RESUMO
Enhancers are crucial in gene expression regulation, dictating the specificity and timing of transcriptional activity, which highlights the importance of their identification for unravelling the intricacies of genetic regulation. Therefore, it is critical to identify enhancers and their strengths. Repeated sequences in the genome are repeats of the same or symmetrical fragments. There has been a great deal of evidence that repetitive sequences contain enormous amounts of genetic information. Thus, We introduce the W2V-Repeated Index, designed to identify enhancer sequence fragments and evaluates their strength through the analysis of repeated K-mer sequences in enhancer regions. Utilizing the word2vector algorithm for numerical conversion and Manta Ray Foraging Optimization for feature selection, this method effectively captures the frequency and distribution of K-mer sequences. By concentrating on repeated K-mer sequences, it minimizes computational complexity and facilitates the analysis of larger K values. Experiments indicate that our method performs better than all other advanced methods on almost all indicators.
RESUMO
On-chip integrated metasurface driven by in-plane guided waves is of great interests in various light-field manipulation applications such as colorful augmented reality and holographic display. However, it remains a challenge to design colorful multichannel holography by a single on-chip metasurface. Here we present metasurfaces integrated on top of a guided-wave photonic slab that achieves multi-channel colorful holographic light display. An end-to-end scheme is used to inverse design the metasurface for projecting off-chip preset multiple patterns. Particular examples are presented for customized patterns that were encoded into the metasurface with a single-cell meta-atom, working simultaneously at RGB color channels and for several different diffractive distances, with polarization dependence. Holographic images are generated at 18 independent channels with such a single-cell metasurface. The proposed design scheme is easy to implement, and the resulting device is viable for fabrication, promising plenty of applications in nanophotonics.
RESUMO
OBJECTIVES: Anti-HER2 targeted therapy significantly reduces risk of relapse in HER2 + breast cancer. New measures are needed for a precise risk stratification to guide (de-)escalation of anti-HER2 strategy. METHODS: A total of 726 HER2 + cases who received no/single/dual anti-HER2 targeted therapies were split into three respective cohorts. A deep learning model (DeepTEPP) based on preoperative breast magnetic resonance (MR) was developed. Patients were scored and categorized into low-, moderate-, and high-risk groups. Recurrence-free survival (RFS) was compared in patients with different risk groups according to the anti-HER2 treatment they received, to validate the value of DeepTEPP in predicting treatment efficacy and guiding anti-HER2 strategy. RESULTS: DeepTEPP was capable of risk stratification and guiding anti-HER2 treatment strategy: DeepTEPP-Low patients (60.5%) did not derive significant RFS benefit from trastuzumab (p = 0.144), proposing an anti-HER2 de-escalation. DeepTEPP-Moderate patients (19.8%) significantly benefited from trastuzumab (p = 0.048), but did not obtain additional improvements from pertuzumab (p = 0.125). DeepTEPP-High patients (19.7%) significantly benefited from dual HER2 blockade (p = 0.045), suggesting an anti-HER2 escalation. CONCLUSIONS: DeepTEPP represents a pioneering MR-based deep learning model that enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thereby providing valuable guidance for anti-HER2 (de-)escalation strategies. DeepTEPP provides an important reference for choosing the appropriate individualized treatment in HER2 + breast cancer patients, warranting prospective validation. CLINICAL RELEVANCE STATEMENT: We built an MR-based deep learning model DeepTEPP, which enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thus guiding anti-HER2 (de-)escalation strategies in early HER2-positive breast cancer patients. KEY POINTS: ⢠DeepTEPP is able to predict anti-HER2 effectiveness and to guide treatment (de-)escalation. ⢠DeepTEPP demonstrated an impressive prognostic efficacy for recurrence-free survival and overall survival. ⢠To our knowledge, this is one of the very few, also the largest study to test the efficacy of a deep learning model extracted from breast MR images on HER2-positive breast cancer survival and anti-HER2 therapy effectiveness prediction.
