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1.
Gynecol Oncol ; 181: 1-7, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38096673

RESUMO

OBJECTIVE: To describe the participation of racial and ethnic minority groups (REMGs) in gynecologic oncology trials. METHODS: Gynecologic oncology studies registered on ClinicalTrials.gov between 2007 and 2020 were identified. Trials with published results were analyzed based on reporting of race/ethnicity in relation to disease site and trial characteristics. Expected enrollment by race/ethnicity was calculated and compared to actual enrollment, adjusted for 2010 US Census population data. RESULTS: 2146 gynecologic oncology trials were identified. Of published trials (n = 252), 99 (39.3%) reported race/ethnicity data. Recent trials were more likely to report these data (36% from 2007 to 2009; 51% 2013-2015; and 53% from 2016 to 2018, p = 0.01). Of all trials, ovarian cancer trials were least likely to report race/ethnicity data (32.1% vs 39.3%, p = 0.011). Population-adjusted under-enrollment for Blacks was 7-fold in ovarian cancer, Latinx 10-fold for ovarian and 6-fold in uterine cancer trials, Asians 2.5-fold in uterine cancer trials, and American Indian and Alaska Native individuals 6-fold in ovarian trials. Trials for most disease sites have enrolled more REMGs in recent years - REMGs made up 19.6% of trial participants in 2007-2009 compared to 38.1% in 2016-2018 (p < 0.0001). CONCLUSION: Less than half of trials that published results reported race/ethnicity data. Available data reveals that enrollment of REMGs is significantly below expected rates based on national census data. These disparities persisted even after additionally adjusting for population size. Despite improvement in recent years, additional recruitment of REMGs is needed to achieve more representative and equitable participation in gynecologic cancer clinical trials.


Assuntos
Neoplasias dos Genitais Femininos , Neoplasias Ovarianas , Neoplasias Uterinas , Humanos , Feminino , Estados Unidos , Neoplasias dos Genitais Femininos/terapia , Etnicidade , Minorias Étnicas e Raciais , Grupos Minoritários , Neoplasias Ovarianas/terapia , Neoplasias Uterinas/terapia
2.
J Lipid Res ; 64(6): 100374, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37075982

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome, but a predominant subset of HFpEF patients has metabolic syndrome (MetS). Mechanistically, systemic, nonresolving inflammation associated with MetS might drive HFpEF remodeling. Free fatty acid receptor 4 (Ffar4) is a GPCR for long-chain fatty acids that attenuates metabolic dysfunction and resolves inflammation. Therefore, we hypothesized that Ffar4 would attenuate remodeling in HFpEF secondary to MetS (HFpEF-MetS). To test this hypothesis, mice with systemic deletion of Ffar4 (Ffar4KO) were fed a high-fat/high-sucrose diet with L-NAME in their water to induce HFpEF-MetS. In male Ffar4KO mice, this HFpEF-MetS diet induced similar metabolic deficits but worsened diastolic function and microvascular rarefaction relative to WT mice. Conversely, in female Ffar4KO mice, the diet produced greater obesity but no worsened ventricular remodeling relative to WT mice. In Ffar4KO males, MetS altered the balance of inflammatory oxylipins systemically in HDL and in the heart, decreasing the eicosapentaenoic acid-derived, proresolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE), while increasing the arachidonic acid-derived, proinflammatory oxylipin 12-hydroxyeicosatetraenoic acid (12-HETE). This increased 12-HETE/18-HEPE ratio reflected a more proinflammatory state both systemically and in the heart in male Ffar4KO mice and was associated with increased macrophage numbers in the heart, which in turn correlated with worsened ventricular remodeling. In summary, our data suggest that Ffar4 controls the proinflammatory/proresolving oxylipin balance systemically and in the heart to resolve inflammation and attenuate HFpEF remodeling.


