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Two Gram-stain-negative, aerobic, rod-shaped, non-endospore-forming and motile bacterial strains, designated IT1137T and S025T, were isolated from an intertidal sediment sample collected from the Fildes Peninsula (King George Island, Maritime Antarctica) and a soil sample under red snow in the Ny-Ålesund region (Svalbard, High Arctic), respectively. The 16S rRNA gene sequence similarity values grouped them in the genus Pseudomonas. The two strains were characterized phenotypically using API 20E, API 20NE, API ZYM and Biolog GENIII tests and chemotaxonomically by their fatty acid contents, polar lipids and respiratory quinones. Multilocus sequence analysis (concatenated 16S rRNA, gyrB, rpoB and rpoD sequences), together with genome comparisons by average nucleotide identity and digital DNA-DNA hybridization, were performed. The results showed that the similarity values of the two isolates with the type strains of related Pseudomonas species were below the recognized thresholds for species definition. Based on polyphasic taxonomy analysis, it can be concluded that strains IT1137T and S025T represent two novel species of the genus Pseudomonas, for which the names Pseudomonas paeninsulae sp. nov. (type strain IT1137T=PMCC 100533T=CCTCC AB 2023226T=JCM 36637T) and Pseudomonas svalbardensis sp. nov. (type strain S025T=PMCC 200367T= CCTCC AB 2023225T=JCM 36638T) are proposed.
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Técnicas de Tipificación Bacteriana , ADN Bacteriano , Ácidos Grasos , Sedimentos Geológicos , Tipificación de Secuencias Multilocus , Hibridación de Ácido Nucleico , Filogenia , Pseudomonas , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Microbiología del Suelo , ARN Ribosómico 16S/genética , Pseudomonas/genética , Pseudomonas/clasificación , Pseudomonas/aislamiento & purificación , Sedimentos Geológicos/microbiología , ADN Bacteriano/genética , Regiones Árticas , Regiones Antárticas , Ácidos Grasos/análisis , Svalbard , Composición de Base , Quinonas/análisisRESUMEN
AIM: To investigate Omicron's impact on clinical presentation of acute primary angle closure (APAC) in China. METHODS: A consecutive case series with historical controls was conducted at Shenzhen Eye Hospital, the largest specialized hospital in Shenzhen, China. Medical records from a two-month period during the Omicron pandemic (December 1, 2022, to January 31, 2023) were compared with records from two control groups (12/2018-1/2019 and 12/2021-1/2022) before pandemic. Patients with APAC were included, and the prevalence of APAC and demographic characteristics in Omicron-infected and non-infected patients were compared. RESULTS: Seventy-one (23.43%) out of 303 patients were diagnosed with APAC in the pandemic cohort, which was 2.98 and 2.61 times higher than that in control cohorts (7.87% in 2019, 8.96% in 2022, P<0.001). The pandemic cohort has significantly higher Omicron-infected rate (78.87% vs 0 vs 0; P<0.001), lower proportion of glaucoma history (16.90% vs 42.86% vs 41.67%, P=0.005), higher surgical rate (95.77% vs 83.33% vs 78.57%, P=0.024), higher total medical costs and larger pupil diameter (5.63±0.15 vs 4.68±0.15 vs 4.69±0.22 mm, P<0.01). In 83% Omicron-infected patients, ocular symptoms appeared within 3d after systemic symptoms onset. In multivariate analysis, Omicron infection (P<0.001) was the only independent predictor of pupil diameter. CONCLUSION: In the Omicron epidemic in China, there is an increase of prevalence and severity of APAC, particularly focusing on the first 3d following infection.