Assuntos
Neoplasias da Mama , Aprendizado Profundo , Imageamento por Ressonância Magnética , Receptor ErbB-2 , Trastuzumab , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Feminino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Trastuzumab/uso terapêutico , Adulto , Idoso , Resultado do Tratamento , Medição de Risco , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Estudos Retrospectivos , Radiômica , Anticorpos Monoclonais HumanizadosRESUMO
Objective: To assess the usefulness of combining positron emission tomography/computed tomography (PET/CT) with lung cancer autoantibody detection in identifying and managing lung nodules. Methods: The researchers identified 160 patients with pulmonary nodules admitted to their hospital between January 2018 and January 2021. These patients were designated as the experimental group. Additionally, 60 healthy individuals without pulmonary nodules were admitted to the hospital during the same period. The individuals constituted the control group. All study participants underwent digital PET/CT detection and had their lung cancer autoantibody levels determined through enzyme-linked immunosorbent assay. Further testing, such as puncture or surgical pathology, was performed for patients with lung nodules. The aim was to evaluate the significance of combining PET/CT with autoantibody detection in diagnosing and treating lung nodules. Results: The study found that testing multiple autoantibodies together increased sensitivity and accuracy compared to testing individual autoantibodies. Combining PET/CT screening with autoantibody detection improved the diagnostic rate for identifying lung nodules, including benign and suspected malignant ones. Several autoantibodies were significantly higher in the experimental group compared to the control group. Testing for multiple autoantibodies showed higher sensitivity and accuracy than testing for one. Pathological examination confirmed 129 benign nodules and 31 malignant nodules. The median SUVmax values were measured at 0.7 for benign nodules and 4.8 for malignant nodules. The diagnostic efficacy of PET/CT combined with autoantibodies was determined through comparison with pathology testing and was as follows: PET/CT combined with autoantibody detection > PET/CT > autoantibody detection. Conclusion: Combining PET/CT with the detection of autoantibodies enhances the positive diagnostic rate and accuracy of lung nodules in the case of lung cancer. The SUVmax also shows excellent potential as a supplement in diagnosing both benign and malignant lung nodules, providing valuable guidance in determining the pathological types.
RESUMO
Tumor-associated antigen (TAA)-based diagnosis has gained prominence for early tumor screening, treatment monitoring, prognostic assessment, and minimal residual disease detection. However, limitations such as low sensitivity and difficulty in extracting non-specific binding membrane proteins still exist in traditional detection methods. Upconversion luminescence (UCL) exhibits unique physical and chemical properties under wavelength near-infrared light excitation. Rolling circle amplification (RCA) is an efficient DNA amplification technique with amplification factors as high as 105. Therefore, the above two excellent techniques can be employed for highly accurate imaging analysis of tumor cells. Herein, we developed a novel nanoplatform for TAA-specific cell imaging based on UCL and RCA technology. An aptamer-primer complex selectively binds to Mucin 1 (MUC1), one of TAA on cell surface, to trigger RCA reaction, generating a large number of repetitive sequences. These sequences provide lots of binding sites for complementary signal probes, producing UCL from lanthanide-doped upconversion nanoparticles (UCNPs) after releasing quencher group. The experimental results demonstrate the specific attachment of upconversion nanomaterials to cancer cells which express a high level of MUC1, indicating the potential of UCNPs and RCA in tumor imaging.
Assuntos
Luminescência , Ácidos Nucleicos , Diagnóstico por Imagem , Membrana Celular , Técnicas de Amplificação de Ácido NucleicoRESUMO
BACKGROUND: Syndecan 4 (SDC4), a type I transmembrane proteoglycan, serves as a critical link between chondrocytes and the extracellular matrix. OBJECTIVE: This study aimed to explore the role of SDC4 in cartilage degeneration of temporomandibular joint osteoathritis (TMJOA). METHODS: Condylar chondrocytes were stimulated with varying concentrations of recombinant rat interleukin-1ß (rrIL-1ß) and SDC4 small interfering RNA (si-SDC4). Anti-SDC4 ectodomain-specific antibodies or IgG were intra-articularly administrated in a TMJOA model rats. SDC4 conditional knockout (SDC4-cKO) and Sdc4flox/flox mice were induced TMJOA. Cartilage degeneration was assessed using haematoxylin & eosin (H&E) and safranin O (SO) staining. Protein levels of SDC4, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with a thrombospondin motifs 5 (ADAMTS5), tumour necrosis factor α (TNFα), type II collagen (Col-II), aggrecan (ACAN), cleaved caspase 3 (CASP3), Ki67 and related pathways in condylar cartilage were evaluated by immunohistochemical (IHC) staining or western blot assays. RESULTS: SDC4 expression was evidently increased in MIA-model animals compared to control groups. rrIL-1ß stimulation increased the expression of SDC4, MMP3 and ADAMTS5 expression in chondrocytes, while decreasing the expression of Col-II. These effects were reversed by si-SDC4 in vitro. In vivo, SDC4 blockade reduced the death of chondrocytes and the loss of cartilage matrix, which was evidenced by increased expression of Col-II and ACAN, and a decrease in SDC4, MMP13 and cleaved-CASP3-positive cells. Furthermore, the protein levels of ACAN and Ki67 were elevated, and the ERK1/2 and P38 signalling pathways were activated following SDC4 inhibition. CONCLUSIONS: SDC4 inhibition significantly ameliorates condylar cartilage degeneration, which was mediated, at least partly, through P38 and ERK1/2 signalling. Inhibition of SDC4 may be of great value for the treatment of TMJOA.
