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1.
EClinicalMedicine ; 72: 102629, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38745967

RESUMEN

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

3.
Ecol Evol ; 14(4): e11279, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38633519

RESUMEN

Wolbachia, one of the most ubiquitous heritable symbionts in lepidopteran insects, can cause mitochondrial introgression in related host species. We recently found mito-nuclear discordance in the Lepidopteran tribe Tagiadini Mabille 1878 from which Wolbachia has not been reported. In this study, we found that 13 of the 46 species of Tagiadini species tested were positive for Wolbachia. Overall, 14% (15/110) of Tagiadini specimens were infected with Wolbachia and nine new STs were found from 15 isolates. A co-phylogenetic comparison, divergence time estimation and Wolbachia recombination analysis revealed that mito-nuclear discordance in Tagiadini species is not mediated by Wolbachia, but Wolbachia acquisition in Tagiadini appears to have occurred mainly through horizontal transmission rather than codivergence.

4.
Heliyon ; 10(6): e27701, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38515659

RESUMEN

Countries face exasperating and inclement climate worldwide. Food and feed security could be their paramount life objective. The study aimed to investigate the impact of selenium on the protein content and distribution in different parts of rice. For this purpose, advanced selenium biofortified breeding material developed after generations of breeding efforts was investigated at the field area, rice research institute, Chengdu, China during cropping season 2021-22. The accumulation and distribution of selenium and protein contents were observed in various fractions of selenium-enriched rice (Z3057B) and positive control (727). The correlation studies for selenium and protein quantification leads to the optimization of the breeding material and relevance in virtue. The rice fractions indicated rice embryo retains highest selenium contents, which gradually decreases in succession (other rice parts). The difference in protein content between the embryo and endosperm of Se-enriched rice is significant, while that between embryo and aleurone layer is not obvious. The selenium protein was found with molecular weight of 13.6-122.6 kDa. The protein of each molecular weight is found to bind with selenium, but the binding strength of selenium is negatively correlated with the molecular weight of protein. The 67.5% of the total selenium sticks with protein having molecular weight less than 38.8 kDa. In summary, protein with low molecular weight (13.4 kDa) binds maximum selenium and accounts for highest total protein content (40.76%).

5.
J Exp Bot ; 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38447063

RESUMEN

In our gene chip analysis, OsSMP2 gene expression was induced under various abiotic stresses, prompting an investigation into its role in drought resistance and ABA signaling. Subsequent experiments, including qRT-PCR and GUS activity detection, affirmed the OsSMP2 gene's predominant induction by drought stress. Subcellular localization experiments indicated the OsSMP2 protein primarily localizes to the cell membrane system. Overexpressing OsSMP2 increased sensitivity to exogenous ABA, reducing drought resistance and leading to reactive oxygen species accumulation under drought stress. Conversely, in simulated drought experiments, OsSMP2-silenced transgenic plants showed significantly longer root lengths compared to the wild-type Nipponbare. These results suggest that OsSMP2 overexpression negatively affects rice drought resistance, offering valuable insights into molecular mechanisms and proposing OsSMP2 as a potential target for enhancing crop resilience to drought stress.

