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Although presepsin, a crucial biomarker for the diagnosis and management of sepsis, has gained prominence in contemporary medical research, its relationship with routine laboratory parameters, including demographic data and hospital blood test data, remains underexplored. This study integrates machine learning with explainable artificial intelligence (XAI) to provide insights into the relationship between presepsin and these parameters. Advanced machine learning classifiers provide a multilateral view of data and play an important role in highlighting the interrelationships between presepsin and other parameters. XAI enhances analysis by ensuring transparency in the model's decisions, especially in selecting key parameters that significantly enhance classification accuracy. Utilizing XAI, this study successfully identified critical parameters that increased the predictive accuracy for sepsis patients, achieving a remarkable ROC AUC of 0.97 and an accuracy of 0.94. This breakthrough is possibly attributed to the comprehensive utilization of XAI in refining parameter selection, thus leading to these significant predictive metrics. The presence of missing data in datasets is another concern; this study addresses it by employing Extreme Gradient Boosting (XGBoost) to manage missing data, effectively mitigating potential biases while preserving both the accuracy and relevance of the results. The perspective of examining data from higher dimensions using machine learning transcends traditional observation and analysis. The findings of this study hold the potential to enhance patient diagnoses and treatment, underscoring the value of merging traditional research methods with advanced analytical tools.
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The purpose of this study was to establish the noninferiority of robotic single-site (RSS) surgery compared with multiport laparoscopic (MPL) surgery in surgical outcomes and overall survival for early endometrial cancer. This study was conducted retrospectively in a single center and included 421 patients who underwent either RSS (n = 146) or MPL (n = 275) surgery between 2014 and 2022. In terms of perioperative outcomes, the RSS group had a longer operating time than the MPL surgery group (mean (standard deviation [SD]) RSS 97.55 [29.79] vs. MPL 85.56 [26.13], p < 0.001). However, no significant differences in estimated blood loss or perioperative complications were found between the groups (p = 0.196 and p = 0.080, respectively). The patients in the RSS group were discharged earlier than those in the MPL group (mean [SD]): 4.06 [3.24] vs. 9.39 [4.76], p < 0.001). Regarding oncologic outcomes, no significant differences in the type of therapy, disease stage, tumor grade, histopathological type, or lymphovascular invasion were found between the groups. No statistically significant differences were found in the disease-free (p = 0.27) and overall survival rates (p = 0.5) either. In conclusion, this study suggests that RSS and MPL surgery are both safe and effective options for staging operations in patients with early-stage endometrial cancer.
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Di-d-psicose anhydride (DPA), derived from functional rare saccharide as d-psicose, is investigated for its strong chelating ability. Methylglyoxal (MGO), an important precursor of advanced glycation end-products (AGEs), promotes obesity, and causes complications such as diabetic nephropathy. On mesangial cells, DPA can substantially reduce the negative effects of MGO. DPA effectively trapping MGO in mesangial cells. The bonding properties of the DPA-MGO adduct were discussed by mass spectrometry and nuclear magnetic resonance (NMR). The NMR spectra of the DPA-MGO adduct provide evidence for chelation bonding. The inhibition of AGE formation and the mass spectrometry results of the DPA-MGO adduct indicate that DPA can scavenge MGO at a molar ratio of 1:1. DPA suppressed 330 % of the up-regulated receptor for an AGEs protein expression to a normal level and restored the suppressed glyoxalase 1 level to 86 % of the normal group. This research provides important evidence and theoretical basis for the development of AGE inhibitors derived from rare saccharide.
