer-specific CV risk algorithms may be warranted for patients initiating VEGFR TKIs.


Assuntos
Carcinoma de Células Renais , Hipertensão , Neoplasias Renais , Neoplasias da Glândula Tireoide , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/epidemiologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/epidemiologia , Pressão Sanguínea , Estudos Retrospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/epidemiologia , Hipertensão/induzido quimicamente , Hipertensão/epidemiologia , Hipertensão/tratamento farmacológico
3.
Environ Res ; 216(Pt 2): 114442, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36202245

RESUMO

The utilization of solid waste for resource recovery and production of value-added products is the theme of green chemistry. Currently, how to using solid wastes to prepare environmentally-functional materials with high performance and strength is one of the hot topics. In this research, electrolytic manganese residue (EMR) was thermally activated with calcite to prepare a silicon-based functionalized adsorbent (C-EMR) for the removal of cadmium (Cd2+, 467.14 mg/g) and lead (Pb2+, 972 mg/g). The thermodynamic results indicated that the removal process of Cd2+ and Pb2+ by C-EMR were endothermic and spontaneous. HNO3 can effectively strip the two adsorbed metals from C-EMR with the stripping efficiency of nearly 80% for Cd2+ and 99.92% for Pb2+, indicating that adsorption and ion exchange may be the main reason for the removal of the metals on C-EMR. Besides, surface precipitation was also responsible for removing some Pb2+ from the aquatic environment according to the X-ray photoelectron spectrometry (XPS) analysis. Results indicate that -SiO3- has stronger affinity with Pb2+ and Cd2+ than other groups ((-MnO2), -OH) by theoretical calculation (VASP, GGA-PBE). This study shows that this novel adsorbent (C-EMR) can be adopted as an environmentally-friendly, inexpensive and efficient adsorbent for removal of Cd2+ and Pb2+ from aquatic solution. This technique not only provides potential adsorbent for the elimination of heavy metals but also proposes an alternative route for the treatment and utilization of waste solid.


Assuntos
Metais Pesados , Poluentes Químicos da Água , Adsorção , Cádmio/análise , Compostos de Manganês/química , Chumbo , Poluentes Químicos da Água/análise , Óxidos/química , Metais Pesados/química , Cinética , Concentração de Íons de Hidrogênio
4.
Mol Genet Genomics ; 297(2): 591-600, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35218396

RESUMO

Long noncoding RNA (lncRNA) are involved in regulating physiological behaviors for various malignant tumors, including non-small-cell lung cancer (NSCLC). However, few studies comprehensively evaluated both lncRNA-lncRNA interaction effects and main effects of lncRNA on overall survival of NSCLC. Hence, we performed a two-phase designed study of lncRNA expression in tumor tissues using 604 NSCLC patients from The Cancer Genome Atlas as the discovery phase and 839 patients from Gene Expression Omnibus as the validation phase. In the discovery phase, we adopted a two-step strategy, Screening before Testing, for dimension reduction and signal detection. These candidate lncRNAs first screened out by the weighted random forest (Ranger), were then tested through the Cox proportional hazards model adjusted for covariates. Significant lncRNAs with either type of effects aforementioned were carried forward into the validation phase to confirm their significances again. As a result, in the discovery phase, 19 lncRNAs were identified by Ranger, among which five lncRNAs and one pair of lncRNA-lncRNA interaction exhibited significant effects (FDR-q ≤ 0.05) main and interaction effects on NSCLC survival, respectively, through Cox model. After the independent validation, we finally observed that one lncRNA (ENSG00000227403.1) with main effect was robustly associated with NSCLC prognosis (HRdiscovery = 0.90, P = 1.20 × 10-3; HRvalidation = 0.94, P = 4.11 × 10-3) and one pair of lncRNAs (ENSG00000267121.4 and ENSG00000272369.1) had significant interaction effect on NSCLC survival (HRdiscovery = 1.12, P = 3.07 × 10-4; HRvalidation = 1.11, P = 0.0397). Our comprehensive NSCLC prognostic study of lncRNA provided population-level evidence for further functional study.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , RNA Longo não Codificante , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
5.
Fish Shellfish Immunol ; 94: 685-696, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31546038

