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This study is aimed to explore the potential molecular mechanism of quercetin reversing paclitaxel (PTX) resistance in breast cancer (BC) by network pharmacology, molecular docking, and experimental verification. Pharmacological platform databases are used to predict quercetin targets and BC PTX-resistance genes and constructed the expression profile of quercetin chemosensitization. The overlapping targets were input into the STRING database and used Cytoscape v3.9.0 to construct the protein-protein interaction (PPI) network. Subsequently, these targets were performed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses and molecular docking. Finally, we further detected the potential role of quercetin in improving PTX sensitivity in BC in vitro experiments. Compounds and targets screening hinted that 220 quercetin predicted targets, 244 BC PTX resistance-related genes, and 66 potential sensitive target genes (PSTGs). Network pharmacology screening revealed the top-15 crucial targets in PPI network of quercetin reversing the sensitivity of BC to PTX. KEGG analysis revealed that they were mainly enriched in the EGFR/ERK signaling pathway. Molecular docking showed that both quercetin and PTX could stably bind to the key targets in the EGFR/ERK signaling pathway. In vitro experiments further confirmed that quercetin inhibited the key targets in the EGFR/ERK axis to the suppression of cell proliferation and promotion of apoptosis in PTX-resistance BC cells, and restoring the activity of the resistant cells to PTX. Our results suggested that quercetin increased the sensitivity of BC to PTX through inhibiting EGFR/ERK axis, and it is an effective treatment for reversing PTX resistance.
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OBJECTIVES: Aberrantly expressed circular RNAs (circRNAs) have been detected in many types of tumors. Hence, they are currently investigated as candidate biomarkers for diagnostic and potential targets for therapy in cancers. The objective of this study was to assess the expression profile of circRNA in lung adenocarcinoma (LUAD). METHODS: This study included 14 pairs of postoperative lung adenocarcinoma specimens, including cancer tissues and matched adjacent tissues. Second-generation sequencing was applied to the specimens to determine the circRNA expression in them among the 5242 distinct circRNAs detected. RESULTS: We identified a total of 18 significantly dysregulated circRNAs in the LUAD tissues: upregulation in four and downregulation in 14. ROC (The receiver operating characteristic curve) further suggested that hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 could potentially be used as biomarkers in the diagnosis of LUAD. Furthermore, study of the circRNA-microRNA (miRNA)-messenger RNA (mRNA) revealed interactions between the 18 dysregulated circRNA and several cancer-related miRNAs. Finally, a further Kyoto Encyclopedia of Genes and Genomes analysis showed that the cell cycle phase transition, p53 signaling pathway, AMP-activated protein kinase (AMPK) relative signaling pathway, and so on were key putative pathways in the process of LUAD. CONCLUSIONS: These findings demonstrated the correlation between abnormality in circRNA expression and LUAD, which lays the foundation of making CircRNAs candidate biomarkers in the diagnosis of LUAD.
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BACKGROUND: Women usually decrease their physical activity (PA) after becoming pregnant. The change in PA may influence their symptom distress (SD). The changes and correlations between SD and PA throughout pregnancy remain unclear. AIMS: The aims of this study were to describe PA and SD trajectories across all three trimesters and examine their correlations during pregnancy. METHODS: A repeated-measure longitudinal study with convenience sampling at a hospital in Northern Taiwan was performed. Participants were recruited at 8-16 weeks of gestation, and two follow-up visits were performed at 24-28 weeks of gestation (second trimester) and after 36 weeks of gestation (third trimester). A total of 225 participants completed the study. The participants completed the Pregnancy Physical Activity Questionnaire (PPAQ) and Pregnancy-related Symptom Disturbance Scale (PSD), and sociodemographic and prenatal variables were recorded. RESULTS: Throughout pregnancy, SD decreased then increased, showing an overall upward trend, whereas PA showed the opposite pattern, increasing then decreasing, with an overall downward trend. Sedentary activity was positively correlated with both physical and psychological SD during the second and third trimesters. Exceeding the Institute of Medicine's recommendations for gestational weight gain, having childcare support, sport/exercise-type, and light-intensity PA were negatively associated with the physical and psychological SD, while a history of miscarriage and sedentary-intensity PA were positively associated with the physical and psychological SD. LINKING EVIDENCE TO ACTION: While several factors, including light-intensity PA, were found negatively associated with the physical and psychological SD, sedentary-intensity PA were positively associated with the physical and psychological SD, our findings shed light on future intervention strategies to relieve SD and decrease sedentary behavior among pregnant women.
