Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led ...to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAFV600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.
Tumor-agnostic, or histology-agnostic, cancer therapy marks a groundbreaking evolution in the realm of precision oncology. In stark contrast to conventional cancer treatments that categorize ...malignancies based on their tissue of origin (eg, breast, lung, renal cell, etc), tumor-agnostic therapies transcend histologic boundaries, honing in on the genetic and molecular attributes of tumors, regardless of their location. This article offers a comprehensive review of the current landscape of tissue-agnostic cancer therapies and provides clinical insights to empower surgical oncologists with a deeper understanding of these innovative therapeutic approaches.
A new heterocyclic azo dye ligand (L) was synthesized by the combination of 4-amino antipyrine with 4-aminophenol. The new Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) ...complexes were synthesized in excellent yields. The metal chelate structures were elucidated using elemental analyses, FT-IR,
H-NMR, mass, magnetic moment, diffused reflectance spectral and thermal analysis (TG-DTG), and molar conductivity measurement. According to the FT-IR study, the azo dye ligand exhibited neutral tri-dentate behavior, binding to the metal ions with the azo N, carbonyl O, and protonated phenolic OH. The
H-NMR spectral study of the Zn(II) complex supported the coordination of the zo dye ligand without proton displacement of the phenolic OH. Diffused reflectance and magnetic moment studies revealed the octahedral geometry of the complexes, as well as their good electrolytic nature, excepting the Zn(II) and Cd(II) complexes, which were nonelectrolytes, as deduced from the molar conductivity study. The theoretical calculations of optimized HOMO-LUMO energies, geometrical parameters, electronic spectra, natural atomic charges, 3D-plots of MEP, and vibrational wavenumbers were computed and elucidated using LANL2DZ and 6-311G (d, p) basis sets of density functional theory (DFT) with the approach of B3LYP DFT and TD-DFT methods. The ligand and complexes have been assayed for their antimicrobial activity and compared with the standard drugs. Most of the complexes have manifested excellent antimicrobial activity against various microbial strains. A molecular docking investigation was also performed, to acquire more information about the binding mode and energy of the ligand and its metal complexes to the
receptor using molecular docking. Altogether, the newly created ligand and complexes showed positive antibacterial effects and are worth future study.
•Present a physical condition assessment model for existing educational buildings.•Predict the future condition data of building components via an ANN and SEM model.•Determine the maintenance level ...metrics for interventions and foreseeable timing.•Prioritize building components for maintenance purposes.•Record the parameters influencing the condition state of building components.
Building facilities condition assessment is considered a fundamental aspect of an effective decision-making maintenance management plan to fulfill service requirements. A noticeable dearth of studies is believed to have delivered condition assessment approaches for existing buildings; however, these approaches are still deemed premature, with some limitations in demand enhancement. This paper presents a novel physical condition assessment framework for existing educational buildings that contribute to the body of knowledge by offering a state-of-the-art approach incorporating an Artificial Neural Network (ANN) predictive model and a Structural Equation Model (SEM). The ANN predictive model aims to forecast the future condition-rating states for each facility component in various building spaces. Simultaneously, the SEM determines the proportionate weights of building facilities components. The primary objectives of this paper are to prioritize building components for maintenance purposes and record the potential effects of several parameters influencing the condition state of building components. These objectives can be achieved via four sequential modules: 1) scan to BIM module; 2) condition assessment prediction module; 3) proportionate weight determination module; and 4) entire space rating value module. Condition-monitoring data on six different buildings' internal components are analyzed to anticipate their future condition. The components carried out are: 1) wooden flooring tiles; 2) gypsum board ceiling tiles; 3) wooden doors; 4) wooden windows, 5) split air conditioner units; and 6) desktop computers. The overall coefficient of determination (R2) of the developed ANN models for the predicted six components conditions are 0.99, 0.99, 0.927, 0.88, 0.97, and 0.972, respectively.
Rearranged during transfection (RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways. Activating RET alterations can occur and lead ...to uncontrolled cellular proliferation as a hallmark of cancer development. Oncogenic RET fusions are present in nearly 2% of patients with non-small cell lung cancer (NSCLC), 10–20% of patients with thyroid cancer, and <1% across the pan-cancer spectrum. In addition, RET mutations are drivers in 60% of sporadic medullary thyroid cancers and 99% of hereditary thyroid cancers. The discovery, rapid clinical translation, and trials leading to FDA approvals of selective RET inhibitors, selpercatinib and pralsetinib, have revolutionized the field of RET precision therapy. In this article, we review the current status on the use of the selective RET inhibitor, selpercatinib, in RET fusion-positive tumors: NSCLC, thyroid cancers, and the more recent tissue-agnostic activity leading to FDA approval.
In the existing building facilities context, the BIM substantial intervention concerning semantics and as-is information based portrayal for maintenance requirements is very confined. This ...confinement stresses the challenges associated with the lack and absence of reusing existing building facilities, as is domain knowledge. Within this scope, this paper proposes a novel approach for existing building facilities semantic-enrichment from indoor digital scanning portrayal phase to semantics depiction and management phase for renovation, rehabilitation, or restoration functions. In this paper, we present an ontological system, which relies on integrating the as-is information BIM and semantic web technology. The developed approach improves existing building facilities, as-is information formalization, and management for maintenance purposes. The paper outcome is a semantically integrated knowledge-based framework that can potentially: 1) constitute a semantic database for building facilities components as-is information using BIM; 2) overcome the lack and absence of retrieving and reusing building facilities as-is domain information; and (3) formalize the building facilities as-is knowledge in a computable way.
•Integrating the as-is information BIM and semantic web technology to ensure versatile formalization and management of existing building as-is information.•Proposing an ontological system by employing semantic web technology to add semantic-enrichment for indoor building facilities.•Constituting a semantic database for the building facilities components using BIM capabilities and open standards.•Formalizing the as-is knowledge of existing building facilities in a computable way.
•SA + L-cys + CA inhibited the browning and microbial growth of lotus root slices.•Visual appearance, physicochemical and bacterial diversity were assessed.•The dominant bacteria in lotus root slices ...before and after storage were found.•The possible regulation mechanism of SA + L-cys + CA in browning were proposed.•SA + L-cys + CA could maintain the quality and extend the shelf-life of lotus root slices.
The effects of a sodium alginate (SA) coating combined withl-cysteine (L-cys) and citric acid (CA) on browning and microbial growth in fresh-cut lotus root slices during storage at 4 °C were investigated. The SA + L-cys + CA treatment was more efficient than separate SA andl-cys + CA treatments in the maintenance of visual appearance and flavour quality. The SA + L-cys + CA coating improved the ability of antioxidant enzymes (superoxide dismutase, catalase and ascorbate peroxidase) to scavenge reactive oxygen species, including O2·− and H2O2. In comparison to the control, the SA + L-cys + CA treatment lowered the activity of phenylalanine ammonia lyase, peroxidase, and membrane lipid-degrading enzymes (phospholipase D, lipase and lipoxygenase) and furthermore, maintained high amounts of unsaturated and saturated fatty acids as well as low levels of phenolics and malondialdehyde. The bacterial diversity in lotus root slices was also determined and discussed. The SA + L-cys + CA treatment could maintain the shelf-life of fresh-cut lotus root slices for 14 d at 4 °C, which provides a theoretical basis for commercial application.
Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic ...anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.
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