Neurodevelopmental disorders and cancer networks share pathways, but differ in mechanisms, signaling strength, and outcome.

Epidemiological studies suggest that individuals with neurodevelopmental disorders (NDDs) are more prone to develop certain types of cancer. Notably, however, the case statistics can be impacted by late discovery of cancer in individuals afflicted with NDDs, such as intellectual disorders, autism, and schizophrenia, which may bias the numbers. As to NDD-associated mutations, in most cases, they are germline while cancer mutations are sporadic, emerging during life.

Dietary risk assessment of benzophenone derivatives using bread consumption estimates in a Taiwanese population.

Listed as endocrine-disrupting chemicals, benzophenone (BP) and its nine analogues (BPs) are an emerging group of contaminants. The migration of BPs from ultraviolet inks to food has been investigated in many studies; however, few studies have investigated BPs in foods and the risks of human exposure to BPs. We validated a trace and multi-residue method for simultaneously determining 10 BPs, including BP, BP-1, BP-2, BP-3, BP-8, 4-MBP, 2-OHBP, 4-OHBP, M2BB, and PBZ.

Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK.

Neurodevelopmental disorders (NDDs) and cancer share proteins, pathways, and mutations. Their clinical symptoms are different. However, individuals with NDDs have higher probabilities of eventually developing cancer.

Pan-cancer clinical impact of latent drivers from double mutations.

Here, we discover potential 'latent driver' mutations in cancer genomes. Latent drivers have low frequencies and minor observable translational potential. As such, to date they have escaped identification.

HMI-PRED 2.0: a biologist-oriented web application for prediction of host-microbe protein-protein interaction by interface mimicry.

Summary: HMI-PRED 2.0 is a publicly available web service for the prediction of host-microbe protein-protein interaction by interface mimicry that is intended to be used without extensive computational experience. A microbial protein structure is screened against a database covering the entire available structural space of complexes of known human proteins.

A New View of Activating Mutations in Cancer.

A vast effort has been invested in the identification of driver mutations of cancer. However, recent studies and observations call into question whether the activating mutations or the signal strength are the major determinant of tumor development. The data argue that signal strength determines cell fate, not the mutation that initiated it.

Allosteric regulation of autoinhibition and activation of c-Abl.

c-Abl, a non-receptor tyrosine kinase, regulates cell growth and survival in healthy cells and causes chronic myeloid leukemia (CML) when fused by Bcr. Its activity is blocked in the assembled inactive state, where the SH3 and SH2 domains dock into the kinase domain, reducing its conformational flexibility, resulting in the autoinhibited state. It is active in an extended 'open' conformation.

Neurodevelopmental disorders, immunity, and cancer are connected.

Immunity could be viewed as the common factor in neurodevelopmental disorders and cancer. The immune and nervous systems coevolve as the embryo develops. Immunity can release cytokines that activate MAPK signaling in neural cells.

The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia.

BCR-ABL drives chronic myeloid leukemia (CML). BCR binding to GRB2 transduces signaling via the Ras/MAPK pathway. Despite considerable data confirming the binding, molecular-level understanding of exactly how the two proteins interact, and, especially, what are the determinants of the specificity of the SH2 domain-phosphorylated BCR (pBCR) recognition are still open questions.

Open Structural Data in Precision Medicine.

Three-dimensional protein structural data at the molecular level are pivotal for successful precision medicine. Such data are crucial not only for discovering drugs that act to block the active site of the target mutant protein but also for clarifying to the patient and the clinician how the mutations harbored by the patient work. The relative paucity of structural data reflects their cost, challenges in their interpretation, and lack of clinical guidelines for their utilization.

Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.

Here, we discuss the principles of allosteric activating mutations, propagation downstream of the signals that they prompt, and allosteric drugs, with examples from the Ras signaling network. We focus on Abl kinase where mutations shift the landscape toward the active, imatinib binding-incompetent conformation, likely resulting in the high affinity ATP outcompeting drug binding. Recent pharmacological innovation extends to allosteric inhibitor (GNF-5)-linked PROTAC, targeting Bcr-Abl1 myristoylation site, and broadly, allosteric heterobifunctional degraders that destroy targets, rather than inhibiting them.

Artificial intelligence approaches to human-microbiome protein-protein interactions.

Host-microbiome interactions play significant roles in human health and disease. Artificial intelligence approaches have been developed to better understand and predict the molecular interplay between the host and its microbiome. Here, we review recent advancements in computational methods to predict microbial effects on human cells with a special focus on protein-protein interactions.

Allostery, and how to define and measure signal transduction.

