Showing papers by "Asif Ahmed published in 2023"

The evolution of lung cancer and impact of subclonal selection in TRACERx

Abstract: Abstract Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS . We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET , ROS1 , ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA

Abstract: Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.

Lung adenocarcinoma promotion by air pollutants

Abstract: A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

The evolution of non-small cell lung cancer metastases in TRACERx

Abstract: Abstract Metastatic disease is responsible for the majority of cancer-related deaths 1 . We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Abstract: B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

Genomic–transcriptomic evolution in lung cancer and metastasis

Abstract: Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.

Delineating associations of progressive pleuroparenchymal fibroelastosis in patients with pulmonary fibrosis

Abstract: Background Computer quantification of baseline computed tomography (CT) radiological pleuroparenchymal fibroelastosis (PPFE) associates with mortality in idiopathic pulmonary fibrosis (IPF). We examined mortality associations of longitudinal change in computer-quantified PPFE-like lesions in IPF and fibrotic hypersensitivity pneumonitis (FHP). Methods Two CT scans 6–36 months apart were retrospectively examined in one IPF (n=414) and one FHP population (n=98). Annualised change in computerised upper-zone pleural surface area comprising radiological PPFE-like lesions (Δ-PPFE) was calculated. Δ-PPFE >1.25% defined progressive PPFE above scan noise. Mixed-effects models evaluated Δ-PPFE against change in visual CT interstitial lung disease (ILD) extent and annualised forced vital capacity (FVC) decline. Multivariable models were adjusted for age, sex, smoking history, baseline emphysema presence, antifibrotic use and diffusion capacity of the lung for carbon monoxide. Mortality analyses further adjusted for baseline presence of clinically important PPFE-like lesions and ILD change. Results Δ-PPFE associated weakly with ILD and FVC change. 22–26% of IPF and FHP cohorts demonstrated progressive PPFE-like lesions which independently associated with mortality in the IPF cohort (hazard ratio 1.25, 95% CI 1.16–1.34, p<0.0001) and the FHP cohort (hazard ratio 1.16, 95% CI 1.00–1.35, p=0.045). Interpretation Progression of PPFE-like lesions independently associates with mortality in IPF and FHP but does not associate strongly with measures of fibrosis progression. Computerised pleuroparenchymal fibroelastosis (PPFE) progression was found to associate with mortality in idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis but PPFE did not correlate strongly with measures of fibrosis progression https://bit.ly/3FKYQn7

Fabricating 2 piece closed hollow obturator with elastomeric impression material: An innovative dental technique

Abstract: Maxillectomy defects are the most common results in oro-nasal communication, which leads to an expected change in speech tone, difficulty in mastication, and deglutition. These affect the quality of life of the patient and also impact them psychosocially in a long run. The most common management of maxillectomy patients for both complete and partial is by maxillary obturator prosthesis. To reduce the weight of the obturators various procedures of hollowing are present in literature. In this article, we will discuss an alternate and innovative laboratory technique for the fabrication of closed hollow obturator which will reduce the time of both dental technicians and clinicians.

Performance Prediction of Evapotranspiration (ET) Cover from Field Monitoring Results

Abstract: The use of water balance (WB) covers in landfills increased over the last decade because of its enhanced performance and low cost of construction. This type of cover system consists of a vegetated soil layer and a storage layer that stores precipitation until the stored water is either evaporated from the soil surface or transpired through vegetation. Water balance covers rely on the storage capacity of the soil layer, rather than the low permeability of the soil, to minimize percolation. The storage capacity of the soil largely depends on the cover thickness and the unsaturated soil properties of the cover soil. On top of that, the local climatic condition also affects the design of cover thickness. The objective of this study was to analyze the water balance components of the WB cover system and execute a performance prediction evaluation based on field monitoring results. To pursue the objective, six large-scale test sections (lysimeters) were constructed side-by-side with locally available fine-grained soil (CH), followed by field instrumentation including moisture and temperature sensors, tensiometers, dosing siphon, and a weather station at the city of Denton municipal solid waste landfill, Texas. From the field monitoring results, the required soil water storage (SR) was determined. The results showed that percolation decreases with increasing cover thickness, and cover thickness is significantly influenced by the distribution of precipitation and the unsaturated properties of the cover soil. Based on the field monitoring results and laboratory investigation of the soil, the cover thickness varied approximately between 1,160 mm (3.8 ft) and 1,700 mm (5.6 ft) for widespread annual percolation for the covers constructed with fine-grained soil.

Effectiveness of Milk Thistle on Human Body against Diseases: A Comprehensive Review

Abstract: Milk thistle (Silybum marianum L.) is a baceous plant that belongs to the Asteraceae (daisy) family and is a member of the Carduae clan. Since antiquity, a several diseases has been treated by milk thistle such as to treat liver problems, spleen problems, gallbladder problems, hepatitis, and gallstones. Milk thistle seeds are utilized in herbal remedies, and there are six flavonolignans that make up silymarins: silychristin, silydianin, silybin A& B, isosilybin A & B. Because of its membrane-stabilizing qualities, silymarin is effective in chronic liver disorders. Many disorders, such as anti-cancer, anti-diabetic, anti-hypertenshaion, and anti- Alzheimer's, are caused by S. Marianum. Milk thistle is now utilized in a diversity of supplements, including oil seed and capsules of soft gel.

Effect of different drying and cooking treatments on phytochemicals and antioxidant activity in broccoli: an experimental in vitro study

Abstract: The current study aimed to assess broccoli's phytochemical profile and determine its antioxidant activity. Fresh broccoli was procured from a local farm and divided into two major treatment groups (cooked and dried). There were five sub-treatments in the cooking group (conventional, microwave, boiling, blanching, and steaming) and three treatments in the drying group (sun drying, freeze drying, and hot air drying). Ascorbic acid content, total carotenoids, TPC, TFC, and antioxidant activity were evaluated for every sub-treatment. The results depicted that the antioxidant constituent of cooked broccoli was complementary to dried broccoli samples. The maximum amount of ascorbic acid content (10.80 mg/100 g), total carotenoids (3.976 mg/g), total phenolic contents (225.80 mg/g), and the total flavonoid contents (42.92 mg/g) were found in freeze-dried broccoli. Freeze-dried broccoli also showed the highest antioxidant activity for DPPH free radical scavenging assay (62.45%), hydrogen peroxide radical scavenging assay (53.67%), and ABTS radical scavenging assay (65.84%).