Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 18.888
Filtrar
1.
Med Oncol ; 41(4): 83, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38436810

RESUMO

Prostate cancer is one of the most common cancers in men. Given the diverse nature of prostate cancer and its tendency to respond differently to various treatments, combination therapies are often employed to enhance outcomes. In this study, the synergetic efficiency of chemotherapeutic drug Navitoclax and heat shock protein 90 (Hsp90) inhibitor Debio-0932 was evaluated in human prostate cancer cell line (PC3). Our results indicated that Navitoclax-Debio-0932 combination exhibited synergistic activity in PC3 cells at concentrations lower than IC50 values. The combination of Navitoclax and Debio-0932 decreased PC3 cell viability in a dose dependent manner at 48 h. To investigate the apoptotic potential of the Navitoclax-Debio-0932 combination against prostate cancer cells, the mRNA and protein expression levels of apoptotic and antiapoptotic markers (Bax, Bcl-2, Bcl-xL, Cyt-c, Apaf-1, Casp-3, Casp-7, and Casp-9) were measured using RT-PCR and ELISA assay. Furthermore, the cleavage activity of Casp-3 was determined by colorimetric assay. The results revealed that Navitoclax-Debio-0932 combination potently induced intrinsic apoptotic pathway in PC3 cells rather than using drugs alone. The combined treatment of Navitoclax and Debio-0932 displayed synergistic cytotoxic and apoptotic effects on prostate cancer cells, presenting a promising approach for combination therapy in prostate cancer.


Assuntos
Compostos de Anilina , Antineoplásicos , Neoplasias da Próstata , Sulfonamidas , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Próstata , Apoptose , Transdução de Sinais , Antineoplásicos/farmacologia
2.
Methods Mol Biol ; 2785: 165-175, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427194

RESUMO

Amyloid plaques are a neuropathologic hallmark of Alzheimer's disease (AD), which can be imaged through positron emission tomography (PET) technology using radiopharmaceuticals that selectively bind to the fibrillar aggregates of amyloid-ß plaques (Amy-PET). Several radiotracers for amyloid PET have been validated (11C-Pittsburgh compound B and the 18F-labeled compounds such as 18F-florbetaben, 18F-florbetapir, and 18F-flutemetamol). Images can be interpreted by means of visual/qualitative, semiquantitative, and quantitative criteria. Here, we summarize the main differences between the available radiotracers for Amy-PET, the proposed interpretation criteria, and main proposed quantification methods.


Assuntos
Doença de Alzheimer , Tomografia por Emissão de Pósitrons , Humanos , Tomografia por Emissão de Pósitrons/métodos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Compostos de Anilina/metabolismo , Placa Amiloide/metabolismo , Encéfalo/metabolismo
3.
Langenbecks Arch Surg ; 409(1): 92, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467934

RESUMO

BACKGROUND: Posthepatectomy liver failure (PHLF) remains a life-threatening complication after hepatectomy. To reduce PHLF, a preoperative assessment of liver function is indispensable. For this purpose, 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT (MSPECT) can be used. The aim of the current study was to evaluate the predictive value of MSPECT for PHLF in patients with non-colorectal liver tumors (NCRLT) compared to patients with colorectal liver metastasis (CRLM) undergoing extended liver resection. METHODS: We included all patients undergoing extended liver resections via two-stage procedures between January 2019 and December 2021 at the University Medical Center Hamburg-Eppendorf, Germany. All patients received a preoperative MSPECT. RESULTS: Twenty patients were included. In every fourth patient, PHLF was observed. Four patients had PHLF grade C. There were no differences between patients with CRLM and NCRLT regarding PHLF rate and future liver remnant (FLR) volume. Patients with CRLM had higher mebrofenin uptake in the FLR compared to those with NCRLT (2.49%/min/m2 vs. 1.51%/min/m2; p = 0.004). CONCLUSION: Mebrofenin uptake in patients with NCRLT was lower compared to those patients with CRLM. However, there was no difference in the PHLF rate and FLR volume. Cut-off values for the mebrofenin uptake might need adjustments for different surgical indications, surgical procedures, and underlying diseases.


Assuntos
Compostos de Anilina , Neoplasias Colorretais , Glicina , Falência Hepática , Neoplasias Hepáticas , Humanos , Compostos Radiofarmacêuticos , Fígado/diagnóstico por imagem , Fígado/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Hepatectomia/efeitos adversos , Falência Hepática/etiologia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/complicações , Estudos Retrospectivos , Complicações Pós-Operatórias
4.
Sci Adv ; 10(10): eadl0026, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457511

RESUMO

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K2CO3) promoted the arylation of acrylamide terminal C(sp2)-H, affording 34 derivatives. Conversely, sodium tert-butoxide (t-BuONa) mediated the aryl C(sp2)-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFRT790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.


