Path Of Discovery Research Articles

Oncogene addiction as a foundation of targeted cancer therapy: The paradigm of the MET receptor tyrosine kinase

Following nearly two decades of its conception, the phenomenon of oncogene addiction still represents a key concept of how progresses in basic research can translate to unprecedented translational breakthroughs. Coined by Bernard Weinstein, this term refers to the phenomenon by which cancer cells can exhibit dependence on a single oncogenic protein or signaling pathway for sustaining proliferation and survival, despite the wide burden of genetic lesions characterizing their genomic background, revealing thus a promising Achilles’ heel of cancer. Importantly, this concept aided the design and clinical implementation of molecularly targeted anticancer therapies, further supporting the paradigm shift witnessed in clinical oncology towards an individual-based, personalized era. In this review, we outline the path of discovery concerning the oncogene addiction concept and focus on the MET receptor tyrosine kinase as a model addicting oncoprotein to further explore potential and pitfalls stemming from the implementation of anticancer strategies targeting tumor dependencies beyond their blending with other therapeutic opportunities.

A Projection Neural Network for Identifying Copy Number Variants.

The identification of copy number variations (CNVs) helps the diagnosis of many diseases. One major hurdle in the path of CNVs discovery is that the boundaries of normal and aberrant regions cannot be distinguished from the raw data, since various types of noise contaminate them. To tackle this challenge, the total variation regularization is mostly used in the optimization problems to approximate the noise-free data from corrupted observations. The minimization using such regularization is challenging to deal with since it is non-differentiable. In this paper, we propose a projection neural network to solve the non-smooth problem. The proposed neural network has a simple one-layer structure and is theoretically assured to have the global exponential convergence to the solution of the total variation-regularized problem. The experiments on several real and simulated datasets illustrate the reasonable performance of the proposed neural network and show that its performance is comparable with those of more sophisticated algorithms.

Abstract 1984: Cell fate reprogramming of liver tumor-initiating stem-like cells via phosphorylated NUMB and TBC1D15

Abstract Tumor-initiating stem-like cells (TICs) are defective in their control of asymmetric division. Stem cells are maintained through asymmetric self-renewing divisions in which one daughter cell commits to a specific fate while the other retains the multipotent characteristics of its parent. The p53 interacting protein NUMB preserves this intrinsic cellular asymmetry and functions as a vital barrier against unchecked expansion as seen in TICs. How TICs overcome this control of asymmetric division to cause cancer is unknown. The hypothesis is that accentuated TLR4-NANOG-mediated NUMB phosphorylation and TBC1D15 upregulation promote self-renewal of TICs in liver oncogenesis caused by HCV and alcohol. Here, we determined the causal roles of NUMB phosphorylation and TBC1D15 oncoprotein in alcohol-induced liver tumorigenesis in HCV-Tg mice. Liver-specific TBC1D15 deficiency or non-phosphorylatable mutations of NUMB, reduce liver tumor incidence and tumor-associated NANOG+ TICs in HCV NS5A Tg mice fed alcohol Western diet. TICs lost asymmetric division capacity and overexpressed TBC1D15, which associated with NUMB to promote aPKCζ activity and NUMB phosphorylation. Thus, TIC self-renewal is dependent on TBC1D15 and NUMB phosphorylation. Similarly, aPKCζ-mediated NUMB phosphorylation and induced TBC1D15 are mutually required for self-renewal. Furthermore, TBC1D15 activated NOTCH via binding to NOTCH intracellular domain to trigger its proteolytic. TBC1D15 interacts with all NOTCH isoforms, activates NOTCH pathway, and induces Nanog and TIC self-renewal in a NOTCH-dependent manner. TBC1D15 cooperates with the NOTCH pathway to support TIC tumorigenic activity and an inhibitor of this interaction is potentially therapeutic. Candidate small molecule antagonists have been tested for their ability to block the interaction of TBC1D15-NOTCH/NICD. The originality of this findings lies within the discovery of the novel oncoprotein TBC1D15 and its unique oncogenic activities involving p53 degradation and cooperation with the NOTCH pathway in TICs and CD133+ Huh7 cells. These mechanistic findings have laid down the foundation for a new translational path for discovery of new therapeutic targets. Citation Format: Keigo Machida, Hifzur R. Siddique, Mengmei Zheng, Peleg Winer, Dinesh Babu Uthaya Kumar, Ahmed Rokan, Linda Sher, Stanley M. Tahara, Michael Elowitz, Chengyu Liang, Hidekazu Tsukamoto. Cell fate reprogramming of liver tumor-initiating stem-like cells via phosphorylated NUMB and TBC1D15 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1984.

Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Revealed LpxC as a Potential Drug Target Against Multi-Drug Resistant Klebsiella pneumoniae

The emergence and dissemination of pan drug resistant clones of Klebsiella pneumoniae are great threat to public health. In this regard new therapeutic targets must be highlighted to pave the path for novel drug discovery and development. Subtractive proteomic pipeline brought forth UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC), a Zn+2 dependent cytoplasmic metalloprotein and catalyze the rate limiting deacetylation step of lipid A biosynthesis pathway. Primary sequence analysis followed by 3-dimensional (3-D) structure elucidation of the protein led to the detection of K. pneumoniae LpxC (KpLpxC) topology distinct from its orthologous counterparts in other bacterial species. Molecular docking study of the protein recognized receptor antagonist compound 106, a uridine-based LpxC inhibitory compound, as a ligand best able to fit the binding pocket with a Gold Score of 67.53. Molecular dynamics simulation of docked KpLpxC revealed an alternate binding pattern of ligand in the active site. The ligand tail exhibited preferred binding to the domain I residues as opposed to the substrate binding hydrophobic channel of subdomain II, usually targeted by inhibitory compounds. Comparison with the undocked KpLpxC system demonstrated ligand induced high conformational changes in the hydrophobic channel of subdomain II in KpLpxC. Hence, ligand exerted its inhibitory potential by rendering the channel unstable for substrate binding.

Consumer Behaviour towards Marketing Mix in Organized Retail: A Study with reference to Supermarkets in Mangalore

Numerous of studies have observed that science & technology (S&T) and intellectual property rights (IPRs) regime are useful and effective to maintain the economic and social development in different economies. However, earlier studies found positive and negative impact of S&T and IPRs on economic growth and development in variouscountries. China, Indonesia, South Korea, Thailand, Malaysia are the greater competitors for Indian economy in IPRs and S&T. These economies have a greater share of manufacturing and industrial sector in their GDP due to their effective contribution in S&T and IPRs related activities. Hence, this study assesses the role of IPRs and S&T in socio-economic development in aforementioned economies based on existing studies. Furthermore, it provides the recent trend in economic, IPRs, S&T and business related indicators for India and selected Asian economies. Thereupon, it makes India’s comparison in IPRs and S&Tassociated indicators among the selected Asian economies. It examines the India’s position in economic, IPRs, S&T and entrepreneurship related indicators as compared to other economies. Finally, it come up with several policy proposal to increase the involvement of IPRs and S&T in socio-economic development in Asian economies. It recommended that research & development (R&D) expenditure is a crucial driver to attract the attention of researchers and scientists towards IPRs, subsequently it give incentive to existing researchers to increase their participation in R&D and S&T related activities. It suggested that S&T and IPRs activities create a path for innovation and discovery of new technologies for production of goods and services

Study of anticancer and antibacterial activities of Foeniculum vulgare, Justicia adhatoda and Urtica dioica as natural curatives.

High-throughput technologies, such as synthetic biology and genomics have paved new paths for discovery and utility of medicinally beneficial plants. Bioactive molecules isolated from different plants have significantly higher biological activities. The present study was done to analyze antibacterial potential of some medicinal plants against multi drug resistant (MDR) pathogens and anticancer effect against MCF-7 cell line. Methanolic and ethanolic extracts were tested for their antibacterial activity by disc diffusion method against six MDR bacterial strains and for cytotoxicity evaluation by MTT assay. Ethanolic extracts of the three tested plants exhibited growth inhibitory effect against Klebsiella pneumonia, Serratia marcescens and Methicillin-resistant S. aureus. Pseudomonas aeruginosa was more resistant to all extracts as its growth was least inhibited by the extracts of all tested plants. Ethanol extract of Foeniculum vulgare exhibited significant inhibition of cancer cells proliferation. Methanol extract of Justicia adhatoda also showed considerable inhibition of cancer cells. Future studies must converge on detailed investigation of modes of action of extracts of tested plants.