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Nefropatias Diabéticas , Produtos Finais de Glicação Avançada , Aldeído Pirúvico , Aldeído Pirúvico/química , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Lactoilglutationa Liase/antagonistas & inibidores , Lactoilglutationa Liase/metabolismo , Humanos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Anidridos/química , Quelantes/química , Quelantes/farmacologiaRESUMO
The accumulation of methylglyoxal (MGO) produced in high-temperature processed foods and excessive production in the body contributes to intestinal barrier dysfunction. In this study, we investigated the effects of chitooligosaccharides (COSs) of different molecular weights (<1â¯kDa, 1-3â¯kDa, 3-5â¯kDa, 5-10â¯kDa, and >10â¯kDa) on MGO-induced intestinal barrier dysfunction. We investigated the effect of COSs on inhibiting intracellular MGO accumulation/MGO-derived AGEs production and regulating the receptor for AGE (RAGE)-mediated downstream protein expression, including proteins related to apoptosis and inflammation, intestinal barrier integrity, and paracellular permeability. Pretreatment with COSs ameliorated MGO-induced increased RAGE protein expression, activation of apoptotic cascade/inflammatory response, loss of intestinal epithelial barrier integrity, and increased paracellular permeability, ameliorating intestinal dysfunction through MGO scavenging. 1-3â¯kDa COSs most effectively ameliorated MGO-induced intestinal dysfunction. Our results suggest the potential of COSs in improving intestinal health by ameliorating intestinal barrier dysfunction by acting as an MGO scavenger and highlighting the need for the optimization of the molecular weight of COSs to optimize its protective effects.
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Quitosana , Produtos Finais de Glicação Avançada , Mucosa Intestinal , Peso Molecular , Oligossacarídeos , Aldeído Pirúvico , Receptor para Produtos Finais de Glicação Avançada , Oligossacarídeos/farmacologia , Oligossacarídeos/química , Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Quitosana/farmacologia , Quitosana/química , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Humanos , Intestinos/efeitos dos fármacos , Intestinos/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/induzido quimicamente , Apoptose/efeitos dos fármacos , Quitina/farmacologia , Quitina/análogos & derivados , Quitina/química , Permeabilidade/efeitos dos fármacosRESUMO
Amylosucrase (ASase) efficiently biosynthesizes α-glucoside using flavonoids as acceptor molecules and sucrose as a donor molecule. Here, ASase from Deinococcus wulumuqiensis (DwAS) biosynthesized more naringenin α-glucoside (NαG) with sucrose and naringenin as donor and acceptor molecules, respectively, than other ASases from Deinococcus sp. The biotransformation rate of DwAS to NαG was 21.3% compared to 7.1-16.2% for other ASases. Docking simulations showed that the active site of DwAS was more accessible to naringenin than those of others. The 217th valine in DwAS corresponded to the 221st isoleucine in Deinococcus geothermalis AS (DgAS), and the isoleucine possibly prevented naringenin from accessing the active site. The DwAS-V217I mutant had a significantly lower biosynthetic rate of NαG than DwAS. The kcat/Km value of DwAS with naringenin as the donor was significantly higher than that of DgAS and DwAS-V217I. In addition, NαG inhibited human intestinal α-glucosidase more efficiently than naringenin.
