Weaning From Tobacco with Nicotine or Varenicline in Severe and Mild Tobacco Dependence—Findings of a Meta-Analysis.

Background: Systematic reviews have documented the beneficial effects of bupropion, cytisine, nicotine, and varenicline as aids to permanent smoking cessation. We investigated the question whether the effect of treatment depends on the severity of tobacco dependence.

Methods: We systematically searched for relevant publications in bibliographic databases and trial registries, made inquiries to manufacturers, and consulted additional sources of information (last search on 1 September 2022).

The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation.

The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear.

Notch signaling in thyrocytes is essential for adult thyroid function and mammalian homeostasis.

The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism, and thyroid diseases comprise the most common endocrine disorders. Nevertheless, high-resolution views of the cellular composition and signals that govern the thyroid have been lacking. Here, we show that Notch signalling controls homeostasis and thermoregulation in adult mammals through a mitochondria-based mechanism in a subset of thyrocytes.

CK2β-regulated signaling controls B cell differentiation and function.

Serine-Threonine kinase CK2 supports malignant B-lymphocyte growth but its role in B-cell development and activation is largely unknown. Here, we describe the first B-cell specific knockout (KO) mouse model of the β regulatory subunit of CK2. CK2β mice present an increase in marginal zone (MZ) and a reduction in follicular B cells, suggesting a role for CK2 in the regulation of the B cell receptor (BCR) and NOTCH2 signaling pathways.

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling.

Notch Signaling Promotes Mature T-Cell Lymphomagenesis.

Unlabelled: Peripheral T-cell lymphomas (PTCL) are agressive lymphomas that develop from mature T cells. The most common PTCLs are genetically, molecularly, and clinically diverse and are generally associated with dismal outcomes. While Notch signaling plays a critically important role in both the development of immature T cells and their malignant transformation, its role in PTCL is poorly understood, despite the increasingly appreciated function of Notch in regulating the proliferation and differentiation of mature T cells.

Stromal Notch ligands foster lymphopenia-driven functional plasticity and homeostatic proliferation of naive B cells.

In lymphopenic environments, secondary lymphoid organs regulate the size of B and T cell compartments by supporting the homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain incompletely understood. To evaluate homeostasis of the mature B cell pool during lymphopenia, we turned to an adoptive transfer model of purified follicular B cells into Rag2-/- mouse recipients.

Resting innate-like B cells leverage sustained Notch2/mTORC1 signaling to achieve rapid and mitosis-independent plasma cell differentiation.

Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naive B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell-cycle arrest.

Delta-like 1-Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in Mouse.

Background & Aims: Notch pathway signaling maintains gastric epithelial cell homeostasis by regulating stem cell proliferation and differentiation. We previously identified NOTCH1 and NOTCH2 as the key Notch receptors controlling gastric stem cell function. Here, we identify the niche cells and critical Notch ligand responsible for regulating stem cell proliferation in the distal mouse stomach.

Population Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia: Treatment Phase Dependency and Predictivity in Case of Missing Data.

Background And Objectives: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance.

Methods: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia.

Dll1 quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.

Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive.

Bioanalysis of doxorubicin aglycone metabolites in human plasma samples-implications for doxorubicin drug monitoring.

The widespread clinical use of the cytostatic doxorubicin together with the induction of chronic cardiomyopathy necessitates the conduct of further pharmacokinetic trials. Novel analytical technologies suitable for point-of-care applications can facilitate drug level analyses but might be prone to interferences from structurally similar compounds. Besides the alcohol metabolite doxorubicinol, aglycone metabolites of doxorubicin might affect its determination in plasma.

Notch Regulates Innate Lymphoid Cell Plasticity during Human NK Cell Development.

Human NK cells develop in tonsils through discrete NK cell developmental intermediates (NKDIs), yet the mechanistic regulation of this process is unclear. We demonstrate that Notch activation in human tonsil-derived stage 3 (CD34CD117CD94NKp80) and 4A (CD34CD117CD94NKp80) NKDIs promoted non-NK innate lymphoid cell differentiation at the expense of NK cell differentiation. In contrast, stage 4B (CD34CD117CD94NKp80) NKDIs were NK cell lineage committed despite Notch activation.

Notch signalling drives synovial fibroblast identity and arthritis pathology.

The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown.

Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure.

Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships.

GCNT1-Mediated -Glycosylation of the Sialomucin CD43 Is a Sensitive Indicator of Notch Signaling in Activated T Cells.

Notch signaling is emerging as a critical regulator of T cell activation and function. However, there is no reliable cell surface indicator of Notch signaling across activated T cell subsets. In this study, we show that Notch signals induce upregulated expression of the glycosyltransferase gene in T cells mediating graft-versus-host disease after allogeneic bone marrow transplantation in mice.

Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma.

EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3-dependent strong reduction in the levels of the transcriptional repressor HES1.

A large pool of actively cycling progenitors orchestrates self-renewal and injury repair of an ectodermal appendage.

The classical model of tissue renewal posits that small numbers of quiescent stem cells (SCs) give rise to proliferating transit-amplifying cells before terminal differentiation. However, many organs house pools of SCs with proliferative and differentiation potentials that diverge from this template. Resolving SC identity and organization is therefore central to understanding tissue renewal.