Publications by authors named "Jit Kong Cheong"

Background: The diagnosis of T-cell lymphomas is typically established through a multiparameter approach that combines clinical, morphologic, immunophenotypic, and genetic features, utilizing a variety of histopathologic and molecular techniques. However, accurate diagnosis of such lymphomas and distinguishing them from reactive lymph nodes remains challenging due to their low prevalence and heterogeneous features, hence limiting the confidence of pathologists. We investigated the use of microRNA (miRNA) expression signatures as an adjunctive tool in the diagnosis and classification of T-cell lymphomas that involve lymph nodes.

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The 5th Workshop IRE on Translational Oncology was held in Rome (Italy) on 27-28 March at the IRCCS Regina Elena National Cancer Institute. This meeting entitled "The New World of RNA diagnostics and therapeutics" highlightes the significant progress in the RNA field made over the last years. Research moved from pure discovery towards the development of diagnostic biomarkers or RNA-base targeted therapies seeking validation in several clinical trials.

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Oncogenic mutations in the RAS family of small GTPases are commonly found in human cancers and they promote tumorigenesis by altering gene expression networks. We previously demonstrated that Casein Kinase 1α (CK1α), a member of the CK1 family of serine/threonine kinases, is post-transcriptionally upregulated by oncogenic RAS signaling. Here, we report that the CK1α mRNA contains an exceptionally long 5'-untranslated region (UTR) harbouring several translational control elements, implicating its involvement in translational regulation.

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Noncoding RNAs (ncRNAs), in the form of structural, catalytic or regulatory RNAs, have emerged to be critical effectors of many biological processes. With the advent of new technologies, we have begun to appreciate how intracellular and circulatory ncRNAs elegantly choreograph the regulation of gene expression and protein function(s) in the cell. Armed with this knowledge, the clinical utility of ncRNAs as biomarkers has been recently tested in a wide range of human diseases.

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Autophagy is a fundamental cellular homeostasis mechanism known to play multifaceted roles in the natural history of cancers over time. It has recently been shown that autophagy also mediates the crosstalk between the tumor and its microenvironment by promoting the export of molecular payloads such as non-coding RNA (ncRNAs) via LC3-dependent Extracellular Vesicle loading and secretion (LDELS). In turn, the dynamic exchange of exosomal ncRNAs regulate autophagic responses in the recipient cells within the tumor microenvironment (TME), for both tumor and stromal cells.

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Precision preventive healthcare aims to improve patient health by integrating preventive measures with early disease detection for timely intervention with precision medicine. Key to the delivery of preventive healthcare is the clinical adoption of novel assays that enable early disease detection. Such assays, typically based on biomarkers such as microRNAs (miRNAs) from liquid biopsy or excreta, are entering clinical practice after years of clinical development and validation.

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Article Synopsis
  • In 2008, guidelines were established for researching autophagy, which has since gained significant interest and new technologies, necessitating regular updates to monitoring methods across various organisms.
  • The new guidelines emphasize selecting appropriate techniques to evaluate autophagy while noting that no single method suits all situations; thus, a combination of methods is encouraged.
  • The document highlights that key proteins involved in autophagy also impact other cellular processes, suggesting genetic studies should focus on multiple autophagy-related genes to fully understand these pathways.
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MicroRNAs (miRNAs) are short single-stranded RNAs that have pivotal roles in disease pathophysiology through transcriptional and translational modulation of important genes. It has been implicated in the development of many diseases, such as stroke, cardiovascular conditions, cancers and inflammatory airway diseases. There is recent evidence that miRNAs play important roles in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and could help to distinguish between T2-low (non-eosinophilic, steroid-insensitive) versus T2-high (eosinophilic, steroid-sensitive) disease endotypes.

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Transfer RNA (tRNA)-derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. However, the underlying cellular and molecular mechanisms of tsRNA function in the context of dynamic cell-state transitions remain unclear. Expression analysis of tsRNAs in distinct heterologous cell and tissue models of stem vs.

