Tumor-Agnostic Treatment for Cancer:When How is Better than Where

In the evolving landscape of precision oncology, genomic characterization of tumor has become crucial in order to move toward a molecular-based therapy for the vast majority of cancers. Recently, translational research has offered new perspectives in systemic cancer treatment thanks to the identification of novel oncogenic targets and the development of new targeted therapies, followed by the latest applications of genomic sequencing. Simultaneously, next-generation sequencing (NGS) has expanded its accessibility, being incorporated into clinical studies at the time of the initial screening, disease progression, and often in longitudinal monitoring of molecular changes. Consequently, new potentially targetable molecular alterations have been identified in several different types of tumors, leading to the development of tumor-agnostic treatments. Being highly selective for specific molecular alterations, these drugs are active against different subtypes of oncogene-addicted cancers. Three of these drugs-pembrolizumab [an anti-programmed death 1 (PD-1) monoclonal antibody (MAb)], larotrectinib [a pan-tropomyosin receptor tyrosine kinase (TRK) inhibitor], and entrectinib [a pan-TRK, anaplastic lymphoma kinase (ALK) and ROS-1 inhibitor]-received US FDA approval in 2017, 2018, and 2019, respectively. In this article, we critically review the clinical studies responsible for FDA approval and the most recently updated results. We then discuss the benefits and limitations of these new methodological approaches, paying particular attention to the largest precision medicine master protocol, NCI-MATCH. Among the benefits, there are the increased chances of offering targeted therapies for patients with specific alterations identified in different types of tumors. Among the limitations, we highlight that the same driver mutation may require different therapeutic strategies in different types of cancers. Additionally, the complex study design undeniably requires a dynamic strategy to enroll patients with considerable economic and managerial efforts.</p

Structural analysis of the double-walled copper-steel cryogenic chamber of the ASTAROTH experiment

This document describes the verification process of structural performance of the double- walled copper-steel cryogenic chamber of the ASTAROTH (All Sensitive crysTal ARray with lOw THreshold) experiment and the evaluation of the stresses generated near the thermal bridge connecting the inner and outer wall. The chamber consists of an external AISI 316L stainless steel dewar and an inner double-walled OF (Oxygen Free) copper dewar connected to an AISI 316L stainless steel flanged collar. The results showed that close to the thermal bridge (copper-steel junction) the stresses slightly exceed the YS of copper at the estimated operating temperature (localised strain-hardening condition). On the other hand, the safety coefficient respect to fracture is well above one for both materials. This condition, together with the fact that limited cooling cycles are expected during the operating life of the system, leads to the assumption that a progressive material hardening will occur in this area, thus locally raising the YS limit

Partially dynamic efficient algorithms for distributed shortest paths

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Mutant p53 as an Antigen in Cancer Immunotherapy

The p53 tumor suppressor plays a pivotal role in cancer and infectious disease. Many oncology treatments are now calling on immunotherapy approaches, and scores of studies have investigated the role of p53 antibodies in cancer diagnosis and therapy. This review summarizes the current knowledge from the preliminary evidence that suggests a potential role of p53 as an antigen in the adaptive immune response and as a key monitor of the innate immune system, thereby speculating on the idea that mutant p53 antigens serve as a druggable targets in immunotherapy. Except in a few cases, the vast majority of published work on p53 antibodies in cancer patients use wild-type p53 as the antigen to detect these antibodies and it is unclear whether they can recognize p53 mutants carried by cancer patients at all. We envision that an antibody targeting a specific mutant p53 will be effective therapeutically against a cancer carrying the exact same mutant p53. To corroborate such a possibility, a recent study showed that a T cell receptor-like (TCLR) antibody, initially made for a wild-type antigen, was capable of discriminating between mutant p53 and wild-type p53, specifically killing more cancer cells expressing mutant p53 than wild-type p53 in vitro and inhibiting the tumour growth of mice injected with mutant p53 cancer cells than mice with wild-type p53 cancer cells. Thus, novel antibodies targeting mutant p53, but not the wild-type isoform, should be pursued in preclinical and clinical studies.</p

Comparative Effectiveness of DPP-4 Inhibitors Versus Sulfonylurea for the Treatment of Type 2 Diabetes in Routine Clinical Practice: A Retrospective Multicenter Real-World Study

Introduction: DPP-4 inhibitors (DPP4i) and sulfonylureas are popular second-line therapies for type 2 diabetes (T2D), but there is a paucity of real-world studies comparing their effectiveness in routine clinical practice. Methods: This was a multicenter retrospective study on diabetes outpatient clinics comparing the effectiveness of DPP4i versus gliclazide extended release. The primary endpoint was change from baseline in HbA1c. Secondary endpoints were changes in fasting plasma glucose, body weight, and systolic blood pressure. Automated software extracted data from the same clinical electronic chart system at all centers. Propensity score matching (PSM) was used to generate comparable cohorts to perform outcome analysis. Results: We included data on 2410 patients starting DPP4i and 1590 patients starting gliclazide (mainly 30–60&nbsp;mg/day). At baseline, the two groups differed in disease duration, body weight, blood pressure, HbA1c, fasting glucose, HDL cholesterol, triglycerides, liver enzymes, eGFR, prevalence of microangiopathy, and use of metformin. Among DPP4i molecules, no difference in glycemic effectiveness was detected. In matched cohorts (n = 1316/group), patients starting DPP4i, as compared with patients starting gliclazide, experienced greater reductions in HbA1c (− 0.6% versus − 0.4%; p &lt; 0.001), fasting glucose (− 14.1&nbsp;mg/dl versus − 8.8&nbsp;mg/dl; p = 0.007), and body weight (− 0.4&nbsp;kg versus − 0.1&nbsp;kg; p = 0.006) after an average 6&nbsp;months follow-up. DPP4i improved glucose control more than gliclazide, especially in patients who had failed with other glucose-lowering medications or were on basal insulin. Conclusions: This large retrospective real-world study shows that, in routine clinical practice, starting a DPP4i allows better glycemic control than starting low-dose gliclazide. Funding: The Italian Diabetes Society, with external support from AstraZeneca

