A novel deletion cluster at 13q14.2-q21.33 in an 80-year man with late onset leukemia: Clinical and molecular findings

Chromosomal deletions are among the most common genetic events observed in hematologic malignancies; loss of genetic material is regarded as a hallmark of putative tumor suppressor gene localization. We have identified an unusual cluster of deletions at 13q14.2-13q21.33 in an 80-year-old father of a monozygotic twin pair discordant for schizophrenia, who developed chronic leukemia (CLL) at age 69.

MATERIALS AND METHODS:

The breakpoints for individual deletions in this cluster was identified by Affymetrix Human Array 6.0 screening.

RESULTS:

The deleted segments harbours a number of genes, most associated with cancer as well as a high concentration of LINEs, SINEs and related repeats. The derived chromosome represents an intra-chromosomal re-arrangement that quickly overtook blood progenitor cells probably before age 69 as a cause of CLL.

CONCLUSIONS:

The study highlights the role of ongoing de novo changes at susceptible sites, such as repeat rich regions, in the human genome. Also, it argues for the involvement of genes/deletions in the 13q(14.2-21.33) region in the development of CCL.     

Role of protein kinase N2 (PKN2) in cigarette smoke-mediated oncogenic transformation of oral cells

Smoking is the leading cause of preventable death worldwide. Though cigarette smoke is an established cause of head and neck cancer (including oral cancer), molecular alterations associated with chronic cigarette smoke exposure are poorly studied. To understand the signaling alterations induced by chronic exposure to cigarette smoke, we developed a cell line model by exposing normal oral keratinocytes to cigarette smoke for a period of 12 months. Chronic exposure to cigarette smoke resulted in increased cellular proliferation and invasive ability of oral keratinocytes. Proteomic and phosphoproteomic analyses showed dysregulation of several proteins involved in cellular movement and cytoskeletal reorganization in smoke exposed cells. We observed overexpression and hyperphosphorylation of protein kinase N2 (PKN2) in smoke exposed cells as well as in a panel of head and neck cancer cell lines established from smokers. Silencing of PKN2 resulted in decreased colony formation, invasion and migration in both smoke exposed cells and head and neck cancer cell lines. Our results indicate that PKN2 plays an important role in oncogenic transformation of oral keratinocytes in response to cigarette smoke. The current study provides evidence that PKN2 can act as a potential therapeutic target in head and neck squamous cell carcinoma, especially in patients with a history of smoking.     

SARS-CoV-2 signaling pathway map: A functional landscape of molecular mechanisms in COVID-19

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has been declared a pandemic by WHO. The clinical manifestation and disease progression in COVID-19 patients varies from minimal symptoms to severe respiratory issues with multiple organ failure. Understanding the mechanism of SARS-CoV-2 interaction with host cells will provide key insights into the effective molecular targets for the development of novel therapeutics. Recent studies have identified virus-mediated phosphorylation or activation of some major signaling pathways, such as ERK1/2, JNK, p38, PI3K/AKT and NF-κB signaling, that potentially elicit the cytokine storm that serves as a major cause of tissue injuries. Several studies highlight the aggressive inflammatory response particularly ‘cytokine storm’ in SARS-CoV-2 patients. A depiction of host molecular dynamics triggered by SARS-CoV-2 in the form of a network of signaling molecules will be helpful for COVID-19 research. Therefore, we developed the signaling pathway map of SARS-CoV-2 infection using data mined from the recently published literature. This integrated signaling pathway map of SARS-CoV-2 consists of 326 proteins and 73 reactions. These include information pertaining to 1,629 molecular association events, 30 enzyme catalysis events, 43 activation/inhibition events, and 8,531 gene regulation events. The pathway map is publicly available through WikiPathways: https://www.wikipathways.org/index.php/Pathway:WP5115.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12079-021-00632-4.     

