top of page

Bobby McCon, EdTech Group

Public·9 members
Bruno Hunchback
Bruno Hunchback

46.pdf - Google Drive


Additionally, a recent study (12) has associated lineage dedifferentiation with malignant progression from pancreatic islet cell neoplasias into metastasis-prone carcinomas; these neuroendocrine cells and derivative tumors arise from a developmental lineage that is distinct from the one generating the far larger number of adjacent cells that form the exocrine and pancreas and the ductal adenocarcinomas that arise therefrom. Notably, the multistep differentiation pathway of islet progenitor cells into mature β cells has been thoroughly characterized (13). Comparative transcriptome profiling reveals that adenoma-like islet tumors are most similar to immature but differentiated insulin-producing β cells, whereas the invasive carcinomas are most similar to embryonic islet cell precursors. The progression toward poorly differentiated carcinomas involves a first step of dedifferentiation that does not initially involve increased proliferation or reduced apoptosis when compared with the well-differentiated adenomas, both of which rather occur later. Thus, the discrete step of dedifferentiation is not driven by observable alterations in the hallmark traits of sustained proliferation and resistance to apoptosis. Rather, upregulation of a miRNA previously implicated in specifying the islet progenitor state, one that is downregulated during terminal differentiation of β cells, has been shown to orchestrate the observed dedifferentiation occurring during malignant progression (12).




46.pdf - Google Drive



A third example, in melanoma, involves a developmental TF, SOX10, which is normally downregulated during melanocyte differentiation. Gain- and loss-of-function studies in a zebrafish model of BRAF-induced melanoma have demonstrated that aberrantly maintained expression of SOX10 blocks differentiation of neural progenitor cells into melanocytes, enabling BRAF-driven melanomas to form (19).


A third example also reveals transdifferentiation as a strategy employed by carcinoma cells to avoid elimination by a lineage-specific therapy, in this case involving basal cell carcinomas (BCC) of the skin treated with a pharmacologic inhibitor of the Hedgehog-Smoothened (HH/SMO) oncogenic signaling pathway known to drive the neoplastic growth of these cells (33). Drug-resistant cancer cells switch, via broad epigenetic shifts in specific chromatin domains and the altered accessibility of two superenhancers, to a developmentally related but distinct cell type. The newly gained phenotypic state of the BCC cells enables them to sustain expression of the WNT oncogenic signaling pathway, which in turn imparts independence from the drug-suppressed HH/SMO signaling pathway (34). As might be anticipated from this transdifferentiation, the transcriptome of the cancer cells shifts from a gene signature reflecting the implicated cell-of-origin of BCCs, namely the stem cells of hair follicle bulge, to one indicative of the basal stem cells that populate the interfollicular epidermis. Such transdifferentiation to enable drug resistance is being increasingly documented in different forms of cancer (35).


A persuasive example of hypoxia-mediated epigenetic regulation involves a form of invariably lethal pediatric ependymoma. Like many embryonic and pediatric tumors, this form lacks recurrent mutations, in particular a dearth of driver mutations in oncogenes and tumor suppressors. Rather, the aberrant growth of these cancer cells is demonstrably governed by a gene regulatory program induced by hypoxia (60, 61). Notably, the putative cell-of-origin of this cancer resides in a hypoxic compartment, likely sensitizing cells resident therein to the initiation of tumorigenesis by as yet unknown cofactors.


Collectively, these illustrative snapshots support the proposition that nonmutational epigenetic reprograming will come to be accepted as a bona fide enabling characteristic that serves to facilitate the acquisition of hallmark capabilities (Fig. 3), distinct from that of genomic DNA instability and mutation. Notably, it can be anticipated that nonmutational epigenetic reprogramming will prove to be integrally involved in enabling the provisional new hallmark capability of phenotypic plasticity discussed above, in particular being a driving force in the dynamic transcriptomic heterogeneity that is increasingly well documented in cancer cells populating malignant TMEs. The advance of single cell multi-omic profiling technologies is envisaged to illuminate the respective contributions of and interplay between mutation-driven versus nonmutational epigenetic regulation to the evolution of tumors during malignant progression and metastasis.


We've been talking a lot about visibility and traffic but haven't really covered how these will help drive revenue yet. One simple way to start generating leads or customers from your website is to implement a conversion tool.


A simple, free option is HubSpot Marketing Free. By using this tool to add a pop-up widget to your website, you can start collecting the email addresses of potential customers. From there, you can send out promotions and offers and convert them into paying customers. You can also implement any of these 24 conversion tools to help you optimize your website and use it to drive leads.


Pinterest is also an excellent option for small businesses to advertise. In fact, Pinterest users say the platform has more influence on their purchasing journey than other platforms. Shopping ads on Pinterst drive three times the conversion of other competting plaforms.


Mechanical ventilation (in combination with sedation) can completely suppress patient respiratory drive and effort. While there are circumstances under which this may be desirable, maintaining spontaneous respiratory effort is generally preferred because it reduces atelectasis, improves oxygenation, reduces pulmonary vascular resistance, and may prevent disuse diaphragm atrophy [1, 2]. Vigorous respiratory effort during assisted ventilation, however, can induce unintentional patient self-inflicted lung injury (P-SILI). Large respiratory efforts increase tidal volumes and elevate both global and regional lung stress, increasing the risk of volutrauma in the baby lung and exacerbating respiratory failure [3, 4]. Vigorous diaphragm contractions may also cause load-induced diaphragm injury [2]. Spontaneous breathing is, therefore, not a panacea, and its benefits and risks depend heavily on the magnitude of respiratory effort. Physiological principles and observational data suggest that a level of effort similar to that of resting quiet breathing is probably optimal [5]. 041b061a72


About

Welcome to the group! You can connect with other members, ge...

Members

bottom of page