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Mutations in the SCN5A gene has been recognized as resulting in a series of life-threatening arrhythmias. However, it also causes idiopathic ventricular fibrillation (IVF) with J wave in inferior leads and prolonged S-wave upstroke in precordial leads, which has not been previously reported. The present study aimed to study the mechanisms of a patient with IVF manifested with J wave in inferior leads and prolonged S-wave upstroke in precordial leads. The electrocardiograms (ECG) of the proband were recorded and genetic testing was conducted. Patch-clamp and immunocytochemical studies were performed in heterologously transfected 293 cells. The VF attacks was documented in a 55-year-old male proband with syncope episodes. 12-lead ECG shown the transient J wave in the inferior leads and prolonged S-wave upstroke in precordial V1-V3 leads in the same timeframe. Genetic analysis revealed a novel 1 base deletion (G) at position 839 in exon 2 in SCN5A gene (C280S*fs61), which causes a severe truncation of the sodium channel. The functional study revealed that in 293 cells transfected with mutant channel, no sodium current could be recorded even though the immunocytochemical experiment confirmed the truncated sodium channel existed in cytosol. The kinetics of the wild-type (WT) channel were not altered when co-transfected with C280S*fs61 mutant which suggested a haploinsufficiency effect of sodium channel in the cells. The present study identified a novel C280Sfs*61 mutation that caused the 'loss of function' of the sodium channel by haploinsufficiency mechanism. The reduced sodium channel function in the heart may cause conduction delay that may underlie the manifestation of J wave and prolonged S-wave upstroke associated with IVF.
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As one of the four major means of cancer treatment including surgery, radiotherapy (RT), chemotherapy, immunotherapy, RT can be applied to various cancers as both a radical cancer treatment and an adjuvant treatment before or after surgery. Although RT is an important modality for cancer treatment, the consequential changes caused by RT in the tumor microenvironment (TME) have not yet been fully elucidated. RT-induced damage to cancer cells leads to different outcomes, such as survival, senescence, or death. During RT, alterations in signaling pathways result in changes in the local immune microenvironment. However, some immune cells are immunosuppressive or transform into immunosuppressive phenotypes under specific conditions, leading to the development of radioresistance. Patients who are radioresistant respond poorly to RT and may experience cancer progression. Given that the emergence of radioresistance is inevitable, new radiosensitization treatments are urgently needed. In this review, we discuss the changes in irradiated cancer cells and immune cells in the TME under different RT regimens and describe existing and potential molecules that could be targeted to improve the therapeutic effects of RT. Overall, this review highlights the possibilities of synergistic therapy by building on existing research.
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Neoplasias Induzidas por Radiação , Microambiente Tumoral , Humanos , Imunoterapia , Terapia CombinadaRESUMO
Increased life expectancy has resulted in an increase in osteoporosis incidence worldwide. The coupling of angiogenesis and osteogenesis is indispensable for bone repair. Although traditional Chinese medicine (TCM) exerts therapeutic effects on osteoporosis, TCM-related scaffolds, which focus on the coupling of angiogenesis and osteogenesis, have not yet been used for the treatment of osteoporotic bone defects.Panax notoginsengsaponin (PNS), the active ingredient ofPanax notoginseng, was added to a poly (L-lactic acid) (PLLA) matrix. Osteopractic total flavone (OTF), the active ingredient ofRhizoma Drynariae, was encapsulated in nano-hydroxyapatite/collagen (nHAC) and added to the PLLA matrix. Magnesium (Mg) particles were added to the PLLA matrix to overcome the bioinert character of PLLA and neutralize the acidic byproducts generated by PLLA. In this OTF-PNS/nHAC/Mg/PLLA scaffold, PNS was released faster than OTF. The control group had an empty bone tunnel; scaffolds containing OTF:PNS = 100:0, 50:50, and 0:100 were used as the treatment groups. Scaffold groups promoted new vessel and bone formation, increased the osteoid tissue, and suppressed the osteoclast activity around osteoporotic bone defects. Scaffold groups upregulated the expression levels of angiogenic and osteogenic proteins. Among these scaffolds, the OTF-PNS (50:50) scaffold exhibited a better capacity for osteogenesis than the OTF-PNS (100:0 and 0:100) scaffolds. Activation of the bone morphogenic protein (BMP)-2/BMP receptor (BMPR)-1A/runt-related transcription factor (RUNX)-2signaling pathway may be a possible mechanism for the promotion of osteogenesis. Our study demonstrated that the OTF-PNS/nHAC/Mg/PLLA scaffold could promote osteogenesis via the coupling of angiogenesis and osteogenesis in osteoporotic rats with bone defects, and activating theBMP-2/BMPR1A/RUNX2signaling pathway may be an osteogenesis-related mechanism. However, further experiments are necessary to facilitate its practical application in the treatment of osteoporotic bone defects.
