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BACKGROUND: This study aims to develop a stacking model for accurately predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) using longitudinal MRI in breast cancer. METHODS: We included patients with node-positive breast cancer who received NAC following surgery from January 2012 to June 2022. We collected MRIs before and after NAC, and extracted radiomics features from the tumour, peritumour, and ALN regions. The Mann-Whitney U test, least absolute shrinkage and selection operator, and Boruta algorithm were used to select features. We utilised machine learning techniques to develop three single-modality models and a stacking model for predicting ALN response to NAC. RESULTS: This study consisted of a training cohort (n = 277), three external validation cohorts (n = 313, 164, and 318), and a prospective cohort (n = 81). Among the 1153 patients, 60.62% achieved ypN0. The stacking model achieved excellent AUCs of 0.926, 0.874, and 0.862 in the training, external validation, and prospective cohort, respectively. It also showed lower false-negative rates (FNRs) compared to radiologists, with rates of 14.40%, 20.85%, and 18.18% (radiologists: 40.80%, 50.49%, and 63.64%) in three cohorts. Additionally, there was a significant difference in disease-free survival between high-risk and low-risk groups (p < 0.05). CONCLUSIONS: The stacking model can accurately predict ALN status after NAC in breast cancer, showing a lower false-negative rate than radiologists. TRIAL REGISTRATION NUMBER: The clinical trial numbers were NCT03154749 and NCT04858529.
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Inteligencia Artificial , Axila , Neoplasias de la Mama , Imagen por Resonancia Magnética , Terapia Neoadyuvante , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico por imagen , Persona de Mediana Edad , Adulto , Imagen por Resonancia Magnética/métodos , Estudios Prospectivos , Ganglios Linfáticos/patología , Ganglios Linfáticos/diagnóstico por imagen , Anciano , Metástasis Linfática , Aprendizaje Automático , Quimioterapia AdyuvanteRESUMEN
In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF's problems via the salification-driven tactic.
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Antifúngicos , Ácidos Cafeicos , Imidazoles , Antifúngicos/farmacología , Antifúngicos/química , Imidazoles/química , Imidazoles/farmacología , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacología , Sales (Química)/química , Teoría Cuántica , Modelos Moleculares , Pruebas de Sensibilidad Microbiana , Cristalografía por Rayos X , Enlace de Hidrógeno , Electricidad EstáticaRESUMEN
OBJECTIVE: To develop an artificial intelligence (AI) system for the early prediction of residual cancer burden (RCB) scores during neoadjuvant chemotherapy (NAC) in breast cancer. SUMMARY BACKGROUND DATA: RCB III indicates drug resistance in breast cancer, and early detection methods are lacking. METHODS: This study enrolled 1048 patients with breast cancer from four institutions, who were all receiving NAC. Magnetic resonance images were collected at the pre- and mid-NAC stages, and radiomics and deep learning features were extracted. A multitask AI system was developed to classify patients into three groups (RCB 0-I, II, and III ) in the primary cohort (PC, n=335). Feature selection was conducted using the Mann-Whitney U- test, Spearman analysis, least absolute shrinkage and selection operator regression, and the Boruta algorithm. Single-modality models were developed followed by model integration. The AI system was validated in three external validation cohorts. (EVCs, n=713). RESULTS: Among the patients, 442 (42.18%) were RCB 0-I, 462 (44.08%) were RCB II and 144 (13.74%) were RCB III. Model-I achieved an area under the curve (AUC) of 0.975 in the PC and 0.923 in the EVCs for differentiating RCB III from RCB 0-II. Model-II distinguished RCB 0-I from RCB II-III, with an AUC of 0.976 in the PC and 0.910 in the EVCs. Subgroup analysis confirmed that the AI system was consistent across different clinical T stages and molecular subtypes. CONCLUSIONS: The multitask AI system offers a noninvasive tool for the early prediction of RCB scores in breast cancer, supporting clinical decision-making during NAC.