Two Basic Scientists Walk into a Translational Space

When John Schiller first joined Douglas Lowy's lab at the National Cancer Institute of the NIH, he could have not predicted that their common interest in the molecular biology of oncogenes would set them in path for discoveries that ultimately enabled the development of a vaccine for the human papillomavirus, which causes the majority of cervical cancers worldwide. John and Doug, the recipients of the 2017 Lasker-DeBakey Clinical Award, have joined Cell editor João Monteiro in a Conversation about science, public health, and the joys and challenges of being basic scientists in a translational space. Annotated excerpts from this conversation are presented below.

Binary Quantitative Structure-Activity Relationship Analysis to Increase the Predictive Ability of Structure-Based Virtual Screening Campaigns Targeting Cyclooxygenase-2

Structure-Based Virtual Screening (SBVS) campaigns employing Protein-Ligand Interaction Fingerprints (PLIF) identification have served as a powerful strategy in fragments and ligands identification, both retro- and prospectively. Most of the SBVS campaigns employed PLIF by comparing them to a reference PLIF to calculate the Tanimoto-coefficient. Since the approach was reference dependent, it could lead to a very different discovery path if a different reference was used. In this article, references independent approach, i.e. decision trees construction using docking score and PLIF as the descriptors to increase the predictive ability of the SBVS campaigns in the identification of ligands for cyclooxygenase-2 is presented. The results showed that the binary Quantitative-Structure Activity Relationship (QSAR) analysis could significantly increase the predictive ability of the SBVS campaign. Moreover, the selected decision tree could also pinpoint the molecular determinants of the ligands binding to cyclooxygenase-2.

Searching with Maps: Impact of the Human Genome Project on Drug Discovery

Scientific maps, like cartographic maps, provide a high-level representation of the knowledge landscape setting the path for new discoveries, but the impact on maps on firm innovation and technolog...

The Consumer Behavior Challenge: Designing an Assignment to Motivate Student Reflection and Self-Growth

The tension caused by change pushes students to reflect on their new situation, examine preconceived ideas, and synthesize new with existing knowledge. In the Consumer Behavior Challenge, students are challenged to step outside of their comfort zone by changing a behavior or trying something new for a period of time. Through guided reflection questions and writing a blog entry, students work to make sense of their challenge experience and recognize consumer behavior concepts that affect their behaviors. The assignment helps motivate deeper levels of thinking and sets students on a path of academic and personal discovery and growth.

One More Thing …

One More Thing …

Path of translational discovery of urological complications of obesity and diabetes

Diabetes mellitus (DM) is a prevalent chronic disease. Type 1 DM (T1DM) is a metabolic disorder that is characterized by hyperglycemia in the context of absolute lack of insulin, whereas type 2 DM (T2DM) is due to insulin resistance-related relative insulin deficiency. In comparison with T1DM, T2DM is more complex. The natural history of T2DM in most patients typically involves a course of obesity to impaired glucose tolerance, to insulin resistance, to hyperinsulinemia, to hyperglycemia, and finally to insulin deficiency. Obesity is a risk factor of T2DM. Diabetes causes some serious microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy, angiopathy and stroke. Urological complications of obesity and diabetes (UCOD) affect quality of life, but are not well investigated. The urological complications in T1DM and T2DM are different. In addition, obesity itself affects the lower urinary tract. The aim of this perspective is to review the available data, combined with the experience of our research teams, who have spent a good part of last decade on studies of association between DM and lower urinary tract symptoms (LUTS) with the aim of bringing more focus to the future scientific exploration of UCOD. We focus on the most commonly seen urological complications, urinary incontinence, bladder dysfunction, and LUTS, in obesity and diabetes. Knowledge of these associations will lead to a better understanding of the pathophysiology underlying UCOD and hopefully assist urologists in the clinical management of obese or diabetic patients with LUTS.

Inverting the design path for self-assembled block copolymers

Recent success of inverse design methodologies in the realm of self-assembled materials has allowed us to envision an inverse path of discovery where we go from a desired target function to building blocks.

The evolution of drug design at Merck Research Laboratories.