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Pseudomonas species are known for their diverse metabolic abilities and broad ecological distribution. They are fundamental components of bacterial communities and perform essential ecological functions in the environment. A psychrotrophic Pseudomonas sp. IT1137 was isolated from intertidal sediment in the coastal region of the Fildes Peninsula, King George Island, Antarctica. The strain contained a circular chromosome of 5,346,697 bp with a G + C content of 61.66 mol% and one plasmid of 4481 bp with a G + C content of 64.61 mol%. A total of 4848 protein-coding genes, 65 tRNA genes and 15 rRNA genes were obtained. Genome sequence analysis revealed that strain IT1137 not only is a potentially novel species of the genus Pseudomonas but also harbors functional genes related to nitrogen, sulfur and phosphorus cycling. In addition, genes involved in alkane degradation, ectoine synthesis and cyclic lipopeptide (CLP) production were detected in the bacterial genome. The results indicate the potential of the strain Pseudomonas sp. IT1137 for biotechnological applications such as bioremediation and secondary metabolite production and are helpful for understanding bacterial adaptability and ecological function in cold coastal environments.
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Alcanos , Frío , Genoma Bacteriano , Sedimentos Geológicos , Pseudomonas , Pseudomonas/genética , Regiones Antárticas , Sedimentos Geológicos/microbiología , Alcanos/metabolismo , Secuenciación Completa del Genoma , Biodegradación AmbientalRESUMEN
Three-amino-loop-extension (TALE) family belongs to the homeobox gene superfamily and occurs widely in plants, playing a crucial role in regulating their growth and development. Currently, genome-wide analysis of the TALE family has been completed in many plants. However, the systematic identification and hormone response analysis of the TALE gene family in barley are still lacking. In this study, 21 TALE candidate genes were identified in barley, which can be divided into KNOX and BELL subfamilies. Barley TALE members in the same subfamily of the phylogenetic tree have analogically conserved motifs and gene structures, and segmental duplications are largely responsible for the expansion of the HvTALE family. Analysis of TALE orthologous and homologous gene pairs indicated that the HvTALE family has mainly undergone purifying selective pressure. Through spatial structure simulation, HvKNOX5-HvKNOX6 and HvKNOX5-HvBELL11 complexes are all formed through hydrogen bonding sites on both the KNOX2 and homeodomain (HD) domains of HvKNOX5, which may be essential for protein interactions among the HvTALE family members. Expression pattern analyses reveal the potential involvement of most HvTALE genes in responses to exogenous hormones. These results will lay the foundation for regulation and function analyses of the barley TALE gene family in plant growth and development by hormone regulation.
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Adaptive gradient algorithms have been successfully used in deep learning. Previous work reveals that adaptive gradient algorithms mainly borrow the moving average idea of heavy ball acceleration to estimate the first- and second-order moments of the gradient for accelerating convergence. However, Nesterov acceleration which uses the gradient at extrapolation point can achieve a faster convergence speed than heavy ball acceleration in theory. In this article, a new optimization algorithm which combines adaptive gradient algorithm with Nesterov acceleration by using a look-ahead scheme, called NALA, is proposed for deep learning. NALA iteratively updates two sets of weights, i.e., the 'fast weights' in its inner loop and the 'slow weights' in its outer loop. Concretely, NALA first updates the fast weights k times using Adam optimizer in the inner loop, and then updates the slow weights once in the direction of Nesterov's Accelerated Gradient (NAG) in the outer loop. We compare NALA with several popular optimization algorithms on a range of image classification tasks on public datasets. The experimental results show that NALA can achieve faster convergence and higher accuracy than other popular optimization algorithms.
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Introduction: Metastasis is responsible for 90% of cancer-related deaths worldwide. However, the potential inhibitory effects of metastasis by various anticancer drugs have been left largely unexplored. Existing preclinical models primarily focus on antiproliferative agents on the primary tumor to halt the cancer growth but not in metastasis. Unlike primary tumors, metastasis requires cancer cells to exert sufficient cellular traction force through the actomyosin machinery to migrate away from the primary tumor site. Therefore, we seek to explore the potential of cellular traction force as a novel readout for screening drugs that target cancer metastasis. Methods: In vitro models of invasive and non-invasive breast cancer were first established using MDA-MB-231 and MCF-7 cell lines, respectively. Cellular morphology was characterized, revealing spindle-like morphology in MDA-MB-231 and spherical morphology in MCF-7 cells. The baseline cellular traction force was quantified using the Traction force Microscopy technique. Cisplatin, a paradigm antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, were selected to evaluate the potential of cellular traction force as a drug testing readout for the in vitro cancer metastasis. Results: MDA-MB-231 cells exhibited significantly higher baseline cellular traction force compared to MCF-7 cells. Treatment with Cisplatin, an antimetastatic drug, and 5-Fluorouracil (5FU), a non-antimetastatic drug, demonstrated distinct effects on cellular traction force in MDA-MB-231 but not in MCF-7 cells. These findings correlate with the invasive potential observed in the two models. Conclusion: Cellular traction force emerges as a promising metric for evaluating drug efficacy in inhibiting cancer metastasis using in vitro models. This approach could enhance the screening and development of novel anti-metastatic therapies, addressing a critical gap in current anticancer drug research.