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Osteogênese , Osteoporose , Ratos , Animais , Engenharia Tecidual/métodos , Tecidos Suporte , Osso e Ossos/metabolismo , Poliésteres/farmacologia , Osteoporose/terapia , Osteoporose/metabolismoRESUMO
BACKGROUND: The effective detection of pathogens is of great importance for the diagnosis and treatment of infectious diseases. We have proposed the novel RT-nestRPA technique for SARS-CoV-2 detection, which is a rapid RNA detection technique with ultra-high sensitivity. RESULTS: The RT-nestRPA technology has a sensitivity of 0.5 copies/uL of synthetic RNA targeting the ORF7a/7b/8 gene or 1 copy/uL synthetic RNA targeting the N gene of SARS-CoV-2. The entire detection process of RT-nestRPA only takes only 20 min, which is significantly shorter than RT-qPCR (nearly 100 min). Additionally, RT-nestRPA is capable of detecting dual genes of SARS-CoV-2 and human RPP30 simultaneously in one reaction tube. The excellent specificity of RT-nestRPA was verified by analyzing twenty-two SARS-CoV-2 unrelated pathogens. Furthermore, RT-nestRPA had great performance in detecting samples treated with cell lysis buffer without RNA extraction. The innovative double-layer reaction tube for RT-nestRPA can prevent aerosol contamination and simplify the reaction operation. Moreover, the ROC analysis revealed that RT-nestRPA had high diagnostic value (AUC = 0.98), while the AUC of RT-qPCR was 0.75. SIGNIFICANCE: Our current findings suggested that RT-nestRPA could serve as a novel technology for nucleic acid detection of pathogens with rapid and ultrahigh sensitive features used in various medical application scenarios.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , Teste para COVID-19 , Técnicas de Laboratório Clínico/métodos , Sensibilidade e Especificidade , RNA Viral/genética , RNA Viral/análise , Técnicas de Amplificação de Ácido Nucleico/métodosRESUMO
PURPOSE: To explore the role and mechanism of curcumin (Cur) in reducing oxidative stress damage in rats with nephrolithiasis induced by ethylene glycol (EG). METHODS: Thirty male rats were divided into normal control, model, positive (10% potassium citrate), Cur-10 (10 mg/kg curcumin) and Cur-20 (20 mg/kg curcumin) groups. RESULTS: The results of kidney tissue section stained by hematoxylin-eosin and von Kossa showed that curcumin treatment can inhibit the formation of kidney stones. The biochemical test results showed that the urea (Ur), creatinine (Cr), uric acid (UA), inorganic phosphorus and Ca2+ concentrations in urine decreased after being treated with curcumin. There were significant differences between different doses of curcumin (P < 0.05). Compared with the Cur-10 group, Cur-20 had a more significant inhibitory effect on malondialdehyde (MDA) (P < 0.05). In addition, reverse transcription polymerase chain reaction (PCR) detection and immunohistochemical results indicated that the osteopontin (OPN) in the kidney was significantly reduced after curcumin treatment. CONCLUSIONS: Curcumin could reduce the oxidative stress damage caused by EG-induced kidney stones.
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Curcumina , Cálculos Renais , Osteopontina , Animais , Masculino , Ratos , Antioxidantes/metabolismo , Curcumina/farmacologia , Rim , Cálculos Renais/tratamento farmacológico , Cálculos Renais/prevenção & controle , Cálculos Renais/metabolismo , Estresse OxidativoRESUMO
Arid and semi-arid forests are important carbon sinks, with implications for the global carbon balance. However, the impacts of climate warming on the growth of arid and semi-arid forest tree species and ecosystem carbon sink dynamics remain uncertain because the effects of the complex interactions between precipitation and temperature on xylem phenology are not clearly understood. Here, we monitored xylem formation over two years in two dominant tree species (Siberian larch, Larix sibirica Ledeb.; Siberian spruce, Picea obovata Ledeb.) along the arid and semi-arid southern Altai Mountains of Central Asia. We determined that temperature interaction with precipitation plays a key role in regulating xylem phenology of these two species, with differences between species. Under rising mean annual temperatures, the growth of L. sibirica advanced as the onset of xylem formation was not limited by early season water availability. However, the earlier cessation of cell enlargement, likely due to legacy effects, compensated for such advancement. In contrast, water stress constrained the advancement of xylem formation under rising temperatures in P. obovata. Nevertheless, water stress was seemingly relieved later in the growing season and consequently did not lead to the earlier cessation of xylem formation. Our results demonstrate that precipitation drives species-specific response to rising temperatures and thus is a key driver of growing season length and carbon sink dynamics in arid and semi-arid forests under climate warming. Integrating the effects of temperature and precipitation on xylem phenology in climate models may improve estimates of climate-carbon feedback in arid and semi-arid forests under future warming scenarios.
