Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma

Objective Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. Design The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses. Results Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of ‘RB1 loss of function’ was found in
Source: Gut - Category: Gastroenterology Authors: Tags: Open access Hepatology Source Type: research

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Molecular Mechanisms of Notch Signaling in Lymphoid Cell Lineages Development: NF-κB and Beyond. Adv Exp Med Biol. 2020;1227:145-164 Authors: Tsaouli G, Barbarulo A, Vacca A, Screpanti I, Felli MP Abstract Notch is a ligand-receptor interaction-triggered signaling cascade highly conserved, that influences multiple lineage decisions within the hematopoietic and the immune system. It is a recognized model of intercellular communication that plays an essential role in embryonic as well as in adult immune cell development and homeostasis. Four members belong to the family of Notch receptors (Notch1-4...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Authors: Aradhya R, Jagla K Abstract Notch plays multiple roles both in development and in adult tissue homeostasis. Notch was first identified in Drosophila in which it has then been extensively studied. Among the flag-ship Notch functions we could mention its capacity to keep precursor and stem cells in a nondifferentiated state but also its ability to activate cell proliferation that in some contexts could led to cancer. In general, both these functions involve, canonical, ligand-dependent Notch activation. However, a ligand-independent Notch activation has also been described in a few cellular contexts. Here, w...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Authors: Salviano-Silva A, Berti FCB, Lobo-Alves SC, de Araujo-Souza PS, Boldt ABW, Malheiros D Abstract The Notch signaling is a crucial pathway involved in cellular development, progression, and differentiation. Deregulation of Notch signaling pathway commonly impacts tissue homeostasis, being highly associated with proliferative disorders. The long noncoding RNAs (lncRNAs), which are transcripts with more than 200 nucleotides that do not code for proteins, were already described as Notch signaling pathway-interacting molecules. Many of them act as important transcriptional and posttranscriptional regulators, aff...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Authors: McIntyre B, Asahara T, Alev C Abstract Notch signaling is an evolutionarily conserved pathway associated with the development and differentiation of all metazoans. It is needed for proper germ layer formation and segmentation of the embryo and controls the timing and duration of differentiation events in a dynamic manner. Perturbations of Notch signaling result in blockades of developmental cascades, developmental anomalies, and cancers. An in-depth understanding of Notch signaling is thus required to comprehend the basis of development and cancer, and can be further exploited to understand and direct the ...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Authors: Reichrath J, Reichrath S Abstract Evolutionary conserved Notch signaling is of high importance for embryogenesis and adult tissues, representing one of the most fascinating pathways that regulate key cell fate decisions and other core processes. This chapter gives a short introduction to the first volume of the book entitled Notch Signaling in Embryology and Cancer, that is intended to provide both basic scientists and clinicians who seek today`s clearest understanding of the molecular mechanisms that mediate Notch signaling with an authoritative day-to-day source. On a first look, Notch signaling, that fi...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
Too often I feel like as pre-dentals all we worry about are how high our stats are, how much we impact others, and if getting into dental school is even possible. Our lives revolve around helping others, however what do we do when we need to help ourselves? I've spent the last 4 years of college trying to make a difference in my community; caring about the well-being of others. Recently my father was diagnosed with cancer and I do not know how to cope with it. Mentally I have been... Dealing with adversity...
Source: Student Doctor Network - Category: Universities & Medical Training Authors: Tags: Pre-Dental Source Type: forums
In this study, we reviewed major human studies on the health risks of radiation exposure and showed that sex-related factors may potentially influence the long-term response to radiation exposure. Available data suggest that long-term radiosensitivity in women is higher than that in men who receive a comparable dose of radiation. The report on the biological effects of ionizing radiation (BEIR VII) published in 2006 by the National Academy of Sciences, United States emphasized that women may be at significantly greater risk of suffering and dying from radiation-induced cancer than men exposed to the same dose of radiation....
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Conclusions and Perspectives In this review, we have discussed important milestones from the early description of “Serum-sickness” as being due to antibodies directed against Neu5Gc epitopes all the way to the present-day therapeutic implications of these antibodies in cancer therapy. Some of these milestones have been represented in a concise timeline (Figure 6). While the “Xenosialitis” hypothesis is well-supported in the human-like mouse models, it has yet to be conclusively proven in humans. It remains to be seen if “Xenosialitis” plays a role in other uniquely-human diseases. FI...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Discussion Suppressor of cytokine signaling 1 is an essential molecule for maintaining immune homeostasis and subverting inflammation. Disorders arising from excess inflammation or SOCS1 deficiency can be potentially treated with SOCS1 mimetics (Ahmed et al., 2015). While SOCS1 has promising potential in many disorders, it should be noted that new targets and actions of SOCS1 are still being discovered and not all the effects of this protein are beneficial in autoimmune diseases and cancer. For instance, SOCS1 degrades IRS1 and IRS2, required for insulin signaling, via the SOCS Box domain, thus, limiting its potential in ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Authors: Zhao D, Cui Z Abstract Retinoblastoma (RB) is the most common type of intraocular malignancy in children. During RB oncogenesis, sonic hedgehog (SHH) is commonly differentially expressed. Additionally, microRNAs (miRs) are known to serve crucial roles as oncogenes or tumor suppressors. Specifically, miR-361-3p has been revealed to serve a vital role in cutaneous squamous cell carcinoma, cervical cancer, prostate cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, breast cancer and lung cancer. However, the role of miR-361-3p in RB and the potential molecular mechanisms involved remain unkn...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
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