RESUMO
BACKGROUND: Exosomes (Exos) can safely and effectively deliver therapeutic substances to glioma cells; however, their blood-brain barrier (BBB) crossing capacity remains limited. Focused ultrasound (FUS) can transiently, reversibly, and locally open the BBB, while the effects of FUS combined with Exos-miRNA on the treatment of glioma have not been explored to date. METHODS: Exos were extracted by differential centrifugation and the efficacy of miR-1208-loaded Exos combined with FUS in the treatment of glioma was detected by CCK-8, colony formation, flow cytometry, transwell and tumour xenografts assays. The METTL3-mediated regulation of IGF2BP2 on mRNA stability of NUP214 was determined by MeRIP-qPCR, half-life and RIP assays. RESULTS: We used Exos secreted by mesenchymal stem cells as carriers for the tumour suppressor gene miR-1208, and following FUS irradiation, more Exos carrying miR-1208 were allowed to pass through the BBB, and the uptake of miR-1208 in Exos by glioma cells was promoted, thereby achieving high-efficiency tumour-suppressive effects. Furthermore, the molecular mechanism underlying this effect was elucidated that miR-1208 downregulated the m6A methylation level of NUP214 mRNA by negatively regulating the expression of METTL3, thereby NUP214 expression and TGF-ß pathway activity were suppressed. CONCLUSIONS: MiR-1208-loaded Exos combined with FUS is expected to become an effective glioma treatment and deserves further clinical evaluation.
Assuntos
Exossomos , Glioma , Células-Tronco Mesenquimais , MicroRNAs , Humanos , Barreira Hematoencefálica/metabolismo , Exossomos/metabolismo , Glioma/genética , Glioma/terapia , Glioma/metabolismo , Células-Tronco Mesenquimais/metabolismo , Metiltransferases , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/metabolismoRESUMO
It is attractive to use an optical nanorouter by artificial nanostructures to substitute the traditional Bayer filter for an image array sensor, which, however, poses great challenges in balancing the design strategy and the ease of fabrication. Here, we implement and compare two inverse design schemes for rapid optimization of RGGB Bayer-type optical nanorouter. One is based on the multiple Mie scattering theory and the adjoint gradient that is applicable to arrays of nanospheres with varying sizes, and the other is based on the rigorous coupled wave analysis and the genetic algorithm. In both cases, we study layered nanostructures that can be efficiently modeled respectively which greatly accelerates the inverse design. It is shown that the color-dependent peak collection efficiencies of nanorouters designed in the two methods for red, green, and blue wavelengths reach 37%, 44%, and 45% and 52%, 50%, and 66%, respectively. We further demonstrate color nanorouters that provide light focusing to four quadrants working in both the visible and infrared bands, which promises multispectral imaging applications.
RESUMO
OBJECTIVES: To explore the different involvement patterns of the knee "synovio-entheseal complex (SEC)" on MRI in patients with spondyloarthritis (SPA), rheumatoid arthritis (RA), and osteoarthritis (OA). METHODS: This study retrospectively included 120 patients (male:female, 55:65) with a mean age of 39.20 years diagnosed with SPA (n = 40), RA (n = 40), and OA (n = 40) at the First Central Hospital of Tianjin between January 2020 and May 2022. Six knee entheses were assessed by two musculoskeletal radiologists according to the SEC definition. Bone marrow lesions associated with entheses include bone marrow edema (BME) and bone erosion (BE), which were classified as entheseal or peri-entheseal based on their relationship to the entheses. Three groups (OA, RA, and SPA) were established to characterize the location of enthesitis and the different SEC involvement patterns. Inter-group and intra-group differences were analyzed using the ANOVA or chi-square tests, and the inter-class correlation coefficient (ICC) test was used to determine inter-reader agreement. RESULTS: The study contained a total of 720 entheses. The SEC-based analysis revealed different involvement patterns in three groups. The OA group had the most abnormal signals in tendons/ligaments (p = 0.002). The RA group had considerably greater synovitis (p = 0.002). The majority of peri-entheseal BE was identified in the OA and RA groups (p = 0.003). Furthermore, entheseal BME in the SPA group was significantly different from those in the other two groups (p < 0.001). CONCLUSIONS: SEC involvement patterns differed in SPA, RA, and OA, which is important for differential diagnosis. SEC should be used as a whole evaluation method in clinical practice. KEY POINTS: ⢠The "synovio-entheseal complex (SEC)" explained differences and characteristic alterations in the knee joint in patients with spondyloarthritis (SPA), rheumatoid arthritis (RA), and osteoarthritis (OA). ⢠The various SEC involvement patterns are crucial for differentiating SPA, RA, and OA. ⢠When "knee pain" is the only symptom, a detailed identification of characteristic alterations in the knee joint of SPA patients may help timely treatment and delay the structural damage.
