Acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 gene internal tandem duplication (FLT3-ITD) mutations has a poor prognosis. The combination of arsenic trioxide (ATO) and all-trans ...retinoic acid (ATRA) has a synergistic killing effect on leukemia cells with FLT3-ITD mutation. However, the mechanism, especially the changes of gene expression and metabolic activity remain unclear. Here we explore the transcriptome and metabolomics changes of FLT3-ITD AML cells treated with ATO/ATRA.
RNA-seq was used to identify differential expressed genes (DEGs), and ultra-high performance liquid chromatography-quadrupole electrostatic field orbital trap mass spectrometry (UHPLC-QE-MS) nontargeted metabolomics method was used to screen out the differential metabolites in FLT3-ITD mutant cell lines treated with ATRA and ATO. KEGG pathway database was utilized for pathway exploration and Seahorse XF24 was used to detect extracellular acidification rate (ECAR). Metabolic polymerase chain reaction (PCR) array and real-time quantitative PCR (RT-qPCR) were used to detect mRNA levels of key metabolic genes of glycolysis and fatty acid after drug treatment.
A total of 3873 DEGs were identified and enriched in 281 Gene Ontology (GO) terms, among which 210 were related to biological processes, 43 were related to cellular components, and 28 were related to molecular functions. Besides, 1794 and 927 differential metabolites were screened in positive and negative ion mode separately, and 59 different metabolic pathways were involved, including alanine-aspartate-glutamate metabolic pathway, arginine, and proline metabolic pathway, glycerophospholipid metabolic pathways, etc. According to KEGG Pathway analysis of transcriptome combined with metabolome, glycolysis/gluconeogenesis pathway and fatty acid metabolism pathway were significantly founded enriched. ATRA + ATO may inhibit the glycolysis of FLT3-ITD AML cells by inhibiting FLT3 and its downstream AKT/HK2-VDAC1 signaling pathway.
The gene transcription profile and metabolites of FLT3-ITD mutant cells changes significantly after treatment, which might be related to the anti-FLT3-ITD AML effect. The screened DEGs, differential metabolites pathway are helpful in studying the mechanism of anti-leukemia effects and drug targets.
Primary squamous cell carcinoma of the thyroid (PSCCT) is a rare clinical disease characterized by rapid growth, high invasiveness, and a poor prognosis. A 66-year-old male patient was admitted due ...to throat pain and dysphagia. Ultrasound revealed a calcified hypoechoic mass in the right lobe of the thyroid gland, measuring approximately 35.3 ml. Ultrasound and PET-CT both indicated high suspicion of malignancy. The patient underwent contrast-enhanced US-guided biopsy, and the pathological results revealed poorly differentiated squamous cell carcinoma. CEUS was performed regularly during the Chemotherapy combined with pembrolizumab (PD-1) treatment courses. The vital area was significantly reduced with neither recurrence nor cervical lymph node metastasis. Surgical resection and chemotherapy combined with immunotherapy had a significant treatment effect in this case. CEUS is helpful for diagnosis confirmation, biopsy guidance and efficacy evaluation and has important clinical application value.
Objectives: To explore the feasibility and efficacy of the segmental localization of lumbar vertebrae by ultrasound (US) compared with X-ray. Methods: From February 2019 to May 2019, 43 patients (24 ...males and 19 females), with an average age of 46±15 years, were prospectively enrolled in this study. Longitudinal paramedian sagittal and transverse process sections were used to determine the lumbar segments by US scan. X-ray examination was used to verify the segmentation. The time for segmentation was recorded, and the learning curve of the average localization time was analyzed. Results: Of all the enrolled patients, 5 had lumbar segmental and alignment abnormalities, and 38 had normal lumbar vertebrae. US accurately located vertebrae in 38 normal cases and 5 abnormal cases, with a 100% accuracy rate, as verified by X-ray examination. The localization time was significantly less for US than for X-ray examination, both in normal cases and in cases with segmental or alignment abnormalities (all P < 0.001). The learning curve of US-guided segmental localization continuously decreased with an increasing number of operations and entered the plateau stage after the third operation day. Conclusions: The US-guided segmental localization of lumbar vertebrae is an accurate new method that is efficient and easy to learn and does not require radiation.
