Identifying enriched drug fragments as possible candidates for metabolic engineering

Background: Fragment-based approaches have now become an important component of the drug discovery process. At the same time, pharmaceutical chemists are more often turning to the natural world and its extremely large and diverse collection of natural compounds to discover new leads that can potentially be turned into drugs. In this study we introduce and discuss a computational pipeline to automatically extract statistically overrepresented chemical fragments in therapeutic classes, and search for similar fragments in a large database of natural products. By systematically identifying enriched fragments in therapeutic groups, we are able to extract and focus on few fragments that are likely to be active or structurally important. Results: We show that several therapeutic classes (including antibacterial, antineoplastic, and drugs active on the cardiovascular system, among others) have enriched fragments that are also found in many natural compounds. Further, our method is able to detect fragments shared by a drug and a natural product even when the global similarity between the two molecules is generally low. Conclusions: A further development of this computational pipeline is to help predict putative therapeutic activities of natural compounds, and to help identify novel leads for drug discovery

Investigating the Role of TP53 in Peripheral T-Cell Lymphoma-GATA3 Subtype

Introduction: Non-Hodgkin Lymphoma (NHL) accounts for 4.1% of all cancers in the United States. Peripheral T-Cell Lymphoma (PTCL) consists of ~10-15% of all NHL in the Western world. 30-50% of these PTCLs are not classifiable/diagnosed and are instead designated as PTCL-Not Otherwise Specified (PTCL-NOS). The two major molecular subgroups within PTCL-NOS are PTCL-TBX21 and PTCL-GATA3, determined by their distinct T-helper (TH) transcriptional programs. GATA3 and TBX21 are the master-transcriptional regulators of TH2- and TH1-cell differentiation, respectively. The overall survival analysis of PTCL-NOS cases illustrates the clinical outcome of PTCL-GATA3 cases are significantly lower than PTCL-TBX21 cases over a broad timeframe. Thus, the need for understanding the underlying mechanism and finding therapeutic targets is at the utmost importance. Background: TP53 mutations and/or TP53 loss deletions are frequent in PTCL-GATA3 cases, compared to PTCL-TBX21. TP53 is a protein that is essential in cycle regulation but also acts as a tumor suppressor. It stops cells from dividing if they have mutated or damaged DNA. Due to the high mutation rates observed in this subtype, we believe TP53 could play a major role in this mechanism. Therefore, it was important to focus on the TP53-GATA3 interaction at the genomic level. Prior studies using chromatin immunoprecipitation (ChIP)-qPCR on the intron 3 full GATA3 region suggested there was more TP53 binding in this intron region compared to other regions. Therefore, we designed a research strategy to determine the specific binding regions of TP53-GATA3 interaction and the function of the TP53 binding.https://digitalcommons.unmc.edu/surp2023/1003/thumbnail.jp

Integrative Analysis of Clinicopathological Features Defines Novel Prognostic Models for Mantle Cell Lymphoma in the Immunochemotherapy Era: A Report from The North American Mantle Cell Lymphoma Consortium

BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p \u3c 0.0001) and progression-free survival (PFS, p \u3c 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p \u3c 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL