RESUMO
AIMS: This investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022. METHODS: Data from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment. RESULTS: First-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively. CONCLUSIONS: Compared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , China/epidemiologia , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Pessoa de Meia-Idade , Estudos Transversais , Adulto , Receptores de Estrogênio/metabolismo , Idoso , Receptores de Progesterona/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients. Comprehensive profiling of matched PDX and patient samples demonstrates that PDXs closely recapitulate parental tumors. By leveraging multi-lineage models, we reveal that the previously reported genomic disparities of PDX could be mainly attributed to intra-patient spatial heterogeneity instead of substantial model-independent genomic evolution. Moreover, DNA damage response pathway inhibitor (DDRi) screening uncovers heterogeneous responses across models. Prolonged iterative drug exposure recapitulates acquired drug resistance in initially sensitive models. Meanwhile, interrogation of induced drug-resistant (IDR) models reveals that suppressed interferon (IFN) response and activated Wnt/ß-catenin signaling contribute to acquired DDRi drug resistance.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Animais , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Via de Sinalização Wnt/genética , Resistencia a Medicamentos Antineoplásicos/genética , Genômica/métodos , Bancos de Espécimes Biológicos , Heterogeneidade Genética , Dano ao DNA/genética , Interferons/metabolismo , Interferons/genética , Linhagem da Célula/genéticaRESUMO
PURPOSE: To characterize the pattern of post-treatment quality of life (QoL) for esophageal cancer (EC) survivors and construct models predicting their long-term QoL. METHODS: On the basis of a randomized trial in an EC high-risk region in China, we interviewed 363 EC survivors and 25,245 permanent residents matched with the survivors on age, sex, and township as the baseline. QoL was measured using three-level version of European Quality of Life 5-Dimensions instrument. We constructed piecewise mixed models estimating the QoL of EC survivors that varied by age, sex, patient type, hospital level, and therapy to ascertain QoL determinants. RESULTS: The post-treatment QoL of EC survivors dropped by 15.7% within the first year and recovered by 9.3% between 1 and 9 years compared with the baseline. Therapy was found to be a determinant of QoL, and a series of therapy-specific models were fitted accordingly, which all showed the pattern of decreasing rapidly and recovering gradually. Endoscopic treatment had the least impact on post-treatment QoL (7.5% drop within 5 years) compared with esophagectomy (12.2% drop within 1 year) and chemoradiotherapy (37.8% drop within 2 years). The usual activities dimension showed the greatest impairment among those patients (34.4% drop within 1 year). CONCLUSION: This community-based study described the long-term QoL trajectory for EC survivors after different therapeutic modalities and constructed models to predict therapy-specific QoL at different time points after treatment. It provided new insights into decision making in treatment for EC from the perspective of QoL protection, offering a convenient tool for estimating quality-adjusted life-years.
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Neoplasias Esofágicas , Qualidade de Vida , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , China , Esofagectomia , Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , AdultoRESUMO
Case report: A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed. Conclusion: Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.
