Biology subjects

Alzetani, A.

Publications and source records attributed to Alzetani, A..

4 recordsLinked to original sources

bioRxiv2026

Ultralow frequency vaso-oscillations in human cerebral arteries are independent from Mayer waves

This study tests the hypothesis that vasomotion, an [~] 0.1 Hz oscillation in arteriole diameter, is generated by intrinsic oscillations within the arterioles that perfuse the brain, and not by external drive from systemic blood pressure oscillations (Mayer waves). During cardio-pulmonary bypass that transiently eliminated systemic blood pressure oscillations in 14 patients, we observed that vasomotor oscillations persist with normal amplitudes and frequencies over the one- to three-hour time course of surgery. In contrast, [~] 0.1 Hz oscillations in peripheral blood pressure were predominantly absent. This implies that cerebral arterioles generate their own rhythmic vaso-dynamics, although we cannot discount that vasomotion can phase-lock with [~] 0.1 Hz systemic physiological rhythms in the awake, healthy state. We discuss the impact of this finding on the role of vasomotion in modulating the perfusion of blood and the transport of interstitial fluid in the brain.

neuroscience↗

bioRxiv2024

Developmental programmes drive cellular plasticity, disease progression and therapy resistance in lung adenocarcinoma

BackgroundCellular plasticity, involving loss of lineage determination and emergence of hybrid cell states, plays a pivotal role in non-small cell lung cancer (NSCLC) disease progression and therapy resistance. However, the full spectrum of atypical states generated in human NSCLC and the pathways that regulate them are yet to be fully elucidated. Here we examine the role of developmental programmes, alveogenesis and branching morphogenesis (BM), in regulating phenotypic diversity in NSCLC. MethodsTranscriptomic analysis of epithelial cells isolated from murine lungs at different stages of organogenesis were used to derive gene signatures for developmental programmes. Bulk tissue transcriptomic datasets from human NSCLC and non-neoplastic control samples were used to identify whether developmental programmes were associated with molecular, morphological, and clinical parameters. Single-cell RNA-sequencing was used to identify malignant cell states in human NSCLC (n = 16,621 epithelial cells from 72 samples) and protein level validation of these states was carried out using multiplexed immunohistochemistry (n = 40). ResultsMutually antagonistic regulation of alveogenesis and BM was found to account for a significant proportion of transcriptomic variance in human NSCLC bulk tissue datasets. BM activation was associated with poor overall survival rates in five independent lung adenocarcinoma (LUAD) cohorts (p=2.04e-13); and was significantly prognostic for resistance to tyrosine kinase inhibitors (TKIs; p=0.003) and immune checkpoint blockade (ICBs; p=0.014), in pre-treatment biopsies. Single-cell RNA-sequencing analysis revealed that malignant LUAD cells with loss of alveolar lineage fidelity predominantly acquired inflamed or basal-like cellular states, which were variably persistent in samples from TKI and ICB recurrence. ConclusionsOur results show LUAD tumours undergo reversion from an alveogenic to branching morphogenic phenotype during disease progression, generating inflamed or basal-like cell states that are variably persistent following TKI or ICB treatments. These findings identify prognostic biomarkers for therapy response and underscore the role of different cell states in resistance to multiple treatment modalities.

cancer biology↗

bioRxiv2021

Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we show that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of oxygen status (pseudohypoxia). Whilst TGF{beta} increased rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting bone-type cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knock down of Factor Inhibiting HIF (FIH) or oxidative stress caused pseudohypoxic HIF activation in normal fibroblasts. In contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of IPF lung mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen structure-function in fibrosis.

cell biology↗

bioRxiv2020

CD4+ follicular helper-like T cells are key players in anti-tumor immunity

To determine the nature of CD4+ T cells that provide help for generating robust anti-tumor CD8+ cytotoxic T cell (CTL) responses, we profiled the transcriptomes of patient-matched CD4+ and CD8+ T cells present in the tumor micro-environment (TME) and analyzed them jointly using integrated weighted gene correlation network analysis. We found the follicular helper T cell (TFH) program in CD4+ T cells was strongly associated with proliferation and tissue-residency in CD8+ CTLs. Single-cell analysis demonstrated the presence of TFH-like cells and features linked to cytotoxic function and their provision of CD8+ T cell help. Tumor-infiltrating TFH-like cells expressed PD-1 and were enriched in tumors following checkpoint blockade, suggesting that they may respond to anti-PD-1 therapy. Adoptive transfer or induction of TFH cells in mouse models resulted in augmented CD8+ CTL responses and impairment of tumor growth, indicating an important role of TFH-like CD4+ T cells in anti-tumor immunity.

immunology↗