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Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.
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Cisplatino , Reparo do DNA , Replicação do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Resistencia a Medicamentos Antineoplásicos , Poli(ADP-Ribose) Polimerase-1 , Humanos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , DNA/metabolismo , DNA/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Replicação do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Proteínas de Ligação a Poli-ADP-RiboseRESUMO
BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).
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Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Trastuzumab/uso terapêutico , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Humanos , Imunoconjugados/efeitos adversos , Estimativa de Kaplan-Meier , Doenças Pulmonares Intersticiais/induzido quimicamente , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversosRESUMO
Recent theoretical and experimental studies of the interlayer Dzyaloshinskii-Moriya interaction (DMI) have sparked great interest in its implementation into practical magnetic random-access memory (MRAM) devices, due to its capability to mediate long-range chiral spin textures. So far, experimental reports focused on the observation of interlayer DMI, leaving the development of strategies to control interlayer DMI's magnitude unaddressed. Here, we introduce an azimuthal symmetry engineering protocol capable of additive/subtractive tuning of interlayer DMI through the control of wedge deposition of separate layers and demonstrate its capability to mediate field-free spin-orbit torque (SOT) magnetization switching in both orthogonally magnetized and synthetic antiferromagnetically coupled systems. Furthermore, we showcase that the spatial inhomogeneity brought about by wedge deposition can be suppressed by specific azimuthal engineering design, ideal for practical implementation. Our findings provide guidelines for effective manipulations of interlayer DMI strength, beneficial for the future design of SOT-MRAM or other spintronic devices utilizing interlayer DMI.
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Fibroblast growth factors (FGFs) control various cellular functions through fibroblast growth factor receptor (FGFR) activation, including proliferation, differentiation, migration, and survival. FGFR amplification in ER + breast cancer patients correlate with poor prognosis, and FGFR inhibitors are currently being tested in clinical trials. By comparing three-dimensional spheroid growth of ER + breast cancer cells with and without FGFR1 amplification, our research discovered that FGF2 treatment can paradoxically decrease proliferation in cells with FGFR1 amplification or overexpression. In contrast, FGF2 treatment in cells without FGFR1 amplification promotes classical FGFR proliferative signaling through the MAPK cascade. The growth inhibitory effect of FGF2 in FGFR1 amplified cells aligned with an increase in p21, a cell cycle inhibitor that hinders the G1 to S phase transition in the cell cycle. Additionally, FGF2 addition in FGFR1 amplified cells activated JAK-STAT signaling and promoted a stem cell-like state. FGF2-induced paradoxical effects were reversed by inhibiting p21 or the JAK-STAT pathway and with pan-FGFR inhibitors. Analysis of patient ER + breast tumor transcriptomes from the TCGA and METABRIC datasets demonstrated a strong positive association between expression of FGF2 and stemness signatures, which was further enhanced in tumors with high FGFR1 expression. Overall, our findings reveal a divergence in FGFR signaling, transitioning from a proliferative to stemness state driven by activation of JAK-STAT signaling and modulation of p21 levels. Activation of these divergent signaling pathways in FGFR amplified cancer cells and paradoxical growth effects highlight a challenge in the use of FGFR inhibitors in cancer treatment.
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Neoplasias da Mama , Transdução de Sinais , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fator 2 de Crescimento de Fibroblastos/uso terapêutico , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Janus Quinases/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/farmacologia , Fatores de Transcrição STAT/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Proliferação de Células , Fatores de Crescimento de Fibroblastos/farmacologia , Linhagem Celular TumoralRESUMO
An increased neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic biomarker in various types of cancer, because it reflects the inhibition of lymphocytes in the circulation and tumors. In urologic cancers, upper tract urothelial carcinoma (UTUC) is known for its aggressive features and lack of T cell infiltration; however, the association between neutrophils and suppressed T lymphocytes in UTUC is largely unknown. In this study, we examined the relationship between UTUC-derived factors and tumor-associated neutrophils or T lymphocytes. The culture supernatant from UTUC tumor tissue modulated neutrophils to inhibit T cell proliferation. Among the dominant factors secreted by UTUC tumor tissue, apolipoprotein A1 (Apo-A1) exhibited a positive correlation with NLR. Moreover, tumor-infiltrating neutrophils were inversely correlated with tumor-infiltrating T cells. Elevated Apo-A1 levels in UTUC were also inversely associated with the population of tumor-infiltrating T cells. Our findings indicate that elevated Apo-A1 expression in UTUC correlates with tumor-associated neutrophils and T cells. This suggests a potential immunomodulatory effect on neutrophils and T cells within the tumor microenvironment, which may represent therapeutic targets for UTUC treatment.