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Antígeno B7-H1 , Inibidor p16 de Quinase Dependente de Ciclina , Pilomatrixoma , Neoplasias Cutâneas , Humanos , Masculino , Pessoa de Meia-Idade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Pilomatrixoma/genética , Pilomatrixoma/patologia , Mutação , Doenças do Cabelo/genética , Doenças do Cabelo/patologiaAssuntos
Artroplastia do Joelho , Readmissão do Paciente , Medidas de Resultados Relatados pelo Paciente , Complicações Pós-Operatórias , Reoperação , Humanos , Artroplastia do Joelho/métodos , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Osteoartrite do Joelho/cirurgiaRESUMO
BACKGROUND: A growing number of studies have demonstrated that the polar regions have the potential to be a significant repository of microbial resources and a potential source of active ingredients. Genome mining strategy plays a key role in the discovery of bioactive secondary metabolites (SMs) from microorganisms. This work highlighted deciphering the biosynthetic potential of an Arctic marine-derived strain Aspergillus sydowii MNP-2 by a combination of whole genome analysis and antiSMASH as well as feature-based molecular networking (MN) in the Global Natural Products Social Molecular Networking (GNPS). RESULTS: In this study, a high-quality whole genome sequence of an Arctic marine strain MNP-2, with a size of 34.9 Mb was successfully obtained. Its total number of genes predicted by BRAKER software was 13,218, and that of non-coding RNAs (rRNA, sRNA, snRNA, and tRNA) predicted by using INFERNAL software was 204. AntiSMASH results indicated that strain MNP-2 harbors 56 biosynthetic gene clusters (BGCs), including 18 NRPS/NRPS-like gene clusters, 10 PKS/PKS-like gene clusters, 8 terpene synthse gene clusters, 5 indole synthase gene clusters, 10 hybrid gene clusters, and 5 fungal-RiPP gene clusters. Metabolic analyses of strain MNP-2 grown on various media using GNPS networking revealed its great potential for the biosynthesis of bioactive SMs containing a variety of heterocyclic and bridge-ring structures. For example, compound G-8 exhibited a potent anti-HIV effect with an IC50 value of 7.2 nM and an EC50 value of 0.9 nM. Compound G-6 had excellent in vitro cytotoxicities against the K562, MCF-7, Hela, DU145, U1975, SGC-7901, A549, MOLT-4, and HL60 cell lines, with IC50 values ranging from 0.10 to 3.3 µM, and showed significant anti-viral (H1N1 and H3N2) activities with IC50 values of 15.9 and 30.0 µM, respectively. CONCLUSIONS: These findings definitely improve our knowledge about the molecular biology of genus A. sydowii and would effectively unveil the biosynthetic potential of strain MNP-2 using genomics and metabolomics techniques.
Assuntos
Aspergillus , Família Multigênica , Aspergillus/genética , Aspergillus/metabolismo , Regiões Árticas , Humanos , Produtos Biológicos/metabolismo , Organismos Aquáticos/genética , Organismos Aquáticos/metabolismo , Linhagem Celular Tumoral , Vias Biossintéticas/genética , Metabolismo Secundário/genética , Genoma FúngicoRESUMO
Using noninvasive biomarkers to identify high-risk individuals prior to endoscopic examination is crucial for optimization of screening strategies for esophageal squamous cell carcinoma (ESCC). We conducted a nested case-control study based on two community-based screening cohorts to evaluate the warning value of serum metabolites for esophageal malignancy. The serum samples were collected at enrollment when the cases had not been diagnosed. We identified 74 differential metabolites and two prominent perturbed metabolic pathways, and constructed Metabolic Risk Score (MRS) based on 22 selected metabolic predictors. The MRS generated an area under the receiver operating characteristics curve (AUC) of 0.815. The model performed well for the within-1-year interval (AUC: 0.868) and 1-to-5-year interval (AUC: 0.845) from blood draw to diagnosis, but showed limited ability in predicting long-term cases (>5 years). In summary, the MRS could serve as a potential early warning and risk stratification tool for establishing a precision strategy of ESCC screening.