RESUMO

The S100 family proteins are a group of small acidic polypeptides and have diverse functions in regulating many aspects of physiological processes. They are structurally conserved and possess two EF-hands which are central for calcium-mediated functions. In this study, 14 S100 cDNA sequences were determined in zebrafish and their genomic organizations confirmed. Re-analyzing the gene synteny of the S100 loci identified two major S100 loci in Chr16 and Chr19 which share remarkable conservation with the S100 locus in human Chr1, suggesting they may have evolved from a single locus during the teleost specific whole genome duplication event. It appears that the homologues of human S100G and S100P have been lost in zebrafish. Expression analysis reveals that S100W, ICN1 and ICN2 are markedly expressed in embryos. Further, the transcripts of S100 genes are relatively abundant in mucosal tissues such as gills and gut. Intraperitoneal injection of poly(I:C) resulted in up-regulation of most S100 genes in the gut and spleen, with highest induction of S100V2 and S100Z detected. In fish challenged with spring viremia of carp virus (SVCV), expression of most S100 family genes was increased in the spleen between day 1 and 7 post infection, with consistent induction seen for the S100A1, S100A10b, S100B, S100ICN1, S100T, S100U, S100V1 and S100Z. Interestingly, intraperitoneal injection of Edwardsiella tarda down-regulated S100 expression in the gut but resulted in induction in the spleen. The results demonstrate that the S100 family genes are differentially modulated by bacterial and viral pathogens in zebrafish.


Assuntos
Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas S100/genética , Transcriptoma/imunologia , Peixe-Zebra/imunologia , Animais , Edwardsiella tarda/fisiologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/veterinária , Proteínas de Peixes/química , Proteínas de Peixes/metabolismo , Poli I-C/farmacologia , Rhabdoviridae/fisiologia , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Proteínas S100/química , Proteínas S100/metabolismo
6.
Fish Shellfish Immunol ; 90: 102-108, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048038

RESUMO

The suppressor of cytokine signaling (SOCS) family members play crucial roles in regulating immune signal pathways by acting as inhibitors of cytokine receptor signaling. In this study, 10 SOCS genes were identified in soiny mullet (Liza haematocheila), an economically important aquaculture mugilid species in China and other Asian countries. Sequence comparison showed that the sequence identity between mullet SOCSs and their counterparts from other vertebrates ranged from 38.2% to 92.5%. All mullet SOCS genes were constitutively expressed in tissues examined, but their expression patterns were different. Further, following Streptococcus dysgalactiae infection, all mullet SOCS genes exhibited distinct expression patterns in tissues. These results suggest that SOCSs are involved in immune response to bacterial infection and provide the basis for understanding the complex cytokine regulatory network of teleosts.


Assuntos
Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Smegmamorpha/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Análise de Sequência de DNA/veterinária , Análise de Sequência de Proteína/veterinária , Smegmamorpha/metabolismo , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus/fisiologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo
9.
Cell Physiol Biochem ; 48(3): 1230-1244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30045021

RESUMO

BACKGROUND/AIMS: Natural compounds are a promising resource for anti-tumor drugs. Myricetin, an abundant flavonoid found in the bark and leaves of bayberry, shows multiple promising anti-tumor functions in various cancers. METHODS: The cytotoxic, pro-apoptotic, and anti-metastatic effects of myricetin on prostate cancer cells were investigated in both in vitro and in vivo studies. Short-hairpin RNA knockdown of the proviral integration site for Moloney murine leukemia virus-1 (PIM1), pull-down and co-immunoprecipitation assays, and an intracellular Ca2+ flux assay were used to investigate the potential underlying mechanism of myricetin. ONCOMINE database data mining and immunohistochemical analysis of prostate cancer tissues were used to evaluate the expression of PIM1 and CXCR4, as well as the correlation between PIM1 and CXCR4 expression and the clinicopathologic characteristics and prognoses of prostate cancer patients. RESULTS: Myricetin exerted selective cytotoxic, pro-apoptotic, and anti-metastatic effects on prostate cancer cells by inhibiting PIM1 and disrupting the PIM1/CXCR4 interaction. Moreover, PIM1 and CXCR4 were coexpressed and associated with aggressive clinicopathologic traits and poor prognosis in prostate cancer patients. CONCLUSION: These results offer preclinical evidence for myricetin as a potential chemopreventive and therapeutic agent for precision medicine tailored to prostate cancer patients characterized by concomitant elevated expression of PIM1 and CXCR4.