Objectives: To determine the efficacy of Doppler-based renal resistive index (RRI) in the prediction of acute kidney injury (AKI) in critically ill patients. Methods: A systematic review and ...meta-analysis of cohort studies was conducted. Relevant studies were identified in PubMed, Embase and Cochrane Library from inception to November 1, 2020, and reference lists of identified primary studies. Prospective studies that examined the diagnostic accuracy of RRI in AKI were included. Results: Among the 126 articles identified, 18 were included, with a total of 1656 patients. Bivariate analysis yielded pooled sensitivity and specificity of 0.81 (95% CI 0.74-0.86) and 0.75 (95% CI 0.65-0.83), respectively. The summary positive likelihood ratio was 3.2 (95% CI 2.2-4.6), and negative likelihood ratio was 0.26 (95% CI 0.19-0.36). Conclusion: Elevated RRI may be an early predictor of AKI in critically ill patients. Further large-scale prospective studies are needed to confirm the predictive efficacy and determine the performance and optimal cutoff value of RRI among the included studies.
Chronic rhinosinusitis (CRS) affects more than 10% of the population in the United States and Europe. Recent findings point to a considerable variation of inflammatory subtypes in patients with CRS ...with nasal polyps and patients with CRS without nasal polyps. According to current guidelines, glucocorticosteroids and antibiotics are the principle pharmacotherapeutic approaches; however, they fail in a group of patients who share common clinical and laboratory markers. Several clinical phenotypes often leading to uncontrolled disease, including adult nasal polyposis, aspirin-exacerbated respiratory disease, and allergic fungal rhinosinusitis, are characterized by a common endotype: a TH 2 bias is associated with a higher likelihood of comorbid asthma and recurrence after surgical treatment. As a consequence, several innovative approaches targeting the TH 2 bias with humanized mAbs have been subjected to proof-of-concept studies in patients with CRS with nasal polyps with or without comorbid asthma: omalizumab, reslizumab, mepolizumab, and recently dupilumab. Future concepts using upstream targets, such as GATA-3, also focus on this endotype. This current development might result in advantages in the treatment of patients with the most severe CRS.
International consensus on allergy immunotherapy Jutel, Marek, MD; Agache, Ioana, MD; Bonini, Sergio, MD ...
Journal of allergy and clinical immunology,
09/2015, Letnik:
136, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Allergen immunotherapy (AIT) has been used to treat allergic disease since the early 1900s. Despite numerous clinical trials and meta-analyses proving AIT efficacious, it remains underused and is ...estimated to be used in less than 10% of patients with allergic rhinitis or asthma worldwide. In addition, there are large differences between regions, which are not only due to socioeconomic status. There is practically no controversy about the use of AIT in the treatment of allergic rhinitis and allergic asthma, but for atopic dermatitis or food allergy, the indications for AIT are not well defined. The elaboration of a wider consensus is of utmost importance because AIT is the only treatment that can change the course of allergic disease by preventing the development of asthma and new allergen sensitizations and by inducing allergen-specific immune tolerance. Safer and more effective AIT strategies are being continuously developed both through elaboration of new allergen preparations and adjuvants and alternate routes of administration. A number of guidelines, consensus documents, or both are available on both the international and national levels. The international community of allergy specialists recognizes the need to develop a comprehensive consensus report to harmonize, disseminate, and implement the best AIT practice. Consequently, the International Collaboration in Asthma, Allergy and Immunology, formed by the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the World Allergy Organization, has decided to issue an international consensus on AIT.