Assuntos
Insuficiência Cardíaca , Síndrome Metabólica , Masculino , Feminino , Camundongos , Animais , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Oxilipinas , Síndrome Metabólica/complicações , Volume Sistólico/fisiologia , Remodelação Ventricular , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Inflamação/complicações
3.
Physiology (Bethesda) ; 37(6): 311-322, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35944007

RESUMO

A surge in the prevalence of obesity and metabolic syndrome, which promote systemic inflammation, underlies an increase in cardiometabolic disease. Free fatty acid receptor 4 is a nutrient sensor for long-chain fatty acids, like ω3-polyunsaturated fatty acids (ω3-PUFAs), that attenuates metabolic disease and resolves inflammation. Clinical trials indicate ω3-PUFAs are cardioprotective, and this review discusses the mechanistic links between ω3-PUFAs, free fatty acid receptor 4, and attenuation of cardiometabolic disease.


Assuntos
Doenças Cardiovasculares , Ácidos Graxos Ômega-3 , Ácidos Graxos não Esterificados , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inflamação , Transdução de Sinais
4.
J Virol ; 96(16): e0097122, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35916512

RESUMO

The continuous antigenic variation of influenza A viruses remains a major hurdle for vaccine selection; however, the molecular determinants and mechanisms of antigenic change remain largely unknown. In this study, two escape mutants were generated by serial passages of the Eurasian avian-like H1N1 swine influenza virus (EA H1N1 SIV) A/swine/Henan/11/2005 (HeN11) in the presence of two neutralizing monoclonal antibodies (mAbs) against the hemagglutinin (HA) protein, which were designated HeN11-2B6-P5 and HeN11-4C7-P8, respectively. The HeN11-2B6-P5 mutant simultaneously harbored the N190D and I230M substitutions in HA, whereas HeN11-4C7-P8 harbored the M269R substitution in HA (H3 numbering). The effects of each of these substitutions on viral antigenicity were determined by measuring the neutralization and hemagglutination inhibition (HI) titers with mAbs and polyclonal sera raised against the representative viruses. The results indicate that residues 190 and 269 are key determinants of viral antigenic variation. In particular, the N190D mutation had the greatest antigenic impact, as determined by the HI assay. Further studies showed that both HeN11-2B6-P5 and HeN11-4C7-P8 maintained the receptor-binding specificity of the parent virus, although the single mutation N190D decreased the binding affinity for the human-type receptor. The replicative ability in vitro of HeN11-2B6-P5 was increased, whereas that of HeN11-4C7-P8 was decreased. These findings extend our understanding of the antigenic evolution of influenza viruses under immune pressure and provide insights into the functional effects of amino acid substitutions near the receptor-binding site and the interplay among receptor binding, viral replication, and antigenic drift. IMPORTANCE The antigenic changes that occur continually in the evolution of influenza A viruses remain a great challenge for the effective control of disease outbreaks. Here, we identified three amino acid substitutions (at positions 190, 230, and 269) in the HA of EA H1N1 SIVs that determine viral antigenicity and result in escape from neutralizing monoclonal antibodies. All three of these substitutions have emerged in nature. Of note, residues 190 and 230 have synergistic effects on receptor binding and antigenicity. Our findings provide a better understanding of the functional effects of amino acid substitutions in HA and their consequences for the antigenic drift of influenza viruses.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Evasão da Resposta Imune , Vírus da Influenza A Subtipo H1N1 , Animais , Anticorpos Monoclonais , Anticorpos Neutralizantes/genética , Anticorpos Antivirais , Deriva e Deslocamento Antigênicos , Antígenos Virais/genética , Hemaglutininas , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Mutação , Suínos
5.
BMC Neurosci ; 24(1): 9, 2023 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-36709248

RESUMO

AIMS/INTRODUCTION: As a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats. METHOD: Before the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze. RESULTS: We found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1ß and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury. CONCLUSIONS: The activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats.