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BACKGROUND: Preterm birth and formula feeding increase the risk of necrotizing enterocolitis (NEC), a gut inflammatory disease known to be associated with gut microbiota (GM) changes in infants. Supplemental bovine colostrum may protect against formula-induced NEC via GM changes. We hypothesised that feeding colostrum before, after, or during formula feeding affects NEC sensitivity via changes to GM. METHODS: Colonic GM (profiled by 16S ribosomal RNA gene amplicon sequencing) was compared in preterm pigs fed colostrum for 4 days, either before, after, or together with formula feeding for 4 days. Correlations between GM and gut parameters were assessed on day 5 or 9. RESULTS: Both exclusive and partial colostrum feeding induced higher GM diversity, lower Enterococcus abundance, and improved intestinal maturation parameters (villus structure, digestive enzyme activities, permeability), relative to exclusive formula feeding (all p < 0.05). Across feeding regimens, Enterococcus abundance was inversely correlated with intestinal maturation parameters. Conversely, there was no correlation between GM changes and early NEC lesions. CONCLUSION: Bovine colostrum inhibits formula-induced Enterococcus overgrowth and gut dysfunctions just after preterm birth but these effects are not causally linked. Optimising diet-related host responses, not GM, may be critical to prevent NEC in preterm newborn pigs and infants. IMPACT: Supplement of bovine colostrum to formula feeding modified the gut microbiota by increasing species diversity and reducing Enterococcus abundance, while concurrently improving intestinal functions in preterm pigs. Diet-related changes to the gut microbiota were not clearly associated with development of necrotizing enterocolitis (NEC) in preterm pigs, suggesting that diet-related gut microbiota effects are not critical for diet-related NEC protection. The study highlights the potential to use bovine colostrum as a supplement to formula feeding for preterm infants lacking human milk.
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Heart failure (HF) has emerged as the most pressing health concerns globally, and extant clinical therapies are accompanied by side effects and patients have a high burden of financial. The protein products of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes have a variety of cardioprotective effects, including antioxidant, metabolic functions and anti-inflammatory. By evaluating established preclinical and clinical research in HF to date, we explored the potential of Nrf2 to exert unique cardioprotective functions as a novel therapeutic receptor for HF. In this review, we generalize the progression, structure, and function of Nrf2 research in the cardiovascular system. The mechanism of action of Nrf2 involved in HF as well as agonists of Nrf2 in natural compounds are summarized. Additionally, we discuss the challenges and implications for future clinical translation and application of pharmacology targeting Nrf2. It's critical to developing new drugs for HF.