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The global phase 3 DESTINY-Breast03 study (ClinicalTrials.gov; NCT03529110) showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) with trastuzumab deruxtecan (T-DXd) over trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. Here, we report a subgroup analysis of Asian patients enrolled in DESTINY-Breast03. In total, 309 patients (149 in the T-DXd arm and 160 in the T-DM1 arm) from Asian countries and regions were randomized. At data cutoff (July 25, 2022), the median duration of follow-up in the Asian subpopulation was 29.0 months with T-DXd and 26.0 months with T-DM1. The PFS (determined by blinded independent central review) hazard ratio was 0.30 (95% confidence interval 0.22-0.41) favoring T-DXd over T-DM1 (median PFS 25.1 vs. 5.4 months). Median OS was not reached in the T-DXd arm and was 37.7 months in the T-DM1 arm. The median treatment duration was 15.4 months with T-DXd and 5.5 months with T-DM1. The incidence of grade ≥3 drug-related treatment-emergent adverse events was similar between both treatment arms (49.0% vs. 46.5%) and was consistent with the overall DESTINY-Breast03 population. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.9% of patients treated with T-DXd and 2.5% treated with T-DM1, with a higher incidence in Japanese patients; none of these were grade ≥4 events. These efficacy and safety data reinforce the favorable benefit-risk profile of T-DXd in HER2-positive mBC, including in the Asian subgroup.
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In ambient ionization mass spectrometry (MS), a customized metal inlet is typically adapted to the orifice of the mass spectrometer for ease of introduction of the sample. We herein explore that the metal inlet coiled with a copper wire (â¼50 µm) can be directly used as an ion source to induce corona discharge-like processes for ionization of analytes in the gas phase. When the metal inlet is subjected to a high voltage in the mass spectrometer, the electric field provided by the mass spectrometer enables the generation of corona discharge to ionize volatile/semivolatile analytes derived from the sample in the condensed phase. The limit of detection for azulene derived from the aqueous sample was as low as â¼1 pM. Moreover, we also demonstrated the feasibility of coupling ultraviolet-visible absorption spectroscopy with MS by using the metal inlet coiled with a thin copper wire as the interface. Integration of these two techniques enables the simultaneous acquisition of spectra from both instruments for quantitative and qualitative analysis of the sample. Furthermore, we showed that polar and nonpolar analytes in a mixture can be acquired in the same mass spectrum by simply depositing a sample droplet (â¼20 µL) on a dielectric substrate near the copper wire-coiled metal inlet of the mass spectrometer. The ionization processes involved both electrospray ionization and corona discharge. To demonstrate the applicability of our method for detecting nonpolar and polar analytes in complex samples, we spiked a nonpolar analyte, benzo[a]pyrene, to a spice sample and successfully detected analytes with different polarities using our approach.