Assuntos
Disfunção Cognitiva , Inflamassomos , Ratos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sevoflurano/farmacologia , Autofagia , Citocinas/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteínas de Transporte
6.
Molecules ; 28(17)2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37687169

RESUMO

The CD13 inhibitor ubenimex is used as an adjuvant drug with chemotherapy for the treatment of cancer due to its function as an immunoenhancer, but it has limitations in its cytotoxic efficacy. The proteasome inhibitor ixazomib is a landmark drug in the treatment of multiple myeloma with a high anti-cancer activity. Herein, we conjugated the pharmacophore of ubenimex and the boric acid of ixazomib to obtain a dual CD13 and proteasome inhibitor 7 (BC-05). BC-05 exhibited potent inhibitory activity on both human CD13 (IC50 = 0.13 µM) and the 20S proteasome (IC50 = 1.39 µM). Although BC-05 displayed lower anti-proliferative activity than that of ixazomib in vitro, an advantage was established in the in vivo anti-cancer efficacy and prolongation of survival time, which may be due to its anti-metastatic and immune-stimulating activity. A pharmacokinetic study revealed that BC-05 is a potentially orally active agent with an F% value of 24.9%. Moreover, BC-05 showed more favorable safety profiles than those of ixazomib in preliminary toxicity studies. Overall, the results indicate that BC-05 is a promising drug candidate for the treatment of multiple myeloma.


Assuntos
Mieloma Múltiplo , Inibidores de Proteassoma , Humanos , Inibidores de Proteassoma/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Terapia Enzimática , Antivirais
7.
J Chem Inf Model ; 62(10): 2352-2364, 2022 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-35442657

RESUMO

A community-reaction network reduction (CNR) approach is presented for mechanism reduction on the basis of a network-based community detection technique, a concept related to pre-equilibrium in chemical kinetics. In this method, the detailed combustion mechanism is first transformed into a weighted network, in which communities of species that have dense inner connections under the critical ignition conditions are identified. By analyzing the community partitions in different regions, we determine the effective functional groups and driving processes. Then, a skeletal model for the overall mechanism is deduced according to the network centrality data, including transition pathway identification and reaction-path flux. The CNR method is illustrated on the hydrogen autoignition system which has been extensively investigated, and a new reduced mechanism involving seven processes is proposed. Dynamics simulations employing the present CNR model show that the computed ignition time and distribution of major species on a wide range of temperature and pressure conditions are in accord with the experiments and results from other methods.


Assuntos
Hidrogênio , Fenômenos Químicos , Temperatura
8.
Phys Chem Chem Phys ; 24(10): 5921-5928, 2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35195640

RESUMO

Owing to the electron-deficient nature of boron atoms, the structures and properties of boron clusters can be enriched by doping various metal atoms, including lanthanide metal atoms. Nevertheless, the viability of actinide analogues has not been fully elucidated up to now. Here we demonstrate a series of highly stable low-valent actinide(III) boron clusters AnB7 (An = Pa, U, Np, and Pu) using first-principles calculations. The predicted global minimum structures of all the AnB7 complexes possess half-sandwich geometries with C6v symmetry and belong to MIII[B7]3--type species. In each AnB7 species, the B73- ligand possesses double aromaticity features with six delocalized π electrons and six delocalized σ electrons. Bonding analysis shows that although there is a substantial contribution of electrostatic interaction in each cluster, covalent interaction is responsible for the stability of AnB7. All the AnB7 species show significantly high formation energies, especially for NpB7, which is in line with the stronger Np-B covalent bonds. In addition, the simulated photoelectron spectroscopy analysis confirms the high electronic stability of neutral AnB7. These results imply that these ultrastable actinide(III) complexes are accessible in the gas phase at room temperature. This work may provide a theoretical basis for the design of highly stable boron-based nanomaterials as well as preparation of low-valent actinide complexes.