Assuntos
Antineoplásicos/uso terapêutico , Flavonoides/uso terapêutico , Invasividade Neoplásica/prevenção & controle , Neoplasias da Próstata/tratamento farmacológico , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Receptores CXCR4/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Flavonoides/farmacologia , Humanos , Masculino , Camundongos Nus , Invasividade Neoplásica/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores
11.
J Manipulative Physiol Ther ; 38(2): 93-101, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25596875

RESUMO

OBJECTIVE: The purpose of this study was to quantify risk of stroke after chiropractic spinal manipulation, as compared to evaluation by a primary care physician, for Medicare beneficiaries aged 66 to 99 years with neck pain. METHODS: This is a retrospective cohort analysis of a 100% sample of annualized Medicare claims data on 1 157 475 beneficiaries aged 66 to 99 years with an office visit to either a chiropractor or primary care physician for neck pain. We compared hazard of vertebrobasilar stroke and any stroke at 7 and 30 days after office visit using a Cox proportional hazards model. We used direct adjusted survival curves to estimate cumulative probability of stroke up to 30 days for the 2 cohorts. RESULTS: The proportion of subjects with stroke of any type in the chiropractic cohort was 1.2 per 1000 at 7 days and 5.1 per 1000 at 30 days. In the primary care cohort, the proportion of subjects with stroke of any type was 1.4 per 1000 at 7 days and 2.8 per 1000 at 30 days. In the chiropractic cohort, the adjusted risk of stroke was significantly lower at 7 days as compared to the primary care cohort (hazard ratio, 0.39; 95% confidence interval, 0.33-0.45), but at 30 days, a slight elevation in risk was observed for the chiropractic cohort (hazard ratio, 1.10; 95% confidence interval, 1.01-1.19). CONCLUSIONS: Among Medicare B beneficiaries aged 66 to 99 years with neck pain, incidence of vertebrobasilar stroke was extremely low. Small differences in risk between patients who saw a chiropractor and those who saw a primary care physician are probably not clinically significant.


Assuntos
Manipulação Quiroprática/efeitos adversos , Manipulação da Coluna/efeitos adversos , Cervicalgia/reabilitação , Acidente Vascular Cerebral/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Manipulação Quiroprática/métodos , Manipulação da Coluna/métodos , Medicare/economia , Medicare/estatística & dados numéricos , Cervicalgia/diagnóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Estados Unidos
12.
Cancer Med ; 13(9): e7228, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38733174

RESUMO

BACKGROUND: The molecular and immunological characteristics of primary tumors and positive lymph nodes in esophageal squamous cell carcinoma (ESCC) are unknown and the relationship with recurrence is unclear, which this study attempted to explore. METHODS: A total of 30 ESCC patients with lymph node positive (IIB-IVA) were enrolled. Among them, primary tumor and lymph node specimens were collected from each patient, and subjected to 551-tumor-targeted DNA sequencing and 289-immuno-oncology RNA panel sequencing to identify the different molecular basis and immunological features, respectively. RESULTS: The primary tumors exhibited a higher mutation burden than lymph nodes (p < 0.001). One-year recurrent ESCC exhibited a higher Mucin16 (MUC16) mutation rate (p = 0.038), as well as univariate and multivariate analysis revealed that MUC16 mutation is independent genetic factor associated with reduced relapse-free survival (univariate, HR: 5.39, 95% CI: 1.67-17.4, p = 0.005; multivariate, HR: 7.36, 95% CI: 1.79-30.23, p = 0.006). Transcriptomic results showed non-relapse group had higher cytolytic activity (CYT) score (p = 0.025), and was enriched in the IFN-α pathway (p = 0.036), while those in the relapsed group were enriched in the TNF-α/NF-κB (p = 0.001) and PI3K/Akt pathway (p = 0.014). CONCLUSION: The difference in molecular characteristics between primary lesions and lymph nodes may be the cause of the inconsistent clinical outcomes. Mutations of MUC16 and poor immune infiltration are associated with rapid relapse of nodes-positive ESCC.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Linfonodos , Metástase Linfática , Mutação , Recidiva Local de Neoplasia , Humanos , Masculino , Feminino , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/mortalidade , Linfonodos/patologia , Linfonodos/imunologia , Idoso , Biomarcadores Tumorais/genética , Prognóstico , Proteínas de Membrana , Antígeno Ca-125
13.
Int J Surg ; 110(3): 1527-1536, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38116673