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Implantes de Mama , Humanos , Feminino , Estudos Retrospectivos , Implantes de Mama/efeitos adversos , Mamoplastia/efeitos adversos , Mamoplastia/métodos , Implante Mamário/efeitos adversos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Infecções Relacionadas à Prótese/etiologia , Neoplasias da Mama/cirurgiaAssuntos
Carcinoma de Células Escamosas , Aprendizado Profundo , Metástase Linfática , Imageamento por Ressonância Magnética , Neoplasias da Língua , Humanos , Neoplasias da Língua/patologia , Neoplasias da Língua/diagnóstico por imagem , Metástase Linfática/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Valor Preditivo dos Testes , RadiômicaAssuntos
Fixação Interna de Fraturas , Fraturas da Tíbia , Humanos , Fraturas da Tíbia/cirurgia , Fraturas da Tíbia/complicações , Estudos Retrospectivos , Fixação Interna de Fraturas/efeitos adversos , Fixação Interna de Fraturas/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/diagnóstico , Adulto , Fatores de Risco , Idoso , Fraturas do Planalto TibialRESUMO
BACKGROUND: Chrysomycin A (CA) is a promising antibiotic for treatment of Gram-positive bacterial infections and cancers. In order to enhance CA yield, optimization of fermentation conditions and medium components was carried out on strain Streptomyces sp. 891-B6, an UV-induced mutant with improved CA titer compared with its wide-type marine strain 891. RESULTS: Using one-way experiment, the optimal fermentation conditions for CA production in 1-L shake flask were obtained as follows: 12 days of fermentation time, 5 days of seed age, 5% of inoculum volume ratio, 200 mL of loading volume and 6.5 of initial pH. By response surface methodology, the optimal medium components determined as glucose (39.283 g/L), corn starch (20.662 g/L), soybean meal (15.480 g/L) and CaCO3 (2.000 g/L). CONCLUSION: Validation tests showed that the maximum yield of CA reached 1601.9 ± 56.7 mg/L, which was a 60% increase compared to the initial yield (952.3 ± 53.2 mg/L). These results provided an important basis for scale-up production of CA by strain 891-B6.
Assuntos
Streptomyces , Fermentação , Streptomyces/genética , Aminoglicosídeos , Antibacterianos , Meios de CulturaAssuntos
Vértebras Torácicas , Tuberculose da Coluna Vertebral , Humanos , Estudos Retrospectivos , Tuberculose da Coluna Vertebral/cirurgia , Tuberculose da Coluna Vertebral/tratamento farmacológico , Estudos de Casos e Controles , Vértebras Torácicas/cirurgia , Vértebras Lombares/cirurgia , Resultado do Tratamento , Seguimentos , Feminino , MasculinoAssuntos
Acetábulo , Fraturas Ósseas , Complicações Pós-Operatórias , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Acetábulo/lesões , Acetábulo/cirurgia , Fraturas Ósseas/cirurgia , Idoso , Bases de Dados Factuais , Feminino , Idoso de 80 Anos ou mais , Masculino , Tempo para o Tratamento , Fatores de TempoRESUMO
Infection with bovine leukemia virus (BLV) leads to enzootic bovine leukosis, the most prevalent neoplastic disease in cattle. Due to the lack of commercially available vaccines, reliable eradication of the disease can be achieved through the testing and elimination of BLV antibody-positive animals. In this study, we developed a novel competitive ELISA (cELISA) to detect antibodies against BLV capsid protein p24. Recombinant p24 protein expressed by Escherichia coli, in combination with the monoclonal antibody 2G11 exhibiting exceptional performance, was used for the establishment of the cELISA. Receiver-operating characteristic curve analysis showed that the sensitivity and specificity of the assay were 98.85 % and 98.13 %, respectively. Furthermore, the established cELISA was specific for detecting BLV-specific antibodies, without cross-reactivity to antisera for six other bovine viruses. Significantly, experimental infection of cattle and sheep with BLV revealed that the cELISA accurately monitors seroconversion. In a performance evaluation, the established cELISA displayed a high agreement with Western blotting and the commercial BLV gp51 cELISA kit in the detection of 242 clinical samples, respectively. In conclusion, the novel p24 cELISA exhibited the potential to be a reliable and efficient diagnostic tool for BLV serological detection with a broad application prospect.
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Anticorpos Monoclonais , Anticorpos Antivirais , Leucose Enzoótica Bovina , Ensaio de Imunoadsorção Enzimática , Vírus da Leucemia Bovina , Vírus da Leucemia Bovina/imunologia , Animais , Ensaio de Imunoadsorção Enzimática/métodos , Bovinos , Anticorpos Antivirais/imunologia , Anticorpos Monoclonais/imunologia , Leucose Enzoótica Bovina/diagnóstico , Leucose Enzoótica Bovina/imunologia , Proteínas do Capsídeo/imunologia , Sensibilidade e Especificidade , Proteínas Recombinantes/imunologia , Curva ROCRESUMO
Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.