An overview of the oxytocin-oxytocin receptor signaling network

Oxytocin, a nine amino acid long neuropeptide hormone, is synthesized in the hypothalamus and stored and released from the neural lobe of the pituitary gland. Although commonly known for its central role in the regulation of parturition and lactation, oxytocin signaling also plays a key role in modulating social behavior, evoking contentment, initiating maternal behavior, inducing trust, generosity and bonding in humans and animals. Oxytocin signaling can prove to be of great importance in therapeutics and drug targeting because of its diverse range of actions. However, a well annotated map of oxytocin signaling pathway is currently lacking in the publicly available pathway resources. Therefore, we systematically curated the available signaling information of oxytocin from published literature and collated the data to develop a more complete map. We cataloged 66 molecules belonging to oxytocin signaling pathway, which included 9 protein-protein interactions, 39 post-translational modifications, 14 protein translocation events and 22 activation/inhibition events. Further, Oxytocin signaling network data is made freely available to academic fraternity by integrating this into NetPath (http://www.netpath.org/), a freely available human signaling pathway resource developed previously by our group.     

Structure and functional characterization of a bile acid 7α dehydratase BaiE in secondary bile acid synthesis

Conversion of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) to the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) is performed by a few species of intestinal bacteria in the genus Clostridium through a multistep biochemical pathway that removes a 7α‐hydroxyl group. The rate‐determining enzyme in this pathway is bile acid 7α‐dehydratase (baiE). In this study, crystal structures of apo‐BaiE and its putative product‐bound [3‐oxo‐Δ^4,6‐lithocholyl‐Coenzyme A (CoA)] complex are reported. BaiE is a trimer with a twisted α + β barrel fold with similarity to the Nuclear Transport Factor 2 (NTF2) superfamily. Tyr30, Asp35, and His83 form a catalytic triad that is conserved across this family. Site‐directed mutagenesis of BaiE from Clostridium scindens VPI 12708 confirm that these residues are essential for catalysis and also the importance of other conserved residues, Tyr54 and Arg146, which are involved in substrate binding and affect catalytic turnover. Steady‐state kinetic studies reveal that the BaiE homologs are able to turn over 3‐oxo‐Δ⁴‐bile acid and CoA‐conjugated 3‐oxo‐Δ⁴‐bile acid substrates with comparable efficiency questioning the role of CoA‐conjugation in the bile acid metabolism pathway. Proteins 2016; 84:316–331. © 2016 Wiley Periodicals, Inc.     

Fermentative Production of Pyranone Derivate I from Marine Vibrio sp. SKMARSP9: Isolation,Characterization and Bioactivity Evaluation

Pyranone derivative I was isolated from fermented broth of isolated marine bacterial strain Vibrio sp. SKMARSP9. The compound I was characterized, and evaluated for its antimicrobial properties. The isolated strain was identified based on 16S rRNA based phylogenetic analysis. The molecular analysis data suggested that this strain is closely related to Vibrio ruber, Vibrio sp. MSSRF10 and Vibrio rhizosphaerae. The best fermentative growth of this isolate was achieved under halophilic conditions and grew efficiently at 30 °C in the presence of 12 % NaCl. The compound I production by this strain is associated with growth. The unpurified extract is hydrophobic in nature, and released only during late growth phase. The extract was purified and characterized by spectral data using NMR, DEPT, and ESI–MS. The purity of I was 97 % which was confirmed by HPLC. The pyranone derivative I exhibited >50 % antioxidant activity and broad spectrum antimicrobial properties against gram negative and gram positive strains. Molecular docking analysis revealed that this pyranone derivative I may be a potential candidate at pharmaceutical sector.

Electronic supplementary material

The online version of this article (doi:10.1007/s12088-015-0521-0) contains supplementary material, which is available to authorized users.     

Compartmentalized Accumulation of cAMP near Complexes of Multidrug Resistance Protein 4 (MRP4) and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Contributes to Drug-induced Diarrhea

Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3′-azido-3′-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.     

Scanning probe recognition microscopy investigation of tissue scaffold properties

Scanning probe recognition microscopy is a new scanning probe microscopy technique which enables selective scanning along individual nanofibers within a tissue scaffold. Statistically significant data for multiple properties can be collected by repetitively fine-scanning an identical region of interest. The results of a scanning probe recognition microscopy investigation of the surface roughness and elasticity of a series of tissue scaffolds are presented. Deconvolution and statistical methods were developed and used for data accuracy along curved nanofiber surfaces. Nanofiber features were also independently analyzed using transmission electron microscopy, with results that supported the scanning probe recognition microscopy-based analysis.