Assuntos
Artrite Reumatoide , Doenças da Medula Óssea , Osteoartrite , Espondilartrite , Humanos , Masculino , Feminino , Adulto , Diagnóstico Diferencial , Estudos Retrospectivos , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/complicações , Articulação do Joelho/patologia , Espondilartrite/complicações , Imageamento por Ressonância Magnética/métodos , Doenças da Medula Óssea/patologiaRESUMO
BACKGROUND: Abdominal aortic aneurysm (AAA) rupture prediction based on sex and diameter could be improved. The goal was to assess whether aortic calcification distribution could better predict AAA rupture through machine learning and LASSO regression. METHODOLOGY: In this retrospective study, 80 patients treated for a ruptured AAA between January 2001 and August 2018 were matched with 80 non-ruptured patients based on maximal AAA diameter, age, and sex. Calcification volume and dispersion, morphologic, and clinical variables were compared between both groups using a univariable analysis with p = 0.05 and multivariable analysis through machine learning and LASSO regression. We used AUC for machine learning and odds ratios for regression to measure performance. RESULTS: Mean age of patients was 74.0 ± 8.4 years and 89% were men. AAA diameters were equivalent in both groups (80.9 ± 17.5 vs 79.0 ± 17.3 mm, p = 0.505). Ruptured aneurysms contained a smaller number of calcification aggregates (18.0 ± 17.9 vs 25.6 ± 18.9, p = 0.010) and were less likely to have a proximal neck (45.0% vs 76.3%, p < 0.001). In the machine learning analysis, 5 variables were associated to AAA rupture: proximal neck, antiplatelet use, calcification number, Euclidian distance between calcifications, and standard deviation of the Euclidian distance. A follow-up LASSO regression was concomitant with the findings of the machine learning analysis regarding calcification dispersion but discordant on calcification number. CONCLUSION: There might be more to AAA calcifications that what is known in the present literature. We need larger prospective studies to investigate if indeed, calcification dispersion affects rupture risk. CLINICAL RELEVANCE STATEMENT: Ruptured aneurysms are possibly more likely to have their calcification volume concentrated in a smaller geographical area. KEY POINTS: ⢠Abdominal aortic aneurysm (AAA) rupture prediction based on sex and diameter could be improved. ⢠For a given calcification volume, AAAs with well-distributed calcification clusters could be less likely to rupture. ⢠A machine learning model including AAA calcifications better predicts rupture compared to a model based solely on maximal diameter and sex alone, although it might be prone to overfitting.
RESUMO
INTRODUCTION: Postoperative hypertension resolution among patients with adrenal incidentalomas and normal hormone levels was unknown. Identifying the predictive factors was beneficial to the management of adrenal incidentalomas. METHODS: We conducted a retrospective cohort study, recruiting patients undergoing laparoscopic adrenal tumor resection for adrenal incidentaloma with hypertension and normal hormone levels. Demographic, clinical, treatment, and laboratory data were collected and compared. We used univariable and multivariable logistic regression methods to identify the predictive factors of postoperative hypertension resolution. RESULTS: Of the 171 patients in our study, 130 (76.0%) patients performed a resolution of hypertension, and 57 (33.3%) patients had a significant reduction. Multivariate logistic regression analysis showed that the male sex (odds ratio (OR) 0.305, 95% confidence interval (CI): 0.098-0.948, p = 0.040), body mass index (BMI) (OR 0.973, 95% CI: 0.670-0.938, p = 0.007), aldosterone and plasma renin activity ratio (APR) in erect position (OR 1.206, 95% CI: 1.042-1.397, p = 0.012), and preoperative systolic pressure (OR 1.044, 95% CI: 1.009-1.080, p = 0.014), were significantly associated with the outcomes of hypertension resolution. DISCUSSION/CONCLUSION: Adrenal incidentalomas patients with hypertension and normal hormone levels would perform hypertension resolution after laparoscopic adrenal tumor resection, especially for females with low BMI, high preoperative systolic blood pressure, and high APR (erect position).
