Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites.

Mucosa-associated lymphoid tissue (MALT) lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterized. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma. The majority of mutations in GPR34 and CCR6 were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for β-arrestin-mediated receptor desensitization and internalization. Screening of these newly identified mutations, together with previously defined genetic changes, revealed distinct mutation profiles in MALT lymphoma of various sites, with those of salivary gland characterized by frequent TBL1XR1 and GPR34 mutations, thyroid by frequent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002). In those of ocular adnexa, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with IGHV3-23 usage (P=0.03) and PIK3CD mutation (P=0.009). These findings unravel novel insights into the molecular mechanisms of MALT lymphoma and provide further evidence for potential oncogenic co-operation between receptor signaling and genetic changes.The research was supported by grants from Bloodwise (13006, 15002, 15019) UK, and Kay Kendal Leukaemia Fund (KKL582), UK. SM was initially supported by a PhD studentship from Medical Research Council, Department of Pathology, University of Cambridge and Addenbrooke’s Charitable Trust

Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Background: In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, H. pylori negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive. Methods: A total of 57 cases of H. pylori negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes. Results: MALT1 translocation, most likely t(11;18)(q21;q21)/BIRC3-MALT1, was detected in 39% (22/57) cases, and IGH translocation was further seen in 12 MALT1-negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways (TNFAIP3 = 23%, CARD11 = 9%, MAP3K14 = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from MALT1, albeit not IGH translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy (p = 0.004). Conclusion: H. pylori negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways

Thyroid MALT lymphoma: self-harm to gain potential T-cell help.

Funder: CUH | Addenbrooke’s Charitable Trust, Cambridge University Hospitals (Addenbrooke’s Charitable Trust, Cambridge University Hospitals NHS Foundation Trust); doi: https://doi.org/10.13039/501100002927Funder: Pathological Society of Great Britain and Ireland; doi: https://doi.org/10.13039/501100000672The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation (p = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274/TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto's thyroiditis (p = 0.01, p = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p = 0.0001). In conclusion, CD274/TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.Bloodwise the Kay Kendall Leukaemia Fund the Addenbrooke’s Charitable Trust Pathological Society of Great Britain and Irelan

Practice and prospect of fully mechanised mininig technology for thin coal seams under complex conditions in China

In China, thin coal seam are rich in resources and complex in conditions, however, the characteristics such as narrow mining space, the low level of mechanised technology, bad working environment and the high cost of mining, directly restrict the development of mining safety and high-efficiency. In thin coal seams with hard gangue which contains concretions of pyrite, LS-DYNA is applied to calculate the rational blasting parameters and carry out the deep-hole pre-splitting blasting technology, the hard gangue is fractured effectively, hence advancing the productivity of thin coal seam mining. In addition, the mining rate is sped up in thin protective layers in extreme close coal seams by enhancing the level of fully mechanised equipment and other effective measures. Safety and high-efficiency mining can be realised in the outburst coal seam. Thin coal seam mining technology faces many problems presently, i.e. the low level of equipment automation, the low advance rate of mixed coal-rock drift, and the big intensity of worker labour. By lowering the labour intensity, improving the efficiency by means of advancing mining automatic equipment and other measures, respectively, thus manless working faces can be successfully realised in thin coal seam mining

Practice and Prospect of Fully Mechanised Mining Technology for Thin Coal Seams under Complex Conditions in China

In China, thin coal seam are rich in resources and complex in conditions, however, the characteristics such as narrow mining space, the low level of mechanised technology, bad workingenvironment and the high cost of mining, directly restrict the development of mining safety andhigh-efficiency. In thin coal seams with hard gangue which contains concretions of pyrite, LS-DYNA isapplied to calculate the rational blasting parameters and carry out the deep-hole pre-splitting blastingtechnology, the hard gangue is fractured effectively, hence advancing the productivity of thin coal seammining. In addition, the mining rate is speeded up in thin protective layers in extreme close coal seams byenhancing the level of fully mechanised equipment and other effective measures. Safety andhigh-efficiency mining can be realised in the outburst coal seam. Thin coal seam mining technology facesmany problems presently, i.e. the low level of equipment automation, the low advance rate of mixedcoal-rock drift, and the big intensity of worker labour. By lowering the labour intensity, improving theefficiency by means of advancing mining automatic equipment and other measures, respectively, thusmanless working faces can be successfully realised in thin coal seam mining

Overlying Strata Movement Laws Induced by Longwall Mining of Deep Buried Coal Seam with Superhigh-Water Material Backfilling Technology