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Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Proteínas Portadoras , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteínas de Microfilamentos , Sirtuinas , Humanos , Acetilación , Actinas/metabolismo , Línea Celular Tumoral , Neoplasias Esofágicas/patología , Histona Acetiltransferasas/metabolismo , Metástasis Linfática , Sirtuinas/metabolismoRESUMEN
Excessive angiogenesis in subchondral bone is a pathological feature of osteoarthritis (OA). Tanshinone IIA (TIIA), an active compound found in Salvia miltiorrhiza, demonstrates significant anti-angiogenic properties. However, the effect of TIIA on abnormal subchondral angiogenesis in OA is still unclear. This study aims to investigate the mechanism of TIIA in modulating subchondral bone angiogenesis during OA and assess its therapeutic potential in OA. Our findings demonstrate that TIIA attenuated articular cartilage degeneration, normalized subchondral bone remodeling, and effectively suppressed aberrant angiogenesis within subchondral bone in monosodium iodoacetate (MIA)-induced OA mice. Additionally, the angiogenesis capacity of primary CD31hiEmcnhi endothelial cells was observed to be significantly reduced after treatment with TIIA in vitro. Mechanically, TIIA diminished the proportion of hypertrophic chondrocytes, ultimately leading to a substantial reduction in the secretion of vascular endothelial growth factor A (VEGFA). The supernatant of hypertrophic chondrocytes promoted the tube formation of CD31hiEMCNhi endothelial cells, whereas TIIA inhibited this process. Furthermore, TIIA effectively suppressed the expression of vascular endothelial growth factor receptor 2 (VEGFR2) along with its downstream MAPK pathway in CD31hiEmcnhi endothelial cells. In conclusion, our data indicated that TIIA could effectively inhibit the abnormal angiogenesis in subchondral bone during the progression of OA by suppressing the VEGFA/VEFGR2/MAPK pathway. These findings significantly contribute to our understanding of the abnormal angiogenesis in OA and offer a promising therapeutic target for OA treatment.
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Abietanos , Cartílago Articular , Osteoartritis , Ratones , Animales , Factor A de Crecimiento Endotelial Vascular , Células Endoteliales/metabolismo , Angiogénesis , Osteoartritis/metabolismoRESUMEN
BACKGROUND: Methods based on paper-based analytical devices (PAD) and smartphone photographic colorimetric detection have become representative instrument-independent point-of-care testing (POCT) platforms due to their low cost and simplicity. However, the detection of target components from whole blood sample still presents challenges in terms of field preparation of small amounts of blood sample and detection sensitivity. This paper presents a rapid online processing method for whole blood samples on PAD based on plasma separation membrane (PSM), and combined with electrokinetic stacking and selective chromatic reaction. Real-time smartphone-based colorimetric detection of free hemoglobin (FHb) and human serum albumin (HSA) was successfully demonstrated. RESULTS: With the proposed method, both detections for low and high concentration analytes could be implemented. The limits of detection of 16.6 mg L-1 for FHb and 0.67 g L-1 for HSA were obtained, respectively, with RSD below 8 %. The reliability of the method was verified by the recovery test and desktop spectrophotometric method. The detection results for real blood samples were in agreement with that by clinical methods. SIGNIFICANCE AND NOVELTY: The PAD method is inexpensive, simple and fast, and detection of a whole blood sample of 5 µL can be finished in 5 min. This work shows that POCT of biomarkers from whole blood with PAD is possible without using any desktop facilities.
