Circadian patterns of growth factor receptor-dependent signaling and implications for carcinogenesis.

Several different signaling pathways that regulate cell proliferation and differentiation are initiated by binding of ligands to cell-surface and membrane-bound enzyme-linked receptors, such as receptor tyrosine kinases and serine-threonine kinases. They prompt phosphorylation of tyrosine and serine-threonine residues and initiate downstream signaling pathways and priming of intracellular molecules that convey the signal in the cytoplasm and nucleus, with transcriptional activation of specific genes enriching cell growth and survival-related cascades. These cell processes are rhythmically driven by molecular clockworks endowed in every cell type and when deregulated play a crucial role in cancer onset and progression.

Role of the Circadian Gas-Responsive Hemeprotein NPAS2 in Physiology and Pathology.

Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix-loop-helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 is a core cog of the molecular clockwork and plays a regulatory role on metabolic pathways, is important for the function of the central nervous system in mammals, and is involved in carcinogenesis as well as in normal biological functions and processes, such as cardiovascular function and wound healing.

The circadian clock circuitry modulates leukemia initiating cell activity in T-cell acute lymphoblastic leukemia.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, characterized by restricted cellular subsets with asymmetrically enriched leukemia initiating cell (LIC) activity. Nonetheless, it is still unclear which signaling programs promote LIC maintenance and progression.

Methods: Here, we evaluated the role of the biological clock in the regulation of the molecular mechanisms and signaling pathways impacting the cellular dynamics in T-ALL through an integrated experimental approach including gene expression profiling of shRNA-modified T-ALL cell lines and Chromatin Immunoprecipitation Sequencing (ChIP-Seq) of leukemic cells.

The circadian clock circuitry deconvolutes colorectal cancer and lung adenocarcinoma heterogeneity in a dynamic time-related framework.

Increasing evidence imputes cancer progression and resistance to therapy to intra-tumor molecular heterogeneity set off by cancer cell plasticity. Re-activation of developmental programs strictly linked to epithelial-to-mesenchymal transition and gaining of stem cells properties are crucial in this setting. Many biological processes involved in cancer onset and progression show rhythmic fluctuations driven by the circadian clock circuitry.

Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway.

Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5'-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock.

Ageing and Low-Level Chronic Inflammation: The Role of the Biological Clock.

Ageing is a multifactorial physiological manifestation that occurs inexorably and gradually in all forms of life. This process is linked to the decay of homeostasis due to the progressive decrease in the reparative and regenerative capacity of tissues and organs, with reduced physiological reserve in response to stress. Ageing is closely related to oxidative damage and involves immunosenescence and tissue impairment or metabolic imbalances that trigger inflammation and inflammasome formation.

Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy characterized by cell subsets and enriched with leukemia-initiating cells (LICs). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown.

Early reduction of estimated Glomerular Filtration Rate (eGFR) predicts poor outcome in acutely ill hospitalized COVID-19 patients firstly admitted to medical regular wards (eGFR-COV19 study).

Background: Analysis of autopsy tissues obtained from patients who died from COVID-19 showed kidney tropism for SARS-COV-2, with COVID-19-related renal dysfunction representing an overlooked problem even in patients lacking previous history of chronic kidney disease. This study aimed to corroborate in a substantial sample of consecutive acutely ill COVID-19 hospitalized patients the efficacy of estimated GFR (eGFR), assessed at hospital admission, to identify acute renal function derangement and the predictive role of its association with in-hospital death and need for mechanical ventilation and admission to intensive care unit (ICU).

Methods: We retrospectively analyzed charts of 764 patients firstly admitted to regular medical wards (Division of Internal Medicine) for symptomatic COVID-19 between March 6th and May 30th, 2020 and between October 1st, 2020 and March 15th, 2021.