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Proteínas de Bactérias , Biotransformação , Deinococcus , Flavanonas , Glucosídeos , Glucosiltransferases , Inibidores de Glicosídeo Hidrolases , Flavanonas/metabolismo , Flavanonas/química , Deinococcus/enzimologia , Deinococcus/metabolismo , Deinococcus/química , Deinococcus/genética , Glucosiltransferases/metabolismo , Glucosiltransferases/química , Glucosiltransferases/genética , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Glucosídeos/metabolismo , Glucosídeos/química , Simulação de Acoplamento Molecular , Cinética , alfa-Glucosidases/metabolismo , alfa-Glucosidases/químicaRESUMO
In this study, we examined the difference in the vaginal microbiota of women infected with human papillomavirus (HPV), according to menopausal status. A total of 75 cervicovaginal swab samples from 38 pre- and 37 postmenopausal women with HPV infection were obtained from the Korean HPV cohort. Vaginal microbiota analysis, including microbial diversity and specific bacterial abundances, was performed using 16S rRNA gene sequencing. The mean age of the pre- and postmenopausal women were 29.5 and 55.8 years, respectively (p < 0.0001). Lactobacillus spp. were predominant in both groups; however, a marked decrease was observed in postmenopausal women compared to premenopausal women (44.3% vs. 74.2%). Various anaerobic bacteria also showed a relatively high abundance in the postmenopausal group; Atopobium vagina and Gardnerella vaginalis significantly increased in postmenopausal women. Interestingly, no significant differences in bacterial richness were observed between the two groups. However, significant differences in beta-diversity were observed using the Bray-Curtis (p = 0.001), Generalized UniFrac (p = 0.002), Jensen-Shannon (p = 0.001), and UniFrac algorithms (p = 0.002). Theres results indicate that postmenopausal women with HPV infection exhibited a higher degree of vaginal dysbiosis than premenopausal women. Further, HPV-infected postmenopausal women had increased vaginal microbial diversity, characterized by an increase in anaerobic bacteria and concomitant depletion of Lactobacillus spp.
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Infecções por Papillomavirus , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Disbiose , Papillomaviridae/genética , Vagina/microbiologia , Bactérias/genética , Lactobacillus/genética , MenopausaRESUMO
OBJECTIVE: Protein disulfide isomerase A3 (PDIA3) promotes the correct folding of newly synthesized glycoproteins in the endoplasmic reticulum. PDIA3 is overexpressed in most tumors, and it may become a biomarker of cancer prognosis and immunotherapy. Our study aims to detect the expression level of PDIA3 in gastric cancer (GC) and its association with GC development as wells as the underlying mechanisms. METHODS: GC cell lines with PDIA3 knockdown by siRNA, CRISPR-cas9 sgRNAs or a pharmacological inhibitor of LOC14 were prepared and used. PDIA3 knockout GC cells were established by CRISPR-cas9-PDIA3 system. The proliferation, migration, invasion and cell cycle of GC cells were analyzed by cell counting kit-8 assay, wound healing assay, transwell assay and flow cytometry, respectively. Immunodeficient nude mice was used to evaluate the role of PDIA3 in tumor formation. Quantitative PCR and western blot were used for examining gene and protein expressions. RNA sequencing was performed to see the altered gene expression. RESULTS: The expressions of PDIA3 in GC tissues and cells were increased significantly, and its expression was negatively correlated with the three-year survival rate of GC patients. Down-regulation of PDIA3 by siRNA, LOC14 or CRISPR-cas9 significantly inhibited proliferation, invasion and migration of GC cells TMK1 and AGS, with cell cycle arrested at G2/M phase. Meanwhile, decreased PDIA3 significantly inhibited growth of tumor xenograft in vivo. It was found that cyclin G1 (encoded by CCNG1 gene) expression was decreased by downregulation of PDIA3 in GC cells both in vitro and in vivo. In addition, protein levels of other cell cycle related factors including cyclin D1, CDK2, and CDK6 were also significantly decreased. Further study showed that STAT3 was associated with PDIA3-mediated cyclin G1 regulation. CONCLUSION: PDIA3 plays an oncogenic role in GC. Our findings unfolded the functional role of PDIA3 in GC development and highlighted a novel target for cancer therapeutic strategy.