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Carcinoma Endometrioide , Hiperplasia Endometrial , Neoplasias do Endométrio , Preservação da Fertilidade , Proteogenômica , Humanos , Feminino , Progestinas/uso terapêutico , Antineoplásicos Hormonais , Hiperplasia Endometrial/tratamento farmacológico , Preservação da Fertilidade/métodos , Estudos Retrospectivos , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologiaRESUMO
Dacomitinib is a highly selective second-generation tyrosine kinase inhibitor that can irreversibly bind to tyrosine kinase and is mainly used in the treatment of lung cancer. The binding characteristics of dacomitinib with human α 1-acid glycoprotein (HAG) were analyzed by multispectral and computational simulation techniques. The fluorescence spectra showed that dacomitinib can quench the fluorescence of HAG by forming the HAG-dacomitinib complex with a molar ratio of 1:1 (static quenching). At the temperature similar to that of the human body, the affinity of dacomitinib to HAG (8.95 × 106 M-1) was much greater than that to BSA (3.39 × 104 M-1), indicating that dacomitinib will give priority to binding onto HAG. Thermodynamics parameters analysis and driving force competition experiments showed that hydrogen bonding and hydrophobic forces were the major sources for keeping the complex of HAG-dacomitinib stable. The experimental outcomes also showed that the binding of dacomitinib can lead to the loosening of the skeleton structure of HAG, which led to a slight change in the secondary structure, and also reduces the hydrophobicity of the microenvironment of Trp and Tyr residues. The binding sites of dacomitinib on HAG and the contribution of key amino acid residues to the binding reaction were determined by molecular docking and molecular dynamics (MD) simulation. In addition, it was found that there was a synergistic effect between dacomitinib and Mg2+ and Co2+ ions. Mg2+ and Co2+ could increase the Kb of dacomitinib to HAG and prolong the half-life of dacomitinib.
Assuntos
Orosomucoide , Quinazolinonas , Humanos , Ligação Proteica , Simulação de Acoplamento Molecular , Orosomucoide/química , Sítios de Ligação , Termodinâmica , Espectrometria de Fluorescência , Dicroísmo CircularRESUMO
Glaucoma is a kind of neurodegenerative disorder characterized by irreversible loss of retinal ganglion cells (RGCs) and permanent visual impairment. It is reported that resveratrol (RES) is a promising drug for neurodegenerative diseases. However, the detailed molecular mechanisms underlying its protective potential have not yet been fully elucidated. The present study sought to investigate whether resveratrol could protect RGCs and retinal function triggered by acute ocular hypertension injury through the SIRT1/NF-κB pathway. An experimental glaucoma model was generated in C57BL/6J mice. Resveratrol was intraperitoneally injected for 5 days. Sirtinol was injected intravitreally on the day of retinal AOH injury. RGC survival was determined using immunostaining. TUNEL staining was conducted to evaluate retinal cell apoptosis. ERG was used to evaluate visual function. The proteins Brn3a, SIRT1, NF-κB, IL-6, Bax, Bcl2, and Cleaved Caspase3 were determined using western blot. The expression and localisation of SIRT1 and NF-κB in the retina were detected by immunofluorescence. Our data indicated that resveratrol treatment significantly increased Brn3a-labelled RGCs and reduced RGC apoptosis caused by AOH injury. Resveratrol administration also remarkably decreased NF-κB, IL-6, Bax, and Cleaved Caspase3 proteins and increased SIRT1 and Bcl2 proteins. Furthermore, resveratrol treatment obviously inhibited the reduction in ERG caused by AOH injury. Importantly, simultaneous administration of resveratrol and sirtinol abrogated the protective effect of resveratrol, decreased NF-κB protein expression, and increased SIRT1 protein levels. These results suggest that resveratrol administration significantly mitigates retinal AOH-induced RGCs loss and retinal dysfunction, and that this neuroprotective effect is partially regulated through the SIRT1/NF-κB pathway.