6.
Cancer ; 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38412283

RESUMEN

BACKGROUND: Penpulimab, a new-generation antiprogrammed cell death-1 immunoglobulin G1 monoclonal antibody, was engineered to optimize receptor occupancy and eliminate fragment crystallizable γ-mediated effector function. In this multicenter, phase 1b/2, multicohort study, the objective was to investigate the efficacy, safety, and immunogenicity of penpulimab in advanced solid tumors. METHODS: Patients who had unresectable, advanced solid tumors were enrolled from six centers and received 200 mg penpulimab on day 1 every 2 weeks for up to 24 months. The primary end point was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version criteria 1.1. RESULTS: Between September 2, 2019, and January 1, 2020, 65 patients were enrolled and received penpulimab. At the time of data cutoff (May 11, 2022), the median follow-up was 12.6 months (range, 1.1-28.6 months). The ORR was 12.3 (95% confidence interval [CI], 5.5%-22.8%), with three (4.6%) complete responses and five (7.7%) partial responses. Twelve patients (18.5%) achieved stable disease, resulting in a disease control rate of 30.8% (95% CI, 19.9%-43.4%). The median duration of response was not reached (95% CI, 6.70 months to not estimable). In all cohorts, the median progression-free survival was 1.74 months (95% CI, 1.41-2.69 months), and the median overall survival was 16.59 months (95% CI, 7.82-22.18 months). Grade 3 or greater treatment-related adverse events and immune-related adverse events occurred in 9.2% and 27.7% of patients, respectively. Positive antidrug antibody responses to penpulimab were observed in one patient (1.8%). CONCLUSIONS: Penpulimab showed promising antitumor activity with an acceptable safety profile, offering a potential new treatment approach for solid tumors. These findings supported the evaluation of penpulimab's durable activity and safety, as monotherapy or in combination therapy, in specific malignancies.

7.
Small ; : e2308265, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38225704

RESUMEN

Bispecific antibodies possess exceptional potential as therapeutic agents due to their capacity to bind to two different antigens simultaneously. However, challenges pertain to unsatisfactory stability, manufacturing complexity, and limited tumor penetration hinder their broad applicability. In this study, a versatile technology is presented for the rapid generation of bispecific nanobody-aptamer conjugates with efficient tumor penetration. The approach utilizes microbial transglutaminase (MTGase) and click chemistry to achieve site-specific conjugation of nanobodies and aptamers, which are termed nanotamers. The nanotamers recognize and bind to two types of molecular targets expressed on cancer cells. As a prototype, a bispecific nanotamer is developed that binds both clusters of differentiation 47 (CD47) and mesenchymal epithelial transition receptor (Met) expressed on the tumor cell membrane. This CD47-Met nanotamer demonstrates high affinity and specificity toward tumor cells expressing both targets, exhibits improved receptor functional inhibition through a strong steric hindrance effect. Moreover, its capacity for deep tumor penetration greatly enhances the impact of conventional chemotherapy on antitumor efficacy. The as-developed nanotamer synthesis approach shows promise to customize bispecific molecular probes targeting different cancer types and different therapeutic goals.

8.
Angew Chem Int Ed Engl ; 63(4): e202314262, 2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-38012811

RESUMEN

Molecular profiling of protein markers on small extracellular vesicles (sEVs) is a promising strategy for the precise detection and classification of ovarian cancers. However, this strategy is challenging owing to the lack of simple and practical detection methods. In this work, using an aptamer-based nanoflow cytometry (nFCM) detection strategy, a simple and rapid method for the molecular profiling of multiple protein markers on sEVs was developed. The protein markers can be easily labeled with aptamer probes and then rapidly profiled by nFCM. Seven cancer-associated protein markers, including CA125, STIP1, CD24, EpCAM, EGFR, MUC1, and HER2, on plasma sEVs were profiled for the molecular detection and classification of ovarian cancers. Profiling these seven protein markers enabled the precise detection of ovarian cancer with a high accuracy of 94.2 %. In addition, combined with machine learning algorithms, such as linear discriminant analysis (LDA) and random forest (RF), the molecular classifications of ovarian cancer cell lines and subtypes were achieved with overall accuracies of 82.9 % and 55.4 %, respectively. Therefore, this simple, rapid, and non-invasive method exhibited considerable potential for the auxiliary diagnosis and molecular classification of ovarian cancers in clinical practice.


Asunto(s)
Vesículas Extracelulares , Neoplasias Ováricas , Humanos , Femenino , Biomarcadores de Tumor/metabolismo , Neoplasias Ováricas/patología , Oligonucleótidos/metabolismo , Proteínas de Choque Térmico/metabolismo , Vesículas Extracelulares/metabolismo
9.
Int J Cancer ; 154(3): 412-424, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37688376

RESUMEN

Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.