Assuntos
Acrilamidas , Compostos de Anilina , Neoplasias Pulmonares , Paládio , Pirimidinas , Humanos , Animais , Camundongos , Paládio/química , Receptores ErbB , Mutação , Inibidores de Proteínas Quinases , Indóis/química , Catálise
8.
Neuromolecular Med ; 26(1): 6, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38504005

RESUMO

Familial Alzheimer's disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aß protein deposition. The cerebrospinal fluid amyloid protein test showed Aß42/Aß40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.


Assuntos
Doença de Alzheimer , Compostos de Anilina , Etilenoglicóis , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Fluordesoxiglucose F18 , Mutação , China , Presenilina-1/genética , Peptídeos beta-Amiloides/metabolismo
9.
Oncotarget ; 15: 232-237, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38497774

RESUMO

Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15-20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some. The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.


Assuntos
Acrilamidas , Compostos de Anilina , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Gefitinibe , Afatinib , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética
10.
BMC Complement Med Ther ; 24(1): 125, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500118

RESUMO

BACKGROUND: Osimertinib is regarded as a promising third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for advanced non-squamous non-small cell lung cancer (NSCLC) patients who developed T790M. However the adverse effects, primarily fatigue, remain an overwhelming deficiency of Osimertinib, hindering it from achieving adequate clinical efficacy for such NSCLC. Ganoderma lucidum has been used for thousands of years in China to combat fatigue, while Ganoderma Lucidum spores powder (GLSP) is the main active ingredient. The aim of this study is to investigate whether GLSP is sufficiently effective and safe in improving fatigue and synergizing with Osimertinib in non-squamous NSCLC patients with EGFR mutant. METHOD/DESIGN: A total of 140 participants will be randomly assigned to receive either de-walled GSLP or placebo for a duration of 56 days. The primary outcome measure is the fatigue score associated with EGFR-TKI adverse reactions at week 8, evaluated by the Chinese version of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30). Secondary outcomes include evaluation of treatment effectiveness, assessment of quality of life (QoL), and exploration of immune indicators and gut microbiota relationships. Following enrollment, visits are scheduled biweekly until week 12. TRIAL REGISTRATION: China Clinical Trial Registry ChiCTR2300072786. Registrated on June 25, 2023.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Reishi , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Qualidade de Vida , Pós/uso terapêutico , Receptores ErbB/genética , Inibidores de Proteínas Quinases/efeitos adversos , Mutação , Esporos Fúngicos , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Int Immunopharmacol ; 130: 111778, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38432147

RESUMO

OBJECTIVE: To investigate the mechanism of action of fatty acid receptors, FFAR1 and FFAR4, on ulcerative colitis (UC) through fatty acid metabolism and macrophage polarization. METHODS: Dextran sulfate sodium (DSS)-induced mouse model of UC mice was used to evaluate the efficacy of FFAR1 (GW9508) and FFAR4 (GSK137647) agonists by analyzing body weight, colon length, disease activity index (DAI), and histological scores. Real-time PCR and immunofluorescence analysis were performed to quantify the levels of fatty acid metabolizing enzymes and macrophage makers. FFA-induced lipid accumulation in RAW264.7 cells was visualized by Oil Red O staining analysis, and cells were collected to detect macrophage polarization by flow cytometry. RESULTS: The combination of GW9508 and GSK137647 significantly improved DSS-induced UC symptoms, caused recovery in colon length, and decreased histological injury. GW9508 + GSK137647 treatment upregulated the expressions of CD206, lipid oxidation enzyme (CPT-1α) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) but downregulated those of CD86, lipogenic enzymes (ACC1, FASN, SCD1), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). Combining the two agonists decreased FFA-induced lipid accumulation and increased CD206 expression in cell-based experiments. CONCLUSION: Activated FFAR1 and FFAR4 ameliorates DSS-induced UC by promoting fatty acid metabolism to reduce lipid accumulation and mediate M2 macrophage polarization.


