scholarly journals Towards Understanding the Pathogenicity of DROSHA Mutations in Oncohematology

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2357
Author(s):  
Dmitrii S. Bug ◽  
Artem V. Tishkov ◽  
Ivan S. Moiseev ◽  
Yuri B. Porozov ◽  
Natalia V. Petukhova
Keyword(s):  
Structural Damage ◽  
Clonal Evolution ◽  
Mirna Biogenesis ◽  
Missense Mutations ◽  
Mutational Pressure ◽  
Computational Screening ◽  
Mutation Burden ◽  
Hematopoietic Disorders ◽  
The Impact

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders, which are characterized by accumulation of somatic mutations. The acquired mutation burden is suggested to define the pathway and consequent phenotype of the pathology. Recent studies have called attention to the role of miRNA biogenesis genes in MDS progression; in particular, the mutational pressure of the DROSHA gene was determined. Therefore, this highlights the importance of studying the impact of all collected missense mutations found within the DROSHA gene in oncohematology that might affect the functionality of the protein. In this study, the selected mutations were extensively examined by computational screening, and the most deleterious were subjected to a further molecular dynamic simulation in order to uncover the molecular mechanism of the structural damage to the protein altering its biological function. The most significant effect was found for variants I625K, L1047S, and H1170D, presumably affecting the endonuclease activity of DROSHA. Such alterations arisen during MDS progression should be taken into consideration as evoking certain clinical traits in the malignifying clonal evolution.

scholarly journals The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer

2019 ◽  
Author(s):  
Burcu Aykac Fas ◽  
Mukesh Kumar ◽  
Valentina Sora ◽  
Maliha Mashkoor ◽  
Matteo Lambrughi ◽  
...  
Keyword(s):  
Physical Models ◽  
Missense Mutations ◽  
Cancer Types ◽  
Neutral Mutations ◽  
And Function ◽  
Cellular Components ◽  
The Impact ◽  
Pan Cancer ◽  
Structural Ensemble

AbstractAutophagy is a cellular process to recycle damaged cellular components and its modulation can be exploited for disease treatments. A key autophagy player is a ubiquitin-like protein, LC3B. Compelling evidence attests the role of autophagy and LC3B in different cancer types. Many LC3B structures have been solved, but a comprehensive study, including dynamics, has not been yet undertaken. To address this knowledge gap, we assessed ten physical models for molecular dynamics for their capabilities to describe the structural ensemble of LC3B in solution using different metrics and comparison with NMR data. With the resulting LC3B ensembles, we characterized the impact of 26 missense mutations from Pan-Cancer studies with different approaches. Our findings shed light on driver or neutral mutations in LC3B, providing an atlas of its modifications in cancer. Our framework could be used to assess the pathogenicity of mutations by accounting for the different aspects of protein structure and function altered by mutational events.

Impact of prior chemotherapy or radiation therapy on tumor mutation burden in NSCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2627-2627 ◽  
Author(s):  
Sushma Jonna ◽  
Ari M. Vanderwalde ◽  
Jorge J. Nieva ◽  
Kelsey Anne Poorman ◽  
Michelle Saul ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Somatic Mutations ◽  
Checkpoint Inhibitors ◽  
Smoking Status ◽  
Cytotoxic Chemotherapy ◽  
Missense Mutations ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Significant Difference ◽  
The Impact

2627 Background: Higher non-synonymous tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC) is associated with a higher likelihood of response to checkpoint inhibitors. Tissue samples subject to TMB analysis may be obtained after exposure to cytotoxic chemotherapy or radiation therapy – both of which introduce somatic mutations in DNA and can influence the number of identified mutations. The role of TMB as a potential predictive marker for immunotherapy is evolving, and the impact of prior therapy on TMB could influence interpretation. Methods: Eligible cases were from patients with confirmed NSCLC, available clinical annotation and tumor molecular profiling including TMB analysis at a CLIA-certified genomics laboratory (Caris Life Sciences, Phoenix, AZ) using the Illumina NextSeq platform. TMB was calculated using only missense mutations that had not been previously reported as germline alterations. Treatment history was obtained for each patient under an IRB approved protocol to determine whether patients had had received chemotherapy or radiation therapy in the year prior to collection of the tissue subject to TMB analysis. Data analysis was performed using the chi-square test of deviance to evaluate whether TMB was statistically significantly different between groups, correcting for smoking status. Results: Out of 1,118 patients identified, 459 cases met all eligibility criteria and were evaluated. 76 patients (17%) received either chemotherapy or radiation prior to tissue collection. Samples acquired prior to any therapy had a median TMB of 10 mut/Mb vs. 11 mut/Mb in samples acquired after any therapy. After adjusting for smoking, there was no significant difference in TMB between these cohorts (p = 0.41). Secondary pair wise analysis showed no statistically significant difference in TMB from chemotherapy-naïve and chemotherapy-treated samples (p = 0.28). The same was true for radiation (p = 0.75). Collection of clinical data is ongoing and further analysis, including additional cases will be presented. Conclusions: Though cytotoxic chemotherapy and radiation therapy can introduce somatic mutations, prior exposure to either was not associated with a significant difference in TMB.

