Clinical bioinformatics desiderata for molecular tumor boards.

Clinical Bioinformatics is a knowledge framework required to interpret data of medical interest via computational methods. This area became of dramatic importance in precision oncology, fueled by cancer genomic profiling: most definitions of Molecular Tumor Boards require the presence of bioinformaticians. However, all available literature remained rather vague on what are the specific needs in terms of digital tools and expertise to tackle and interpret genomics data to assign novel targeted or biomarker-driven targeted therapies to cancer patients.

Picosecond quantum-classical dynamics reveals that the coexistence of light-induced microbial and animal chromophore rotary motion modulates the isomerization quantum yield of heliorhodopsin.

Rhodopsins are light-responsive proteins forming two vast and evolutionary distinct superfamilies whose functions are invariably triggered by the photoisomerization of a single retinal chromophore. In 2018 a third widespread superfamily of rhodopsins called heliorhodopsins was discovered using functional metagenomics. Heliorhodopsins, with their markedly different structural features with respect to the animal and microbial superfamilies, offer an opportunity to study how evolution has manipulated the chromophore photoisomerization to achieve adaptation.

Experimental Assessment of the Electronic and Geometrical Structure of a Near-Infrared Absorbing and Highly Fluorescent Microbial Rhodopsin.

The recently discovered Neorhodopsin (NeoR) exhibits absorption and emission maxima in the near-infrared spectral region, which together with the high fluorescence quantum yield makes it an attractive retinal protein for optogenetic applications. The unique optical properties can be rationalized by a theoretical model that predicts a high charge transfer character in the electronic ground state (S) which is otherwise typical of the excited state S in canonical retinal proteins. The present study sets out to assess the electronic structure of the NeoR chromophore by resonance Raman (RR) spectroscopy since frequencies and relative intensities of RR bands are controlled by the ground and excited state's properties.

Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet.

The RNA-binding protein FUS/TLS interacts with SPO11 and PRDM9 and localize at meiotic recombination hotspots.

In mammals, meiotic recombination is initiated by the introduction of DNA double strand breaks (DSBs) into narrow segments of the genome, defined as hotspots, which is carried out by the SPO11/TOPOVIBL complex. A major player in the specification of hotspots is PRDM9, a histone methyltransferase that, following sequence-specific DNA binding, generates trimethylation on lysine 4 (H3K4me3) and lysine 36 (H3K36me3) of histone H3, thus defining the hotspots. PRDM9 activity is key to successful meiosis, since in its absence DSBs are redirected to functional sites and synapsis between homologous chromosomes fails.

Inhibition of the PI3K/AKT/mTOR signaling promotes an M1 macrophage switch by repressing the ATF3-CXCL8 axis in Ewing sarcoma.

Ewing sarcomas are aggressive pediatric tumors of bone and soft tissues driven by in frame chromosomal translocations that yield fusion proteins guiding the oncogenic program. Promising alternative strategies to ameliorate current treatments involve inhibition of the PI3K/AKT/mTOR pathway. In this study, we identified the activating transcription factor 3 (ATF3) as an important mediator of the PI3K/AKT/mTOR pathway in Ewing sarcoma cells.

Retinal chromophore charge delocalization and confinement explain the extreme photophysics of Neorhodopsin.

The understanding of how the rhodopsin sequence can be modified to exactly modulate the spectroscopic properties of its retinal chromophore, is a prerequisite for the rational design of more effective optogenetic tools. One key problem is that of establishing the rules to be satisfied for achieving highly fluorescent rhodopsins with a near infrared absorption. In the present paper we use multi-configurational quantum chemistry to construct a computer model of a recently discovered natural rhodopsin, Neorhodopsin, displaying exactly such properties.

Oncogenic Dysregulation of Circulating Noncoding RNAs: Novel Challenges and Opportunities in Sarcoma Diagnosis and Treatment.

Sarcomas comprise a heterogeneous group of rare mesenchymal malignancies. Sarcomas can be grouped into two categories characterized by different prognosis and treatment approaches: soft tissue sarcoma and primary bone sarcoma. In the last years, research on novel diagnostic, prognostic or predictive biomarkers in sarcoma management has been focused on circulating tumor-derived molecules as valuable tools.

Engages an Inhibitory Protein Network to Downregulate Expression upon DNA Damage.