9.
Phys Chem Chem Phys ; 24(48): 29705-29711, 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36453525

RESUMO

Similar to graphene and fullerene, metal-doping has been considered to be an effective approach to the construction of highly stable boron clusters. In this work, a series of actinide metal-doped boron clusters AnB36 (An = Pa, Np, Pu, Am, Cm, Bk, and Cf) have been explored using extensive first-principles calculations. We found that the quasi-planar structure of B36 transforms to an endohedral borospherene An@B36 after actinide metal doping. Actinoborospherenes exhibit C2h symmetry with Pa, Np, and Pu dopants and for Am, Cm, Bk and Cf dopants with larger atomic radii, the symmetry of An@B36 is reduced to Ci. Bonding property analyses such as bond order, molecular orbital (MO) and quantum theory of atoms in molecules (QTAIM) analysis show that the covalency of the An-B bonds in C2h An@B36 (An = Pa, Np, and Pu) is higher than that in Ci An@B36 (An = Am, Cm, Bk, and Cf). These endohedral borospherenes are robust according to thermodynamic and dynamic analyses. As expected, the Ci An@B36 clusters are less stable compared to C2h An@B36, which is consistent with the stronger covalent bonds of the latter. These results indicate that the existence of the actinide-boron bonding is essential for the high stability of the An@B36 clusters, confirming that the fullerene-like boron cages can be stabilized by actinide encapsulation. This work is expected to provide potential routes for the construction of robust borospherenes.

10.
Phys Chem Chem Phys ; 24(42): 25767-25772, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36222115

RESUMO

As an allotrope of graphene, T-graphene was predicted to be an intrinsic two-dimensional (2D) superconductor with a superconducting critical temperature (Tc) of about 20.8 K [Gu et al., Chin. Phys. Lett. 36, 097401 (2019)]. In this work, based on first-principles calculations, hole doping and biaxial tensile strain (BTS) are considered to modulate the electron-phonon coupling (EPC) and superconductivity of T-graphene. It is found that the EPC constant of T-graphene is 0.807 and the calculated critical temperature Tc is 28.2 K at a doping level of 0.5 hole per unit cell (3.31 × 1014 cm-2) and 12% BTS. Furthermore, when 0.8 hole per unit cell (5.43 × 1014 cm-2) doping and 10% BTS are applied, the EPC constant is 0.939, and the Tc can be boosted to 35.2 K, which is higher than those of the pristine T-graphene and many other 2D carbon-based superconductors.

11.
Int J Gynecol Cancer ; 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680136

RESUMO

OBJECTIVE: Radiofrequency ablation and microwave ablation are used to vaporize tumors not amenable to surgical resection. We sought to evaluate the safety and efficacy of radiofrequency and microwave ablation for the treatment of isolated lesions in patients with recurrent gynecologic malignancy. METHODS: Patients with gynecologic malignancies treated with radiofrequency or microwave ablation at a university-affiliated cancer center from April 2007 to January 2020 were evaluated. Clinical records were reviewed for number of prior chemotherapy regimens, response to ablation, time to progression, and location of progression. RESULTS: Thirty-two patients received ablative therapy for treatment of isolated recurrences. Seventeen (53%) patients had ovarian cancer, seven (22%) had endometrial cancer, and eight (25%) had cervical cancer. Thirteen (41%) patients received radiofrequency ablation and 19 (59%) received microwave ablation. Patients had a median of 2 (range 1-12) prior lines of chemotherapy. Sixteen (50%) patients achieved a partial or complete response with two patients experiencing no progression at time of submission. Six (19%) patients had stable disease and 10 (31%) patients had progression at time of initial follow-up imaging. Median progression-free survival for the cohort was 7.3 months (range 1.4-64.7). No significant improvement in median progression-free survival was seen with the addition of adjuvant systemic therapy to radiofrequency or microwave ablation (6.9 vs 7.7 months; HR 0.7, 95% CI 0.3 to 1.7). Clinical benefit, defined as absence of definitive progression at the site of ablation or new target lesions at 4 months, was seen in 22 (68.8%) patients. No major complications occurred, with two patients reporting pain or weakness at the site of ablation. CONCLUSION: Radiofrequency and microwave ablation demonstrated that 68.8% (n=22) of patients experienced clinical benefit at 4 months. Ablative therapy may be considered for the treatment of isolated lesions in patients with recurrent gynecologic malignancies.