scholarly journals Pathogenesis beyond the cancer clone(s) in multiple myeloma

Blood ◽  
2015 ◽  
Vol 125 (20) ◽  
pp. 3049-3058 ◽  
Author(s):  
Giada Bianchi ◽  
Nikhil C. Munshi
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clonal Evolution ◽  
Bone Marrow Microenvironment ◽  
Plasma Cell Dyscrasia ◽  
Cancer Microenvironment ◽  
Resistance To Therapy ◽  
Cancer Pathogenesis ◽  
The Impact

Abstract Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment.

scholarly journals 707. Clarifying the Role of CrrB in Polymxyin-resistant Klebsiella pneumoniae Clinical Isolates Utilizing a Novel CRISPR-Cas9 System

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S254-S255
Author(s):  
Thomas McConville ◽  
Marla Giddins ◽  
Nenad Macesic ◽  
Anne-Catrin Uhlemann
Keyword(s):  
Genetic Manipulation ◽  
Alternative Pathway ◽  
Negative Regulator ◽  
Missense Mutations ◽  
Downstream Targets ◽  
Qrt Pcr ◽  
Carbapenem Resistant ◽  
The Impact ◽  
Carbapenem Resistant Enterobacteriaceae

Abstract Background Polymyxin resistance (PR) threatens the mainstay of therapy for carbapenem-resistant Enterobacteriaceae (CRE) infections. While mgrB disruption accounts for most cases of PR, missense mutations in crrB have been proposed as an alternative pathway for PR through PmrA/B/C upregulation of the pmrHFIJKLM operon. It remains unknown if CrrB acts as a positive or negative regulator on its downstream targets. Methods We assembled a CRISPR-Cas9 system for gene knockouts (KO) in CRE K. pneumoniae (CRKP) using zeocin as a selectable marker. We chose a polymyxin susceptible (PS) and a PR isolate with a missense mutation in crrB (L87V) (NR5337 and NR5083, respectively) for KO. Isolates were transformed with a crrB KO plasmid, grown with zeocin selection, induced with arabinose, and plated on low-salt LB-zeocin/arabinose. KOs were confirmed via PCR and Sanger sequencing. Polymyxin susceptibility was performed with broth-microdilution. Gene expression was determined by qRT-PCR of cDNA extracts. Results Colistin MIC following crrB KO of NR5337 (PS) remained unchanged. In contrast, crrB KO of NR5083 (PR), decreased polymyxin MIC (MIC >128 to 1.0 μg/mL). qRT-PCR of NR5083 did not show increased expression of pmrA/C, nor pmrK. NR5083 ^crrB showed a small decrease in phoQ expression, compared with NR5083, but similar expression of phoP, pmrA/C and pmrK (Table 1). Conclusion Polymyxin MIC decreased >128 fold after crrB KO in a PR isolate, but colistin MIC remained unchanged after KO in a PS isolate. CrrB mutations in PR isolates may confer a gain of function with CrrB acting as a positive regulator on its downstream targets. Contrary to previous literature, no upregulation of pmrA/C and pmrHFIJKLM was detected. Differences in crrB mutations or clonal background may explain this finding. CRISPR-Cas9 may serve as a reliable system for genetic manipulation of CRKP. Further data on the impact of individual crrB missense mutations are needed. Disclosures A. C. Uhlemann, Merck: Investigator, Grant recipient.

Intergroup Threat and Outgroup Attitudes

2013 ◽  
Vol 44 (5) ◽  
pp. 311-319 ◽  
Author(s):  
Marco Brambilla ◽  
David A. Butz
Keyword(s):  
Gay Men ◽  
Social Group ◽  
Welfare Recipients ◽  
Intergroup Attitudes ◽  
Social Policies ◽  
Intergroup Threat ◽  
Economic Threat ◽  
The Impact ◽  
General Climate

Two studies examined the impact of macrolevel symbolic threat on intergroup attitudes. In Study 1 (N = 71), participants exposed to a macrosymbolic threat (vs. nonsymbolic threat and neutral topic) reported less support toward social policies concerning gay men, an outgroup whose stereotypes implies a threat to values, but not toward welfare recipients, a social group whose stereotypes do not imply a threat to values. Study 2 (N = 78) showed that, whereas macrolevel symbolic threat led to less favorable attitudes toward gay men, macroeconomic threat led to less favorable attitudes toward Asians, an outgroup whose stereotypes imply an economic threat. These findings are discussed in terms of their implications for understanding the role of a general climate of threat in shaping intergroup attitudes.

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