Tumor cells pose a challenge to the adaptive immune system, and its key cell types, T and B cells, have frequently been associated with an improved prognosis. The success of immune checkpoint ...blockade has confirmed the relevance of T cells. However, the role of B cells is increasingly recognized, and highlighted in this review. Recent data suggest that tumors contain a diverse set of B cells reflecting different developmental states and exerting functions such as antigen presentation, antibody production, and regulatory effects. Further, B cells are frequently located in tertiary lymphoid structures (TLS), which are immune cell niches that sustain an immune response at sites of chronic inflammation. TLSs in tumors display substantial heterogeneity, ranging from cell aggregates to mature structures with an active germinal center. Recent studies have provided insights into initiation, cellular and spatial composition, and function of TLS in a variety of cancer types; however, several critical issues still need to be resolved. Currently, initial reports are discerning the role of TLSs in immunotherapy, with the majority of studies observing TLSs to confer favorable patient outcome. Finally, TLS induction in tumors is evaluated, with the therapeutic aim to reactivate the host immune response.
Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes
. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation ...necessary for tumour evolution
. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2
breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
Recent evidence suggests a link between autoimmunity and the intestinal microbial composition in several rheumatic diseases including systemic sclerosis (SSc). The objective of this study was to ...investigate the prevalence of intestinal dysbiosis in SSc and to characterise patients suffering from this potentially immunomodulatory deviation.
This study consisted of 98 consecutive patients subject to in-hospital care. Stool samples were analysed for intestinal microbiota composition using a validated genome-based microbiota test (GA-map™ Dysbiosis Test, Genetic Analysis, Oslo, Norway). Gut microbiota dysbiosis was found present as per this standardised test. Patients were examined regarding gastrointestinal and extraintestinal manifestations of SSc by clinical, laboratory, and radiological measures including esophageal cineradiography, the Malnutrition Universal Screening Tool (MUST), levels of plasma transthyretin (a marker of malnutrition) and faecal (F-) calprotectin (a marker of intestinal inflammation).
A majority (75.5%) of the patients exhibited dysbiosis. Dysbiosis was more severe (r
= 0.31, p = 0.001) and more common (p = 0.013) in patients with esophageal dysmotility. Dysbiosis was also more pronounced in patients with abnormal plasma levels of transthyretin (p = 0.045) or micronutrient deficiency (p = 0.009). In 19 patients at risk for malnutrition according to the MUST, 18 exhibited dysbiosis. Conversely, of the 24 patients with a negative dysbiosis test, only one was at risk for malnutrition. The mean ± SEM levels of F-calprotectin were 112 ± 14 and 45 ± 8 μg/g in patients with a positive and negative dysbiosis test, respectively. Dysbiosis was more severe in patients with skin telangiectasias (p = 0.020), pitting scars (p = 0.023), pulmonary fibrosis (p = 0.009), and elevated serum markers of inflammation (p < 0.001). However, dysbiosis did not correlate with age, disease duration, disease subtype, or extent of skin fibrosis.
In this cross-sectional study, intestinal dysbiosis was common in patients with SSc and was associated with gastrointestinal dysfunction, malnutrition and with some inflammatory, fibrotic and vascular extraintestinal features of SSc. Further studies are needed to elucidate the potential causal relationship of intestinal microbe-host interaction in this autoimmune disease.
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•Biomethane produced from organic fraction of municipal solid waste(OFMSW)•151.4 kg CH4 and 355.6 kg negative emissions are obtained from 1 ton dry OFMSW.•The process reach energy ...efficiency of 0.40 and cost of 6.74 MJ to store 1 kg of CO2.•Operating expenses calculation result indicates a positive net profit.
The use of bioenergy with carbon capture and storage (BECCS) is vital to reaching the desired climate goals. This study proposed a novel process combining anaerobic digestion, pyrolysis, catalytic reforming and methanation (APRM) to produce biomethane and to capture carbon emission from the organic fraction of municipal solid waste (OFMSW). The evaluation of the process was conducted by using modelling software and techno-economic analysis. The process modelling and evaluation result showed that 151.4 kg CH4 and 355.64 kg stored carbon emission can be produced from 1 ton dry matter of OFMSW with an energy efficiency of 0.40. 6.74 MJ electricity was required to capture 1 kg of CO2 via the proposed process. The energy balance of the pyrolysis reaction was investigated. The sensitivities of the pyrolysis temperatures, dewatering technologies and conversion of catalytic reforming on the process performance were analyzed. The result also indicated a positive net profit when using the APRM process to treat the OFMSW based on the calculation of operating expenses and revenue, when the CO2 negativity can be sold as commodity.