Assuntos
Compostos de Anilina , Colite Ulcerativa , Colite , Metilaminas , Propionatos , Sulfonamidas , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Macrófagos/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Sulfato de Dextrana , Colo/patologia , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente
12.
Sci Rep ; 14(1): 6491, 2024 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499619

RESUMO

The EGFR tyrosine kinase inhibitor osimertinib has been approved for the first-line treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patients. Despite its efficacy, patients develop resistance. Mechanisms of resistance are heterogeneous and not fully understood, and their characterization is essential to find new strategies to overcome resistance. Ceramides are well-known regulators of apoptosis and are converted into glucosylceramides (GlcCer) by glucosylceramide synthase (GCS). A higher content of GlcCers was observed in lung pleural effusions from NSCLC patients and their role in osimertinib-resistance has not been documented. The aim of this study was to determine the therapeutic potential of inhibiting GCS in NSCLC EGFR-mutant models resistant to osimertinib in vitro and in vivo. Lipidomic analysis showed a significant increase in the intracellular levels of glycosylceramides, including GlcCers in osimertinib resistant clones compared to sensitive cells. In resistant cells, the GCS inhibitor PDMP caused cell cycle arrest, inhibition of 2D and 3D cell proliferation, colony formation and migration capability, and apoptosis induction. The intratumoral injection of PDMP completely suppressed the growth of OR xenograft models. This study demonstrated that dysregulation of ceramide metabolism is involved in osimertinib-resistance and targeting GCS may be a promising therapeutic strategy for patients progressed to osimertinib.


Assuntos
Acrilamidas , Carcinoma Pulmonar de Células não Pequenas , Glucosiltransferases , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
13.
Clin Transl Sci ; 17(3): e13766, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38511563

RESUMO

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent ~6%-12% of all EGFR-mutated non-small cell lung cancer (NSCLC) cases. First-, second-, and third-generation tyrosine kinase inhibitors (TKIs) have limited clinical activity against EGFR ex20ins mutations. Mobocertinib is a first-in-class oral EGFR TKI that selectively targets in-frame EGFR ex20ins mutations in NSCLC; accelerated approval in the United States was granted for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based chemotherapy. Accelerated approval was based on the results from the three-part, open-label, multicenter, pivotal phase I/II nonrandomized clinical trial (NCT02716116) that enrolled 114 patients with locally advanced or metastatic EGFR ex20ins mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and received mobocertinib at the recommended dosage of 160 mg once daily. At the November 1, 2021, data cutoff date, the confirmed objective response rate per independent review committee (IRC) was 28%, median duration of response was 15.8 months, median progression-free survival per IRC was 7.3 months, and median overall survival was 20.2 months. The most common treatment-emergent adverse events were gastrointestinal- and skin-related. The phase III EXCLAIM-2 study evaluated mobocertinib versus chemotherapy as first-line therapy for locally advanced or metastatic EGFR ex20ins-positive NSCLC; however, the primary end point was not met, resulting in initiating voluntary withdrawal of mobocertinib worldwide. This mini-review article summarizes the mechanism of action, pharmacokinetic characteristics, key clinical trials, and clinical efficacy and safety data for mobocertinib.


Assuntos
Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Adulto , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Ciência Translacional Biomédica
14.
Rinsho Ketsueki ; 65(2): 63-68, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38447999

RESUMO

A 28-year-old man was diagnosed with acute myelomonocytic leukemia. He achieved complete remission (CR) after two cycles of induction therapy. However, after consolidation therapy, bone marrow aspiration performed to prepare for allogeneic hematopoietic stem cell transplantation revealed disease relapse. Companion diagnostics confirmed the presence of the FLT3-ITD mutation. The patient received gilteritinib monotherapy and achieved CR. Subsequently, he underwent unrelated allogeneic bone marrow transplantation. One year after transplantation, the patient relapsed, and gilteritinib was resumed. However, the leukemia progressed, and panel sequencing using a next-generation sequencer showed that the FLT3-ITD mutation disappeared. A mutation in PTPN11, which regulates the RAS/MAPK signaling pathway, was also detected. Gilteritinib was discontinued, and the patient achieved CR with salvage chemotherapy. He underwent related haploidentical peripheral blood stem cell transplantation but died of relapse. This was a case in which genetic analysis revealed clonal transition and acquisition of resistance to treatment.


Assuntos
Leucemia Mieloide Aguda , Masculino , Humanos , Adulto , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Compostos de Anilina , Pirazinas , Doença Crônica , Mutação , Tirosina Quinase 3 Semelhante a fms/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
15.
J Nucl Med ; 65(3): 453-461, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302152