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PURPOSE: Thoracic endovascular aortic repair (TEVAR) is a treatment for traumatic blunt thoracic aortic injury (BTAI) with good survival rates and safety. However, there is limited study on the risk factors for in-hospital mortality and complications. This study aimed to identify risk factors associated with poor in-hospital outcomes after TEVAR. MATERIALS AND METHODS: This is a population-based, retrospective observational study. Data of adults ≥20 years admitted for BTAI who received TEVAR were extracted from the Nationwide Inpatient Sample (NIS) database 2005 to 2018. The primary outcome was in-hospital mortality, and the secondary outcomes were length of stay (LOS) and unfavorable discharge (ie, non-routine discharge, including nursing homes or long-term care facilities). Associations between study variables and in-hospital outcomes were determined using univariate and multivariable logistic and linear regression analyses. RESULTS: Data of 1095 participants (representing 5360 hospitalized patients in the United States) were analyzed. Multivariable analysis revealed that older age (adjusted odds ratio [aOR]=1.02) and having at least 1 perioperative complication (aOR=4.01) were significantly associated with increased risk for in-hospital mortality. Patients with at least 1 perioperative complication (aOR=11.19) had significantly increased odds for prolonged LOS. Risk for unfavorable discharge was significantly increased by older age (aOR=1.02), household income at quartile 2 (aOR=1.58), Charlson Comorbidity Index (CCI) 2 to 3 (aOR=1.66), and having at least 1 complication (aOR=3.94). Complications including perioperative cerebrovascular accident (CVA) (aOR=2.75), venous thromboembolism (VTE) (aOR=2.87), pneumonia (aOR=3.93), sepsis (aOR=4.69), infection (aOR=4.49), respiratory failure (aOR=4.55), mechanical ventilation (aOR=3.27), and acute kidney injury (AKI) (aOR=3.09) significantly predicted prolonged LOS. CONCLUSIONS: In adults with traumatic BTAI undergoing TEVAR, advanced age and perioperative complications are risk factors for poor in-hospital outcomes. Acute kidney injury, CVA, respiratory failure, and sepsis are strong predictors of prolonged LOS, unfavorable discharge, and in-hospital mortality. CLINICAL IMPACT: The study identifies advanced age and perioperative complications as key risk factors for poor in-hospital outcomes in patients undergoing TEVAR for BTAI. Clinicians should be vigilant in managing these patients, particularly those with comorbidities, to mitigate risks. The findings suggest a need for tailored perioperative care strategies to improve survival rates and reduce complications. This research highlights the critical importance of early identification and intervention in high-risk patients, offering an innovative approach to refining TEVAR protocols and enhancing patient outcomes in trauma care.
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BACKGROUND: Pre-hospital delay in China is a serious issue with unclear relevant reasons, seriously impeding the adoption of appropriate measures. Herein, we analyzed the onset-to-door time (ODT) in Chinese patients with acute ischemic stroke (AIS) and its influencing factors. METHODS: We prospectively recruited 3,459 patients with AIS from nine representative tertiary general hospitals in China between January and June 2022. Patients were divided into ODT ≤ 3 h and ODT > 3 h groups. Following single-factor analysis, binary logistic regression analysis was performed to evaluate the risk factors leading to pre-hospital delay. RESULTS: In total, 763 (21.83%) patients arrived at the hospital within 3 h of onset. After adjusting for confounding factors, the risk factors for ODT were residence in rural areas (odds ratio [OR]: 1.478, 95% credibility interval [CI]: 1.024-2.146) and hospital transfer (OR: 7.479, 95% CI: 2.548-32.337). The protective factors for ODT were location of onset ≤ 20 km from the first-visit hospital (OR: 0.355, 95% CI: 0.236-0.530), transportation by emergency medical services (OR: 0.346, 95% CI: 0.216-0.555), history of atrial fibrillation (OR: 0.375, 95% CI: 0.207-0.679), moderate stroke (OR: 0.644, 95% CI: 0.462-0.901), and severe stroke (OR: 0.506, 95% CI: 0.285-0.908). CONCLUSIONS: Most patients with AIS fail to reach a hospital within the critical 3-h window. The following measures are recommended to reduce pre-hospital delays: reasonable distribution of hospitals accessible to nearby residents, minimizing interhospital transfer, paying attention to patients with mild stroke, and encouraging patients to use ambulance services. Pre-hospital delays for patients can be reduced by implementing these measures, ultimately improving the timeliness of treatment and enhancing patient prognosis. This study was carried out amid the COVID-19 pandemic, which presented challenges and constraints.
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COVID-19 , AVC Isquêmico , Tempo para o Tratamento , Humanos , COVID-19/epidemiologia , Feminino , Masculino , China/epidemiologia , Estudos Prospectivos , AVC Isquêmico/epidemiologia , AVC Isquêmico/terapia , Idoso , Pessoa de Meia-Idade , Tempo para o Tratamento/estatística & dados numéricos , Fatores de Risco , SARS-CoV-2 , Idoso de 80 Anos ou mais , População do Leste AsiáticoRESUMO
The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.