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Colorimetría , Teléfono Inteligente , Humanos , Colorimetría/métodos , Reproducibilidad de los Resultados , Pruebas en el Punto de Atención , Albúmina Sérica HumanaRESUMEN
BACKGROUND: The high false negative rate (FNR) associated with sentinel lymph node biopsy often leads to unnecessary axillary lymph node dissection following neoadjuvant chemotherapy (NAC) in breast cancer. The authors aimed to develop a multifactor artificial intelligence (AI) model to aid in axillary lymph node surgery. MATERIALS AND METHODS: A total of 1038 patients were enrolled, comprising 234 patients in the primary cohort, 723 patients in three external validation cohorts, and 81 patients in the prospective cohort. For predicting axillary lymph node response to NAC, robust longitudinal radiomics features were extracted from pre-NAC and post-NAC magnetic resonance images. The U test, the least absolute shrinkage and selection operator, and the spearman analysis were used to select the most significant features. A machine learning stacking model was constructed to detect ALN metastasis after NAC. By integrating the significant predictors, we developed a multifactor AI-assisted surgery pipeline and compared its performance and false negative rate with that of sentinel lymph node biopsy alone. RESULTS: The machine learning stacking model achieved excellent performance in detecting ALN metastasis, with an area under the curve (AUC) of 0.958 in the primary cohort, 0.881 in the external validation cohorts, and 0.882 in the prospective cohort. Furthermore, the introduction of AI-assisted surgery reduced the FNRs from 14.88 (18/121) to 4.13% (5/121) in the primary cohort, from 16.55 (49/296) to 4.05% (12/296) in the external validation cohorts, and from 13.64 (3/22) to 4.55% (1/22) in the prospective cohort. Notably, when more than two SLNs were removed, the FNRs further decreased to 2.78% (2/72) in the primary cohort, 2.38% (4/168) in the external validation cohorts, and 0% (0/15) in the prospective cohort. CONCLUSION: Our study highlights the potential of AI-assisted surgery as a valuable tool for evaluating ALN response to NAC, leading to a reduction in unnecessary axillary lymph node dissection procedures.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Terapia Neoadyuvante/métodos , Inteligencia Artificial , Estudios Retrospectivos , Estudios Prospectivos , Metástasis Linfática/patología , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela/métodos , Escisión del Ganglio Linfático , Axila/patologíaRESUMEN
To emphasize the superiority of uracil (UR) in ameliorating biopharmaceutical characteristics of marine antitumor medicine cytarabine (ARA), thus gaining some innovative opinions for the exploitation of nanococrystal formulation, a cocrystal nanonization strategy is proposed by integrating cocrystallization and nanosize preparation techniques. For one thing, based on UR's unique structural features and natures together with advantages of preferential uptake by tumor cells, cocrystallizing ARA with UR is expected to improve the in vitro/vivo performances. For another, the nanonization procedure is oriented towards maintaining the long-term effective drug level. Along this route, a cocrystal of ARA with UR, viz., ARA-UR, is successfully synthesized and then transformed into nano-cocrystal. The cocrystal structure is precisely confirmed by various methods, demonstrating that a 1:1 ARA and UR in the crystal forms cytosine-UR hydrogen-bonding interactions, thus constructing supramolecular frameworks by strong π-π stacking interplays; while the nano-cocrystal is block-shaped particles of 562.70 nm with zeta potential -33.40 mV. The properties of cocrystal ARA-UR and its nano-cocrystal in vitro/vivo are comparatively explored by theoretical calculations and experimental analyses, revealing that permeability of both is significantly increased than ARA per se. Notably, the meliorative natures of both the cocrystal and nano-cocrystal in vitro bring excellent antitumor activity, but the latter has greater strengths over the former. More notably, the nano-cocrystal can sustain effective concentration for a relatively longer time, causing lengthened retention time and better absorption in vivo. The contribution offers a fire-new dosage form of ARA for long-lasting delivery, thus filling the vacancy in nanococrystal studies about marine drugs.