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Insuficiencia Cardíaca , Factor 2 Relacionado con NF-E2 , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Animales , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Hypercoagulability emerges as a central pathological feature and clinical complication in nephrotic syndrome. Increased platelet activation and aggregability are closely related to hypercoagulability in nephrotic syndrome. Monocyte-platelet aggregates (MPAs) have been proposed to represent a robust biomarker of platelet activation. The aim of this study was to investigate levels of the circulating MPAs and MPAs with the different monocyte subsets to evaluate the association of MPAs with hypercoagulability in nephrotic syndrome. METHODS: Thirty-two patients with nephrotic syndrome were enrolled. In addition, thirty-two healthy age and sex matched adult volunteers served as healthy controls. MPAs were identified by CD14 monocytes positive for CD41a platelets. The classical (CD14 + + CD16-, CM), the intermediate (CD14 + + CD16+, IM) and the non-classical (CD14 + CD16++, NCM) monocytes, as well as subset specific MPAs, were measured by flow cytometry. RESULTS: Patients with nephrotic syndrome showed a higher percentage of circulating MPAs as compared with healthy controls (p < 0.001). The percentages of MPAs with CM, IM, and NCM were higher than those of healthy controls (p = 0.012, p < 0.001 and p < 0.001, respectively). Circulating MPAs showed correlations with hypoalbuminemia (r=-0.85; p < 0.001), hypercholesterolemia (r = 0.54; p < 0.001), fibrinogen (r = 0.70; p < 0.001) and D-dimer (r = 0.37; p = 0.003), but not with hypertriglyceridemia in nephrotic syndrome. The AUC for the prediction of hypercoagulability in nephrotic syndrome using MPAs was 0.79 (95% CI 0.68-0.90, p < 0.001). The sensitivity of MPAs in predicting hypercoagulability was 0.71, and the specificity was 0.78. CONCLUSION: Increased MPAs were correlated with hypercoagulability in nephrotic syndrome. MPAs may serve as a potential biomarker for thrombophilic or hypercoagulable state and provide novel insight into the mechanisms of anticoagulation in nephrotic syndrome.
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BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.
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Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Cetuximab , Neoplasias Colorrectales , Fluorouracilo , Leucovorina , Neoplasias Hepáticas , Compuestos Organoplatinos , Proteínas Proto-Oncogénicas B-raf , Humanos , Cetuximab/administración & dosificación , Cetuximab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Femenino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/administración & dosificación , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/administración & dosificación , Resultado del Tratamiento , Proteínas ras/genéticaRESUMEN
BACKGROUND: As the primary microtubule organizing center in animal cells, centrosome abnormalities are involved in human colon cancer. AIM: To explore the role of centrosome-related genes (CRGs) in colon cancer. METHODS: CRGs were collected from public databases. Consensus clustering analysis was performed to separate the Cancer Genome Atlas cohort. Univariate Cox and least absolute shrinkage selection operator regression analyses were performed to identify candidate prognostic CRGs and construct a centrosome-related signature (CRS) to score colon cancer patients. A nomogram was developed to evaluate the CRS risk in colon cancer patients. An integrated bioinformatics analysis was conducted to explore the correlation between the CRS and tumor immune microenvironment and response to immunotherapy, chemotherapy, and targeted therapy. Single-cell transcriptome analysis was conducted to examine the immune cell landscape of core prognostic genes. RESULTS: A total of 726 CRGs were collected from public databases. A CRS was constructed, which consisted of the following four genes: TSC1, AXIN2, COPS7A, and MTUS1. Colon cancer patients with a high-risk signature had poor survival. Patients with a high-risk signature exhibited decreased levels of plasma cells and activated memory CD4+ T cells. Regarding treatment response, patients with a high-risk signature were resistant to immunotherapy, chemotherapy, and targeted therapy. COPS7A expression was relatively high in endothelial cells and fibroblasts. MTUS1 expression was high in endothelial cells, fibroblasts, and malignant cells. CONCLUSION: We constructed a centrosome-related prognostic signature that can accurately predict the prognosis of colon cancer patients, contributing to the development of individualized treatment for colon cancer.
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Anaplastic lymphoma kinase (ALK) fusion-positive colorectal cancer (CRC) is a rare and chemotherapy-refractory subtype that lacks established and effective treatment strategies. Additionally, the efficacy and safety of ALK inhibitors (ALKi) in CRC remain undetermined. Herein, we examined a series of ALK-positive CRC patients who underwent various lines of ALKi treatment. Notably, we detected an ALK 1196M resistance mutation in a CRC patient who received multiple lines of chemotherapy and ALKi treatment. Importantly, we found that Brigatinib and Lorlatinib demonstrated some efficacy in managing this patient, although the observed effectiveness was not as pronounced as in non-small cell lung cancer cases. Furthermore, based on our preliminary analyses, we surmise that ALK-positive CRC patients are likely to exhibit inner resistance to Cetuximab. Taken together, our findings have important implications for the treatment of ALK-positive CRC patients.