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Alcaloides , Flavanonas , Sophora , Camundongos , Animais , Flavonoides/química , Sophora flavescens , Sophora/química , Flavanonas/farmacologia , Flavanonas/química , Prenilação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Citocinas , QuimiocinasRESUMO
BACKGROUND: The study aimed to investigate anatomical changes in the neck region and evaluate their impact on dose distribution in patients with nasopharyngeal carcinoma (NPC) undergoing intensity modulated radiation therapy (IMRT). Additionally, the study sought to determine the optimal time for replanning during the course of treatment. METHODS: Twenty patients diagnosed with NPC underwent IMRT, with weekly pretreatment kV fan beam computed tomography (FBCT) scans in the treatment room. Metastasized lymph nodes in the neck region and organs at risk (OARs) were redelineation using the images from the FBCT scans. Subsequently, the original treatment plan (PLAN0) was replicated to each FBCT scan to generate new plans labeled as PLAN 1-6. The dose-volume histograms (DVH) of the new plans and the original plan were compared. One-way repeated measure ANOVA was utilized to establish threshold(s) at various time points. The presence of such threshold(s) would signify significant change(s), suggesting the need for replanning. RESULTS: Progressive volume reductions were observed over time in the neck region, the gross target volume for metastatic lymph nodes (GTVnd), as well as the submandibular glands and parotids. Compared to PLAN0, the mean dose (Dmean) of GTVnd-L significantly increased in PLAN5, while the minimum dose covering 95% of the volume (D95%) of PGTVnd-L showed a significant decrease from PLAN3 to PLAN6. Similarly, the Dmean of GTVnd-R significantly increased from PLAN4 to PLAN6, whereas the D95% of PGTVnd-R exhibited a significant decrease during the same period. Furthermore, the dose of bilateral parotid glands, bilateral submandibular glands, brainstem and spinal cord was gradually increased in the middle and late period of treatment. CONCLUSION: Significant anatomical and dosimetric changes were noted in both the target volumes and OARs. Considering the thresholds identified, it is imperative to undertake replanning at approximately 20 fractions. This measure ensures the delivery of adequate doses to target volumes while mitigating the risk of overdosing on OARs.
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Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Pescoço , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/patologia , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Masculino , Radioterapia de Intensidade Modulada/métodos , Pessoa de Meia-Idade , Feminino , Adulto , Tomografia Computadorizada por Raios X/métodos , Carcinoma/diagnóstico por imagem , Carcinoma/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Órgãos em Risco/efeitos da radiação , Órgãos em Risco/diagnóstico por imagem , Radiometria/métodosRESUMO
Permeable pavements help reduce surface temperatures and have been widely implemented in urban areas. This study utilized an in-use permeable pavement sidewalk in front of a mass rapid transit station in the Taipei city center of Taiwan to determine the actual pavement surface temperature performance. A neighboring asphalt road and impervious pavement were also monitored. With a full year of continuous monitoring, the results showed that the temperature of permeable pavement was 3.7 °C lower than that of impervious pavement and 4.5 °C lower than that of asphalt pavement in the hot season. The frequent rainfall in spring resulted in the smallest temperature differences between the different pavement types. The cooling effects of permeable pavement differed at the different air temperatures. At air temperatures lower than 15 °C, the differences among pavement surface temperatures were noticeable. However, when the air temperature was higher than 35 °C, the surface temperature of permeable pavement was not different from that of impervious pavement and was greater than 55 °C. Field observations were carried out to determine the effects on the apparent temperature and the future surface temperature of climate change scenarios. The results showed that permeable pavement could reduce the average apparent temperature to near the air temperature, and asphalt pavement could increase the apparent temperature by 1.2 °C, assuming that the pavement temperature completely affects the air temperature. With the good prediction ability of the machine learning approach and 15 environmental factors, the preliminary prediction showed the projected surface temperature change in Taipei city in 2033. In the worst-case scenario, the average impervious pavement temperature is as high as 39.12 °C, whereas the average permeable pavement temperature is 32.50 °C.