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Benzotiazóis , Neoplasias Gástricas , Animais , Camundongos , Humanos , Neoplasias Gástricas/patologia , Regulação para Baixo/genética , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Camundongos Nus , Ciclina G1/genética , RNA Guia de Sistemas CRISPR-Cas , Proliferação de Células/genética , Linhagem Celular Tumoral , Ciclo Celular/genética , RNA Interferente Pequeno/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genéticaRESUMO
OBJECTIVE: This study aimed to determine the safety and efficacy of the RKP00156 vaginal tablet, a CDK9 inhibitor, in healthy women and patients with cervical intraepithelial neoplasia grade 2 (CIN2). METHODS: We conducted a phase 1/2a clinical trial of RKP00156. In step 1, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered transvaginally to 24 healthy women. In step 2, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered once daily for 4 weeks in 62 patients with CIN2. The primary endpoints of this trial were the safety of RKP00156 and the change in the human papillomavirus (HPV) viral load. RESULTS: A total of 86 patients were enrolled and randomized. RKP00156 administration did not cause serious drug-associated adverse events (AEs). Although no significant difference in the HPV viral load was found between the experimental and placebo groups, a reduction in the HPV viral load was observed in the 25 mg-dose group (-98.61%; 95% confidence interval=-99.83%, 4.52%; p=0.046) after treatment completion in patients with a high HPV viral load, despite a lack of statistical power. No differences in histologic regression and HPV clearance were observed. CONCLUSION: The safety of RKP00156 was proved with no serious AEs. Although the study did not show any significance in histologic regression and HPV clearance, our findings indicate that RKP00156 may have a possibility of short-term inhibitory effect on HPV replication in patients with higher viral loads. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02139267.
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Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Carga Viral , Humanos , Feminino , Displasia do Colo do Útero/virologia , Displasia do Colo do Útero/tratamento farmacológico , Adulto , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/complicações , Adulto Jovem , Relação Dose-Resposta a Droga , Administração Intravaginal , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Comprimidos , Método Duplo-Cego , Papillomaviridae/isolamento & purificação , Resultado do TratamentoRESUMO
BACKGROUND: Distinguishing ovarian cancer from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of ovarian cancer pathogenesis. Accumulating evidence suggests a link between ovarian cancer and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved ovarian cancer diagnosis and prevention. METHODS: Here, we profiled the serum lipidome of 208 ovarian cancer, including 93 early-stage patients with ovarian cancer and 117 nonovarian cancer (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning (ML) approaches. RESULTS: We found that lipidome alterations unique to ovarian cancer were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in ovarian cancer in comparison with other gynecological diseases. ML methods selected a panel of 17 lipids that discriminated ovarian cancer from nonovarian cancer cases with an AUC value of 0.85 for an independent test set. CONCLUSIONS: This study provides a systemic analysis of lipidome alterations in human ovarian cancer, specifically in Korean women. IMPACT: Here, we show the potential of circulating lipids in distinguishing ovarian cancer from nonovarian cancer conditions.
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Lipidômica , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/sangue , Lipidômica/métodos , República da Coreia/epidemiologia , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Adulto , Idoso , Metabolismo dos Lipídeos , Lipídeos/sangueRESUMO
BACKGROUND: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. METHODS: The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.
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The role of N6-methyladenosine (m6A) modification of host mRNA during bacterial infection is unclear. Here, we show that Helicobacter pylori infection upregulates host m6A methylases and increases m6A levels in gastric epithelial cells. Reducing m6A methylase activity via hemizygotic deletion of methylase-encoding gene Mettl3 in mice, or via small interfering RNAs targeting m6A methylases, enhances H. pylori colonization. We identify LOX-1 mRNA as a key m6A-regulated target during H. pylori infection. m6A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for H. pylori catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of Lox-1, reduces H. pylori colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of H. pylori to human gastric sections. Our results indicate that m6A modification of host LOX-1 mRNA contributes to protection against H. pylori infection by downregulating LOX-1 and thus reducing H. pylori adhesion.
