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"Pennel"
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Droughts and heatwaves in the Western Mediterranean: impact on vegetation and wildfires using the coupled WRF-ORCHIDEE regional model (RegIPSL)
Droughts and heatwaves in the Mediterranean can induce plant activity decline and severe wildfires leading to considerable economic, social and environmental damages. This study aims at statistically quantifying the isolated and combined impacts of these extreme events based on a combination of regional land surface-atmosphere modeling and satellite observations of surface properties (MODIS). A simulation by the RegIPSL coupled regional model (ORCHIDEE-WRF) over the 1979–2016 period in the Western Mediterranean is used to identify heatwaves and droughts. After an evaluation of the model performance against surface observations of temperature and precipitation, a spatio-temporal analysis is conducted using specific indicators of extreme events: Percentile Limit Anomalies (PLA) and the Standardized Precipitation Evapotranspiration Index (SPEI). The impact on vegetation and wildfires is assessed using the MODIS observations of Leaf Area Index (LAI), burned area (BA) and fire radiative power (FRP), clustered by simulated extreme weather events. Due to water stress, droughts lead to significant biomass decrease (− 10
%
LAI on average and reaching − 23
%
in some areas). The isolated effect of heatwaves is smaller (
∼
− 3
%
LAI) so that the combined effect is dominated by the impact of droughts. Heatwaves and droughts significantly exacerbate wildfire regimes. Through synergistic effects, simultaneous droughts and heatwaves increase BA and FRP by 2.1 and 2.9 times, respectively, compared to normal conditions. By reducing biomass, droughts slightly decrease fuel availability. However, our results show that the inter-annual variation in fire activity is mainly driven by weather conditions rather than fuel load.
Journal Article
Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer
BackgroundTo understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.MethodsImmunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.ResultsTwo patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete ‘punctate’ areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high ‘punctate’ IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.ConclusionsThese results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.
Journal Article
The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer
Background
The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy.
Methods
Two cohorts were utilised; 862 TNM I–III CRC validation cohort, and 2912 TNM II–III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.
Results
GMS independently associated with DFS (
p
= 0.001) and RFS (
p
< 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85–5.68,
p
< 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39–3.41,
p
= 0.001). In TransSCOT, chemotherapy type (
p
interaction
= 0.013), but not duration (
p
= 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19–4.16,
p
= 0.012).
Conclusions
This study validates the GMS as a prognostic tool for patients with stage I–III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.
Journal Article
IL6 and IL6R as Prognostic Biomarkers in Colorectal Cancer
Colorectal cancer is the third most diagnosed malignancy worldwide and survival outcomes remain poor. Research is focused on the identification of novel prognostic and predictive biomarkers to improve clinical practice. There is robust evidence in the literature that inflammatory cytokine interleukin-6 (IL6) is elevated systemically in CRC patients and that this phenomenon is a predictor of poor survival outcome. However, evidence is more limited for the role of IL6 and its cognate receptor, IL6R, within the tumour epithelium and microenvironment. This study aimed to investigate IL6 and IL6R expression in a large cohort of retrospectively collected patient tumour specimens and determine association with clinical outcomes and characteristics. High expression of IL6R in the tumour epithelium was associated with reduced cancer-specific survival in patients with right-sided colon cancer. In these patients, high IL6R expression was also associated with an increased systemic neutrophil-to-lymphocyte ratio. A high number of copies of IL6 mRNA within the tumour-associated stroma, but not epithelium, was associated with reduced cancer-specific survival. The results from this study have validated IL6R as a marker of poor prognosis in a subgroup of CRC patients and identified the spatially resolved prognostic nature of intra-tumoural IL6 expression. This study has also highlighted the need for investigation of IL6/IL6R-targeted therapies as novel treatment strategies for patients with colon cancer.
Journal Article
The Glasgow Microenvironment Score and risk and site of recurrence in TNM I–III colorectal cancer
BackgroundGlasgow Microenvironment Score (GMS) stratifies long-term survival into three groups based on tumour phenotype: peritumoural inflammation (Klintrup–Mäkinen (KM)) and tumour stroma percentage (TSP). However, it is not known if the location of disease recurrence is influenced by the GMS category.MethodsSeven hundred and eighty-three TNM I–III colorectal cancers (CRC) were included. GMS (GMS0—high KM; GMS1—low KM, low TSP; GMS2—low KM, high TSP) and cancer-specific survival (CSS), overall survival (OS) and disease recurrence were assessed using Cox regression analysis.ResultsOf the 783 patients, 221 developed CRC recurrence; 65 developed local recurrence + systemic disease. GMS was independent for CSS (HR 1.50, 95% CI 1.17–1.92, p < 0.001) and OS (HR 1.23, 1.05–1.44, p = 0.01). Higher GMS category was associated with T-stage, N-stage, emergency presentation and venous invasion. GMS was independent for local+systemic recurrence (HR 11.53, 95% CI 1.45–91.85, p = 0.04) and distant-only recurrence (HR 3.01, 95% CI 1.59–5.71, p = 0.002). GMS 2 disease did not appear to have statistically better outcomes with adjuvant chemotherapy in high-risk disease.ConclusionAlthough confounded by a higher rate of T4 and node-positive disease, GMS 1 and 2 are associated with an increased risk of local and distant recurrence. GMS is an independent poor prognostic indicator for recurrent colorectal cancer. Higher GMS patients may benefit from enhanced postoperative surveillance.