Promoter-associated noncoding RNAs (pancRNAs) represent a class of noncoding transcripts driven from the promoter region of protein-coding or non-coding genes that operate as cis-acting elements to regulate the expression of the host gene. PancRNAs act by altering the chromatin structure and recruiting transcription regulators. is driven by the promoter region of and regulates expression in Ewing sarcoma through recruitment of a multi-molecular complex composed of the RNA binding protein Sam68 and the DNA/RNA helicase DHX9.

Exercise-mediated downregulation of MALAT1 expression and implications in primary and secondary cancer prevention.

Long non-coding RNAs (lncRNAs) play critical roles in various biological functions and disease processes including cancer. The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was initially identified as a lncRNA with elevated expression in primary human non-small cell lung tumors with high propensity to metastasize, and subsequently shown to be highly expressed in numerous other human cancers including breast, ovarian, prostate, cervical, endometrial, gastric, pancreatic, sarcoma, colorectal, bladder, brain, multiple myeloma, and lymphoma. MALAT1 is deeply involved in several physiological processes, including alternative splicing, epigenetic modification of gene expression, cellular senescence, healthy aging, and redox homeostasis.

Emerging Contribution of PancRNAs in Cancer.

"Cancer" includes a heterogeneous group of diseases characterized by abnormal growth beyond natural boundaries. Neoplastic transformation of cells is orchestrated by multiple molecular players, including oncogenic transcription factors, epigenetic modifiers, RNA binding proteins, and coding and noncoding transcripts. The use of computational methods for global and quantitative analysis of RNA processing regulation provides new insights into the genomic and epigenomic features of the cancer transcriptome.

Poison-Exon Inclusion in DHX9 Reduces Its Expression and Sensitizes Ewing Sarcoma Cells to Chemotherapeutic Treatment.

Alternative splicing is a combinatorial mechanism by which exons are joined to produce multiple mRNA variants, thus expanding the coding potential and plasticity of eukaryotic genomes. Defects in alternative splicing regulation are associated with several human diseases, including cancer. Ewing sarcoma is an aggressive tumor of bone and soft tissue, mainly affecting adolescents and young adults.

Role of the TAp63 Isoform in Recurrent Nasal Polyps.

The pathogenic molecular mechanisms underlying the insurgence of nasal polyps has not been completely defined. In some patients, these lesions can have a recurrence after surgery removal, and the difference between recurrent and not recurrent patients is still unclear. To molecularly characterize and distinguish between these two classes, a cohort of patients affected by nasal polyposis was analysed.

Small molecule inhibition of Ewing sarcoma cell growth via targeting the long non coding RNA HULC.

Ewing sarcomas (ES) are aggressive pediatric cancers of bone and soft tissues characterized by in frame chromosomal translocations giving rise to chimeric transcription factors, such as EWS-FLI1. An emerging strategy to block EWS-FLI1 activity is represented by the small molecule YK-4-279, which binds to EWS-FLI1 and alters its transcriptional activity. The specific effectors of the anti-oncogenic activity of YK-4-279 are still largely unknown.

Luteolin-7--β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes.

Flavonoids have been demonstrated to affect the activity of many mammalian enzyme systems. Their functional phenolic groups are able to mediate antioxidant effects by scavenging free radicals. Molecules of this class have been found able to modulate the activity of kinases, phospholipase A2, cyclooxygenases, lipoxygenase, glutathione S-transferase, and many others.

The Promoter-Associated Noncoding RNA Assembles a Protein-RNA Complex to Regulate Cyclin D1 Transcription in Ewing Sarcoma.

Most Ewing sarcomas are characterized by the in-frame chromosomal translocation t(11;22) generating the EWS-FLI1 oncogene. EWS-FLI1 protein interacts with the RNA helicase DHX9 and affects transcription and processing of genes involved in neoplastic transformation, including (the cyclin D1 gene), which contributes to cell-cycle dysregulation in cancer. In this study, we found that expression is significantly higher in patients with Ewing sarcoma compared with other sarcomas and that the RNA, a previously uncharacterized promoter-associated noncoding (pnc) transcript, is expressed in Ewing sarcoma cells.

Luteolin-7-glucoside inhibits IL-22/STAT3 pathway, reducing proliferation, acanthosis, and inflammation in keratinocytes and in mouse psoriatic model.