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Diabetic Foot in Primary and Tertiary (DEFINITE) Care is an inter-institutional, multidisciplinary team (MDT) program for patients with diabetic foot ulcers (DFU) within a healthcare cluster in Singapore. This is one of our subgroup analyses within DEFINITE Care, assessing clinical outcomes of lower extremity amputation prevention program (LEAPP), a multidisciplinary diabetic foot clinic, and non-LEAPP patients within the program. From June 2020 to June 2022, 2798 patients within the DEFINITE cohort completed a minimum of 12-month follow up. Of these patients, 20.6% were managed by LEAPP, whereas 79.4% were non-LEAPP patients. Patients in the LEAPP cohort were older with co-existing metabolic conditions and complications of diabetes. Using non-LEAPP cohort as the reference group and after adjusting for age, gender, ethnicity, comorbidities, and medications, there was a significantly lower risk of death (odds ratio [OR] 0.60, P = .001) and composite major lower extremity amputation (LEA) or death (OR 0.66, P = .002) among LEAPP patients at 1 year with longer mean days from enrollment to minor LEA, major LEA, and death. The adjusted 1-year healthcare utilization outcomes for LEAPP patients demonstrated an increase in inpatient admissions, primary care polyclinic visits, hospital specialist outpatient clinic (SOC) visits and elective day surgery procedures. Despite the increased in inpatients admissions, cumulative hospital length of stay in LEAPP patients were lower. This subgroup analysis has demonstrated that the MDT approach to caring for patients with DFU in tertiary centers not only improves mortality by 40%, but also delayed the incidence of minor LEA, major LEA, and death.
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An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we evaluated the prognostic significance of serum albumin levels. We recognized baseline serum albumin as a prognostic factor by univariate Cox regression analysis (albumin-high vs albumin-low: overall survival [OS]: hazard ratio [HR]: 0.679, 95% confidence interval [CI]: 0.529-0.870, P = .002; cumulative incidence of relapse [CIR]: HR: 0.705, 95% CI: 0.530-0.938, P = .017) and multivariate Cox regression analysis (OS: HR per g/L: 0.966, 95% CI: 0.940-0.993, P = .014; CIR: HR per g/L: 0.959, 95% CI: 0.927-0.993, P = .017). In the subgroup analysis, serum albumin was prognostic significant in patients who received intermediate-dose cytarabine combined with daunorubicin and omacetaxine mepesuccinate induction (albumin-high vs albumin-low: OS: HR: 0.585, 95% CI: 0.397-0.863, P = .007; CIR: HR: 0.551, 95% CI: 0.353-0.861, P = .009) rather than those receiving conventional-dose induction regimens. In addition, the impact of baseline serum albumin level was evident in patients with intermediate European LeukemiaNet risk (albumin-high vs albumin-low: OS: HR: 0.617, 95% CI: 0.424-0.896, P = .011; CIR: HR: 0.617, 95% CI: 0.388-0.979, P = .040). Gene set enrichment analysis revealed that leukemia stem cell signatures were enriched in patients with low serum albumin levels. Our study suggested that baseline serum albumin level was associated with the inherent properties of AML and correlated with patient outcomes.