This article presents a review of the research into gas stirring in ladle metallurgy carried out over the past few decades. Herein, the physical modeling experiments are divided into four major ...areas: (1) mixing and homogenization in the ladle; (2) gas bubble formation, transformation, and interactions in the plume zone; (3) inclusion behavior at the steel–slag interface and in the molten steel; and (4) open eye formation. Several industrial trials have also been carried out to optimize gas stirring and open eye formation. Approaches for selecting criteria for scaling to guarantee flow similarity between industrial trials and physical modeling experiments are discussed. To describe the bubble behavior and two-phase plume structure, four main mathematical models have been used in different research fields: (1) the quasi-single-phase model, (2) the volume of fluid (VOF) model, (3) the Eulerian multiphase (E–E) model, and (4) the Eulerian–Lagrangian (E–L) model. In recent years, the E–E model has been used to predict gas stirring conditions in the ladle, and specific models in commercial packages, as well as research codes, have been developed gradually to describe the complex physical and chemical phenomena. Furthermore, the coupling of turbulence models with multiphase models is also discussed. For physical modeling, some general empirical rules have not been analyzed sufficiently. Based on a comparison with the available experimental results, it is found that the mathematical models focusing on the mass transfer phenomenon and inclusion behaviors at the steel-slag interface, vacuum degassing at the gas–liquid interface, dissolution rate of the solid alloy at the liquid–solid interface, and the combination of fluid dynamics and thermodynamics need to be improved further. To describe industrial conditions using mathematical methods and improve numerical modeling, the results of physical modeling experiments and industrial trials must offer satisfactory validations for the improvement of numerical modeling.
Primary lung adenocarcinoma remains a deadly disease. Gene-expression phenotypes (GEPs) in adenocarcinoma have potential to provide clinically relevant disease stratification for improved prognosis ...and treatment prediction, given appropriate clinical and methodologic validation.
2,395 transcriptional adenocarcinoma profiles were assembled from 17 public cohorts and classified by a nearest centroid GEP classifier into three subtypes: terminal respiratory unit (TRU), proximal-proliferative, and proximal-inflammatory, and additionally scored by five transcriptional metagenes representing different biologic processes, including proliferation. Prognostic- and chemotherapy-predictive associations of the subtypes were analyzed by univariate and multivariate analysis using overall survival or distant metastasis-free survival as endpoints.
Overall, GEPs were associated with patient outcome in both univariate and multivariate analyses, although not in all individual cohorts. The prognostically relevant division was between TRU- and non-TRU-classified cases, with expression of proliferation-associated genes as a key prognostic component. In contrast, GEP classification was not predictive of adjuvant chemotherapy response. GEP classification showed stability to random perturbations of genes or samples and alterations to classification procedures (typically <10% of cases/cohort switching subtype). High classification variability (>20% of cases switching subtype) was observed when removing larger or entire fractions of a single subtype, due to gene-centering shifts not addressable by the classifier.
In a large-scale evaluation, we show that GEPs add prognostic value to standard clinicopathologic variables in lung adenocarcinoma. Subject to classifier refinement and confirmation in prospective cohorts, GEPs have potential to affect the prognostication of adenocarcinoma patients through a molecularly driven disease stratification.
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•The O/C and H/C rates of AWD decreased from 0.36 and 1.31 to 0.35 and 1.22 by HTC.•Anaerobic digestion decreased the pyrolytic Ea of the hydrochar from lignocellulose.•Mean ...activation energy of pseudo 2 decreased from 203.75 to 175.64 kJ/mol by HTC.•The ΔH‡ value of the pseudo 2 of hydrochar was ∼ 28 kJ/mol lower than that of AWD.•A pyrolytic peak temperature of at least 450 °C should be used in further studies.
Anaerobic digestion is the most promising disposal methods to treat organic waste. Also, a feasible management is necessary for the resulted digestate. Hydrothermal carbonization (HTC) combination with pyrolysis could be a proper solution to use for the treatment of digestate. In this study, the effect of an HTC on the pyrolysis of the digestate of agricultural waste (AWD) was investigated, focusing on the kinetic and thermodynamic aspects. Three model-free methods, including Friedman, KAS, and OFW methods, were used to evaluate the kinetic performance of the total and pseudo pyrolytic reactions of AWD and its hydrochar. Furthermore, kinetic predictions were made to provide more information for further studies. It was found that the HTC treatment decreased the activation energy ranges of the pyrolysis of AWD from 182.9–274.43 kJ/mol to 144.59–205.20 kJ/mol by using the Friedman method. For a more thorough understanding of the effect of HTC treatment on the pyrolysis of AWD, the pyrolysis reactions of AWD and its hydrochar were divided into two pseudoreactions using the Fraser-Suzuki deconvolution method. The mean activation energy of the deduced pseudo 2 pyrolytic reaction of hydrochar was 175.64 kJ/mol, which was 28.11 kJ/mol less than that of AWD. In addition, the ΔH‡ values of the pseudo 2 reactions of AWD and its hydrochar were 197.97 and 169.68 kJ/mol, respectively. The results of kinetic isothermal predictions suggested that the peak temperature for the further research and application of the pyrolysis of AWD and its hydrochar should not be lower than 450 °C.
Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential ...expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10
) and overall survival (HR = 1.61, p = 1.67 × 10
), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (p
= 7.03 × 10
), or published prognostic signatures (p
< 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = -0.75, p < 2.2 × 10
), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in ...nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, “driver” oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.
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