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Antineoplásicos , Citarabina , Preparaciones Farmacéuticas , Antineoplásicos/farmacologíaRESUMEN
OBJECTIVE: To analyze the prevalence, genotype distribution and hematological characteristics of α,ß-thalassaemia carriers in Huizhou area of Guangdong Province. METHODS: 10 809 carriers of simple ß-thalassaemia and 1 757 carriers of α,ß-thalassaemia were enrolled as our study cohort. The hematological parameters were detected by automated blood cell counters and automatic capillary electrophoresis. Suspension array technology, gap-polymerase chain reaction (gap-PCR) and PCR-reverse dot blot were used for the genotyping of thalassaemia carriers. RESULTS: The prevalence of α,ß-thalassaemia in Huizhou area of Guangdong Province was 1.99%. A total of 62 genotypes were detected, and the most prevalent genotype was --SEA/ αα, ßCD41-42/ ßN (19.29%), the next was --SEA/ αα, ßIVS-II-654/ ßN (16.73%). Significant differences in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were found between different genotype groups for simple ß-thalassaemia and α,ß-thalassaemia. Violin plots showed that carriers with co-inheritance of ß-thalassaemia and mild α-thalassaemia expressed the lightest anemia, and carriers with co-inheritance of ß-thalassaemia and hemoglobin H (Hb H) disease expressed the most severe anemia. CONCLUSION: There is a high prevalence of α,ß-thalassaemia in Huizhou area of Guangdong Province. Because of the lack of specific hematological makers for diagnosis of α,ß-thalassaemia, it is necessary to distinguish it from simple ß-thalassaemia by genotyping of α- and ß-thalassaemia in order to correctly guide genetic counseling and prenatal disgnosis.
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Talasemia alfa , Talasemia beta , Embarazo , Femenino , Humanos , Talasemia beta/epidemiología , Talasemia beta/genética , Genotipo , Heterocigoto , Fenotipo , Talasemia alfa/epidemiología , Talasemia alfa/genética , China/epidemiología , MutaciónRESUMEN
Correction for 'Supramolecular self-assembly of amantadine hydrochloride with ferulic acid via dual optimization strategy establishes a precedent of synergistic antiviral drug-phenolic acid nutraceutical cocrystal' by Ling-Yang Wang et al., Analyst, 2021, 146, 3988-3999, https://doi.org/10.1039/D1AN00478F.
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The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL's biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA-]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA-] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.
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Productos Biológicos , Cardiotónicos , Milrinona , Cristalización/métodos , Solubilidad , Cloruro de Sodio , Agua/químicaRESUMEN
Anillin (ANLN) is a mitosis-related protein that promotes contractile ring formation and cytokinesis, but its cell cycle-dependent degradation mechanisms in cancer cells remain unclear. Here, we show that high expression of ANLN promotes cytokinesis and proliferation in esophageal squamous cell carcinoma (ESCC) cells and is associated with poor prognosis in ESCC patients. Furthermore, the findings of the study showed that the deubiquitinating enzyme USP10 interacts with ANLN and positively regulates ANLN protein levels. USP10 removes the K11- and K63-linked ubiquitin chains of ANLN through its deubiquitinase activity and prevents ANLN ubiquitin-mediated degradation. Importantly, USP10 promotes contractile ring assembly at the cytokinetic furrow as well as cytokinesis by stabilizing ANLN. Interestingly, USP10 and the E3 ubiquitin ligase APC/C co-activator Cdh1 formed a functional complex with ANLN in a non-competitive manner to balance ANLN protein levels. In addition, the macrolide compound FW-04-806 (F806), a natural compound with potential for treating ESCC, inhibited the mitosis of ESCC cells by targeting USP10 and promoting ANLN degradation. F806 selectively targeted USP10 and inhibited its catalytic activity but did not affect the binding of Cdh1 to ANLN and alters the balance of the USP10-Cdh1-ANLN complex. Additionally, USP10 expression was positively correlated with ANLN level and poor prognosis of ESCC patients. Overall, targeting the USP10-ANLN axis can effectively inhibit ESCC cell-cycle progression.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/metabolismo , Proteínas Contráctiles/metabolismo , Ubiquitina/metabolismo , Proliferación Celular , Línea Celular Tumoral , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
BACKGROUND: Although standard bicaval techniques has become popular in orthotopic heart transplantation, distortion, bleeding, thrombosis and arrhythmia were still causes for concern. This study was designed to compare the standard bicaval techniques and modified bicaval techniques in our institution. MATERIALS AND METHODS: A total of 70 recipients underwent orthotopic heart transplantation at our center from June 2015 to April 2019 (standard group = 24 cases, modified group = 46 cases). The average follow-up period was 46.4 ± 17.4 months. Atrioventricular cavity diameter was measured by ultrasonography and left atrial morphology was evaluated by CT-angiography and three-dimensional reconstruction. RESULTS: Recipients in both groups were similar with pre-operative characteristics. Total ischemic, cardiopulmonary bypass and cross-clamp times were similar. The modified bicaval techniques group has a significantly fewer blood transfusion, lower post-transplant tricuspid regurgitation grade and the incidence of post-operative atrial arrhythmia than standard bicaval techniques group. CT-angiography and three-dimensional reconstruction illustrated ideal and physiologic left atrial morphological structure. Short-term survival differed significantly and the cumulative proportion of survival was significantly higher in the modified bicaval techniques group than that in the standard bicaval techniques group. CONCLUSIONS: This study showed that modified bicaval techniques offers a better early outcome than standard bicaval techniques. The significant reduction of intraoperative blood transfusion and post-transplant tricuspid regurgitation grade in the modified bicaval techniques group may has a major impact on the short-term survival.