MSI and EBV Positive Gastric Cancer's Subgroups and Their Link With Novel Immunotherapy

Gastric cancers have been historically classified based on histomorphologic features. The Cancer Genome Atlas network reported the comprehensive identification of genetic alterations associated with gastric cancer, identifying four distinct subtypes- Epstein-Barr virus (EBV)-positive, microsatellite-unstable/instability (MSI), genomically stable and chromosomal instability. In particular, EBV-positive and MSI gastric cancers seem responsive to novel immunotherapies drugs. The aim of this review is to describe MSI and EBV positive gastric cancer's subgroups and their relationship with novel immunotherapy.</p

Hetoroporous heterogeneous ceramics for reusable thermal protection systems

Reusable thermal protection systems of reentry vehicles are adopted for temperatures ranging between 1000 and 2000 °C, when gas velocity and density are relatively low; they exploit the low thermal conductivity of their constituent materials. This paper presents a new class of light structural thermal protection systems comprised of a load bearing structure made of a macroporous reticulated SiSiC, filled with compacted short alumina/mullite fibers. Their manufacturing process is very simple and does not require special devices or ambient conditions. The produced hetoroporous heterogeneous ceramics showed high radiations shielding capabilities up to 2000 °C in vacuum. Even after repeated exposures at higher temperatures, a significant degradation of the SiSiC scaffold was not observe

Filtering "genic" open reading frames from genomic DNA samples for advanced annotation

<p>Abstract</p> <p>Background</p> <p>In order to carry out experimental gene annotation, DNA encoding open reading frames (ORFs) derived from real genes (termed "genic") in the correct frame is required. When genes are correctly assigned, isolation of genic DNA for functional annotation can be carried out by PCR. However, not all genes are correctly assigned, and even when correctly assigned, gene products are often incorrectly folded when expressed in heterologous hosts. This is a problem that can sometimes be overcome by the expression of protein fragments encoding domains, rather than full-length proteins. One possible method to isolate DNA encoding such domains would to "filter" complex DNA (cDNA libraries, genomic and metagenomic DNA) for gene fragments that confer a selectable phenotype relying on correct folding, with all such domains present in a complex DNA sample, termed the “domainome”.</p> <p>Results</p> <p>In this paper we discuss the preparation of diverse genic ORF libraries from randomly fragmented genomic DNA using ß-lactamase to filter out the open reading frames. By cloning DNA fragments between leader sequences and the mature ß-lactamase gene, colonies can be selected for resistance to ampicillin, conferred by correct folding of the lactamase gene. Our experiments demonstrate that the majority of surviving colonies contain genic open reading frames, suggesting that ß-lactamase is acting as a selectable folding reporter. Furthermore, different leaders (Sec, TAT and SRP), normally translocating different protein classes, filter different genic fragment subsets, indicating that their use increases the fraction of the “domainone” that is accessible.</p> <p>Conclusions</p> <p>The availability of ORF libraries, obtained with the filtering method described here, combined with screening methods such as phage display and protein-protein interaction studies, or with protein structure determination projects, can lead to the identification and structural determination of functional genic ORFs. ORF libraries represent, moreover, a useful tool to proceed towards high-throughput functional annotation of newly sequenced genomes.</p

A Speed-Up Technique for Distributed Shortest Paths Computation

International audienceWe propose a simple and practical speed-up technique, which can be combined with every distance vector routing algorithm based on shortest paths, allowing to reduce the total number of messages sent by that algorithm. We combine the new technique with two algorithms known in the literature: DUAL, which is part of CISCO's widely used EIGRP protocol, and the recent DUST, which has been shown to be very effective on networks with power law node degree distribution. We give experimental evidence that these combinations lead to an important gain in terms of the number of messages sent by DUAL and DUST at the price of a little increase in terms of space occupancy per node

Predictive and Prognostic Value of Non-Coding RNA in Breast Cancer

For decades since the central dogma, cancer biology research has been focusing on the involvement of genes encoding proteins. It has been not until more recent times that a new molecular class has been discovered, named non-coding RNA (ncRNA), which has been shown to play crucial roles in shaping the activity of cells. An extraordinary number of studies has shown that ncRNAs represent an extensive and prevalent group of RNAs, including both oncogenic or tumor suppressive molecules. Henceforth, various clinical trials involving ncRNAs as extraordinary biomarkers or therapies have started to emerge. In this review, we will focus on the prognostic and diagnostic role of ncRNAs for breast cancer