Background To date, no study has evaluated the diversity of TH cell cytokine patterns of patients with chronic rhinosinusitis (CRS) among centers in different continents using identical methods. ...Objective We sought to assess TH cytokine profiles in patients with CRS from Europe, Asia, and Australia. Methods Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP; n = 435) and control subjects (n = 138) were recruited from centers in Adelaide, Benelux, Berlin, Beijing, Chengdu, and Tochigi. Nasal mucosal concentrations of TH 2, TH 17, and TH 1 cytokines; eosinophilic cationic protein (ECP); myeloperoxidase (MPO); IL-8; and tissue total and Staphylococcus aureus enterotoxin (SE)–specific IgE were measured by using identical tools. Results Combinations of TH 1/TH 2/TH 17 cytokine profiles in patients with CRSwNP varied considerably between regions. CRSwNP tissues from patients from Benelux, Berlin, Adelaide, and Tochigi were TH 2 biased, whereas those from Beijing mainly demonstrated TH 2/TH 1/TH 17 mixed patterns, and patients from Chengdu showed an even lower TH 2 expression. Concentrations of IL-8 and tissue total IgE in patients with CRSwNP were significantly higher than those in control subjects in all regions. More than 50% of patients with CRSwNP in Benelux, Berlin, Adelaide, and Tochigi showed a predominantly eosinophilic endotype compared with less than 30% of patients in Beijing and Chengdu. SE-specific IgE was found in significantly greater numbers in patients with CRSwNP from Benelux, Adelaide, and Tochigi and significantly lower numbers in patients from Beijing and Chengdu. Moreover, the TH 1/TH 2/TH 17 cytokine profiles in patients with CRSsNP showed diversity among the 6 regions. Conclusion TH cytokine levels, eosinophilic/neutrophilic patterns, and SE-specific IgE expressions show extreme diversity among patients with CRS from Europe, Asia, and Oceania.
Objective: To evaluate the carotid viscoelasticity using ultrasound shear wave dispersion imaging (USWD) and determine its feasibility.Methods: Fifty-three volunteers were recruited and divided into ...the group1 (≥50 years old) and group 2 (<50 years old). The shear wave elastic modulus (SWE-AR and SWE-PR) and shear wave dispersion indexes (SWD-AR and SWD-PR), which located at the anterior and posterior walls of the common carotid artery (CCA), were obtained by USWD, and compared with pulse wave velocity (PWV). Pearson correlation analysis was applied to analyze the related factors of viscoelasticity.Results: Before and after body mass index, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were adjusted, SWE-AR, SWE-PR, SWD-AR and SWD-PR were all higher in the group 2 than those of group 1 (all P < 0.05). In all subjects, SWE was negatively correlated with age, SBP, DBP and PWV, respectively (r = -0.282, -0.374, -0.321, -0.256 and all P < 0.05). The SWD was negatively correlated with PWV in the group 1, while positively correlated with SBP in the group 2 (r=-0.393 and r=0.366, all P < 0.05).Conclusion: The viscoelasticity of arterial wall can be assessed by USWD. It provides a new way to describe arterial disease for clinical study.
This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal . The conclusions below ...focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein.
Objective: The purpose of this study was to optimize ultrasound-targeted microbubble destruction (UTMD) on RAGE plasmid transfection in human coronary artery endothelial cells (HCAECs) and improve ...gene transfection efficiency in vitro.Methods: SonoVue microbubble suspension was prepared and mixed with HCAECs, while the cells were adherent and suspended, respectively. After RAGE plasmids being added, they were exposed to ultrasonic irradiation for 10, 20, and 30 s by a therapeutic US machine with 0.4W, respectively. The samples with adherent HCAECs (adherent group) were irradiated directly, while the samples with suspended HCAECs (suspended group) were irradiated via the water. The combined effect of ultrasound and microbubble on RAGE plasmid transfection in HCAECs was evaluated by detecting protein expression of RAGE by western blot. In addition, the viability of the HCAECs was analyzed by CCK8 in order to explore the optimal transfection condition.Results: In suspension group, compared with control, the expression of RAGE was gradually increased from 5 to 20s, and decreased from 20 to 30s. The expression of RAGE peaked in 20s and indicated statistical significance. However, compared with the control, the expression of RAGE did not significantly increase with prolonged ultrasound irradiation in the adherent group. On the other hand, viability of the HCAECs did not decrease significantly with extended exposure time in both groups.Conclusion: UTMD represents an efficient and safe method for the transfection of cells in suspension and optimal exposure.
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