Assuntos
Neoplasias das Glândulas Suprarrenais , Hipertensão , Laparoscopia , Feminino , Humanos , Masculino , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/cirurgia , Estudos Retrospectivos , Hipertensão/complicações , AldosteronaRESUMO
PURPOSE: Propofol can be used alone or in combination with opioids during gastroscopy. This study aimed to assess the efficacy and safety of intravenous propofol and different doses of alfentanil in patients undergoing gastroscopy. METHODS: A total of 300 patients undergoing sedative gastroscopy were randomly divided into four groups, and 0.9% saline (group A), 2 µg/kg alfentanil (group B), 3 µg/kg alfentanil (group C) or 4 µg/kg alfentanil (group D) were injected intravenously 1 min before the intravenous injection of 1.5 mg/kg propofol. If body movement and coughing occurred during the procedure, 0.5 mg/kg propofol would be administered intravenously. The primary outcome (awakening time) and secondary outcomes were recorded and analyzed, including hemodynamic changes, the incidences of body movement, coughing, hypoxemia, hypotension, hypertension, bradycardia, tachycardia, nausea and vomiting, drowsiness and dizziness. RESULTS: Patients in group C (7.0 [5.0 to 8.0] min) and group D (6.0 [5.0 to 7.0] min) woke up significantly earlier than those in group A (8.0 [6.0 to 10.0] min) (P < 0.001). Patients in group A experienced more body movement (P = 0.001) and coughing (P < 0.001) than the other groups. With the increasing dose of alfentanil, the morbidity of hypotension and bradycardia increased significantly (P = 0.001), while the incidence of dizziness decreased significantly (P = 0.037). The incidences of hypoxemia, tachycardia, drowsiness, nausea and vomiting were similar among the four groups (P > 0.05). CONCLUSIONS: Intravenous 1.5 mg/kg propofol combined with 3 µg/kg alfentanil is more suitable for patients undergoing gastroscopy, and the dose of alfentanil can be reduced according to the patient's actual physical condition.
Assuntos
Hipotensão , Propofol , Humanos , Alfentanil/efeitos adversos , Anestésicos Intravenosos/efeitos adversos , Gastroscopia/métodos , Bradicardia , Tontura/induzido quimicamente , Tontura/epidemiologia , Tontura/tratamento farmacológico , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Vômito/induzido quimicamente , Hipóxia , Hipotensão/induzido quimicamenteRESUMO
PURPOSE: Music intervention is commonly used as a non-pharmacologic therapeutic modality to alleviate anxiety in perioperative patients. This study aimed to assess the sedative and anxiolytic effects of music on elderly patients receiving transurethral resection of prostate (TURP) under spinal anesthesia. METHODS: This was a prospective randomized controlled trial on patients who aged over 60 and received TURP under spinal anesthesia. Participants were randomized to the music group or the control group (no music). The primary outcome was perioperative BIS values, and the secondary outcomes were patient's perioperative anxiety levels, heart rate (HR), blood pressure, and patient satisfaction score. RESULTS: A total of 82 patients were analyzed. The perioperative BIS values in the music group were significantly lower than those of the control group at almost all time points (P < 0.001), as well as showed a significant reduction compared with baseline (P < 0.001), whereas the control group did not. In comparison with the control group, systolic blood pressure (SBP) significantly decreased in the music group at the beginning (mean difference, - 8.0 mmHg; 95% CI - 15.70 to 0.35; P = 0.041) and the 60th minute (mean difference, - 7.9 mmHg; 95% CI - 15.30 to 0.51; P = 0.037) of TURP. Furthermore, compared with baseline within the music group, diastolic blood pressure (DBP) and HR significant reduced at whole time points (P < 0.05), yet the control group not. CONCLUSION: Music intervention effectively provided slight sedation for elderly patients when undergoing TURP under spinal anesthesia without sedatives.
