Cluster-based radiomics reveal spatial heterogeneity of bevacizumab response for treatment of radiotherapy-induced cerebral necrosis.

Background: Bevacizumab is used in the treatment of radiation necrosis (RN), which is a debilitating toxicity following head and neck radiotherapy. However, there is no biomarker to predict if a patient would respond to bevacizumab.

Purpose: We aimed to develop a cluster-based radiomics approach to characterize the spatial heterogeneity of RN and map their responses to bevacizumab.

Meta-GWAS identifies the heritability of acute radiation-induced toxicities in head and neck cancer.

Background And Purpose: We aimed to the genetic components and susceptibility variants associated with acute radiation-induced toxicities (RITs) in patients with head and neck cancer (HNC).

Materials And Methods: We performed the largest meta-GWAS of seven European cohorts (n = 4,042). Patients were scored weekly during radiotherapy for acute RITs including dysphagia, mucositis, and xerostomia.

NEAR trial: A single-arm phase II trial of neoadjuvant apalutamide monotherapy and radical prostatectomy in intermediate- and high-risk prostate cancer.

Objective: Treatment efficacy of androgen deprivation therapy with radical prostatectomy for intermediate- to high-risk prostate cancer is less well-studied. The NEAR trial is a single-arm, phase II investigation of neoadjuvant apalutamide monotherapy and radical prostatectomy (RP) in the treatment of D'Amico intermediate- and high-risk prostate cancer (NCT03124433).

Materials And Methods: Patients with histologically-proven, D'Amico intermediate- to high-risk prostate adenocarcinoma received apalutamide 240 mg once-daily for 12 weeks followed by RP + /-lymphadenectomy.

Development of a risk classification system combining TN-categories and circulating EBV DNA for non-metastatic NPC in 10,149 endemic cases.

Background: The objective of this study was to construct a risk classification system integrating cell-free Epstein-Barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC).

Methods: Clinical records of 10,149 biopsy-proven, non-metastatic NPC were identified from two cancer centers; this comprised a training ( = 9,259) and two validation cohorts ( = 890; including one randomized controlled phase 3 trial cohort). Adjusted hazard ratio (AHR) method using a two-tiered stratification by cfEBV DNA and TN-categories was applied to generate the risk model.

Lactate dehydrogenase kinetics predict chemotherapy response in recurrent metastatic nasopharyngeal carcinoma.

Background: Lactate dehydrogenase (LDH) is a known prognostic biomarker for the endemic variant of nasopharyngeal carcinoma (NPC). Here, we investigate whether serial changes in LDH level between chemotherapy (CT) cycles are associated with tumour response to CT.

Methods: Patients with biopsy-proven, recurrent or treatment-naïve metastatic NPC (mNPC) were recruited.

The role of gelsolin domain 3 in familial amyloidosis (Finnish type).

In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin.

Structure mapping of dengue and Zika viruses reveals functional long-range interactions.

Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform structure and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates.

Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody.

Dengue virus (DENV) particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the envelope (E) protein fusion loop.

Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches.

The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes.

Modeling the Structure of Keratin 1 and 10 Terminal Domains and their Misassembly in Keratoderma.

The terminal domains of suprabasal keratins of the skin epithelium are very resistant to evidence-based structural analysis because of their inherent flexibility and lack of predictable structure. We present a model for the structure and interactions of the head and tail domains of epidermal keratins 1 and 10, based on all-atom 3D simulations of keratin primary amino acid sequences, and tyrosine phosphorylation predictions, extracted from published databases. We observed that keratin 1 and 10 end domains are likely to form a tetrameric terminal domain complex incorporating a reversibly extendable region potentially acting as a molecular spring.

Designing dual inhibitors of Mdm2/MdmX: Unexpected coupling of water with gatekeeper Y100/99.

Mdm2 and MdmX share high structural similarity in their N-terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99. These observations lead us to speculate that dual inhibitors either (i) stabilize both Mdm2 and MdmX with Y100/99 in the open conformation typically seen in complexes of Mdm2 with p53, or (ii) the dual inhibitors are agnostic to the conformation of Y100/99.

Topology independent comparison of RNA 3D structures using the CLICK algorithm.

RNA molecules are attractive therapeutic targets because non-coding RNA molecules have increasingly been found to play key regulatory roles in the cell. Comparing and classifying RNA 3D structures yields unique insights into RNA evolution and function. With the rapid increase in the number of atomic-resolution RNA structures, it is crucial to have effective tools to classify RNA structures and to investigate them for structural similarities at different resolutions.

Tertiary Element Interaction in HIV-1 TAR.