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BACKGROUND: Neoadjuvant and adjuvant immunotherapies for cancer have evolved through a series of remarkable and critical research advances; however, addressing their similarities and differences is imperative in clinical practice. Therefore, this study aimed to examine their similarities and differences from the perspective of informatics analysis. METHODS: This cross-sectional study retrospectively analyzed extensive relevant studies published between 2014 and 2023 using stringent search criteria, excluding nonpeer-reviewed and non-English documents. The main outcome variables are publication volume, citation volume, connection strength, occurrence frequency, relevance percentage, and development percentage. Furthermore, an integrated comparative analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression statistics, and Walktrap algorithm analysis. RESULTS: This analysis included 1373 relevant studies. Advancements in neoadjuvant and adjuvant immunotherapies have been promising over the last decade, with an annual growth rate of 25.18 vs. 6.52% and global collaboration (International Co-authorships) of 19.93 vs. 19.84%. Respectively, five dominant research clusters were identified through unsupervised hierarchical clustering based on machine learning, among which Cluster 4 (Balance of neoadjuvant immunotherapy efficacy and safety) and Cluster 2 (Adjuvant immunotherapy clinical trials) [Average Publication Year (APY): 2021.70±0.70 vs. 2017.54±4.59] are emerging research populations. Burst and regression curve analyses uncovered domain pivotal research signatures, including microsatellite instability (R 2 =0.7500, P =0.0025) and biomarkers (R 2 =0.6505, P =0.0086) in neoadjuvant scenarios, and the tumor microenvironment (R 2 =0.5571, P =0.0209) in adjuvant scenarios. The Walktrap algorithm further revealed that 'neoadjuvant immunotherapy, nonsmall cell lung cancer (NSCLC), immune checkpoint inhibitors, melanoma' and 'adjuvant immunotherapy, melanoma, hepatocellular carcinoma, dendritic cells' (Relevance Percentage: 100 vs. 100%, Development Percentage: 37.5 vs. 17.1%) are extremely relevant to this field but remain underdeveloped, highlighting the need for further investigation. CONCLUSION: This study identified pivotal research signatures and provided substantial predictions for neoadjuvant and adjuvant cancer immunotherapies. In addition, comprehensive quantitative comparisons revealed a notable shift in focus within this field, with neoadjuvant immunotherapy taking precedence over adjuvant immunotherapy after 2020; such a qualitative finding facilitate proper decision-making for subsequent research and mitigate the wastage of healthcare resources.
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Inmunoterapia , Terapia Neoadyuvante , Neoplasias , Humanos , Estudios Transversales , Inmunoterapia/métodos , Neoplasias/terapia , Neoplasias/inmunología , Estudios Retrospectivos , Aprendizaje AutomáticoRESUMEN
Due to the limited semantic information extraction with small objects and difficulty in distinguishing similar targets, it brings great challenges to target detection in remote sensing scenarios, which results in poor detection performance. This paper proposes an improved YOLOv5 remote sensing image target detection algorithm, SEB-YOLO (SPD-Conv + ECSPP + Bi-FPN + YOLOv5). Firstly, the space-to-depth (SPD) layer followed by a non-strided convolution (Conv) layer module (SPD-Conv) was used to reconstruct the backbone network, which retained the global features and reduced the feature loss. Meanwhile, the pooling module with the attention mechanism of the final layer of the backbone network was designed to help the network better identify and locate the target. Furthermore, a bidirectional feature pyramid network (Bi-FPN) with bilinear interpolation upsampling was added to improve bidirectional cross-scale connection and weighted feature fusion. Finally, the decoupled head is introduced to enhance the model convergence and solve the contradiction between the classification task and the regression task. Experimental results on NWPU VHR-10 and RSOD datasets show that the mAP of the proposed algorithm reaches 93.5% and 93.9%respectively, which is 4.0% and 5.3% higher than that of the original YOLOv5l algorithm. The proposed algorithm achieves better detection results for complex remote sensing images.
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Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .
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Aminopiridinas , Benzamidas , Neoplasias Colorrectales , Inhibidores de Histona Desacetilasas , Humanos , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Microambiente Tumoral , Factor A de Crecimiento Endotelial VascularRESUMEN
Many prognostic factors have been identified in acute myeloid leukemia (AML). In this study, we investigated novel prognostic biomarkers using machine learning and Cox regression models in a prospective cohort of 591 patients with AML and tried to identify potential therapeutic targets based on transcriptomic data. We found that elevated red blood cell distribution width (RDW) at diagnosis was an adverse prognostic factor for AML, independent of the 2022 European LeukemiaNet (ELN2022) genetic risk. As a continuous variable, higher RDW was associated with shorter overall survival (OS) (hazard ratio [HR] 1.087, 95% confidence interval [CI] 1.036-1.139, p < 0.001) and event-free survival (EFS) (HR 1.078, 95% CI 1.033-1.124, p < 0.001). Elevated RDW returned to normal after consolidation therapy, which indicated that leukemia cells resulted in abnormal RDW. We further investigated the relationship between RDW and transcriptome in another cohort of 191 patients with AML and public datasets using gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). We found that patients in the high-RDW group were significantly enriched in the positive regulation of erythroid differentiation and inflammation-related pathways. Finally, we identified the inflammation-associated gene IL12RB2 and verified its prognostic relevance with patients with AML in public databases, suggesting it as a potential therapy target.
