Identification of the Germline Mutation Profile in Esophageal Squamous Cell Carcinoma by Whole Exome Sequencing

Background: Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis and occurs with high frequency in China. The germline mutation profile in ESCC remains unclear, and therefore, the discovery of oncogenic alterations in ESCC is urgently needed. This study investigates the germline mutation profile and reveals associations among genotype-environment interactions in ESCC.Methods: Whole exome sequencing and follow-up analysis were performed in 77 matched tumor-normal ESCC specimens to examine the germline profiles. Additionally, associations among genotype-environment interactions were investigated.Results: We identified 84 pathogenic/likely pathogenic mutations and 51 rare variants of uncertain significance (VUS). Twenty VUS with InterVar evidence of a score of moderate pathogenicity (PM) 2/PM2+ supporting pathogenicity (PP) 1 were found to have pathogenic significance. CYP21A2 was the most frequently mutated gene, and the p.Gln319* variant was identified in 6.5% (5/77) of patients. The TP53 p.V197E mutation, located within the DNA binding domain, was found in 1.3% (1/77) of patients. In total, the 11.7% (9/77) of individuals with homologous recombination (HR) VUS were more likely to have well-differentiated tumors than those without (P = 0.003). The degree of lymph node metastasis was correlated with homologous recombination deficiency (HRD) and VUS group (P < 0.05). Moreover, the 10.4% (8/77) of individuals with mismatch repair (MMR) VUS had a higher tumor mutational burden (TMB), although the correlation was not significant.Conclusions: Our study identified the germline mutation profiles in ESCC, providing novel insights into the molecular pathogenesis of this disease. Our results may also serve as a useful resource for the exploration of the underlying mechanism of ESCC and may provide information for the prevention, diagnosis and risk management of ESCC

Interim position emission tomography-computed tomography during multimodality treatment of locally advanced esophageal cancer: a scoping review.

BACKGROUND Among cancers, esophageal cancer (EC) has one of the highest incidences and mortality in Asia. As recognized in many national guidelines, functional imaging performed with position emission tomography is recommended for patients with locally advanced disease. This review evaluated evidence for the use of fluorodeoxyglucose (FDG) interim positron emission tomography (PETint) in bimodality (chemoradiation) and trimodality (chemoradiation followed by surgery) management of locally advanced esophageal cancer (LAEC), with a focus on its prognostic and predictive value. METHODS The MEDLINE database was searched from January 1, 2001, to January 1, 2022, as part of a scoping review. References of selected articles were manually checked to identify other articles meeting the inclusion criteria; only original articles were included, and reviews, guidelines, letters, editorials, and case reports were excluded. RESULTS A total of 63 articles were included in this review. PET-computed tomography (PET-CT) is recognized as having a significant role in the assessment of treatment response. Studies on the predictive PETint suggest that it has a certain value, particularly for early response. Identification of poor responders or nonresponders soon after commencement of multimodality treatment allows for treatment modification. CONCLUSIONS The scoping review indicated variable utility for the prognostic value of PETint. There is a need to improve its accuracy, which can likely be achieved through greater standardization of measurements and reporting and testing as well as combination with other promising measures of response to residual disease

A randomized phase 3 trial comparing paclitaxel plus 5-fluorouracil versus cisplatin plus 5-fluorouracil in Chemoradiotherapy for locally advanced esophageal carcinoma—the ESO-shanghai 1 trial protocol