The “Three Under Mining” (mining under the buildings, the railways, and the waters) coal resources are stored in the central and eastern China. Many large-scale mine disasters occurred due to overburden strata movement and surface subsidence. Longwall mining with superhigh-water material backfilling technology has been improved efficiently to prevent the underground disasters and protect the surface ecological environment. Since underground mine pressure behavior and overlying strata movement are influenced by the backfilling strength and backfilling rates, rational design of backfilling parameters is key to realize the green mining of deep buried coal seams. Based on the combination of geological and production conditions of a deep buried coal seam with composite beam theory, the roof fracture distance was analyzed. The software of UDEC was used to simulate the overlying strata movement laws affected by the different backfilling strength and backfilling rates. With the comparative analysis of the vertical displacement movements and the vertical stress distributions, the reasonable filling rate and water volume fraction were determined to be 90% and 95%, respectively. According to the field experiments, the underground dynamic load was low enough for the safe mining, and the village building can be kept in a stable state with the application of the backfilling technology. The research results in a scientific basis for the coordinated development between the safe and efficient mining of deep buried coal resources and protection of the surface ecological environment

New medium-low temperature hydrothermal geothermal district heating system based on distributed electric compression heat pumps and a centralized absorption heat transformer

© 2021 Elsevier Ltd. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.energy.2021.120974Development of geothermal heat for district heating has attracted considerable attention in China. However, transporting geothermal heat for long distance has become the bottleneck for developing large-scale medium-low temperature hydrothermal geothermal fields that located far away from heat load areas. To solve this problem, a new medium-low temperature hydrothermal geothermal district heating system based on distributed electric compression heat pumps and a centralized absorption heat transformer is proposed and evaluated both from the aspects of thermodynamic performance and economic benefit. Analysis of the results may lead to following main conclusions: (i) for the proposed system, its cost-effective main line length of the primary heating network is about 10 kilometers. (ii) the annual coefficient of performance, annual product exergy efficiency, and heating cost of the proposed system are found to be 24.5, 61.4% and 55.62 ¥/GJ, respectively. The centralized absorption heat transformer can reduce irreversible loss of the heating station and improve performance of distributed electric compression heat pumps. (ⅲ) Unlike the conventional medium-low temperature hydrothermal geothermal district heating system with longer distance of transporting geothermal heat, the annual coefficient of performance and annual product exergy efficiency of the proposed one can be improved by about 4.34 and 7.4%, respectively.Peer reviewe

Mechanism, Cause, and Control of Water, Solutes, and Gas Migration Triggered by Mining Activities

Although the growth in global coal consumption has been sharply slowed with the falls in China offset to a greater extent by the increasing demand in India and other emerging Asian countries, coal still remains the largest source of energy for the world with a share of almost 30% by 2040 [1]. Mining industry plays an important role in extracting underground resources, including coal [2]. However, a large number of disastrous mine accidents, such as flood, water inrush, tunnel collapse, gas outburst, and gas explosion, have been reported due to water and gas migration caused by the mining activities, posing a threat to the environment and also to the health and safety of field workers [3–5]. According to incomplete statistics, mining-induced accidents kill over thousands of workers around the world every year, especially in developing countries such as China and India. Water inrush and gas explosion accidents are the major causes for the reported mine accidents [6, 7]

Bullatacin triggers immunogenic cell death of colon cancer cells by activating endoplasmic reticulum chaperones

Abstract Background It is well accepted that the immune system efficiently contributes to positive outcomes of chemotherapeutic cancer treatment by activating immunogenic cell death (ICD). However, only a limited number of ICD-inducing compounds are well characterized at present; therefore, identification of novel ICD inducers is urgently needed for cancer drug discovery, and the need is becoming increasingly urgent. Methods Herein, we assessed the antitumour activity of bullatacin by MTS assay and apoptosis assay. ICD biomarkers, such as calreticulin (CRT), high-mobility group protein B1 (HMGB-1), heat shock protein (HSP)70, HSP90 and ATP, were assessed by Western blotting, ELISA and flow cytometry. Western blot and qPCR assays were performed to explore the underlying mechanisms of bullatacin-induced ICD. Flow cytometry was used to detect macrophage phagocytosis. Results First, bullatacin induced apoptosis in both SW480 cells and HT-29 cells in a time-dependent manner at 10 nM, as assessed by flow cytometry. Moreover, Western blot and flow cytometry assays showed that CRT and HSP90 (biomarkers of early ICD) significantly accumulated on the cell membrane surface after approximately 6 h of treatment with bullatacin. In addition, ELISAs and Western blot assays showed that the second set of hallmarks required for ICD (HMGB1, HSP70 and HSP90) were released in the conditioned media of both SW480 and HT-29 cells after 36 h of treatment. Furthermore, qPCR and Western blot assays indicated that bullatacin triggered ICD via activation of the endoplasmic reticulum stress (ERS) signalling pathway. Finally, bullatacin promoted macrophage phagocytosis. Conclusion This study documents that bullatacin, a novel ICD inducer, triggers immunogenic tumour cell death by activating ERS even at a relatively low concentration in vitro