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OBJECTIVE: Gene expression profiling techniques measure the transcription of thousands of genes in a parallel manner. With more and more hepatocellular carcinoma (HCC) transcriptomic data becoming available, the high-throughput data provides an unprecedented opportunity to discover HCC diagnostic biomarkers. In this work, we propose a bioinformatics method based on dynamic network entropy analysis, called DNEA, to identify potential pathway biomarkers for HCC occurrence and development by integrating transcriptome and interactome. METHODS: We firstly collect the pathways documented in different knowledge-bases and then impose the genome-wide human transcriptomic data of multistage cancerous tissues during the development and progression of HCC. After linking the gene sets of pathways into individual connected networks, we map the corresponding gene expression information onto these pathways. The dynamic network entropy of individual pathways is calculated to evaluate its activities and dysfunctionalities during the disease occurrence and development. We use the overall significant difference in the entropic dynamics during the time course to prioritize distinctive pathways during disease progression. Then machine learning classification methods are employed to screen out pathway biomarkers with the classification ability to distinguish different-stage samples of HCC progression. RESULTS: Pathway biomarkers discovered based on DNEA demonstrate good classification performance in measuring HCC progression. The classification accuracy is as follows: DNA replication pathway (mean AUC = 0.82, 20 genes) from KEGG, FMLP pathway (mean AUC = 0.84, 14 genes) from BioCarta, and downstream signaling of activated FGFR pathway (mean AUC = 0.80, 15 genes) from Reactome. At the same time, previous studies have shown that these genes and pathways screened are closely related to the occurrence and development of HCC in terms of oncogenesis dysfunctions. CONCLUSIONS: Our method for cancer biomarker discovery based on dynamic network entropy analysis is effective and efficient in identifying pathway biomarkers related to the progression of complex diseases.
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Pancreatic adenocarcinoma (PAAD) has a poor prognosis and is relatively unresponsive to immunotherapy. Gasdermin C (GSDMC) induces pyroptosis in cancer cells and inflammation in the tumor microenvironment. However, whether GSDMC expression in PAAD is associated with survival or response to immunotherapy remains unknown. GSDMC expression and the relationship between GSDMC and patient survival or immune infiltration in PAAD were examined using data in the The Cancer Genome Atlas (TCGA), Gene Expression Ominbus (GEO), Genotype-Tissue Expression (GTEx) and Cancer Cell Line Encyclopedia (CCLE) databases. The TCGA PAAD cohort could be divided into two distinct risk groups based on the expression of GSDMC-related genes (GRGs). The TIDE algorithm predicted that the low-risk group was more responsive to immune checkpoint blockade therapy than the high-risk group. A novel 15-gene signature was constructed and could predict the prognosis of PAAD. In addition, the 15-gene signature model predicted the infiltration of immune cells and Immune checkpoint blockade (ICB) treatment response. Immunohistochemical staining assessment of patient-derived human tissue microarray (TMA) from 139 cases of local PAAD patients revealed a positive correlation between GSDMC expression and PD-L1 expression but a negative correlation between GSDMC expression and infiltration of low CD8+ T cells. Moreover, the overexpression of GSDMC was related to poor overall survival (OS). This study suggests that GSDMC is a valuable biomarker for predicting PAAD prognosis and predicts the immunotherapy response of PAAD.
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Exosomes are small extracellular vesicles that contain RNA, lipids, and proteins and can act as cellular messengers, carrying information to cells and tissues in the body. Thus, sensitive, label-free, and multiplexed analysis of exosomes may help in early diagnosis of important diseases. Here, we describe the process of pretreatment of cell-derived exosomes, preparation of surface-enhanced Raman scattering (SERS) substrates, and label-free SERS detection of exosomes using sodium borohydride aggregators. This method can enable the observation of SERS signals of exosomes that are clear and stable and have a good signal-to-noise ratio.