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Fibrilación Atrial , Trasplante de Corazón , Insuficiencia de la Válvula Tricúspide , Humanos , Insuficiencia de la Válvula Tricúspide/etiología , Tracción/efectos adversos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/métodos , Anastomosis Quirúrgica/métodos , Técnicas de Sutura/efectos adversosRESUMEN
In order to highlight the advantages of cocrystallization technique in perfecting in vitro/vivo natures of marine drug cytarabine (ARC), and fill the gap of the research of marine pharmaceutical cocrystals with synergistic antitumor effects, the first dual-drug cocrystal simultaneously containing ARC and antitumor drug 5-fluorouracil (FU), viz. ARC-FU, is successfully designed and assembled. The accurate structure is perfectly resolved by single-crystal X-ray diffraction and other approaches. The analytical outcomes demonstrate that the codrug cocrystal consists of ARC and FU with a molar ratio of 1:1, in which FU molecule plays an important role by participating in the formation of both "pyrimidine-pyrimidine" and "pyrimidine-sugar" cyclic hydrogen-bonding systems with ARC molecules. In the cocrystal, there are twofold hydrogen-bonding helixes of ARC molecules and a whole three-dimensional hydrogen-bonding network which also contains the aromatic stacking interaction between pyrimidine rings of both components. Such structural feature and aggregation model have crucial influences on the improvements of in vitro/vivo properties, which is methodically verified by the combination of theoretical analyses and experimental measurements. The in vitro studies exhibit the suitably reduced solubility and obviously increased permeability for the cocrystal that is in accord with the theoretical prediction. Importantly, the ameliorated in vitro peculiarities realize in vivo pharmacokinetic optimization including the extended residence time and enhanced relative bioavailability. Of greater significance, ARC exerts synergistic antitumor effects in association with FU that brings about potentiation of cell growth inhibition with lower IC50. Thus, this research not only provides a novel crystalline form for ARC with forward-looking development value, but also breaks new ground for the development of synergistic antitumor pharmaceutical cocrystals with marine characteristics.
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Productos Biológicos , Fluorouracilo , Preparaciones Farmacéuticas/química , Fluorouracilo/farmacología , Fluorouracilo/química , Citarabina/farmacología , Cristalización , Solubilidad , Administración Oral , HidrógenoRESUMEN
Amino acids are closely related to human health, and their rapid determination is important for the rapid diagnosis, timely treatment, and assessment of serious diseases. In this work, we propose a novel paper-based sample-processing device combined with isotope-dilution MS for the fast analysis of 11 amino acids from blood samples. By using an isoelectric focusing electrokinetic separation method, without the aid of carrier ampholytes and the addition of inhibitors, this approach uses only the characteristic of the isoelectric point of the target amino acids to achieve separation and purification from other coexisting components in the medium; it can meet the requirements for mass spectrometry detection. Driven by a DC voltage, a stable and sharp pH gradient (pH 3-10.5 over 5 mm) can be established in a glass-fiber paper-based fluidic channel with a MS-friendly electrolyte. Amphoteric species can be well separated from the complex blood matrix and concentrated into a narrow band in the channel within 2 min, which is 20 times faster than a commercial kit method. The method can be applied to both liquid and dry spot samples, and the cleaned sample band can be simply dissolved for direct IDMS detection in ESI MRM mode. This method is a promising strategy for the rapid MS-based detection of amino acids from serum without pre-separation via liquid chromatography.