Journal Article
An Optoelectronics-Based Compressive Force Sensor with Scalable Sensitivity
There is an increasing need to accurately measure compressive force for biomedical and industrial applications. However, this need has not been fully addressed, as many sensors are bulky, have high power requirements, and/or are susceptible to electromagnetic interference. This paper presents an optoelectronics-based force sensor that can overcome the limitations of many sensors in the market. The sensor uses a light emitting diode (LED) to transmit visible broad-spectrum light into a photoresistor through an optically clear spacer on top of an elastomeric medium. In the absence of an external force, the light path is mostly blocked by the opaque elastomeric medium. Under a compressive force, the clear spacer compresses the elastomer, moving itself into the light path, and thus increasing the overall light transmission. The amount of light received by the photoresistor is used to quantify compressive force based on elastomer displacement/compression and a priori knowledge of elastomer stiffness. This sensing scheme was tested under eight different configurations: two different sized sensors with four types of elastomers per size (20A neoprene, 30A neoprene, 50A neoprene, and 75A styrene–butadiene rubber (SBR)). All configurations measured force with R2 > 0.97, RMSE < 1.9 N, and sensitivity values ranging from 17 to 485 N/V. This sensing scheme provides a low-cost, low-power method for accurate force sensing with a wide force range.
Journal Article
JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors
Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSP
high
) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSP
high
group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.
Journal Article
Immunotherapy in the Context of Aortic Valve Diseases
PurposeAortic valve disease (AVD) affects millions of people around the world, with no pharmacological intervention available. Widely considered a multi-faceted disease comprising both regurgitative pathogenesis, in which retrograde blood flows back through to the left ventricle, and aortic valve stenosis, which is characterized by the thickening, fibrosis, and subsequent mineralization of the aortic valve leaflets, limiting the anterograde flow through the valve, surgical intervention is still the main treatment, which incurs considerable risk to the patient.ResultsThough originally thought of as a passive degeneration of the valve or a congenital malformation that has occurred before birth, the paradigm of AVD is shifting, and research into the inflammatory drivers of valve disease as a potential mechanism to modulate the pathobiology of this life-limiting pathology is taking center stage. Following limited success in mainstay therapeutics such as statins and mineralisation inhibitors, immunomodulatory strategies are being developed. Immune cell therapy has begun to be adopted in the cancer field, in which T cells (chimeric antigen receptor (CAR) T cells) are isolated from the patient, programmed to attack the cancer, and then re-administered to the patient. Within cardiac research, a novel T cell–based therapeutic approach has been developed to target lipid nanoparticles responsible for increasing cardiac fibrosis in a failing heart. With clonally expanded T-cell populations recently identified within the diseased valve, their unique epitope presentation may serve to identify novel targets for the treatment of valve disease.ConclusionTaken together, targeted T-cell therapy may hold promise as a therapeutic platform to target a multitude of diseases with an autoimmune aspect, and this review aims to frame this in the context of cardiovascular disease, delineating what is currently known in the field, both clinically and translationally.
Journal Article
Impact of Landes forest fires on air quality in France during the 2022 summer
The atypical huge forest fires observed in France during the summer of 2022 are modeled using the CHIMERE model. The impact of these emissions is quantified on ozone, aerosols and aerosol optical depth (AOD). The fires also influence the surface by destroying the vegetation and creating new erodible surfaces. This increases the mineral dust emissions but also reduces the leaf area index (LAI), and then it decreases the biogenic emissions and the dry deposition of gases such as ozone. Results show that the fires induce numerous increases in surface ozone and particulate matter (PM) concentrations close to the sources but also in downwind remote sites such as the Paris area. During the period of the most intense fires in July, the impact of concentrations is mainly due to emissions themselves, and later, in August, ozone and PM concentrations continue to increase but this time due to changes in the burned surfaces.
Journal Article