RESUMO

We investigated the longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients in the Alzheimer disease (AD) continuum using 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5c']dipyridine ([18F]PI-2620) PET. Methods: We prospectively enrolled 52 participants (age, 69.7 ± 8.4 y; 18 men and 34 women): 7 with normal cognition, 28 with mild cognitive impairment, and 17 with AD. They all completed the [18F]PI-2620 and [18F]florbetaben PET, MRI, and neuropsychologic tests at baseline and, excepting the [18F]florbetaben PET, at the 1-y follow-up. Amyloid-ß (Aß) PET images were visually scored as positive (+) or negative (-). Patients on the AD continuum, including Aß+ mild cognitive impairment and AD, were classified into early-onset (EO+) (<65 y old) or late-onset (LO+) (≥65 y old) groups. [18F]PI-2620 PET SUV ratios (SUVRs) were determined by calculating the cerebral-to-inferior cerebellar ratio. Cortical volumes were calculated using 3-dimensional T1-weighted MRI. The correlation between tau accumulation progression and cognitive decline was also investigated. Results: The global [18F]PI-2620 PET SUVRs were 1.04 ± 0.07 in 15 Aß- patients, 1.18 ± 0.21 in 20 LO+ patients (age, 76.7 ± 3.8 y), and 1.54 ± 0.38 in 17 EO+ patients (age, 63.4 ± 5.4 y; P < 0.001) at baseline. The global SUVR increased over 1 y by 0.05 ± 0.07 (3.90%) and 0.13 ± 0.22 (8.41%) in the LO+ and EO+ groups, respectively, whereas in the Aß- groups, it remained unchanged. The EO+ group showed higher global and regional tau deposition than did the Aß- and LO+ groups (P < 0.05 for each) and rapid accumulation in Braak stage V (0.15 ± 0.25; 9.10% ± 12.27%; P = 0.016 and 0.008), Braak stage VI (0.08 ± 0.12; 7.16% ± 10.06%; P < 0.006 and 0.005), and global SUVR (P = 0.013) compared with the Aß- group. In the EO+ group, the changes in SUVR in Braak stages II-VI were strongly correlated with the baseline and changes in verbal memory (P < 0.03). The LO+ group showed higher tau accumulation in Braak stage I-IV areas than did the Aß- group (P < 0.001 for each). In the LO+ group, the change in SUVR in Braak stages III and IV moderately correlated with the change in attention (P < 0.05), and the change in SUVR in Braak stages V and VI moderately correlated with the change in visuospatial function (P < 0.005). Conclusion: These findings suggest that [18F]PI-2620 PET can be a biomarker to provide regional and chronologic information about tau pathology in the AD continuum.


Assuntos
Doença de Alzheimer , Compostos de Anilina , Piridinas , Estilbenos , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Tomografia por Emissão de Pósitrons
16.
Biomed Pharmacother ; 172: 116252, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38325265

RESUMO

PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABAA) receptor, amyloid-ß, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats. METHODS: Positron emission tomography (PET) using [18F]SDM-8 (SV2A), [18F]flumazenil (GABAA receptor), [18F]florbetapir (amyloid-ß), [18F]PM-PBB3 (tau), and [18F]FPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats. RESULTS: Reduced cortical [18F]SDM-8 uptake and cortical and hippocampal [18F]flumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of [18F]florbetapir and [18F]PM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABAA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats. CONCLUSION: These findings provide in vivo evidence for regional reductions in SV2A and GABAA receptor levels in the brains of aged T2DM ZDF rats.


Assuntos
Compostos de Anilina , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Etilenoglicóis , Radioisótopos de Flúor , Piridinas , Pirrolidinas , Ratos , Animais , Flumazenil/metabolismo , Receptores de GABA-A/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Vesículas Sinápticas/metabolismo , Proteômica , Ratos Zucker , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ácido gama-Aminobutírico/metabolismo
17.
Cell Rep ; 43(2): 113771, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38335093

RESUMO

EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical success in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and then gain resistance. We identify transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumors. ZNF263 overexpression improves the initial response of cells and delays the formation of persister cells with osimertinib treatment. We further show that ZNF263 binds and recruits DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 interacts with nuclear EGFR, impairing the EGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also makes tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or adeno-associated virus (AAV)-mediated ZNF263 overexpression synergistically suppresses tumor growth and regrowth with osimertinib treatment in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.