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Monitoramento Ambiental , Hidrocarbonetos , Chuva , Temperatura , Movimentos da ÁguaRESUMO
Downregulation of ARHGAP25 was found in the tumor samples from breast cancer patients and five breast cancer cell lines. However, its precise role and molecular mechanisms in breast cancer remain completely unknown. Herein, we found that knockdown of ARHGAP25 in breast cancer cells promoted proliferation, migration and invasion of breast cancer cells. Mechanistically, ARHGAP25 silence facilitated the activation of the Wnt/ß-catenin pathway and the upregulation of its downstream molecules (including c-Myc, Cyclin D1, PCNA, MMP2, MMP9, Snail and ASCL2) by directly regulating Rac1/PAK1 in breast cancer cells. In vivo xenograft experiments indicated ARHGAP25 silence promoted tumor growth and activated the Wnt/ß-catenin pathway. In contrast, overexpression of ARHGAP25 in vitro and in vivo impeded all of the above cancer properties. Intriguingly, ASCL2, a downstream target of the Wnt/ß-catenin pathway, transcriptionally repressed the expression of ARHGAP25 and therefore constituted a negative feedback loop. Moreover, bioinformatics analysis indicated that ARHGAP25 was significantly correlated with tumor immune cell infiltration and the survival of patients with different immune cell subgroups in breast cancer. Collectively, our work revealed that ARHGAP25 suppressed tumor progression of breast cancer. It provides a novel insight for the treatment of breast cancer.
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Neoplasias da Mama , Proteínas Ativadoras de GTPase , beta Catenina , Feminino , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , beta Catenina/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Proteínas Ativadoras de GTPase/genética , Regulação para Cima , Via de Sinalização Wnt/genéticaRESUMO
The linear photogalvanic effect (LPGE) is investigated by using the non-equilibrium Green's function (NEGF) technique combined with density functional theory (DFT) in monolayer Na2MgSn. We consider the cases of three different central regions, which are pure Na2MgSn, Na-vacancy, and Pb-substituted. It is found that both pure and defective Na2MgSn monolayers induce photoresponse under linearly polarized light. The photoresponse varies periodically as a form of either sinusoidal or cosinoidal function of the polarization angle. In the near-infrared and visible ranges, the photoresponse is more sensitive to the long wave range of visible light. In the case of single-atom defects, the photoresponse with Na-vacancy is larger than that of pb-substitution defects. Compared with the other two central regions, the maximum extinction ratio (ER) of Na-vacancy is larger, so it has higher polarization sensitivity. When the location of Na-vacancy is adjusted, the photoresponse changes obviously, and the Na 1*- vacancy has the largest photoresponse. With the increase of the Na-vacancy concentration, the photoresponse changes nonlinearly but is smaller than that of a single vacancy. A small bias voltage can greatly improve the photoresponse. Our results suggest an effective method to enhance the photoresponse and show the promise of Na2MgSn monolayers in optical detection.
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Linear photogalvanic effects in monolayer WSe2 with defects are investigated by non-equilibrium Green's function technique combined with density functional theory. Monolayer WSe2 generates photoresponse in the absence of external bias voltage, showing potential applications in low-power consumption photoelectronic devices. Our results show that the photocurrent changes in perfect sine form with the polarization angle. The maximum photoresponse Rmax produced in the monoatomic S substituted defect material is 28 times that of the perfect material when the photon energy is 3.1â eV irradiated, which is the most outstanding among all the defects. Monoatomic Ga substitution extinction ratio (ER) is the largest, and its ER value is more than 157 times that of the pure condition at 2.7â eV. As the defects concentration increases, the photoresponse is changed. The concentrations of Ga substituted defects have little effect on the photocurrent. The concentrations of Se/W vacancy and S/Te substituted defect have a great influence on the photocurrent increase. Our numerical results also show that monolayer WSe2 is a candidate material for solar cells in the visible light range and a promising polarization detector material.