Assuntos
Raquianestesia , Musicoterapia , Música , Ressecção Transuretral da Próstata , Masculino , Idoso , Humanos , Pessoa de Meia-Idade , Raquianestesia/efeitos adversos , Estudos Prospectivos , Hipnóticos e SedativosRESUMO
Hepatic lipid deposition is one of the basic manifestations of obesity, and nowadays pharmacological treatment is the most important tool. Punicalagin(PU), a polyphenol derived from pomegranate peel, is a potential anti-obesity substance. In this study, 60 C57BL/6J mice were randomly divided into a normal group and a model group. After establishing a model of simple obesity with a high-fat diet for 12 weeks, the successfully established rat models of obesity were then regrouped into a model group, an orlistat group, a PU low-dose group, a PU medium-dose group, and a PU high-dose group. The normal group was kept on routine diet and other groups continued to feed the high-fat diet. The body weight and food intake were measured and recorded weekly. After 8 weeks, the levels of the four lipids in the serum of each group of mice were determined by an automatic biochemical instrument. Oral glucose tole-rance and intraperitoneal insulin sensitivity were tested. Hemoxylin-eosin(HE) staining was applied to observe the hepatic and adipose tissues. The mRNA expression levels of peroxisome proliferators-activated receptor γ(PPARγ) and C/EBPα were determined by real-time quantitative polymerase chain reaction(Q-PCR), and the mRNA and protein expression levels of adenosine 5'-monophosphate-activated protein kinase(AMPK), anterior cingulate cortex(ACC), and carnitine palmitoyltransferase 1A(CPT1A) were determined by Western blot. Finally, the body mass, Lee's index, serum total glyceride(TG), serum total cholesterol(TC), and low-density lipoprotein cholesterol(LDL-C) levels were significantly higher and high-density lipoprotein cholesterol(HDL-C) levels were significantly lower in the model group as compared with the normal group. The fat deposition in the liver was significantly increased. The mRNA expression levels of hepatic PPARγ and C/EBPα and the protein expression level of ACC were increased, while the mRNA and protein expression levels of CPT-1α(CPT1A) and AMPK were decreased. After PU treatment, the above indexes of obese mice were reversed. In conclusion, PU can decrease the body weight of obese mice and control their food intake. It also plays a role in the regulation of lipid metabolism and glycometabolism metabolism, which can significantly improve hepatic fat deposition. Mechanistically, PU may regulate liver lipid deposition in obese mice by down-regulating lipid synthesis and up-regulating lipolysis through activation of the AMPK/ACC pathway.
Assuntos
Proteínas Quinases Ativadas por AMP , PPAR gama , Ratos , Camundongos , Animais , Camundongos Obesos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Obesidade/tratamento farmacológico , Obesidade/genética , Peso Corporal , Metabolismo dos Lipídeos , Dieta Hiperlipídica/efeitos adversos , Lipídeos , ColesterolRESUMO
The critical factors regulating stem cell endothelial commitment and renewal remain not well understood. Here, using loss- and gain-of-function assays together with bioinformatic analysis and multiple model systems, we show that PDGFD is an essential factor that switches on endothelial commitment of embryonic stem cells (ESCs). PDGFD genetic deletion or knockdown inhibits ESC differentiation into EC lineage and increases ESC self-renewal, and PDGFD overexpression activates ESC differentiation towards ECs. RNA sequencing reveals a critical requirement of PDGFD for the expression of vascular-differentiation related genes in ESCs. Importantly, PDGFD genetic deletion or knockdown increases ESC self-renewal and decreases blood vessel densities in both embryonic and neonatal mice and in teratomas. Mechanistically, we reveal that PDGFD fulfills this function via the MAPK/ERK pathway. Our findings provide new insight of PDGFD as a novel regulator of ESC fate determination, and suggest therapeutic implications of modulating PDGFD activity in stem cell therapy.