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is associated with a dismal prognosis. Immune checkpoint inhibitors have shown promising antitumor activity in neoadjuvant settings. This single-arm, phase II trial aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy as the neoadjuvant therapy (NAT) in early TNBC. METHODS: Patients received eight cycles of camrelizumab plus nonplatinum-based chemotherapy. The primary endpoint was total pathological complete response (pCR). Secondary endpoints included the breast pathological complete response (bpCR), adverse events (AEs). Multiomics biomarkers were assessed as exploratory objective. RESULTS: Twenty of 23 TNBC patients receiving NAT underwent surgery, with the total pCR rate of 65% (13/20) and bpCR rate of 70% (14/20). Grade ≥3 treatment-related AEs were observed in 14 (60.9%) patients, with the most common AE being neutropenia (65.2%). Tumor immune microenvironment was analyzed between pCR and non-pCR samples before and after the NAT. Gene expression profiling showed a higher immune infiltration in pCR patients than non-pCR patients in pre-NAT samples. Through establishment of a predictive model for the NAT efficacy, TAP1 and IRF4 were identified as the potential predictive biomarkers for response to the NAT. Gene set enrichment analysis revealed the glycolysis and hypoxia pathways were significantly activated in non-pCR patients before the NAT, and this hypoxia was aggravated after the NAT. CONCLUSION: Camrelizumab plus nonplatinum-based chemotherapy shows a promising pCR rate in early-stage TNBC, with an acceptable safety profile. TAP1 and IRF4 may serve as potential predictive biomarkers for response to the NAT. Aggravated hypoxia and activated glycolysis after the NAT may be associated with the treatment resistance.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias de Mama Triplo Negativas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hipóxia/tratamento farmacológico , Hipóxia/etiologia , Terapia Neoadjuvante , Projetos Piloto , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral , Feminino
14.
N Engl J Med ; 363(1): 45-53, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20463332

RESUMO

BACKGROUND: Current methods of risk adjustment rely on diagnoses recorded in clinical and administrative records. Differences among providers in diagnostic practices could lead to bias. METHODS: We used Medicare claims data from 1999 through 2006 to measure trends in diagnostic practices for Medicare beneficiaries. Regions were grouped into five quintiles according to the intensity of hospital and physician services that beneficiaries in the region received. We compared trends with respect to diagnoses, laboratory testing, imaging, and the assignment of Hierarchical Condition Categories (HCCs) among beneficiaries who moved to regions with a higher or lower intensity of practice. RESULTS: Beneficiaries within each quintile who moved during the study period to regions with a higher or lower intensity of practice had similar numbers of diagnoses and similar HCC risk scores (as derived from HCC coding algorithms) before their move. The number of diagnoses and the HCC measures increased as the cohort aged, but they increased to a greater extent among beneficiaries who moved to regions with a higher intensity of practice than among those who moved to regions with the same or lower intensity of practice. For example, among beneficiaries who lived initially in regions in the lowest quintile, there was a greater increase in the average number of diagnoses among those who moved to regions in a higher quintile than among those who moved to regions within the lowest quintile (increase of 100.8%; 95% confidence interval [CI], 89.6 to 112.1; vs. increase of 61.7%; 95% CI, 55.8 to 67.4). Moving to each higher quintile of intensity was associated with an additional 5.9% increase (95% CI, 5.2 to 6.7) in HCC scores, and results were similar with respect to laboratory testing and imaging. CONCLUSIONS: Substantial differences in diagnostic practices that are unlikely to be related to patient characteristics are observed across U.S. regions. The use of clinical or claims-based diagnoses in risk adjustment may introduce important biases in comparative-effectiveness studies, public reporting, and payment reforms.