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Exossomos , Nanopartículas Metálicas , Análise Espectral Raman/métodos , Prata , Exossomos/metabolismo , Proteínas/metabolismoRESUMO
Research and development of electroencephalogram (EEG) based brain-computer interfaces (BCIs) have advanced rapidly, partly due to deeper understanding of the brain and wide adoption of sophisticated machine learning approaches for decoding the EEG signals. However, recent studies have shown that machine learning algorithms are vulnerable to adversarial attacks. This paper proposes to use narrow period pulse for poisoning attack of EEG-based BCIs, which makes adversarial attacks much easier to implement. One can create dangerous backdoors in the machine learning model by injecting poisoning samples into the training set. Test samples with the backdoor key will then be classified into the target class specified by the attacker. What most distinguishes our approach from previous ones is that the backdoor key does not need to be synchronized with the EEG trials, making it very easy to implement. The effectiveness and robustness of the backdoor attack approach is demonstrated, highlighting a critical security concern for EEG-based BCIs and calling for urgent attention to address it.
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Interfaces Cérebro-Computador , Humanos , Eletroencefalografia , Algoritmos , Aprendizado de Máquina , EncéfaloRESUMO
This work presents a new, to the best of our knowledge, porous graphene dispersion in ethanol that can achieve a good nonlinear optical limiting (NOL) effect at the wavelength of 1064 nm. Using the Z-scan system, the nonlinear absorption coefficient of the porous graphene dispersion with a concentration of 0.01 mg/mL was measured as 9.69×10-9 c m/W. The NOL of the porous graphene dispersions in ethanol under three different concentrations (0.01, 0.02, and 0.03 mg/mL) were measured. Among them, the 1-cm-thick porous graphene dispersion with a concentration of 0.01 mg/mL has the best optical limiting effect, in which the linear transmittance is 76.7%, and the lowest transmittance is 24.9%. By using the pump-probe technique, we detected the formation and annihilation times of the scatter when the suspension interacts with the pump light. The analysis shows that the NOL mechanisms of the novel porous graphene dispersion are mainly nonlinear scattering and nonlinear absorption.
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Background: Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city. Methods: We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist-hip ratio (WHR) in Hong Kong's population-representative 'Children of 1997' birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity risk n ≤ 7119, WHR n = 5691) and ~17.6 years (n = 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression (n = 308) and CpG by CpG analysis (n = 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies. Results: At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR. Conclusions: These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings. Funding: This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.
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Coorte de Nascimento , Obesidade Pediátrica , Humanos , Criança , Peso ao Nascer , Epigenoma , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/genética , Índice de Massa CorporalRESUMO
BACKGROUND: Treatment options for pretreated triple-negative breast cancer (TNBC) are limited. This study aimed to evaluate the efficacy and safety of apatinib, an antiangiogenic agent, in combination of etoposide for pretreated patients with advanced TNBC. METHODS: In this single-arm phase II trial, patients with advanced TNBC who failed to at least one line of chemotherapy were enrolled. Eligible patients received oral apatinib 500 mg on day 1 to 21, plus oral etoposide 50 mg on day 1 to 14 of a 3-week cycle until disease progression or intolerable toxicities. Etoposide was administered up to six cycles. The primary endpoint was progression-free survival (PFS). RESULTS: From September 2018 to September 2021, 40 patients with advanced TNBC were enrolled. All patients received previous chemotherapy in the advanced setting, with the median previous lines of 2 (1-5). At the cut-off date on January 10, 2022, the median follow-up was 26.8 (1.6-52.0) months. The median PFS was 6.0 (95% confidence interval [CI]: 3.8-8.2) months, and the median overall survival was 24.5 (95%CI: 10.2-38.8) months. The objective response rate and disease control rate was 10.0% and 62.5%, respectively. The most common adverse events (AEs) were hypertension (65.0%), nausea (47.5%) and vomiting (42.5%). Four patients developed grade 3 AE, including two with hypertension and two with proteinuria. CONCLUSIONS: Apatinib combined with oral etoposide was feasible in pretreated advanced TNBC, and was easy to administer. CLINICAL TRIAL REGISTRATION: Chictr.org.cn, (registration number: ChiCTR1800018497, registration date: 20/09/2018).