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Aminoácidos , Mezclas Anfólitas , Humanos , Mezclas Anfólitas/química , Focalización Isoeléctrica/métodos , Espectrometría de Masas , Aminoácidos/análisis , Manejo de Especímenes , Cromatografía Líquida de Alta Presión/métodosRESUMEN
BACKGROUND: Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). AIM: To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC. METHODS: This multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups. RESULTS: The median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05). CONCLUSION: A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.
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Esophageal squamous cell carcinoma (ESCC) is one of the world's leading causes of death, and its primary clinical therapy relies on surgical resection, chemotherapy, radiotherapy, and chemoradiotherapy. Although the genomic features and clinical significance of ESCC have been identified, the outcomes of targeted therapies are still unsatisfactory. Here, we demonstrate that mitogen-activated protein kinase (MAPK) signaling is highly activated and associated with poor prognosis in patients with ESCC. Mitogen-activated protein kinase kinase (MEK) inhibitors efficiently blocked the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in ESCC, while signal transducer and activator of transcription 3 (STAT3) signaling was rapidly activated. Combined STAT3 inhibition prevented the emergence of resistance and enhanced MEK inhibitor-induced cell cycle arrest and senescence in vitro and in vivo. Mechanistic studies revealed that the suppressor of cytokine signaling 3 (SOCS3) was downregulated, resulting in an increase in STAT3 phosphorylation in MEK-inhibited cells. Furthermore, chromatin immunoprecipitation showed that ELK1, which was activated by MEK/ERK signaling, induced SOCS3 transcription. These data suggest that the development of combined MEK and STAT3 inhibition could be a useful strategy in ESCC targeted therapy.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Sistema de Señalización de MAP Quinasas , Quinasas de Proteína Quinasa Activadas por Mitógenos , Inhibidores de Proteínas Quinasas , Factor de Transcripción STAT3 , Línea Celular Tumoral , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
In this paper, simultaneous enrichment and separation of ions and amphoteric components were successfully demonstrated by using electric field (E) and pH gradient (double gradient) in the ion depletion zone of anion concentration polarization interface established on a paper fluid channel. Experimental results were visualized with colored ions (bright blue and amaranth) and protein probes (phycocyanin and cytochrome C). With optimization, colored phycocyanin and bovine hemoglobin with similar pI as that of albumin and immunoglobulin respectively were well separated in 900 s with 10-fold enrichment effect. Based on the separation and enrichment function of this paper-based analytical device (PAD) and rapid selective staining of human serum albumin (HSA) with bromophenol blue, a rapid colorimetric detection of HSA was implemented with smartphone camera. A limit of detection (LOD) of 5.2 mg·L-1 was achieved in the clinically significant range of 10-300 mg·L-1 (R2 = 0.99). This method was applied to real human urine samples with good agreement (É = 0.01) to clinical detection method (immunoturbidimetry). With the separation and enrichment functions of PAD, both the specificity and sensitivity were enhanced, which provides a solid basis for point-of-care test of microalbuminuria. Therefore, this PAD device is potential for sample pretreatment and detection of target components from complex physiological samples.