12.
Phys Chem Chem Phys ; 23(47): 26967-26973, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34842871

RESUMO

The exploration of metal-doped boron clusters has a great significance in the design of high coordination number (CN) compounds. Actinide-doped boron clusters are probable candidates for achieving high CNs. In this work, we systematically explored a series of actinide metal atom (U, Np, and Pu) doped B20 boron clusters An@B20 (An = U, Np, and Pu) by global minimum structural searches and density functional theory (DFT). Each An@B20 cluster is confirmed to be a twenty-coordinate complex, which is the highest CN obtained in the chemistry of actinide-doped boron clusters so far. The predicted global minima of An@B20 are tubular structures with actinide atoms as centers, which can be considered as boron molecular drums. In An@B20, U@B20 has a relatively high symmetry of C2, while both Np@B20 and Pu@B20 exhibit C1 symmetry. Extensive bonding analysis demonstrates that An@B20 has σ and π delocalized bonding, and the U-B bonds possess a relatively higher covalency than the Np-B and Pu-B bonds, resulting in the higher formation energy of U@B20. Therefore, the covalent character of An-B bonding may be crucial for the formation of these high CN actinide-centered boron clusters. These results deepen our understanding of actinide metal doped boron clusters and provide new clues for developing stable high CN boron-based nanomaterials.

13.
Cell Microbiol ; 20(11): e12889, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29993167

RESUMO

Miltefosine is an important drug for the treatment of leishmaniasis; however, its mechanism of action is still poorly understood. In these studies, we tested the hypothesis that like in cancer cells, miltefosine's efficacy in leishmaniasis is due to its inhibition of Akt activation in host cells. We show using pharmacologic agents that block Akt activation by different mechanisms and also using an inducible knockdown approach that miltefosine loses its efficacy when its access to Akt1 is limited. Interestingly, limitation of Akt activation results in clearance of established Leishmania infections. We then show, using fluorophore-tagged probes that bind to phosphoinositides, that Leishmania parasitophorous vacuole membranes (LPVMs) display the relevant phosphoinositides to which Akt can be recruited and activated continuously. Taken together, we propose that the acquisition of PI(4) P and the display of PI (3,4)P2 on LPVMs initiate the machinery that supports continuous Akt activation and sensitivity to miltefosine.


Assuntos
Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fosfatidilinositóis/metabolismo , Fosforilcolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antiprotozoários/farmacologia , Técnicas de Silenciamento de Genes , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/metabolismo , Leishmaniose/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Fosforilcolina/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transfecção , Vacúolos/efeitos dos fármacos
15.
Genome Biol ; 25(1): 34, 2024 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-38268000

RESUMO

BACKGROUND: Various laboratory-developed metabolomic methods lead to big challenges in inter-laboratory comparability and effective integration of diverse datasets. RESULTS: As part of the Quartet Project, we establish a publicly available suite of four metabolite reference materials derived from B lymphoblastoid cell lines from a family of parents and monozygotic twin daughters. We generate comprehensive LC-MS-based metabolomic data from the Quartet reference materials using targeted and untargeted strategies in different laboratories. The Quartet multi-sample-based signal-to-noise ratio enables objective assessment of the reliability of intra-batch and cross-batch metabolomics profiling in detecting intrinsic biological differences among the four groups of samples. Significant variations in the reliability of the metabolomics profiling are identified across laboratories. Importantly, ratio-based metabolomics profiling, by scaling the absolute values of a study sample relative to those of a common reference sample, enables cross-laboratory quantitative data integration. Thus, we construct the ratio-based high-confidence reference datasets between two reference samples, providing "ground truth" for inter-laboratory accuracy assessment, which enables objective evaluation of quantitative metabolomics profiling using various instruments and protocols. CONCLUSIONS: Our study provides the community with rich resources and best practices for inter-laboratory proficiency tests and data integration, ensuring reliability of large-scale and longitudinal metabolomic studies.


Assuntos
Espectrometria de Massa com Cromatografia Líquida , Metabolômica , Humanos , Reprodutibilidade dos Testes , Linhagem Celular , Gêmeos Monozigóticos
16.
Adv Sci (Weinh) ; : e2307747, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38896791

RESUMO

PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient-derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy.

17.
Nat Cancer ; 5(4): 673-690, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38347143

RESUMO

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR+HER2+ cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches.