The epidermis is a dynamic tissue in which keratinocytes proliferate in the basal layer and undergo a tightly controlled differentiation while moving into the suprabasal layers. The balance between keratinocyte proliferation, differentiation, and death is essential, and its perturbation can result in pathological changes. Some common skin diseases, such as psoriasis, are characterized by hyperproliferation accompanied by inflammatory reactions, suggesting that molecules with topical anti-inflammatory and ROS scavenging abilities may be useful for their treatment.

OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development.

OTX proteins, homologs of the Drosophila orthodenticle (Otd), are important for the morphogenesis of the neuroectoderm, and for the central nervous system formation. OTX1 and OTX2 are important for the cochlea and macula development, indeed when OTX1 is knocked down, these organs undergo developmental failure. Moreover OTX2 transfection revert this effect in OTX1(-/-) mice.

Cutaneous mosaicism, in KRT1 pI479T patient, caused by the somatic loss of the wild-type allele, leads to the increase in local severity of the disease.

Background: Epidermolytic ichthyosis (BCIE, OMIM 113800), is an autosomal dominant disorder of the skin caused by mutations in keratin genes KRT1 and KRT10. We present two sporadic patients showing a mild diffuse ichthyosis with palmoplantar keratoderma. Interestingly, one of them shows a significant hyperkeratosis of palms and soles similar to those present in the Meleda disease (OMIM 248300).

Antimicrobial particles from emulsion polymerization of methyl methacrylate in the presence of quaternary ammonium surfactants.

The purpose of this Article is to characterize polymeric particles of poly(methylmethacrylate) (PMMA) synthesized in the presence of one of two different quaternary ammonium surfactants (QACs): cetyltrimethylammonium bromide (CTAB) or dioctadecyldimethylammonium bromide (DODAB). The methods used are dynamic light scattering for sizing, polydispersity and zeta potential analysis, scanning electron microscopy (SEM) for morphology visualization, and plating plus colony-forming unities (CFU) counting for the determination of antimicrobial activity. The results point out the high QAC concentration required to obtain cationic and bioactive antimicrobial particles with good colloidal stability and a permanent load of the polymeric network with QACs.

Novel transglutaminase 1 mutations in patients affected by lamellar ichthyosis.

Lamellar Ichthyosis (LI) is a form of congenital ichthyosis that is caused by mutations in the TGM1 gene that encodes for the transglutaminase 1 (TG1) enzyme. Functional inactivation of TG1 could be due to mutations, deletion or insertions. In this study, we have screened 16 patients affected by LI and found six new mutations: two transition/transversion (R37G, V112A), two nonsense mutations and two putative splice site both leading to a premature stop codon.

Structure-activity relationship for quaternary ammonium compounds hybridized with poly(methyl methacrylate).

Hybrid films from poly (methylmethacrylate) (PMMA) and dioctadecyldimethylammonium bromide (DODAB), cetyltrimethylammonium bromide (CTAB), or tetrapropylammonium bromide (TPAB) were characterized by determination of wettability, ellipsometry, atomic force microscopy, active compounds diffusion to water, X-ray photoelectron spectroscopy (XPS) with determination of atomic composition on the films surface, and biocidal activity against Pseudomonas aeruginosa or Staphylococcus aureus. QAC mobility in the films increased from DODAB to CTAB to TPAB. Diffusion and optimal hydrophobic-hydrophilic balance imparted the highest bioactivity to CTAB.

Strength training and older women: a cross-sectional study examining factors related to exercise adherence.

Background: Despite the recognized health benefits, few older women participate in strength-training exercises.

Methods: The purpose of this study was to examine factors related to older women's adherence to strength training after participation in the StrongWomen Program, a nationally disseminated community program. Adherence was defined as > or =4 months of twice-weekly strength training.

Factors related to leader implementation of a nationally disseminated community-based exercise program: a cross-sectional study.

Background: The benefits of community-based health programs are widely recognized. However, research examining factors related to community leaders' characteristics and roles in implementation is limited.

Methods: The purpose of this cross-sectional study was to use a social ecological framework of variables to explore and describe the relationships between socioeconomic, personal/behavioral, programmatic, leadership, and community-level social and demographic characteristics as they relate to the implementation of an evidence-based strength training program by community leaders.