Assuntos
Acrilamidas , Adenocarcinoma de Pulmão , Compostos de Anilina , Indóis , Neoplasias Pulmonares , Pirimidinas , Animais , Humanos , Fatores de Transcrição/genética , Neoplasia Residual , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Ligação a DNA
18.
Phys Chem Chem Phys ; 26(9): 7765-7771, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38372974

RESUMO

The responsive mechanisms of cationic quinolinium-vinyl-N,N-dimethylaniline boronate (QVD-B) derivative probes to hydrogen peroxide (H2O2), proteins and DNA/RNA are theoretically investigated in this study. The potential energy curves of QVD-B scanned on a dihedral angle (N+-C-CC) in the first singlet (S1) state exhibit large torsional energy barriers. Additionally, the energy of the lowest unoccupied molecular orbital (LUMO) of an acceptor moiety (-3.14 eV) is lower than that of a donor moiety (-1.13 eV) in QVD-B. This demonstrates that photoinduced electron transfer (PET) quenches the fluorescence of QVD-B, as opposed to the previous report of intramolecular single-bond rotation. After reacting with H2O2, the reaction product of quinoline-vinyl-N,N-dimethylaniline (QVD) turns off the PET pathway and turns on the fluorescence at 550 nm, which is consistent with the experimental results (580 nm). Among the possible configurations of QVD-B that forms with proteins and DNA, the calculated fluorescence values of corresponding twisted QVD-B-P (638 nm) and QVD-B-D (686 nm) are consistent with the experimental results (632 and 688 nm). The frontier molecular orbital and electron-hole analysis show that the charge transfer distance follows the order of QVD (1.88 Å) < QVD-B-P (4.49 Å) < QVD-B-D (6.39 Å), which induces the fluorescence red-shifts of QVD-B-P and QVD-B-D compared to that of QVD. The multi-detection mechanism of the fluorescent probe QVD-B is attributed to PET progress and different degrees of local charge transfer after photoexcitation.


Assuntos
Corantes Fluorescentes , Peróxido de Hidrogênio , Corantes Fluorescentes/química , Compostos de Anilina/química , Transporte de Elétrons
19.
Nanoscale ; 16(9): 4647-4655, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38299660

RESUMO

Polyaniline (PANI), a nanostructured conducting polymer, has shown significant potential in optical and bioelectrochemical devices. However, its performance and stability on various substrates are hindered by weak adhesion to the surface. In this study, a strongly adherent polyaniline conducting polymer layer with a thickness of five nanometers was electrografted onto an initiating monolayer on gold and tin-doped indium oxide substrates. These electrografted monolayers consist of vertically oriented fully oxidized-protonated (pernigraniline salt) and deprotonated (pernigraniline base) forms of polyaniline. The monolayer exhibits pH-dependent colour changes and it is suitable for enzyme compatibility. In light of these findings, we have developed and characterized an electrochemical glucose biosensor based on the monolayer of polyaniline on a gold electrode. The biosensor utilizes glucose oxidase as the biorecognition element for the selective detection of glucose concentrations in real blood plasma samples.


Assuntos
Técnicas Biossensoriais , Glucose , Glucose/química , Compostos de Anilina/química , Glucose Oxidase/química , Ouro/química , Polímeros
20.
BMC Cancer ; 24(1): 189, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336654

RESUMO

BACKGROUND: The partitioned survival model (PSM) and the state transition model (STM) are widely used in cost-effectiveness analyses of anticancer drugs. Using different modeling approaches with or without consideration of brain metastasis, we compared the quality-adjusted life-year (QALY) estimates of Osimertinib and pemetrexed-platinum in advanced non-small cell lung cancer with epidermal growth factor receptor mutations. METHODS: We constructed three economic models using parametric curves fitted to patient-level data from the National Health Insurance Review and Assessment claims database from 2009 to 2020. PSM and 3-health state transition model (3-STM) consist of three health states: progression-free, post-progression, and death. The 5-health state transition model (5-STM) has two additional health states (brain metastasis with continuing initial therapy, and with subsequent therapy). Time-dependent transition probabilities were calculated in the state transition models. The incremental life-year (LY) and QALY between the Osimertinib and pemetrexed-platinum cohorts for each modeling approach were estimated over seven years. RESULTS: The PSM and 3-STM produced similar incremental LY (0.889 and 0.899, respectively) and QALY (0.827 and 0.840, respectively). However, 5-STM, which considered brain metastasis as separate health states, yielded a slightly higher incremental LY (0.910) but lower incremental QALY (0.695) than PSM and 3-STM. CONCLUSIONS: Our findings indicate that incorporating additional health states such as brain metastases into economic models can have a considerable impact on incremental QALY estimates. To ensure appropriate health technology assessment decisions, comparison and justification of different modeling approaches are recommended in the economic evaluation of anticancer drugs.


Assuntos
Acrilamidas , Compostos de Anilina , Antineoplásicos , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirimidinas , Humanos , Pemetrexede/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Platina/uso terapêutico , Neoplasias Pulmonares/patologia , Antineoplásicos/uso terapêutico , Análise Custo-Benefício , Neoplasias Encefálicas/tratamento farmacológico , Anos de Vida Ajustados por Qualidade de Vida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...