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Antineoplásicos , Hipertensão , Neoplasias de Mama Triplo Negativas , Humanos , Etoposídeo/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Hipertensão/induzido quimicamenteRESUMO
Background: TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC) is a type of kidney cancer with a low incidence, with no consensus about whether it has a worse prognosis than clear cell renal cell carcinoma (ccRCC). This study attempted to elucidate the impact of TFE3-rearranged RCC by analyzing its clinical features and prognosis. Methods: Patients treated in Sun Yat-sen Memorial Hospital (SYSMH) who were suspected to be diagnosed with TFE3-rearranged RCC were divided into two groups, TFE3-rearranged RCC and ccRCC with positive TFE3 protein expression on immunohistochemistry [TFE3(+) ccRCC], by dual-color, break-apart fluorescence in situ hybridization (FISH). After balancing the baseline characteristics with TFE3(+) ccRCC using the propensity score matching (PSM) method in a ratio of 2, we selected patients diagnosed with ccRCC with negative TFE3 protein expression on immunohistochemistry [TFE3(-) ccRCC]. The impact of TFE3 gene rearrangement and protein expression on renal cell carcinoma was determined by feature comparison with a nonparametric test and survival analysis with the KaplanâMeier method. Results: Among 37 patients suspected of having TFE3-rearranged RCC, 13 patients were diagnosed with TFE3-rearranged RCC, and 24 patients had TFE3(+) ccRCC. The recurrence and new metastasis of TFE3-rearranged RCC was relatively common, even if the tumor stage was early at the first diagnosis. Through feature comparison and survival analysis, we found that TFE3-rearranged RCC was quite similar to TFE3(+) ccRCC. Compared with TFE3(-) ccRCC, TFE3(+) ccRCC tended to have a larger tumor diameter (P = 0.011), higher neutrophil/lymphocyte ratio (NLR) (P = 0.017) and metastatic potential (P = 0.022), and worse overall survival (OS) (P = 0.043) and PFS (P = 0.016). The survival analysis showed that TFE3-rearranged RCC had a worse PFS than ccRCC (P = 0.002), and TFE3(+) RCC had a worse PFS than TFE3(-) RCC (P = 0.001). According to the stratification system based on the combination of TFE3 and lymphovascular invasion (LVI), we further found that the prognosis from good to poor was TFE3(-) LVI(-), TFE3(+) LVI(-), TFE3(+) LVI(+) and TFE3(-) LVI(+), with statistically significant differences in both OS (P = 0.001) and PFS (P < 0.001). In addition, we also reported two cases with poor prognosis, of which one was TFE3-rearranged RCC and the other was TFE3(+) ccRCC. Conclusions: This is a novel finding that both FISH confirmed TFE3 gene rearrangement-mediated TFE3-rearranged RCC and IHC confirmed positive TFE3 protein expression [TFE3(+)] contribute to a poor prognosis in RCC, suggesting more active treatment and careful follow-up for TFE3(+) RCC patients. The combination of TFE3 and LVI may be a new risk stratification system for RCC.
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Background: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis -Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,162 cancer cases and up to 824,556 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant ( P < 5.0 x 10 -8 ) cis -acting SNPs (i.e. in or ±250 kb from the gene encoding the relevant protein) in weak linkage disequilibrium (LD, r 2 < 0.10). Effect estimates were generated using inverse-variance weighted random-effects models and standard errors were inflated to account for weak LD between variants with reference to the 1000 Genomes Phase 3 CEU panel. A false discovery rate (FDR)-corrected P -value (" q -value") < 0.05 was used as a threshold to define "strong evidence" to support associations and 0.05 ≤ q -value < 0.20 to define "suggestive evidence". A colocalisation posterior probability (PPH 4 ) > 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Results: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR 1.19, 95% CI 1.10-1.29, q -value=0.033, PPH 4 =84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR 1.42, 95% CI 1.20-1.69, q -value=0.055, PPH 4 =73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR 0.66, 95% CI 0.53-0.81, q -value=0.067, PPH 4 =81.8%), macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR 1.14, 95% CI 1.05-1.23, q -value=0.072, PPH 4 =76.1%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR 0.92, 95% CI 0.88-0.97, q -value=0.15), PPH 4 =85.6%). For 22 of 30 cancer outcomes examined, there was little evidence ( q -value ≥ 0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Conclusion: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 5 circulating inflammatory markers in risk of 5 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated.