On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc. To this end, the concept of design is now front and center in all aspects of discovery, safety assessment and early clinical development. At present, the Merck design group includes computational chemistry, protein structure determination, and cheminformatics. By bringing these groups together under one umbrella, we were able to align activities and capabilities across multiple research sites and departments. This alignment from 2010 to 2016 resulted in an 80% expansion in the size of the department, reflecting the increase in impact due to a significant emphasis across the organization to "design first" along the entire drug discovery path from lead identification (LID) to first in human (FIH) dosing. One of the major advantages of this alignment has been the ability to access all of the data and create an adaptive approach to the overall LID to FIH pathway for any modality, significantly increasing the quality of candidates and their probability of success. In this perspective, we will discuss how we crafted a new strategy, defined the appropriate phenotype for group members, developed the right skillsets, and identified metrics for success in order to drive continuous improvement. We will not focus on the tactical implementation, only giving specific examples as appropriate.

Reverse Pharmacology Effectuated by Studies of Ayurvedic Products for Arthritis

Reverse pharmacology (RP) is a trans-disciplinary path for drug discovery and development from bedside observations on drug effects to bench-side experiments. This approach generates evidence of safety and efficacy at different levels of biological organization, ranging from cell to community. Eventually the innovative integration of research methods will be translated back to the bedside as a new drug. The experiential wisdom of traditional systems like Ayurveda is scientifically explored by systematic RP. This is meant to enrich modern medicine, by the relevant application of the drug discovery sciences. The evidence by RP would also help to rationally understand Ayurveda. This article highlights how the bedside experience in arthritis has been translated by RP into evidence by defined experimental and clinical studies. There is a need to understand and apply the basic principles and practices of Ayurveda in the specific protocols and models in RP so as to truly integrate effective and safe usage for definite indications. The article also discusses the RP approach for Ayurvedic medicines used for treatment of arthritis.

A armadilha do conto: um mapa de leitura

By combining some convergent concepts for a theory of reading, this article attempts to explore the basis on which are founded the construction of semantic atmosphere and aesthetics of a short story. It is analyzed some structural aspects of Good night, Mary by Lygia Fagundes Telles, focusing on comprehension strategies of a certain line of perspective and diagnosis for reader training. Both teacher and student become partners of a somewhat endless and discovery paths involving pleasure and technical knowledge of the text, particularly taking it as a human phenomenon to understand.

A Novel Phenanthridionone Based Scaffold As a Potential Inhibitor of the BRD2 Bromodomain: Crystal Structure of the Complex.

Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET (bromodomain and extra-terminal) family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases. By a rational structure-based approach, we have identified a new inhibitor (NSC127133) of the second bromodomain (BD2) of the BET family protein BRD2 using the NCI Diversity Set III library. A high-resolution crystal structure of the BRD2-BD2 in complex with this compound and in apo- form is refined to 0.91 and 0.94 Å, respectively. The compound, which is a phenanthridinone derivative, binds well to the acetyl-lysine binding pocket of BD2 and displays significant hydrophobic and hydrophilic interactions. Moreover, the atomic resolution data obtained in this study allowed us to visualize certain structural features of BD2 which remained unobserved so far. We propose that the discovered compound may be a potential molecule to develop a new library for inhibiting the BRD2-BD2 function.

From Protein Folding to Cognition: The Serendipitous Path of Discovery

A screen for small molecule modulators of the unfolded protein response yielded ISRIB, a drug‐like compound that with high efficacy renders cells insensitive to translational inhibition by phosphorylation of eIF2. ISRIB proved to be a cognitive enhancer in rodents, significantly improving long‐term memory of wild‐type animals in behavioral assays.

Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer.

For more than half a century the pharmaceutical industry has sifted through natural products produced by microbes, uncovering new scaffolds and fashioning them into a broad range of vital drugs. We sought a strategy to reinvigorate the discovery of natural products with distinctive structures using bacterial genome sequencing combined with metabolomics. By correlating genetic content from 178 actinomycete genomes with mass spectrometry-enabled analyses of their exported metabolomes, we paired new secondary metabolites with their biosynthetic gene clusters. We report the use of this new approach to isolate and characterize tambromycin, a new chlorinated natural product, composed of several nonstandard amino acid monomeric units, including a unique pyrrolidine-containing amino acid we name tambroline. Tambromycin shows antiproliferative activity against cancerous human B- and T-cell lines. The discovery of tambromycin via large-scale correlation of gene clusters with metabolites (a.k.a. metabologenomics) illuminates a path for structure-based discovery of natural products at a sharply increased rate.

Use of synthetic grafts in pelvic reconstruction: A path of continued discovery

Use of synthetic grafts in pelvic reconstruction: A path of continued discovery