The interactions between cancer cells and their micro- and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.

/pdf/putting-tumours-in-context-34s3il1it4.pdf

Putting tumours in context

MicroRNAs (miRNAs) are critical regulators of gene expression. Amplification and overexpression of individual 'oncomiRs' or genetic loss of tumour suppressor miRNAs are associated with human cancer and are sufficient to drive tumorigenesis in mouse models. Furthermore, global miRNA depletion caused by genetic and epigenetic alterations in components of the miRNA biogenesis machinery is oncogenic. This, together with the recent identification of novel miRNA regulatory factors and pathways, highlights the importance of miRNA dysregulation in cancer.

MicroRNA biogenesis pathways in cancer

MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that function in regulation of gene expression. Compelling evidences have demonstrated that miRNA expression is dysregulated in human cancer through various mechanisms, including amplification or deletion of miRNA genes, abnormal transcriptional control of miRNAs, dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. MiRNAs may function as either oncogenes or tumor suppressors under certain conditions. The dysregulated miRNAs have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, activating invasion and metastasis, and inducing angiogenesis. An increasing number of studies have identified miRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools, which needs further investigation and validation. In this review, we focus on how miRNAs regulate the development of human tumors by acting as tumor suppressors or oncogenes.

/pdf/the-role-of-micrornas-in-human-cancer-2ggotut2k7.pdf

The role of MicroRNAs in human cancer

https://www.jbc.org/content/273/10/5419.full.pdf

Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signaling Complexes” at the Plasma Membrane

The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.

Cutting Edge: 1,25-dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression


Conference Title: 2nd QuIESCENT (Quantifying the Indirect Effect: from Sources to Climate Effects of Natural and Transported aerosol in the Arctic) Workshop
What: Atmospheric scientists, shared and discussed recent work to understand the complex interactions between aerosols, clouds, precipitation, radiation and dynamics at northern high latitudes, as well as recent and upcoming field campaigns to improve that understanding.
When: 30 March – 1 April, 2022
Where: Tromsø, Norway

/pdf/furthering-understanding-of-aerosol-cloud-precipitation-24ttbksz.pdf

Furthering Understanding of Aerosol-Cloud-Precipitation Interactions in the Arctic

Computational Cloning and Analysis of Human Kallikrein 6 Orthologue Genes

The role of metal cations in the photosynthesis of the blue-green bacteria (cyanobacteria) has interested researchers for more than two decades. Recent extraction experiments of membranes subfractions with metal chelators and experiments with Ca-deficient cultures of giese organisms emphasize the fundamental importance of tightly-bound Ca2+ for PSII (reviewed by Brand; ref 1).

Functional Interactions of Anions and Cations with the outer Surface of Intact Thylakoids: Studies with the Blue-Green Bacterium AnacystisNidulans National Research Center Demokritos, Department of Biology, Athens 153 10, Greece

La presente invention concerne des methodes et des compositions pharmaceutiques de traitement du syndrome de Netherton. La presente invention concerne en particulier une methode de traitement du syndrome de Netherton chez un sujet en ayant besoin, consistant a administrer au sujet une quantite therapeutiquement efficace d'au moins un inhibiteur de l'elastase.

Méthodes et compositions pharmaceutiques de traitement du syndrôme de netherton

Dear Editors We read with great interest the recent publication by Lee et al., in which the important paper by Lovell et al. is presented as the first report of activity-based protein profiling (ABPP) selective for individual KLKs in a complex biological context. Fairly, at the exact same time when the manuscript by Lovell et al. appeared, a novel KLK7-specific phosphonate activity-based probe (ABP) was reported, which could discriminate KLK7 from other active KLKs. That ABP was used to quantify the active KLK7 in situ, specifically, in the epidermis, in a pathological setting in which multiple KLK proteases are active and functionally implicated in disease. The KLK7-ABP was also modified to a quenched ABP (qABP) to enable monitoring of KLK7 activity in vivo. Notably, the KLK7-ABP rescued major disease hallmarks, when applied onto the epidermis of Spink5Klk5 mice. Spink5 mice represent an established preclinical model that recapitulates the overdesquamating and inflammatory skin disease named Netherton syndrome, a rare ichthyosis caused by inactivating mutations in SPINK5 encoding the LEKTI inhibitor of serine proteases. It is well established that LEKTI deficiency causes unopposed (disease causative) proteolytic activities in the epidermis. In Spink5Klk5, Klk5 was genetically ablated on the Netherton background to provide proof of concept for drugging the KLK5 activity for pharmacotherapy of Netherton syndrome and, potentially, other diseases like atopic dermatitis. The Spink5Klk5 model proved that KLK5 represents a novel drug target. Nevertheless, inhibition of KLK5 is not sufficient for permanent rescue/therapy of this very severe (potentially lethal) disease, since delayed inflammation develops soon in these mice due to KLK7 activity. This was also revealed by the fact that inhibition with the KLK7-ABP attenuates inflammation. Thus, additional targeting of inflammation is required in Spink5Klk5 with either KLK7 inhibitors or anti-TNFα biologics. Overall, these studies have provided a strong rational for drugging the KLK family and set the grounds for pharmaceutical development of the recently described boronate inhibitor for KLK5. For the first time, use of the KLK7-ABP (in combination with genetic knockout) allowed validation of the given KLK7 activity as a drug target in a well-established disease context in vivo and provided preclinical proof of concept for using ABPs targeting the KLKs as theranostics, namely dually exploitable for disease diagnosis and treatment. Previously, ABPs for cathepsins were used as theranostics and cancer imaging tools by the group of Galia Blum. Beyond these studies that established KLKs as druggable targets in skin pathologies, targeting KLKs for treatment of prostate cancer was the subject of studies performed more than a decade ago. Specifically, the prostate proteases KLK2 and KLK3 were exploited for activation of anticancer prodrugs developed for treatment of prostate cancer. Drugging KLKs for prostate cancer, for example, resulted in a boronic acidbased inhibitor of KLK3, while KLKs have been clinically tested by various approaches, and there have been success stories in this respect, PROSTVAC (an active immunotherapy vaccine that contains KLK3/PSA) being one such example. In contrast to the Lee et al. KLKs are druggable. Following mapping of the KLK gene cluster in 2000, extensive knowledge was accumulated on the abundance of immunoreactive KLKs in normal and cancer-related settings, revealing these enzymes as potential biomarkers and/or therapeutic targets for cancer but also other diseases, including viral infections of high current interest. This triggered attempts to quantify the active forms of KLK proteases in biological and clinical samples. Coordinated dysregulation of specific KLKs in disease states (including cancer, inflammation, and neurodegeneration) suggested that multiple KLK enzymes could interplay in the mode of “proteolytic cascades,” which could also crosstalk with proteases of differing specificities. It was proposed that specific regulatory KLK cascades could be functionally implicated in (patho)physiology in certain tissues like the skin and the prostate. Of note, a proteolytic cascade pathway involving KLK5 (and putatively other KLK proteases) was proposed to be implicated in prostate physiology (i.e., seminal clot liquefaction) and prostate cancer progression, originally by Michael et al., more than 15 years ago. In fact, the prime attempt to quantify the proportion of enzymatically active KLK6 relative to total immunoreactive KLK6 was in 2008, by Oikonomopoulou et al., who developed an ELISA using an ABP that targets trypsin-like serine proteases,

https://www.tandfonline.com/doi/pdf/10.1080/15384047.2022.2074775?needAccess=true

Georgia Sotiropoulou

Papers

Furthering Understanding of Aerosol-Cloud-Precipitation Interactions in the Arctic

Computational Cloning and Analysis of Human Kallikrein 6 Orthologue Genes

Functional Interactions of Anions and Cations with the outer Surface of Intact Thylakoids: Studies with the Blue-Green Bacterium AnacystisNidulans National Research Center Demokritos, Department of Biology, Athens 153 10, Greece

Méthodes et compositions pharmaceutiques de traitement du syndrôme de netherton

Novel specific activity-based probes validate KLK proteases as druggable targets