Asunto(s)
Neoplasias , Macrófagos Asociados a Tumores , Humanos , Macrófagos/metabolismo , Neoplasias/patología , Glucólisis , Glucosa/metabolismo , Microambiente Tumoral
10.
Int J Mol Sci ; 24(19)2023 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-37833888

RESUMEN

Cold stress is the main factor limiting rice production and distribution. Chaling wild rice can survive in cold winters. AP2/EREBP is a known transcription factor family associated with abiotic stress. We identified the members of the AP2/EREBP transcription factor family in rice, maize, and Arabidopsis, and conducted collinearity analysis and gene family analysis. We used Affymetrix array technology to analyze the expression of AP2/EREBP family genes in Chaling wild rice and cultivated rice cultivar Pei'ai64S, which is sensitive to cold. According to the GeneChip results, the expression levels of AP2/EREBP genes in Chaling wild rice were different from those in Pei'ai64S; and the increase rate of 36 AP2/EREBP genes in Chaling wild rice was higher than that in Pei'ai64S. Meanwhile, the MYC elements in cultivated rice and Chaling wild rice for the Os01g49830, Os03g08470, and Os03g64260 genes had different promoter sequences, resulting in the high expression of these genes in Chaling wild rice under low-temperature conditions. Furthermore, we analyzed the upstream and downstream genes of the AP2/EREBP transcription factor family and studied the conservation of these genes. We found that the upstream transcription factors were more conserved, indicating that these upstream transcription factors may be more important in regulating cold stress. Meanwhile, we found the expression of AP2/EREBP pathway genes was significantly increased in recombinant inbred lines from Nipponbare crossing with Chaling wild rice, These results suggest that the AP2/EREBP signaling pathway plays an important role in Chaling wild rice tolerance to cold stress.


Asunto(s)
Respuesta al Choque por Frío , Oryza , Arabidopsis/metabolismo , Frío , Respuesta al Choque por Frío/genética , Regulación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
11.
Int J Gynecol Cancer ; 33(12): 1861-1868, 2023 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-37875323

RESUMEN

OBJECTIVE: There is an unmet need to improve clinical outcomes for patients with recurrent/metastatic cervical cancer. Checkpoint inhibitors represent a promising treatment strategy. We evaluated the safety and anti-tumor activity of zimberelimab, an anti-programmed cell death protein-1 antibody, in patients with previously treated, recurrent, metastatic cervical cancer. METHODS: This phase II, single-arm, open-label study used a Simon two-stage minimax design. Eligible patients were women aged 18-75 years with programmed death ligand-1-positive recurrent or metastatic cervical cancer that had progressed after first- or subsequent-line chemotherapy (Eastern Cooperative Oncology Group (ECOG) performance status 0-1). Patients received intravenous zimberelimab (240 mg every 2 weeks) for 2 years until disease progression, intolerable adverse effects, or withdrawal from the study. The primary endpoint was objective response rate assessed per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, by an independent review committee. RESULTS: A total of 105 patients were enrolled. Median age was 51 (range, 31-75) years; 63.8% had an ECOG performance status of 1. The median number of previous treatment lines was 1 (range, 1-4). Median follow-up was 16.9 (range, 16.3-18.4) months. The objective response rate was 27.6%, and the disease control rate was 55.2%. Median duration of response was not reached. Median overall survival was 16.8 months, and median progression-free survival was 3.7 months. The incidence of treatment-related adverse events of any grade was 78.1%, of which the most common were hypothyroidism (26.7%) and anemia (19.0%). CONCLUSION: Zimberelimab monotherapy demonstrated durable anti-tumor activity and an acceptable safety profile in patients with cervical cancer. CLINICAL TRIAL REGISTRATION: NCT03972722.