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Índices de Eritrocitos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Pronóstico , Anciano , Adulto , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Transcriptoma , Estudios ProspectivosRESUMEN
BACKGROUND: Genus Paeonia, which is the main source of Traditional Chinese Medicine (TCM) Paeoniae Radix Rubra (Chishao in Chinese), Paeoniae Radix Alba (Baishao in Chinese) and Moutan Cortex (Mudanpi in Chinese), is rich in active pharmaceutical ingredient such as monoterpenoid glycosides (MPGs). MPGs from Paeonia have extensive pharmacological effects, but the pharmacological effects and molecular mechanisms of MPGs has not been comprehensively reviewed. PURPOSE: MPGs compounds are one of the main chemical components of the genus Paeonia, with a wide variety of compounds and strong pharmacological activities, and the structure of the mother nucleus-pinane skeleton is similar to that of a cage. The purpose of this review is to summarize the pharmacological activity and mechanism of action of MPGs from 2012 to 2023, providing reference direction for the development and utilization of Paeonia resources and preclinical research. METHODS: Keywords and phrases are widely used in database searches, such as PubMed, Web of Science, Google Scholar and X-Mol to search for citations related to the new compounds, extensive pharmacological research and molecular mechanisms of MPGs compounds of genus Paeonia. RESULTS: Modern research confirms that MPGs are the main compounds in Paeonia that exert pharmacological effects. MPGs with extensive pharmacological characteristics are mainly concentrated in two categories: paeoniflorin derivatives and albiflflorin derivatives among MPGs, which contains 32 compounds. Among them, 5 components including paeoniflorin, albiflorin, oxypaeoniflorin, 6'-O-galloylpaeoniflorin and paeoniflorigenone have been extensively studied, while the other 28 components have only been confirmed to have a certain degree of anti-inflammatory and anticomplementary effects. Studies of pharmacological effects are widely involved in nervous system, endocrine system, digestive system, immune system, etc., and some studies have identified clear mechanisms. MPGs exert pharmacological activity through multilateral mechanisms, including anti-inflammatory, antioxidant, inhibition of cell apoptosis, regulation of brain gut axis, regulation of gut microbiota and downregulation of mitochondrial apoptosis, etc. CONCLUSION: This systematic review delved into the pharmacological effects and related molecular mechanisms of MPGs. However, there are still some compounds in MPGs whose pharmacological effects and pharmacological mechanisms have not been clarified. In addition, extensive clinical randomized trials are needed to verify the efficacy and dosage of MPGs.
Asunto(s)
Medicamentos Herbarios Chinos , Glucósidos , Paeonia , Glicósidos/farmacología , Paeonia/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Monoterpenos/farmacología , Monoterpenos/química , AntiinflamatoriosRESUMEN
Hedgehog signaling is activated in response to liver injury, and modulates organogenesis. However, the role of non-canonical hedgehog activation via TGF-ß1/SMAD3 in hepatic carcinogenesis is poorly understood. TGF-ß1/SMAD3-mediated non-canonical activation was found in approximately half of GLI2-positive hepatocellular carcinoma (HCC), and two new GLI2 isoforms with transactivating activity were identified. Phospho-SMAD3 interacted with active GLI2 isoforms to transactivate downstream genes in modulation of stemness, epithelial-mesenchymal transition, chemo-resistance and metastasis in poorly-differentiated hepatoma cells. Non-canonical activation of hedgehog signaling was confirmed in a transgenic HBV-associated HCC mouse model. Inhibition of TGF-ß/SMAD3 signaling reduced lung metastasis in a mouse in situ hepatic xenograft model. In another cohort of 55 HCC patients, subjects with high GLI2 expression had a shorter disease-free survival than those with low expression. Moreover, co-positivity of GLI2 with SMAD3 was observed in 87.5% of relapsed HCC patients with high GLI2 expression, indicating an increased risk of post-resection recurrence of HCC. The findings underscore that suppressing the non-canonical hedgehog signaling pathway may confer a potential strategy in the treatment of HCC.