Abstract Background Concurrent chemoradiotherapy is a standard modality for locally advanced esophageal squamous cell carcinoma (ESCC) patients. Cisplatin combined with 5-fluorouracil continuous infusion (PF) remains the standard concurrent chemotherapy regimen. However, radiotherapy concurrent with PF showed a high incidence of severe side effects. Paclitaxel showed a promising radiosensitivity enhancement in the treatment of esophageal carcinoma in both vitro and vivo studies. The ESO-Shanghai 1 trial examines the hypothesis that paclitaxel plus 5-fluorouracil (TF) concurrent with radiotherapy has better overall survival and lower toxicity for patients with local advanced ESCC. Method Four hundred thirty-six ESCC patients presenting with stage IIa to IVa will be enrolled in a prospective multicenter randomized phase 3 study. Patients will be randomized to either concurrent chemoradiotherapy with PF (cisplatin 25 mg/m2/d, d1–3, plus 5-fluorouracil 1800 mg/m2, continuous infusion for 72 h) once every 4 weeks for 2 cycles followed by consolidation chemotherapy for 2 cycles or concurrent chemoradiotherapy with weekly TF (5-fluorouracil 300 mg/m2, continuous infusion for 96 h plus paclitaxel 50 mg/m2, d1) for 5 weeks followed by consolidation chemotherapy (5-fluorouracil 1800 mg/m2, continuous infusion for 72 h, plus paclitaxel 175 mg/m2 d1) once every 4 weeks for 2 cycles. The radiotherapy dose is 61.2 Gy delivered in 34 fractions to the primary tumor including lymph nodes. The primary end-point is the 3-yr overall survival analyzed by intention to treat. The secondary endpoints are disease progression-free survival, local progression-free survival, and number and grade of participants with adverse events. Discussion The aim of this phase 3 study is to determine whether the TF regimen could replace the standard PF regimen for inoperable ESCC patients. An overall survival benefit of 12% at 3 years should be expected in the TF group to achieve this goal. Trial registration ClinicalTrials.gov Identifier: NCT01591135. Registered 18 April 2012

Suspension and transfer printing of ZnCdMgSe membranes from an InP substrate

Wide bandgap II-VI semiconductors, lattice-matched to InP substrates, show promise for use in novel, visible wavelength photonic devices; however, release layers for substrate removal are still under development. An under-etch method is reported which uses an InP substrate as an effective release layer for the epitaxial lift-off of lattice-matched ZnCdMgSe membranes. An array of 100-pm-square membranes is defined on a ZnCdMgSe surface using dry etching and suspended from the InP substrate using a three-step wet etch. The ZnCdMgSe membranes are transfer-printed onto a diamond heatspreader and have an RMS surface roughness < 2 nm over 400 |jm 2, similar to the epitaxial surface. Membranes on diamond show a photoluminescence peak at ∼520 nm and a thermal redshift of 4 nm with ∼3.6 MWm −2 continuous optical pumping at 447 nm. Effective strain management during the process is demonstrated by the absence of cracks or visible membrane bowing and the high brightness photoluminescence indicates a minimal non-radiative defect introduction. The methodology presented will enable the heterogeneous integration and miniaturization of II-VI membrane devices

Table_1_Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells.xlsx

Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.</p

Effects of Different Altitudes on Coffea arabica Rhizospheric Soil Chemical Properties and Soil Microbiota

Coffee is one of the most valuable agricultural commodities worldwide, second only to oil in terms of international trade. Coffea arabica L. is a widely cultivated and economically important crop that is responsible for about 90% of the global production of coffee. In this study, we selected five C. arabica cultivation sites at different altitudes to clarify the effects of altitude on rhizospheric soil physical&ndash;chemical characteristics and microbial communities. The samples collected at low altitudes were more nutrient-deficient and acidic than the soil samples collected at medium&ndash;high altitudes. The Proteobacteria-to-Acidobacteria ratio increased from lower altitudes to medium&ndash;high altitudes. Additionally, although Ascomycota was the dominant fungal phylum, it was unaffected by the altitude. Furthermore, the alpha richness and diversity of the bacterial and fungal communities were higher at medium&ndash;high altitudes than at low altitudes. Moreover, the redundancy analysis indicated that microbial phyla were closely associated with pH. These findings suggest that C. arabica should be cultivated at medium&ndash;high altitudes, which is conducive to sustainable management and the production of high-quality C. arabica beans

DataSheet_1_Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells.docx

Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.</p

DataSheet_2_Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells.pdf

Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.</p