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BACKGROUND: MRI is crucial in diagnosing hepatocellular carcinoma (HCC). Superparamagnetic iron oxide particles (SPIO) are liver-specific contrast agents which enhance lesions in T2 -weighted images. Iron oxide nano-particle m-PEG-silane (IOP) Injection, a newly developed SPIO, showed promising imaging effects and good safety profile in preclinical studies and in phase I clinical trial. PURPOSE: To evaluate the safety and clinical validity of IOP Injection as MRI contrast agent in diagnosing HCC. STUDY TYPE: Prospective. SUBJECTS: A total of 52 subjects (61.6 ± 11.05 years, 45 males/7 females) with suspected HCC. FIELD STRENGTH/SEQUENCE: 1.5 T, T1 -weighted in/opposed phase, T2 *-weighted gradient echo, T2 -weighted fast spin echo, true fast imaging with steady-state free precession. ASSESSMENT: Adverse effects and clinical monitoring were recorded throughout the 5-day study. Two independent readers (M.G.H. with 30 years of experience, S.P.K. with 26 years of experience) made the diagnosis. The diagnostic performance of IOP-enhanced MRI was evaluated with sensitivity and positive predictive value by comparing to the pathology reports from subsequent hepatic resection. The number of lesions with various sizes and degrees of differentiation detected by IOP-enhanced MRI was assessed. The relative change in signal intensities over time was indirectly measured from acquired images. STATISTICAL TESTS: Sensitivity and positive predictive value were used to evaluate the diagnostic performance of IOP-enhanced MRI. Prevalence-adjusted and bias-adjusted ð coefficient was used to assess the interreader variability. RESULTS: No serious adverse event related to IOP Injection was found. IOP Injection enhanced the lesion-to-liver contrast ratio in T2 *-weighted images by 50.1% ± 4.8%. IOP-enhanced MRI detected HCC with 100% sensitivity by subject and 96% sensitivity by lesion. IOP Injection visualized subtle vascular invasion as filling defect within vessels in true fast imaging with steady-state free precession (TrueFISP) images. DATA CONCLUSION: IOP Injection was safe and efficacious as MRI contrast agent in diagnosing HCC in a limited group of subjects. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas de Magnetita , Masculino , Feminino , Humanos , Carcinoma Hepatocelular/patologia , Meios de Contraste , Neoplasias Hepáticas/patologia , Estudos Prospectivos , Óxido Ferroso-Férrico , Ferro , Imageamento por Ressonância Magnética/métodos , Dextranos , Sensibilidade e EspecificidadeRESUMO
Thioredoxin-interacting protein (TXNIP), also known as Vitamin-D upregulated protein-1 (VDUP-1), interacts with thioredoxin to regulate redox responses and participates in diverse disorders including metabolic, cardiovascular, inflammatory and malignant diseases. Psoriasis is characterized by chronic skin inflammation and an aberrant pattern of keratinocyte differentiation. Clinically, psoriasis is associated with various cardiometabolic comorbidities but studies on TXNIP's biological role in skin disorders are limited. In this study, we investigated TXNIP expression in psoriasis and its regulation in normal human epidermal keratinocytes (NHEKs), and then explored how TXNIP regulated skin keratinocyte differentiation to determine its role in psoriasis pathogenesis. Our immunohistochemical study demonstrated extensive TXNIP expression in the upper and lower epidermis of psoriasis compared to predominant TXNIP expression in the basal layer of normal skin. 1, 25-dihydroxyvitamin D3 suppressed but TGF-α and EGF enhanced TXNIP expression in NHEKs. An inducer of keratinocyte differentiation, phorbol 12-myristate 13-acetate (PMA), also diminished TXNIP expression, which was reversed by PKC-δ knockdown. TXNIP knockdown reduced PMA-induced involucrin and transglutaminse-1 expression, and increased p63 expression in NHEKs but did not significantly affect cell proliferation. H2 O2 -induced ROS production and EGFR phosphorylation decreased in NHEKs with TXNIP knockdown. Furthermore, PMA-induced PKC-δ phosphorylation, TGF-α, and EGF-triggered EGFR phosphorylation were attenuated by TXNIP knockdown. Our results unraveled the regulation and function of TXNIP expression in skin keratinocytes and the cross-regulation between TXNIP and EGFR signaling. These findings imply a role of TXNIP in psoriasis and provide insight into the possible impact of TXNIP regulators on the skin or psoriasis.