Asunto(s)
Neoplasias del Cuello Uterino , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico
12.
J Obstet Gynaecol Res ; 49(12): 2905-2909, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37813122

RESUMEN

AIM: The prognosis of patients with ovarian cancer with lung metastasis is poor; data on pulmonary metastasectomy for such patients are lacking. This study aimed to determine the safety and feasibility of pulmonary resection as part of cytoreductive surgery for recurrent metastatic ovarian cancer. METHODS: Medical records of patients with ovarian cancer, who underwent pulmonary resection for lung metastasis in our hospital from April 2012 to February 2022, were retrospectively reviewed. RESULTS: Ten patients were included (median age, 53 years). Five patients had metastatic disease limited to the lungs. Additional surgeries included diaphragm resection, partial hepatectomy, para-aortic lymph node dissection, and cytoreduction. We achieved complete cytoreduction for all patients without severe complications, and the 30-day mortality was zero. After a median follow-up of 23 months, four of the patients experienced recurrence. One patient recurred 9 months after the operation and was lost to follow-up at 17 months, two died at 68 and 26 months respectively, one is alive with disease (23 months), and six are alive without recurrence, among whom two have survived for 56 and 124 months. CONCLUSIONS: Pulmonary resection for recurrent metastatic ovarian cancer seems safe and feasible, with long-term survival observed in certain patients. Pulmonary metastasectomy can be performed as part of the debulking surgery for selected patients with relapsed metastatic ovarian cancer. Both the patient lost to follow-up and the one who died at 26 months, had two lung metastatic nodules and did not receive postoperative chemotherapy, which might have led to relatively poor prognosis.


Asunto(s)
Neoplasias Pulmonares , Metastasectomía , Neoplasias Ováricas , Humanos , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Recurrencia Local de Neoplasia/cirugía , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/secundario
13.
Plants (Basel) ; 12(18)2023 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-37765501

RESUMEN

Drought stress is one of the major causes of crop losses. The WRKY families play important roles in the regulation of many plant processes, including drought stress response. However, the function of individual WRKY genes in plants is still under investigation. Here, we identified a new member of the WRKY families, OsWRKY97, and analyzed its role in stress resistance by using a series of transgenic plant lines. OsWRKY97 positively regulates drought tolerance in rice. OsWRKY97 was expressed in all examined tissues and could be induced by various abiotic stresses and abscisic acid (ABA). OsWRKY97-GFP was localized to the nucleus. Various abiotic stress-related cis-acting elements were observed in the promoters of OsWRKY97. The results of OsWRKY97-overexpressing plant analyses revealed that OsWRKY97 plays a positive role in drought stress tolerance. In addition, physiological analyses revealed that OsWRKY97 improves drought stress tolerance by improving the osmotic adjustment ability, oxidative stress tolerance, and water retention capacity of the plant. Furthermore, OsWRKY97-overexpressing plants also showed higher sensitivity to exogenous ABA compared with that of wild-type rice (WT). Overexpression of OsWRKY97 also affected the transcript levels of ABA-responsive genes and the accumulation of ABA. These results indicate that OsWRKY97 plays a crucial role in the response to drought stress and may possess high potential value in improving drought tolerance in rice.

14.
Neural Netw ; 168: 1-13, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37734135

RESUMEN

Due to the prevalent data-dependent nature of existing pruning criteria, norm criteria with data independence play a crucial role in filter pruning criteria, providing promising prospects for deploying deep neural networks on resource-constrained devices. However, norm criteria based on amplitude measurements have long posed challenges in terms of theoretical feasibility. Existing methods rely on data-derived information such as derivatives to establish reasonable pruning standards. Nonetheless, achieving quantitative analysis of the "smaller-norm-less-important" notion remains elusive within the norm criterion context. To address the need for data independence and theoretical feasibility, we conducted saliency analysis on filters and proposed a regularization-based amplitude saliency pruning criterion (RASP). This amplitude saliency not only attains data independence but also establishes norm criteria for usage guidelines. Furthermore, we further investigated the amplitude saliency, addressing the issues of data dependency in model evaluation and inter-class filter selection. We introduced model saliency and an adaptive parameter group lasso (AGL) regularization approach sensitive to different layers. Theoretically, we thoroughly analyzed the feasibility of amplitude saliency and employed quantitative saliency analysis to validate the advantages of our method over previous approaches. Experimentally, conducted on the CIFAR-10 and ImageNet image classification benchmarks, we extensively validated the improved top-level performance of our method compared to previous methods. Even when the pruned model has the same or even smaller number of FLOP, our method can achieve equivalent or higher model accuracy. Notably, in our ImageNet experiment, RASP achieved a 51.9% reduction in FLOPs while maintaining an accuracy of 76.19% on ResNet-50.