Assuntos
Técnicas e Procedimentos Diagnósticos/estatística & dados numéricos , Medicare/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Técnicas e Procedimentos Diagnósticos/tendências , Feminino , Humanos , Masculino , Dinâmica Populacional , Padrões de Prática Médica/tendências , Análise de Regressão , Características de Residência , Risco Ajustado , Estados Unidos
15.
Med Care ; 51(4): 361-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23481033

RESUMO

BACKGROUND: The National Oncologic PET Registry (NOPR) ascertained changes in the intended management of cancer patients using questionnaire data obtained before and after positron emission tomography (PET) under Medicare's coverage with evidence development policy. OBJECTIVE: To assess the concordance between intended care plans and care received as ascertained through administrative claims data. RESEARCH DESIGN: Analysis of linked data of NOPR participants from 2006 to 2008 and their corresponding Medicare claims. SUBJECTS: Consenting patients aged older than 65 years having their first PET for restaging of bladder, kidney, ovarian, pancreas, prostate, small cell lung, or stomach cancer. MEASURES: : Agreement (positive predictive values and κ) between NOPR post-PET intended management plans for treatment (systemic therapy, radiotherapy, surgery, or combinations), biopsy, or watching as compared to claims-inferred care 30 days after PET. RESULTS: A total of 8460 patients with linked data were assessed. A total of 43.5% had metastatic disease and 45.3% had treatment planned (predominantly systemic therapy only), 11.1% biopsy and 43.5% watching. Claims-confirmed intended plans (positive predictive value) for single-mode systemic therapy in 62.0%, radiation in 66.0%, surgery in 45.6%, and biopsy in 55.7%. A total of 25.7% of patients with a plan of watching had treatment claims. By cancer type, κ ranged for systemic therapy only from 0.17 to 0.40 and for watching from 0.21 to 0.41. Agreement rates varied by cancer types but were minimally associated with patient age, performance status, comorbidity, or stage. CONCLUSIONS: Among elderly cancer patients undergoing PET for restaging, there was moderate concordance between their physicians' planned management and claims-inferred actions within a narrow time window. When higher accuracy levels are required in future coverage with evidence development studies, alternative designs will be needed.


Assuntos
Revisão da Utilização de Seguros/estatística & dados numéricos , Medicare , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Tomografia por Emissão de Pósitrons/economia , Idoso , Idoso de 80 Anos ou mais , Biópsia/economia , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Estadiamento de Neoplasias/economia , Neoplasias/economia , Neoplasias/terapia , Avaliação de Processos e Resultados em Cuidados de Saúde/economia , Sistema de Registros , Estudos Retrospectivos , Inquéritos e Questionários , Estados Unidos
16.
Clin Epigenetics ; 15(1): 97, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37296474

RESUMO

The majority of these existing prognostic models of head and neck squamous cell carcinoma (HNSCC) have unsatisfactory prediction accuracy since they solely utilize demographic and clinical information. Leveraged by autophagy-related epigenetic biomarkers, we aim to develop a better prognostic prediction model of HNSCC incorporating CpG probes with either main effects or gene-gene interactions. Based on DNA methylation data from three independent cohorts, we applied a 3-D analysis strategy to develop An independently validated auTophagy-related epigenetic prognostic prediction model of HEad and Neck squamous cell carcinomA (ATHENA). Compared to prediction models with only demographic and clinical information, ATHENA has substantially improved discriminative ability, prediction accuracy and more clinical net benefits, and shows robustness in different subpopulations, as well as external populations. Besides, epigenetic score of ATHENA is significantly associated with tumor immune microenvironment, tumor-infiltrating immune cell abundances, immune checkpoints, somatic mutation and immunity-related drugs. Taken together these results, ATHENA has the demonstrated feasibility and utility of predicting HNSCC survival ( http://bigdata.njmu.edu.cn/ATHENA/ ).


Assuntos
Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Prognóstico , Neoplasias de Cabeça e Pescoço/genética , Metilação de DNA , Epigênese Genética , Autofagia/genética , Microambiente Tumoral
17.
JAMA Neurol ; 80(11): 1166-1173, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37812437