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Colorimetría , Ficocianina , Colorimetría/métodos , Humanos , Iones , Límite de Detección , Papel , Albúmina Sérica Humana/orina , Teléfono InteligenteRESUMEN
Background: Patients who achieve a tumor pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have better outcomes than patients with residual tumor. However, tumors still recur in the pCR patients. Therefore, we aim to explore factors associated with tumor recurrence in this patient population. Methods: A total of 1,913 patients diagnosed with breast cancer between 1995 and 2020 and received NAC were included in this analysis. Clinicopathological data of the patients were retrospectively collected. We used Cox regression analysis to assess the associations of clinicopathological factors with patients' outcome. Proteomic study of tumors was applied to identify differentially expressed proteins (DEPs) between tumors from the pCR patients with tumor recurrence and tumors from those without tumor recurrence. PPI network analysis of the corresponding genes of DEPs was used to identify the hub genes. The prognostic value of the corresponding genes of DEPs was evaluated using two online databases, Kaplan-Meier Plotter and bc-GenExMiner. The genes that were significantly associated with patients' survival in both databases, as well as being identified as hub genes, were considered as potential prognostic markers for pCR patients. Publicly available data from Gene Expression Omnibus (GEO) was used to verify the prognostic value of the identified marker. Results: Among the 1,913 included patients, 420 had tumor pCR. The median follow-up for the pCR patients was 32.6 months (IQR, 16.3-55.5). Overall estimated 5-year risk of tumor recurrence for the pCR patients was 11%. Multivariable analysis showed that a higher pre-NAC clinical T stage and N stage were independent predictors for increased risk of tumor recurrence (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.01-6.51, P=0.047 for clinical T stage and HR 3.48, 95%CI 1.37-8.83, P=0.009 for clinical N stage). NAC regimens, the type of breast and axillary surgery, and adjuvant chemotherapy were not associated with tumor recurrence. Finally, aldehyde dehydrogenase (ALDH) 3A2 was identified by the proteomic study and was verified as a potential predictor for tumor recurrence in the pCR patients (with a median follow up of 3.78 years for dataset GSE32603 and 2.74 years for dataset GSE25066 from GEO, tumor recurrence rate: low versus high expression, 20.7% versus 4.5% [data from GSE32603]; 10.9% versus 0% [data from GSE25066]). Conclusions: Clinical T stage, clinical N stage and tumor expression of ALDH3A2 were potential markers for predicting tumor recurrence in the pCR patients after NAC.
RESUMEN
Objective: Integrins have been shown to play an important role in the tumorigenesis of many cancers. In this work, we aimed to explore the expression and clinical value of Integrin α5ß1 in esophageal squamous cell carcinoma (ESCC), and the effect of integrin ß1 on the development and chemo-resistance of ESCC cells. Methods: The expression profiling of integrins was analyzed in the mRNA expression dataset of ESCC. The expression of Integrin α5ß1 in 278 cases of ESCC tissues and 62 cases of paracancerous tissues was detected by immunohistochemistry (IHC). The association between the expression of Integrin α5ß1 and the survival of ESCC patients was analyzed by Kaplan-Meier analysis. The effect of Integrin ß1 on the proliferation, migration, and invasion of ESCC cells was examined by MTS, Transwell migration, and Transwell invasion assay. The effect of Integrin ß1 and L1 cell adhesion molecule (L1CAM) on cisplatin resistance was detected by MTS and the signal pathways involved were analyzed by Western blotting. Results: Integrin ß1 and Integrin α5 were significantly up-regulated in ESCC. High expression of Integrin ß1 was also related to worse overall survival of ESCC patients and patients with low levels of both Integrin ß1 and Integrin α5 showed the shortest survival. Results of IHC revealed that Integrin α5ß1 was up-regulated in ESCC and its high expression was associated with poor prognosis and could serve as an independent prognostic factor. siRNA-mediated Integrin ß1 silencing or antibody blocking restrained the proliferation, migration, and invasion of ESCC cells. Simultaneous knockdown of Integrin ß1 and L1CAM reduced the cisplatin resistance of ESCC cells. Further studies showed that knockdown of Integrin ß1 and L1CAM suppressed the activity of Akt signaling with or without cisplatin treatment. Moreover, dual high expression of Integrin ß1 and L1CAM was related to worse overall survival of ESCC patients treated with preoperative chemotherapy. Conclusion: Integrin α5ß1 was up-regulated in ESCC and could be used as a new prognostic indicator for ESCC patients. In addition, Integrin ß1 was involved in the proliferation, invasion, and chemo-resistance of ESCC cells.