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Adenosina , Infecções por Helicobacter , Helicobacter pylori , Receptores Depuradores Classe E , Animais , Humanos , Camundongos , Adenosina/análogos & derivados , Catalase/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , RNA Mensageiro/genética , Receptores Depuradores Classe E/genéticaRESUMO
Background: This study describes experiences and perspectives of pediatric weight management (PWM) providers on the implementation of genetic testing for rare causes of obesity. Methods: Purposive and snowball sampling recruited PWM providers via email to complete a 23-question survey with multiple choice and open-ended questions. Analyses include descriptive statistics, Fisher's exact test, one-way ANOVA with Tukey's post hoc test, and qualitative analysis. Results: Of the 55 respondents, 80% reported ordering genetic testing. Respondents were primarily physicians (82.8%) in practice for 11-20 years (42%), identified as female (80%), White (76.4%), and non-Hispanic (92.7%) and provided PWM care 1-4 half day sessions per week. Frequently reported patient characteristics that prompted testing did not vary by provider years of experience (YOE). These included obesity onset before age 6, hyperphagia, dysmorphic facies, and developmental delays. The number of patient characteristics that prompted testing varied by YOE (p = 0.03); respondents with 6-10 YOE indicated more patient characteristics than respondents with >20 YOE (mean 10.3 vs. mean 6.2). The reported primary benefit of testing was health information for patients/families; the primary drawback was the high number of indeterminate tests. Ethical concerns expressed were fear of increasing weight stigma, discrimination, and impact on insurance coverage. Respondents (42%) desired training and guidance on interpreting results and counseling patients and families. Conclusions: Most PWM providers reported genetic testing as an option for patient management. Provider training in genetics/genomics and research into provider and family attitudes on the genetics of obesity and the value of genetic testing are next steps to consider.
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Smoking is a serious global health issue. Cigarette smoking contains over 7000 different chemicals. The main harmful components include nicotine, acrolein, aromatic hydrocarbons and heavy metals, which play the key role for cigarette-induced inflammation and carcinogenesis. Growing evidences show that cigarette smoking and its components exert a remarkable impact on regulation of immunity and dysregulated immunity promotes inflammation and cancer. Therefore, this comprehensive and up-to-date review covers four interrelated topics, including cigarette smoking, inflammation, cancer and immune system. The known harmful chemicals from cigarette smoking were summarized. Importantly, we discussed in depth the impact of cigarette smoking on the formation of inflammatory or tumor microenvironment, primarily by affecting immune effector cells, such as macrophages, neutrophils, and T lymphocytes. Furthermore, the main molecular mechanisms by which cigarette smoking induces inflammation and cancer, including changes in epigenetics, DNA damage and others were further summarized. This article will contribute to a better understanding of the impact of cigarette smoking on inducing inflammation and cancer.
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Fumar Cigarros , Neoplasias , Humanos , Fumar Cigarros/efeitos adversos , Neoplasias/induzido quimicamente , Inflamação , Nicotiana/química , Nicotina , Microambiente TumoralRESUMO
Helicobacter pylori (H. pylori) causes infection in the stomach and is a major factor for gastric carcinogenesis. The application of antimicrobial peptides (AMPs) as an alternative treatment to traditional antibiotics is limited by their facile degradation in the stomach, their poor penetration of the gastric mucosa, and the cost of peptide production. Here, the design and characterization of a genetically encoded H. pylori-responsive microbicidal protein crystal Cry3Aa-MIIA-AMP-P17 is described. This designed crystal exhibits preferential binding to H. pylori, and when activated, promotes the targeted release of the AMP at the H. pylori infection site. Significantly, when the activated Cry3Aa-MIIA-AMP-P17 crystals are orally delivered to infected mice, the Cry3Aa crystal framework protects its cargo AMP against degradation, resulting in enhanced in vivo efficacy against H. pylori infection. Notably, in contrast to antibiotics, treatment with the activated crystals results in minimal perturbation of the mouse gut microbiota. These results demonstrate that engineered Cry3Aa crystals can serve as an effective platform for the oral delivery of therapeutic peptides to treat gastrointestinal diseases.