RESUMO

Importance: Results of amyloid positron emission tomography (PET) have been shown to change the management of patients with mild cognitive impairment (MCI) or dementia who meet Appropriate Use Criteria (AUC). Objective: To determine if amyloid PET is associated with reduced hospitalizations and emergency department (ED) visits over 12 months in patients with MCI or dementia. Design, Setting, and Participants: This nonrandomized controlled trial analyzed participants in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, an open-label, multisite, longitudinal study that enrolled participants between February 2016 and December 2017 and followed up through December 2018. These participants were recruited at 595 clinical sites that provide specialty memory care across the US. Eligible participants were Medicare beneficiaries 65 years or older with a diagnosis of MCI or dementia within the past 24 months who met published AUC for amyloid PET. Each IDEAS study participant was matched to a control Medicare beneficiary who had not undergone amyloid PET. Data analysis was conducted on December 13, 2022. Exposure: Participants underwent amyloid PET at imaging centers. Main Outcomes and Measures: The primary end points were the proportions of patients with 12-month inpatient hospital admissions and ED visits. One of 4 secondary end points was the rate of hospitalizations and rate of ED visits in participants with positive vs negative amyloid PET results. Health care use was ascertained from Medicare claims data. Results: The 2 cohorts (IDEAS study participants and controls) each comprised 12 684 adults, including 6467 females (51.0%) with a median (IQR) age of 77 (73-81) years. Over 12 months, 24.0% of the IDEAS study participants were hospitalized, compared with 25.1% of the matched control cohort, for a relative reduction of -4.49% (97.5% CI, -9.09% to 0.34%). The 12-month ED visit rates were nearly identical between the 2 cohorts (44.8% in both IDEAS study and control cohorts) for a relative reduction of -0.12% (97.5% CI, -3.19% to 3.05%). Both outcomes fell short of the prespecified effect size of 10% or greater relative reduction. Overall, 1467 of 6848 participants (21.4%) with positive amyloid PET scans were hospitalized within 12 months compared with 1081 of 4209 participants (25.7%) with negative amyloid PET scans (adjusted odds ratio, 0.83; 95% CI, 0.78-0.89). Conclusions and Relevance: Results of this nonrandomized controlled trial showed that use of amyloid PET was not associated with a significant reduction in 12-month hospitalizations or ED visits. Rates of hospitalization were lower in patients with positive vs negative amyloid PET results.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Demência , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/terapia , Amiloide , Proteínas Amiloidogênicas , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/terapia , Atenção à Saúde , Demência/diagnóstico por imagem , Demência/terapia , Estudos Longitudinais , Medicare , Tomografia por Emissão de Pósitrons/métodos , Estados Unidos , Masculino
18.
Cell Rep Med ; 4(3): 100972, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36889321

RESUMO

This is a phase II study of PD-1 blockade plus chemoradiotherapy as preoperative therapy for patients with locally advanced or borderline resectable pancreatic cancer (LAPC or BRPC, respectively). Twenty-nine patients are enrolled in the study. The objective response rate (ORR) is 60%, and the R0 resection rate is 90% (9/10). The 12-month progression-free survival (PFS) rate and 12-month overall survival (OS) rate are 64% and 72%, respectively. Grade 3 or higher adverse events are anemia (8%), thrombocytopenia (8%), and jaundice (8%). Circulating tumor DNA analysis reveals that patients with a >50% decline in maximal somatic variant allelic frequency (maxVAF) between the first clinical evaluation and baseline have a longer survival outcome and a higher response rate and surgical rate than those who are not. PD-1 blockade plus chemoradiotherapy as preoperative therapy displays promising antitumor activity, and multiomics potential predictive biomarkers are identified and warrant further verification.


Assuntos
Neoplasias Pancreáticas , Receptor de Morte Celular Programada 1 , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamento farmacológico , Terapia Neoadjuvante , Quimiorradioterapia , Intervalo Livre de Progressão
19.
Mol Oncol ; 17(1): 173-187, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36408734

RESUMO

Epigenome-wide gene-gene (G × G) interactions associated with non-small-cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three-step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with PBonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two-phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans-omics analysis, which had significant (P ≤ 0.05) epigenetic cis-regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (ßinteraction  = 0.018, P = 1.87 × 10-12 ), which mapped to RELA × HLA-G (ßinteraction  = 0.218, P = 8.82 × 10-11 ) and cg08872738 × cg27077312 (ßinteraction  = -0.010, P = 1.16 × 10-11 ), which mapped to TUBA1B × TOMM40 (ßinteraction =-0.250, P = 3.83 × 10-10 ). A trans-omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans-omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Metilação de DNA/genética , Carcinoma de Pequenas Células do Pulmão/genética , Epigenoma
20.
Nat Commun ; 14(1): 1340, 2023 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-36906670

RESUMO

The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.


Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Cisplatino/uso terapêutico , Desoxicitidina/uso terapêutico , Gencitabina
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