Here we ask: What is productive signaling? How to define it, how to measure it, and most of all, what are the parameters that determine it? Further, what determines the strength of signaling from an upstream to a downstream node in a specific cell? These questions have either not been considered or not entirely resolved. The requirements for the signal to propagate downstream to activate (repress) transcription have not been considered either. Yet, the questions are pivotal to clarify, especially in diseases such as cancer where determination of signal propagation can point to cell proliferation and to emerging drug resistance, and to neurodevelopmental disorders, such as RASopathy, autism, attention-deficit/hyperactivity disorder (ADHD), and cerebral palsy.

How can same-gene mutations promote both cancer and developmental disorders?

The question of how same-gene mutations can drive both cancer and neurodevelopmental disorders has been puzzling. It has also been puzzling why those with neurodevelopmental disorders have a high risk of cancer. Ras, MEK, PI3K, PTEN, and SHP2 are among the oncogenic proteins that can harbor mutations that encode diseases other than cancer.

Anticancer drug resistance: An update and perspective.

Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action of the mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer drug resistance is based upon a plethora of distinct mechanisms.

SARS-CoV-2 Interactome 3D: A Web interface for 3D visualization and analysis of SARS-CoV-2-human mimicry and interactions.

Summary: We present a web-based server for navigating and visualizing possible interactions between SARS-CoV-2 and human host proteins. The interactions are obtained from HMI_Pred which relies on the rationale that virus proteins mimic host proteins. The structural alignment of the viral protein with one side of the human protein-protein interface determines the mimicry.

Mechanism of activation and the rewired network: New drug design concepts.

Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism.

Signaling in the crowded cell.

High-resolution technologies have clarified some of the principles underlying cellular actions. However, understanding how cells receive, communicate, and respond to signals is still challenging. Questions include how efficient regulation of assemblies, which execute cell actions at the nanoscales, transmits productively at micrometer scales, especially considering the crowded environment, and how the cell organization makes it happen.

A new precision medicine initiative at the dawn of exascale computing.

Which signaling pathway and protein to select to mitigate the patient's expected drug resistance? The number of possibilities facing the physician is massive, and the drug combination should fit the patient status. Here, we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel (or redundant) proliferation pathways in specialized cells. It considers the availability of each protein in each pathway in the specific cell, its activating mutations, and the chromatin accessibility of its encoding gene.

Phosphorylation and Driver Mutations in PI3Kα and PTEN Autoinhibition.

PI3K and PTEN are the second and third most highly mutated proteins in cancer following only p53. Their actions oppose each other. PI3K phosphorylates signaling lipid PIP to PIP PTEN dephosphorylates it back.

Are Parallel Proliferation Pathways Redundant?

Are the receptor tyrosine kinase (RTK) and JAK-STAT-driven proliferation pathways 'parallel' or 'redundant'? And what about those of K-Ras4B versus N-Ras? 'Parallel' proliferation pathways accomplish a similar drug resistance outcome. Thus, are they 'redundant'? In this paper, it is argued that there is a fundamental distinction between 'parallel' and 'redundant'. Cellular proliferation pathways are influenced by the genome sequence, 3D organization and chromatin accessibility, and determined by protein availability prior to cancer emergence.

The Mystery of Rap1 Suppression of Oncogenic Ras.

Decades ago, Rap1, a small GTPase very similar to Ras, was observed to suppress oncogenic Ras phenotype, reverting its transformation. The proposed reason, persisting since, has been competition between Ras and Rap1 for a common target. Yet, none was found.

HMI-PRED: A Web Server for Structural Prediction of Host-Microbe Interactions Based on Interface Mimicry.

Microbes, commensals, and pathogens, control the numerous functions in the host cells. They can alter host signaling and modulate immune surveillance by interacting with the host proteins. For shedding light on the contribution of microbes to health and disease, it is vital to discern how microbial proteins rewire host signaling and through which host proteins they do this.

Ras assemblies and signaling at the membrane.

Here, we review mechanisms of Ras spatiotemporal clustering with PI3Kα and Raf at the membrane. The large RTK‒Ras‒PI3Kα lipid kinase assembly is at the membrane to generate signaling lipid PIP. Raf, but not PI3Kα, has long linker extending from the membrane to the kinase domain.

Oncogenic K-Ras4B Dimerization Enhances Downstream Mitogen-activated Protein Kinase Signaling.

Ras recruits and activates effectors that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, Raf's activation requires dimerization, which can be facilitated by Ras dimerization. Previously, we showed that active K-Ras4B dimerizes in silico and in vitro through two major interfaces: (i) β-interface, mapped to Switch I and effector-binding regions, (ii) α-interface at the allosteric lobe.