Assuntos
Proteínas de Transporte , Psoríase , Fator de Crescimento Transformador alfa , Proteínas de Transporte/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Humanos , Queratinócitos/metabolismo , Psoríase/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador alfa/metabolismoRESUMO
Cytoskeleton-associated protein 2-like (CKAP2L) is a mitotic spindle protein and its high expression is reported to be associated with the poor prognosis of cancer patients. Interestingly, TNMplot website analysis indicated that CKAP2L expression was significantly higher in breast cancer (BC) tissues than in normal breast tissues (P < 0.001). Thus, this study was conducted to investigate the role of CKAP2L in breast carcinogenesis and its underlying molecular mechanisms. The mRNA and protein expression levels of CKAP2L in 40 paired fresh BC and para-carcinoma specimens were first analyzed, and the results confirmed the high expression of CKAP2L in BC tissues. Functional studies revealed that CKAP2L silencing dramatically suppressed the proliferation, migration, and invasion, induced cell cycle arrest and apoptosis of BC cells in vitro, and inhibited the growth of xenografted tumors in vivo. However, CKAP2L overexpression produced the opposite results. Mechanically, CKAP2L could activate the AKT/mTOR signaling pathway in BC cells accompanied by increased phosphorylation levels of AKT, mTOR, and p70S6K in CKAP2L-overexpressed cells. Forkhead box protein P3 (FOXP3), a transcription factor with tumor-suppressive properties, was proved to negatively regulate CKAP2L expression in BC cells through binding to the promoter of CKAP2L and inhibiting its transcription. In summary, the present study demonstrates that CKAP2L, transcriptionally regulated by FOXP3, activates the AKT/mTOR signaling pathway and promotes breast carcinogenesis. CKAP2L may serve as a promising target of therapeutic intervention for BC.
Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Proteínas do Citoesqueleto/genética , Fatores de Transcrição Forkhead/genética , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Transcrição Gênica/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/genéticaRESUMO
BACKGROUND Circulating calcium mainly carries out its physiologic function in its ionized form (iCa). Clinically, iCa is usually estimated by multiplying the total calcium (TCa) level by 0.5 in the general population, but this method is not accurate when applied to patients on long-term hemodialysis (CHD). Accordingly, this study aimed to develop a predictive function for iCa in patients on CHD by incorporating TCa and other additional variables. MATERIAL AND METHODS This was a retrospective cross-sectional study consisting of 2 cross-sectional datasets: a derivation set including 469 CHD patients in June 2019, and a validation set including 446 CHD patients in September 2019. The derivation set's data were analyzed using the stepwise model selection of machine learning with 10-fold cross-validation to develop a predictive function for iCa. This predictive function was then applied to the validation set's data, and the predictive function's estimated iCa was compared with the actual laboratory iCa by using the paired-samples t test and intraclass correlation coefficient. RESULTS After analyzing the routine laboratory data parameters of patients in the derivation set, the following 5 variables were included in the predictive function of iCa: blood urea nitrogen, creatinine, phosphate, TCa, and albumin. This predictive function was applied to the validation set to yield an estimated iCa level that was not significantly different from the laboratory-measured iCa level of the validation dataset (P=0.676) with an excellent ICC of 0.905. CONCLUSIONS We developed a new predictive function that accurately measures the iCa in patients on CHD by using routine laboratory data.
Assuntos
Cálcio , Hipercalcemia , Diálise Renal , Insuficiência Renal Crônica , Humanos , Cálcio/sangue , Estudos Transversais , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapiaRESUMO
INTRODUCTION: Cardiovascular (CV) events are the major cause of morbidity and mortality associated with blood pressure (BP) in hemodialysis (HD) patients. BP varies significantly during HD treatment, and the dramatic variation in BP is a well-recognized risk factor for increased mortality. The development of an intelligent system capable of predicting BP profiles for real-time monitoring is important. Our aim was to build a web-based system to predict changes in systolic BP (SBP) during HD. METHODS: In this study, dialysis equipment connected to the Vital Info Portal gateway collected HD parameters that were linked to demographic data stored in the hospital information system. There were 3 types of patients: training, test, and new. A multiple linear regression model was built using the training group with SBP change as the dependent variable and dialysis parameters as the independent variables. We tested the model's performance on test and new patient groups using coverage rates with different thresholds. The model's performance was visualized using a web-based interactive system. RESULTS: A total of 542,424 BP records were used for model building. The accuracy was greater than 80% in the prediction error range of 15%, and 20 mm Hg of true SBP in the test and new patient groups for the model of SBP changes suggested the good performance of our prediction model. In the analysis of absolute SBP values (5, 10, 15, 20, and 25 mm Hg), the accuracy of the SBP prediction increased as the threshold value increased. DISCUSSION: This databae supported our prediction model in reducing the frequency of intradialytic SBP variability, which may help in clinical decision-making when a new patient receives HD treatment. Further investigations are needed to determine whether the introduction of the intelligent SBP prediction system decreases the incidence of CV events in HD patients.