Assuntos
Células-Tronco Embrionárias , Modelos Biológicos , Animais , Diferenciação Celular/genética , Células-Tronco Embrionárias/metabolismo , Sistema de Sinalização das MAP Quinases , CamundongosRESUMO
BACKGROUND: Combining immune checkpoint inhibitors with chemotherapy can synergistically improve antitumor activity and are generally well tolerated. Recently, the efficacy and safety of combination therapy has been demonstrated for many cancers, including urothelial carcinomas. The aim of this retrospective pilot study was to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer. METHODS: We conducted a retrospective analysis of 31 patients with locally advanced or metastatic bladder cancer from December 2020 to January 2022 with an Eastern Cooperative Oncology Group performance status of 0/1. Of the 31 patients, 14 patients received tislelizumab (200 mg i.v. every 3 weeks, Q3W) plus 21 days cycles of chemotherapy (gemcitabine, 1000 mg/m2 i.v. on days 1 and 8 of each cycle + cisplatin, 70 mg/m2 i.v. on day 2 of each cycle) (TGC) treatment and 17 patients received gemcitabine plus cisplatin chemotherapy (GC) treatment. All patients treated with bladder cytoreductive surgery and were treated for four 21 days cycles until disease progression or intolerable treatment-related adverse events (TRAEs). The objective progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and TRAEs were recorded and reviewed. RESULTS: As of the cut-off date (March 25, 2022), PFS, OS, ORR, DCR, CBR and TRAEs were evaluated in 14 patients receiving combination therapy and 17 patients in the chemotherapy alone group. The median PFS was 36.0 [95% confidence interval (CI) 33.1-38.9] weeks in the TGC group and 29.0 (95% CI 25.4-32.6) weeks in the GC group [hazard ratio (HR) 0.15 (95% CI 0.04-0.55)]. In the GC group, the median OS was 48.0 (95% CI 39.7-56.3) weeks; the median OS was not yet mature for the TGC group [HR 0.26 (95% CI 0.07-0.94)]. Treatment with TGC resulted in improved DCR (TGC 71.4%; GC 65.0%) and CBR (TGC 64.3%; GC 52.9%) compared with GC. However, although higher incidences of grade ≥ 3 TRAEs were observed with TGC compared with GC (35.7% vs 23.5%), the difference was not statistically significant (p = 0.47). CONCLUSION: This study suggested that TGC provided survivors of locally advanced or metastatic bladder cancer with encouraging antitumor activity and was generally well tolerated.
Assuntos
Cisplatino , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Humanos , Projetos Piloto , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , GencitabinaRESUMO
BACKGROUND: Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease affecting the spine and sacroiliac joints. To investigate whether there are differences in inflammatory and chronic structural damages, as assessed by a semiquantitative MRI scoring method, between non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) patients with active inflammation at baseline, and to evaluate the treatment response in these patients after 3 months of tumor necrosis factor-alpha (TNF-α) inhibitor treatment. METHODS: Fifty-eight axSpA patients with active inflammation were included in the study. The patients were divided into nr-axSpA group and AS group. MRI examinations of the sacroiliac joints were performed before and after treatment. Inflammatory and structural damages in these patients were assessed using the established Spondyloarthritis Research Consortium of Canada (SPARCC) inflammation and sacroiliac joint structural (SSS) scoring methods, which are two MRI-based scoring methods. The SPARCC score, SSS score, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level were compared between the two groups. RESULTS: At baseline, SPARCC scores for patients in the nr-axSpA and AS groups did not differ significantly (P > 0.05); however, SSS scores for fat metaplasia, erosion, and backfill for patients in the AS group were significantly higher (P < 0.001). Compared with baseline, SPARCC scores were significantly decreased in both groups after treatment (P < 0.001); however, after treatment, no statistically significant difference was found regarding SPARCC scores between the AS and nr-axSpA groups. Compared with baseline, a significant increase in the SSS scores for fat metaplasia and backfill (P < 0.001) and a significant decrease in the SSS scores for erosion (P < 0.001) were observed in all axSpA patients. Changes in the SPARCC score was inversely correlated with the changes in the SSS score for fat metaplasia (r = - 0.634, P < 0.001). Changes in the SSS score for backfill were positively correlated with the changes in the SSS score for fat metaplasia (r = 0.277, P < 0.05) and inversely correlated with those for erosion (r = - 0.443, P < 0.001). CONCLUSION: The SPARCC and SSS scoring systems can be used to assess inflammatory and chronic structural damages as well as treatment responses in patients with axSpA. More severe structural damages were seen in AS patients. TNF-α inhibitor treatment for 3 months could effectively reduce inflammation in axSpA patients.