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Infecções por Helicobacter , Helicobacter pylori , Animais , Camundongos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/metabolismo , Estômago , Mucosa Gástrica/metabolismo , AntibacterianosRESUMO
Reactive oxygen species (ROS) are a class of highly reactive oxidizing molecules, including superoxide anion (O2â¢-) and hydrogen peroxide (H2O2), among others. Moderate levels of ROS play a crucial role in regulating cellular signaling and maintaining cellular functions. However, abnormal ROS levels or persistent oxidative stress can lead to changes in the tumor microenvironment (TME) that favor cancer development. This review provides an overview of ROS generation, structure, and properties, as well as their effects on various components of the TME. Contrary to previous studies, our findings reveal a dual effect of ROS on different components of the TME, whereby ROS can either enhance or inhibit certain factors, ultimately leading to the promotion or suppression of the TME. For example, H2O2 has dual effects on immune cells and non-cellular components within the TME, while O2â¢- has dual effects on T cells and fibroblasts. Furthermore, each component demonstrates distinct mechanisms of action and ranges of influence. In the final section of the article, we summarize the current clinical applications of ROS in cancer treatment and identify certain limitations associated with existing therapeutic approaches. Therefore, this review aims to provide a comprehensive understanding of ROS, highlighting their dual effects on different components of the TME, and exploring the potential clinical applications that may pave the way for future treatment and prevention strategies.
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OBJECTIVE: Bone marrow (BM) samples reflective of the BM condition are more suitable than peripheral blood samples for the measurement of vascular endothelial growth factor (VEGF) levels in relation to hematologic malignancy. However, BM VEGF levels require calibration, with respect to the platelet count, to eliminate any influence of VEGF released from platelets during sample processing. This parameter is termed the BM VEGF per platelet count. Our aim was to measure BM VEGF per platelet count of patients diagnosed with hematologic malignancy and to analyze its association with several hematological parameters, including BM blast percentages. We also compared the BM VEGF per platelet count and BM blast percentage between the disease and control groups. METHODS: BM plasma samples were collected from 73 patients classified into myeloproliferative neoplasm, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), plasma cell neoplasm (PCN), and control groups. Luminex assays were used to quantify BM VEGF levels. BM cellularity and cell percentage were assessed using BM biopsy and aspiration slides, respectively. Data on hematological parameters were collected from medical records. Single and multiple regression analyses were performed to analyze the relationships between different parameters. Intergroup comparisons were performed using the Kruskal-Wallis H-test. RESULTS: Independent factors associated with BM VEGF per platelet count included BM blast percentage (%), BM band neutrophil %, BM neutrophil %, and BM cellularity. Multiple regression analyses using the four factors generated the following model (adjusted R2=0.290): BM VEGF per platelet count (×10-6 pg)=1.488+0.059×BM blast (%). BM VEGF per platelet count was the highest in the AML group (n=13) and lowest in the control group (n=14). Similarly, BM blast % was the highest in the AML group. Compared to that in the PCN group (n=11), the BM blast % in the MDS group (n=12) was higher. CONCLUSION: BM VEGF per platelet count was related to BM blast %, and both parameters showed similar intergroup patterns, indicating an association.