Assuntos
Povo Asiático , Neoplasias da Mama , Receptor ErbB-2 , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Feminino , Povo Asiático/genética , Receptor ErbB-2/genética , Mutação , Proteômica/métodos , Perfilação da Expressão Gênica/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Pessoa de Meia-Idade , China/epidemiologia , Ferroptose/genética , Adulto , Metabolômica/métodos , Transcriptoma , Biomarcadores Tumorais/genética , População do Leste Asiático
18.
Gynecol Oncol Rep ; 47: 101196, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37168405

RESUMO

Intraplacental choriocarcinoma (IC), or choriocarcinoma in situ, is a rare disease on the gestational trophoblastic disease (GTD) spectrum, with <100 case reports available in the literature. We propose that many patients with IC are likely to be missed as the majority of patients do not present with metastases. Currently, there are no standardized protocols in existence for postpartum monitoring of these patients. We present a case of IC identified in the term placenta of a 21-year-old who delivered by primary cesarean due to concern for fetal intolerance of labor. Subsequently, we review the recommendations available on postpartum monitoring of this likely under-diagnosed condition.

19.
Water Res ; 243: 120238, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37506632

RESUMO

As a stable and effective approach for NO2--N accumulation, partial denitrification (PD) could significantly cut down operation cost, and PD/Anammox (PD/A) is a promising nitrogen removal process in wastewater treatment. The biotoxicity of free ammonia (FA) to nitrifying bacteria and anammox bacteria has been demonstrated, while whether FA affects PD bacteria is an open question. Here, long-term operation of PD-fixed bed biofilm reactor (PD-FBBR) treating synthetic wastewater and mature landfill leachate was conducted to reveal the mechanism concerning the effect of FA on PD bacteria. Stable NO2--N accumulation was achieved with NO3--N to NO2--N transformation ratio (NTR) of 60-70% during 280-day operation with FA ranged from 0 to 20.71 ±â€¯0.23 mg/L, while NTR decreased and maintained at ∼30% when FA reached 40.59 ±â€¯0.19 mg/L. Specific NOx--N reduction rate improved at low FA concentration (< 12 mg/L), while high FA level (> 25 mg/L) had inhibitory effect on PD bacteria. Under FA stress, more extracellular polymeric substances (EPS) were secreted, and the glnA gene abundance, glutamine synthase concentration, and glutamine concentration in cell and EPS significantly increased, indicating the enhancement of glutamine biosynthesis in PD bacteria for ammonia assimilation played an important role in response to FA stress. Metagenomic sequencing showed that FA stimulated the upregulation of narK (NO3--N/NO2--N antiporter) gene abundance and enhanced uptake of NO3--N and extrusion of NO2--N. Comamonas, unclassified_f__Comamonadaceae and Thauera were highly enriched in biofilm, which played a key role in the stable NO2--N accumulation. Furthermore, a novel two stage PD/A-FBBR was applied to mature landfill leachate treatment, and satisfactory total inorganic nitrogen removal efficiency ranged from 81.38 ±â€¯3.56% to 89.16 ±â€¯1.57% was obtained at relatively low COD/NO3--N of 2.57-2.84. Overall, these findings demonstrated how PD bacteria respond to FA stress and confirmed the feasibility of PD/A process in high FA wastewater treatment.


Assuntos
Amônia , Poluentes Químicos da Água , Desnitrificação , Oxidação Anaeróbia da Amônia , Estudos de Viabilidade , Glutamina , Dióxido de Nitrogênio , Oxirredução , Reatores Biológicos/microbiologia , Nitrogênio , Bactérias , Esgotos
20.
Gynecol Oncol Rep ; 45: 101133, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36647550

RESUMO

Pelvic metastasis of melanoma is extremely rare and may pose a diagnostic challenge. We present a case report of a female with a history of colon cancer who underwent exploratory surgery for a pelvic mass that was suspicious for ovarian malignancy. Pathology was consistent with both recurrent colon cancer as well as synchronous newly diagnosed metastatic melanoma.

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