Using machine learning models to identify the risk of depression in middle-aged and older adults with frequent and infrequent nicotine use: A cross-sectional study.

Background: Depression is very prevalent in middle-aged and older smokers. Therefore, we aimed to identify the risk of depression among middle-aged and older adults with frequent and infrequent nicotine use, as this is quite necessary for supporting their well-being.

Methods: This study included a total of 10,821 participants, which were derived from the China Health and Retirement Longitudinal Study Wave 5, 2020 (CHARLS-5).

Genomic and transcriptomic profiling of peripheral T cell lymphoma reveals distinct molecular and microenvironment subtypes.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphomas varying in clinical, phenotypic, and genetic features. The molecular pathogenesis and the role of the tumor microenvironment in PTCL are poorly understood, with limited biomarkers available for genetic subtyping and targeted therapies. Through an integrated genomic and transcriptomic study of 221 PTCL patients, we delineate the genetic landscape of PTCL, enabling molecular and microenvironment classification.

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7.

Receptor tyrosine kinases (RTKs) are a class of membrane spanning cell-surface receptors that transmit extracellular signals through the membrane to trigger diverse intracellular signaling through tyrosine kinases (TKs), and play important role in cancer development. Therapeutic approaches targeting RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and TKs, such as c-Src, ABL, JAK, are widely used to treat human cancers. Despite favorable benefits in cancer treatment that prolong survival, these tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting RTKs are also accompanied by adverse effects, including cardiovascular toxicity.

Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells.

SIRT6 belongs to the conserved NAD-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD.

Targeting RAS phosphorylation in cancer therapy: Mechanisms and modulators.

RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades.

Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy.

Allostery, which is one of the most direct and efficient methods to fine-tune protein functions, has gained increasing recognition in drug discovery. However, there are several challenges associated with the identification of allosteric sites, which is the fundamental cornerstone of drug design. Previous studies on allosteric site predictions have focused on communication signals propagating from the allosteric sites to the orthosteric sites.

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication.

Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example.

Mechanistic insights into the effect of phosphorylation on Ras conformational dynamics and its interactions with cell signaling proteins.

Ras undergoes interconversion between the active GTP-bound state and the inactive GDP-bound state. This GTPase cycle, which controls the activities of Ras, is accelerated by Ras GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (SOS). Oncogenic Ras mutations could affect the GTPase cycle and impair Ras functions.

Computational methods-guided design of modulators targeting protein-protein interactions (PPIs).

Protein-protein interactions (PPIs) play a pivotal role in extensive biological processes and are thus crucial to human health and the development of disease states. Due to their critical implications, PPIs have been spotlighted as promising drug targets of broad-spectrum therapeutic interests. However, owing to the general properties of PPIs, such as flat surfaces, featureless conformations, difficult topologies, and shallow pockets, previous attempts were faced with serious obstacles when targeting PPIs and almost portrayed them as "intractable" for decades.

Combining Allosteric and Orthosteric Drugs to Overcome Drug Resistance.

Historically, most drugs target protein orthosteric sites. The gradual emergence of resistance hampers their therapeutic effectiveness, posing a challenge to drug development. Coadministration of allosteric and orthosteric drugs provides a revolutionary strategy to circumvent drug resistance, as drugs targeting the topologically distinct allosteric sites can restore or even enhance the efficacy of orthosteric drugs.

Emergence of allosteric drug-resistance mutations: new challenges for allosteric drug discovery.

Allosteric drugs have several significant advantages over traditional orthosteric drugs, encompassing higher selectivity and lower toxicity. Although allosteric drugs have potential advantages as therapeutic agents to treat human diseases, allosteric drug-resistance mutations still occur, rendering these drugs ineffective. Here, we review the emergence of allosteric drug-resistance mutations with an emphasis on examples covering clinically important therapeutic targets, including Breakpoint cluster region-Abelson tyrosine kinase (Bcr-Abl), Akt kinase [also called Protein Kinase B (PKB)], isocitrate dehydrogenase (IDH), MAPK/ERK kinase (MEK), and SRC homology 2 domain-containing phosphatase 2 (SHP2).