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Neoplasias Hematológicas , Síndromes Mielodisplásicas , Humanos , Medula Óssea , Fator A de Crescimento do Endotélio Vascular , Contagem de PlaquetasRESUMO
Although expression of ribosomal protein L27 (RPL27) is upregulated in clinical colorectal cancer (CRC) tissue, to the best of our knowledge, the oncogenic role of RPL27 has not yet been defined. The present study aimed to investigate whether targeting RPL27 could alter CRC progression and determine whether RPL27 gains an extraribosomal function during CRC development. Human CRC cell lines HCT116 and HT29 were transfected with RPL27specific small interfering RNA and proliferation was assessed in vitro and in vivo using proliferation assays, fluorescenceactivated cell sorting (FACS) and a xenograft mouse model. Furthermore, RNA sequencing, bioinformatic analysis and western blotting were conducted to explore the underlying mechanisms responsible for RPL27 silencinginduced CRC phenotypical changes. Inhibiting RPL27 expression suppressed CRC cell proliferation and cell cycle progression and induced apoptotic cell death. Targeting RPL27 significantly inhibited growth of human CRC xenografts in nude mice. Notably, pololike kinase 1 (PLK1), which serves an important role in mitotic cell cycle progression and stemness, was downregulated in both HCT116 and HT29 cells following RPL27 silencing. RPL27 silencing reduced the levels of PLK1 protein and G2/Massociated regulators such as phosphorylated cell division cycle 25C, CDK1 and cyclin B1. Silencing of RPL27 reduced the migration and invasion abilities and sphereforming capacity of the parental CRC cell population. In terms of phenotypical changes in cancer stem cells (CSCs), RPL27 silencing suppressed the sphereforming capacity of the isolated CD133+ CSC population, which was accompanied by decreased CD133 and PLK1 levels. Taken together, these findings indicated that RPL27 contributed to the promotion of CRC proliferation and stemness via PLK1 signaling and RPL27 may be a useful target in a nextgeneration therapeutic strategy for both primary CRC treatment and metastasis prevention.
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Neoplasias Colorretais , Proteínas Serina-Treonina Quinases , Humanos , Animais , Camundongos , Camundongos Nus , Proteínas Serina-Treonina Quinases/genética , Neoplasias Colorretais/genética , Quinase 1 Polo-LikeRESUMO
BACKGROUND: The mainstay of treatment for early-stage cervical cancer is surgery; we present a 5-year experience of robotic single-site radical hysterectomy (RSRH) focused on surgical and oncologic outcomes. METHODS: This retrospective study included 44 cases of RSRH performed in patients with early-stage cervical cancer. RESULTS: The median follow-up period for the 44 patients was 34 months. The mean total operation time was 156.07 ± 31.77 min, while mean console time was 95.81 ± 24.95 min. Two cases had complications, which required surgical management, while four cases (9.1%) exhibited recurrence. The disease-free survival rate at 5 years was 90.9%. The sub-division analysis showed that Stage Ia2 and stage Ib1 patient sub-group showed better DFS than that of the stage Ib2 patient sub-group. The learning curve analysis showed that the CUSUM-T initially peaks at the sixth case then gradually decreases before rising and peaking at the 24th case. After 24th case, the CUSUM-T gradually decreases and reaches zero. CONCLUSION: The surgical outcomes of RSRH for early-stage cervical cancer treatment were safe and acceptable. However, RSRH could be considered carefully only in well-selected patient groups. Large-scale prospective studies are necessary in the future to validate the results.
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The formation of advanced glycation end products (AGE) is linked to the pathogenesis of diabetic nephropathy. The aim of this work was to assess the therapeutic potential and underlying mechanism of action of dieckol (DK), isolated from Ecklonia cava, on renal damage induced by methylglyoxal (MGO) in mouse glomerular mesangial cells. The antiglycation properties of DK were evaluated using ELISA. We conducted molecular docking, immunofluorescence analysis, and Western blotting to confirm the mechanism by which DK prevents AGE-related diabetic nephropathy. DK treatment exhibited antiglycation properties through the inhibition of AGE production, inhibition of cross-linking between AGE and collagen, and breaking of its cross-linking. DK pretreatment exhibited protective effects on renal cells by suppressing MGO-induced intracellular reactive oxygen species (ROS) formation, intracellular MGO and AGE accumulation, activation of the apoptosis cascade and apoptosis-related protein expression, activation of receptor for AGE (RAGE) protein expression, and suppression of the glyoxalase system. Furthermore, DK exhibited a stronger binding affinity for RAGE than AGE, which was confirmed as exerting a competitive inhibitory effect on the AGE-RAGE interaction. These results demonstrated that DK is a potential natural AGE inhibitor that can be utilized to prevent and treat AGE-induced diabetic nephropathy.
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Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.