Asunto(s)
Benchmarking , Redes Neurales de la Computación
15.
JAMA Oncol ; 9(9): 1230-1237, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37440217

RESUMEN

Importance: The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. Objective: To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Interventions: Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/µL [to convert to ×109/µL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. Main Outcomes and Measurements: The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. Results: A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. Conclusion and Relevance: This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03709316.


Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Supervivencia sin Progresión , Indazoles/efectos adversos , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
16.
J Cancer Res Clin Oncol ; 149(12): 10189-10201, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37270461

RESUMEN

PURPOSE: The expression of NKG2D ligands and PD-L1 has been detected on acute myeloid leukaemia (AML) cells, as well as normal cells of the myeloid lineage. To target leukemic cells while minimizing collateral damage to normal cells, we constructed a split dual CAR system based on the AND-gate logic. METHODS: The NKG2D extracellular domain linked with DAP12 without a co-stimulatory signal was used for the basal activation of T cells, and used together with the PD-L1-specific chimeric costimulatory receptor containing the 4-1BB activating domain for co-stimulatory signal 2 input. This dual CAR displayed cell-type specificity and activity similar as a 2nd generation NKG2D ligand-specific CAR. RESULTS: When compared to CD64 and PD-L1-specific 2nd generation CARs, we observed that the split dual CAR offered an improved myeloid cell type selectivity. For example, PD-L1-specific CAR-T cells lysed all tested myeloid cell types that expressed PD-L1, including M0 macrophages (Mø0), LPS-polarized Mø1, IFN-γ polarized Mø1, IL-4 polarized Mø2, monocytes, immature dendritic cells (imDCs), mature DCs, as well as KG-1 AML cells, while the dual CAR-T cells displaying killing activity only towards LPS polarized Mø1, mature DCs and KG-1 cells that expressed both NKG2D ligands and PD-L1. In a mouse liquid tumor model, the dual CAR-T cells were effective in eradicating established KG-1 AML xenografts. CONCLUSION: The improved cell type specificity offered by our split dual CAR-T cell system targeting paired antigens would favour the reduction of the on-target off-tumor toxicity towards normal myeloid cells during the treatment of myeloid leukaemia.


Asunto(s)
Leucemia Mieloide Aguda , Linfocitos T , Humanos , Ratones , Animales , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Monocitos/metabolismo , Ligandos , Antígeno B7-H1/metabolismo , Lipopolisacáridos , Leucemia Mieloide Aguda/metabolismo , Línea Celular Tumoral , Inmunoterapia Adoptiva
17.
Int J Mol Sci ; 24(12)2023 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-37372942

RESUMEN

As the human population grows rapidly, food shortages will become an even greater problem; therefore, increasing crop yield has become a focus of rice breeding programs. The maize gene, ZmDUF1645, encoding a putative member of the DUF1645 protein family with an unknown function, was transformed into rice. Phenotypic analysis showed that enhanced ZmDUF1645 expression significantly altered various traits in transgenic rice plants, including increased grain length, width, weight, and number per panicle, resulting in a significant increase in yield, but a decrease in rice tolerance to drought stress. qRT-PCR results showed that the expression of the related genes regulating meristem activity, such as MPKA, CDKA, a novel crop grain filling gene (GIF1), and GS3, was significantly changed in the ZmDUF1645-overexpression lines. Subcellular colocalization showed that ZmDUF1645 was primarily localized on cell membrane systems. Based on these findings, we speculate that ZmDUF1645, like the OsSGL gene in the same protein family, may regulate grain size and affect yield through the cytokinin signaling pathway. This research provides further knowledge and understanding of the unknown functions of the DUF1645 protein family and may serve as a reference for biological breeding engineering to increase maize crop yield.