Assuntos
Espondiloartrite Axial , Sacroileíte , Espondilartrite , Espondilite Anquilosante , Humanos , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Inflamação/patologia , Imageamento por Ressonância Magnética/métodos , Metaplasia/patologia , Articulação Sacroilíaca/diagnóstico por imagem , Articulação Sacroilíaca/patologia , Sacroileíte/diagnóstico por imagem , Sacroileíte/tratamento farmacológico , Sacroileíte/patologia , Índice de Gravidade de Doença , Espondilartrite/diagnóstico por imagem , Espondilartrite/tratamento farmacológico , Espondilartrite/patologia , Espondilite Anquilosante/patologia , Fator de Necrose Tumoral alfaRESUMO
Peregrine rogue wave excitation has applications in gaining high-intensity pulses, etc., and a high-order rogue wave exhibits higher intensity. An exact solution and collision between breathers are two existing ways to excite high-order ones. Here we numerically report a new, to the best of our knowledge, possible method, which is by multi-Gaussian perturbations on a continuous wave. The order and maximal intensity of rogue waves can be adjusted by the number of perturbations. The maximal intensity approaches 63.8 times that of the power of the initial background wave, and it retains a large value under the influence of fiber loss and noise. Our results provide guidance in gaining high-intensity pulses in experiment and understanding the universality of rogue wave generation.
RESUMO
PURPOSE: To investigate the diagnostic capability of whole-lesion (WL) histogram and texture analysis of dynamic contrast-enhanced (DCE) MRI inline-generated quantitative parametric maps using CAIPIRINHA-Dixon-TWIST-VIBE (CDTV) to differentiate malignant from benign breast lesions and breast cancer subtypes. MATERIALS AND METHODS: From February 2018 to November 2018, DCE MRI using CDTV was performed on 211 patients. The inline-generated parametric maps included Ktrans, kep, Ve, and IAUGC60. Histogram and texture features were extracted from the above parametric maps respectively based on a WL analysis. Student's t tests, one-way ANOVAs, Mann-Whitney U tests, Jonckheere-Terpstra tests, and ROC curves were used for statistical analysis. RESULTS: Compared with benign breast lesions, malignant breast lesions showed significantly higher Ktrans_median, 5th percentile, entropy, and diff-entropy, IAUGC60_median, 5th percentile, entropy, and diff-entropy, kep_mean, median, 5th percentile, entropy, and diff-entropy, and Ve_95th percentile, diff-variance, and contrast, and significantly lower kep_skewness and Ve_SD, entropy, diff-entropy, and skewness (all p ≤ 0.011). The combination of all the extracted parameters yielded an AUC of 0.85 (sensitivity 76%, specificity 86%). kep_contrast showed a significant difference among different subtypes of breast cancer (p = 0.006). kep_skewness showed a significant difference between lymph node-positive and lymph node-negative breast cancer (p = 0.007). The IAGC60_5th percentile had an AUC of 0.71 (sensitivity 50%, specificity 91%) for differentiating between high- and low-proliferation groups of breast cancer. CONCLUSIONS: The WL histogram and texture analyses of CDTV-DCE-derived parameters may give additional information for further evaluation of breast cancer. KEY POINTS: ⢠Inline DCE mapping with CDTV is effective and time-saving. ⢠WL histogram and texture-extracted features could distinguish breast cancer from benign lesions accurately. ⢠kep_contrast, kep_skewness, and IAUGC60_5th percentile could predict breast cancer subtypes, lymph node metastasis, and proliferation abilities, respectively.
Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Meios de Contraste , Entropia , Métodos Epidemiológicos , Feminino , Humanos , Metástase Linfática , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Adulto JovemRESUMO
The roll-out of molecular diagnostic tools continues to be the most important shift in the tuberculosis diagnostic landscape. The aim of this study was to develop a novel external quality assessment (EQA) panels for molecular TB diagnostics. In addition, we also assessed the performance of the laboratories with the EQA panels in China. Dried Mycobacterium tuberculosis (MTB) DNA in the chelex resin was designed as part of an EQA program. The storage of genomic DNA in the chelex resin layer had no effect on the stability of genomic DNA, even after 12 weeks of storage. Seventy-one laboratories have participated in EQA of molecular diagnostics for TB diagnosis in 2018. GeneXpert (74.6%, 53/71) was the most predominant molecular method, followed by GeneChip (32.3%, 23/71), MeltPro (22.5%, 16/71), and TB-LAMP (7.0%, 5/71). Out of 105 EQA panels, 103 EQA results (98.1%) achieved perfect scores, whereas the other two (1.9%) had satisfactory scores. There were a total of two false-negative results reported from two laboratories with local LAMP, respectively. In conclusion, we firstly develop feasible EQA panels for molecular diagnostics for tuberculosis in China. Our data demonstrate that a majority of participating laboratories are able to produce perfect results with molecular diagnostics in China, giving us important hints for the implementation of molecular diagnostics.