HIV-1 replication requires binding to occur between Trans-activation Response Element (TAR) RNA and the TAT protein. This TAR-TAT binding depends on the conformation of TAR, and therapeutic development has attempted to exploit this dynamic behavior. Here we simulate TAR dynamics in the context of mutations inhibiting TAR binding.

In Vivo Mapping of Eukaryotic RNA Interactomes Reveals Principles of Higher-Order Organization and Regulation.

Identifying pairwise RNA-RNA interactions is key to understanding how RNAs fold and interact with other RNAs inside the cell. We present a high-throughput approach, sequencing of psoralen crosslinked, ligated, and selected hybrids (SPLASH), that maps pairwise RNA interactions in vivo with high sensitivity and specificity, genome-wide. Applying SPLASH to human and yeast transcriptomes revealed the diversity and dynamics of thousands of long-range intra- and intermolecular RNA-RNA interactions.

Nucleic acid polymeric properties and electrostatics: Directly comparing theory and simulation with experiment.

Nucleic acids are biopolymers that carry genetic information and are also involved in various gene regulation functions such as gene silencing and protein translation. Because of their negatively charged backbones, nucleic acids are polyelectrolytes. To adequately understand nucleic acid folding and function, we need to properly describe its i) polymer/polyelectrolyte properties and ii) associating ion atmosphere.

R248Q mutation--Beyond p53-DNA binding.

R248 in the DNA binding domain (DBD) of p53 interacts directly with the minor groove of DNA. Earlier nuclear magnetic resonance (NMR) studies indicated that the R248Q mutation resulted in conformation changes in parts of DBD far from the mutation site. However, how information propagates from the mutation site to the rest of the DBD is still not well understood.

Dynamical traps in Wang-Landau sampling of continuous systems: Mechanism and solution.

We study the mechanism behind dynamical trappings experienced during Wang-Landau sampling of continuous systems reported by several authors. Trapping is caused by the random walker coming close to a local energy extremum, although the mechanism is different from that of the critical slowing-down encountered in conventional molecular dynamics or Monte Carlo simulations. When trapped, the random walker misses the entire or even several stages of Wang-Landau modification factor reduction, leading to inadequate sampling of the configuration space and a rough density of states, even though the modification factor has been reduced to very small values.

How does a hydrocarbon staple affect peptide hydrophobicity?

Water is essential for the proper folding of proteins and the assembly of protein-protein/ligand complexes. How water regulates complex formation depends on the chemical and topological details of the interface. The dynamics of water in the interdomain region between an E3 ubiquitin ligase (MDM2) and three different peptides derived from the tumor suppressor protein p53 are studied using molecular dynamics.

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2.

The interaction of p53 and MDM2 is modulated by the phosphorylation of p53. This mechanism is key to activating p53, yet its molecular determinants are not fully understood. To study the spatiotemporal characteristics of this molecular process we carried out Brownian dynamics simulations of the interactions of the MDM2 protein with a p53 peptide in its wild type state and when phosphorylated at Thr18 (pThr18) and Ser20 (pSer20).

Mechanism of Stapled Peptide Binding to MDM2: Possible Consequences for Peptide Design.

MDM2 is a negative regulator of p53. The N terminal domain of MDM2 interacts with a helical region of the transcriptional activation domain of p53. Stapled peptides have been designed to mimic this interaction, in order to inhibit p53-MDM2 binding and thereby activate the p53 response.

In vitro selection of mutant HDM2 resistant to Nutlin inhibition.

HDM2 binds to the p53 tumour suppressor and targets it for proteosomal degradation. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2 and abrogates its repressive function. Using a novel in vitro selection methodology, we simulated the emergence of resistance by evolving HDM2 mutants capable of binding p53 in the presence of Nutlin concentrations that inhibit the wild-type HDM2-p53 interaction.

Salt dependence of the radius of gyration and flexibility of single-stranded DNA in solution probed by small-angle x-ray scattering.

Short single-stranded nucleic acids are ubiquitous in biological processes; understanding their physical properties provides insights to nucleic acid folding and dynamics. We used small-angle x-ray scattering to study 8-100 residue homopolymeric single-stranded DNAs in solution, without external forces or labeling probes. Poly-T's structural ensemble changes with increasing ionic strength in a manner consistent with a polyelectrolyte persistence length theory that accounts for molecular flexibility.

Evaluating mixture models for building RNA knowledge-based potentials.

Ribonucleic acid (RNA) molecules play important roles in a variety of biological processes. To properly function, RNA molecules usually have to fold to specific structures, and therefore understanding RNA structure is vital in comprehending how RNA functions. One approach to understanding and predicting biomolecular structure is to use knowledge-based potentials built from experimentally determined structures.