Asunto(s)
Sequías , Oryza , Humanos , Oryza/metabolismo , Zea mays/genética , Zea mays/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Expresión Génica Ectópica , Fitomejoramiento , Grano Comestible/genética , Grano Comestible/metabolismo , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo , Regulación de la Expresión Génica de las Plantas
18.
Sensors (Basel) ; 23(9)2023 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-37177410

RESUMEN

Multi-modal (i.e., visible, near-infrared, and thermal-infrared) vehicle re-identification has good potential to search vehicles of interest in low illumination. However, due to the fact that different modalities have varying imaging characteristics, a proper multi-modal complementary information fusion is crucial to multi-modal vehicle re-identification. For that, this paper proposes a progressively hybrid transformer (PHT). The PHT method consists of two aspects: random hybrid augmentation (RHA) and a feature hybrid mechanism (FHM). Regarding RHA, an image random cropper and a local region hybrider are designed. The image random cropper simultaneously crops multi-modal images of random positions, random numbers, random sizes, and random aspect ratios to generate local regions. The local region hybrider fuses the cropped regions to let regions of each modal bring local structural characteristics of all modalities, mitigating modal differences at the beginning of feature learning. Regarding the FHM, a modal-specific controller and a modal information embedding are designed to effectively fuse multi-modal information at the feature level. Experimental results show the proposed method wins the state-of-the-art method by a larger 2.7% mAP on RGBNT100 and a larger 6.6% mAP on RGBN300, demonstrating that the proposed method can learn multi-modal complementary information effectively.

19.
Artículo en Inglés | MEDLINE | ID: mdl-37022078

RESUMEN

Transformers are more and more popular in computer vision, which treat an image as a sequence of patches and learn robust global features from the sequence. However, pure transformers are not entirely suitable for vehicle re-identification because vehicle re-identification requires both robust global features and discriminative local features. For that, a graph interactive transformer (GiT) is proposed in this paper. In the macro view, a list of GiT blocks are stacked to build a vehicle re-identification model, in where graphs are to extract discriminative local features within patches and transformers are to extract robust global features among patches. In the micro view, graphs and transformers are in an interactive status, bringing effective cooperation between local and global features. Specifically, one current graph is embedded after the former level's graph and transformer, while the current transform is embedded after the current graph and the former level's transformer. In addition to the interaction between graphs and transforms, the graph is a newly-designed local correction graph, which learns discriminative local features within a patch by exploring nodes' relationships. Extensive experiments on three large-scale vehicle re-identification datasets demonstrate that our GiT method is superior to state-of-the-art vehicle re-identification approaches.

20.
Foods ; 12(8)2023 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-37107451

RESUMEN

Cadmium (Cd), a highly toxic heavy metal for crops in China, poses a significant threat to rice cultivation. It is crucial to identify the genotypes with robust resistance to heavy metals, including Cd, in rice. The experiment was conducted to examine the mitigation effect of silicon (Si) on Cd toxicity levels in Se-enriched Z3055B and non-Se-enriched G46B rice genotypes. A basal dose of Si improved the growth and the quality of rice significantly by reducing the Cd content in rice roots, stems, leaves and grains and increased the yield, biomass and selenium (Se) content of brown rice in both genotypes. Additionally, Se content in brown rice and polished rice was notably higher in Se-enriched rice than in non-Se-enriched rice, with the highest amount at 0.129 mg/kg and 0.085 mg/kg, respectively. The results demonstrated that a basal fertilizer concentration of 30 mg/kg of Si was more effective in reducing Cd transport from roots to shoots in Se-enriched rice than in non-Se-enriched rice genotypes. Therefore, it can be concluded that Se-enriched rice genotypes are a viable option for food crop production in Cd-contaminated areas.

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