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Aberrant Wnt signaling has been widely accepted to be a key driver of a subset of human cancers and a heavily scrutinized molecular pathway for the development of personalized medicine. In a recently published issue of , Rosenberg and coworkers reported that the delta isoform of the CK1 family of serine/threonine kinases (CK1δ), an important mediator of intracellular Wnt signaling, is amplified and overexpressed in human breast tumors. They further demonstrated that pharmacological inhibition of CK1δ is efficacious for these cancers and implicate β-catenin signaling as a key target of CK1δ.

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Mutant RAS-driven cancer cells cope with proliferative stress by increasing basal autophagy to maintain protein/organelle and energy homeostasis. We recently demonstrated that casein kinase 1 alpha (CK1α), a therapeutically tractable enzyme, is critical for fine-tuning the transcriptional regulation of mutant RAS-induced autophagy and the development of mutant RAS-driven cancers.

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The RAS genes encode for members of a large superfamily of guanosine-5'-triphosphate (GTP)-binding proteins that control diverse intracellular signaling pathways to promote cell proliferation. Somatic mutations in the RAS oncogenes are the most common activating lesions found in human cancers. These mutations invariably result in the gain-of-function of RAS by impairing GTP hydrolysis and are frequently associated with poor responses to standard cancer therapies.

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The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells.

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Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target. RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses. Here we report that casein kinase 1α (CK1α), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS-induced autophagy.

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Obesity develops as a result of altered energy homeostasis favoring fat storage. Here we describe a new transcription co-regulator for adiposity and energy metabolism, SERTA domain containing 2 (TRIP-Br2, also called SERTAD2). TRIP-Br2-null mice are resistant to obesity and obesity-related insulin resistance.

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Genome-wide association studies have identified genetic markers in kallikrein-related peptidase 3 (KLK3) associated with prostate cancer. However, some of these markers are also associated with prostate-specific antigen (PSA) levels, so it is unclear whether the polymorphisms are causal or if the association with risk is solely due to detection bias through PSA screening. PSA is a biologically active serine protease, cleaving insulin-like growth factor-binding protein.

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The CK1 family of serine/threonine kinases regulates diverse cellular processes, through binding to and phosphorylation a myriad of protein substrates. CK1 prefers substrates primed by prior phosphorylation, and works closely with other kinases in the Wnt pathway. CK1 is itself regulated by posttranslational modification, including autophosphorylation.

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Background: Members of the TRIP-Br/SERTAD family of mammalian transcriptional coregulators have recently been implicated in E2F-mediated cell cycle progression and tumorigenesis. We, herein, focus on the detailed functional characterization of the least understood member of the TRIP-Br/SERTAD protein family, TRIP-Br2 (SERTAD2).

Methods: Oncogenic potential of TRIP-Br2 was demonstrated by (1) inoculation of NIH3T3 fibroblasts, which were engineered to stably overexpress ectopic TRIP-Br2, into athymic nude mice for tumor induction and (2) comprehensive immunohistochemical high-throughput screening of TRIP-Br2 protein expression in multiple human tumor cell lines and human tumor tissue microarrays (TMAs).

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TRIP-Br proteins are a novel family of transcriptional coregulators involved in E2F-mediated cell cycle progression. Three of the four mammalian members of TRIP-Br family, including TRIP-Br1, are known oncogenes. We now report the identification of the Balpha regulatory subunit of serine/threonine protein phosphatase 2A (PP2A) as a novel TRIP-Br1 interactor, based on an affinity binding assay coupled with mass spectrometry.

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Overexpression of the proto-oncogene TRIP-Br2 (SERTAD2) has been shown to induce E2F activity and promote tumorigenesis, whereas ablation of TRIP-Br2 arrests cell proliferation. Timely degradation of many cell cycle regulators is fundamental to the maintenance of proper cell cycle progression. Here we report novel mechanism(s) that govern the tight regulation of TRIP-Br2 levels during cell cycle progression.

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TRIP-Br1 and TRIP-Br2 are potent cell growth promoting factors that function as components of the E2F1/DP1 transcription complex to integrate positive growth signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors. TRIP-Br1 has been demonstrated to be an oncogene. We recently reported that antagonism of the TRIP-Br integrator function by synthetic decoy peptides that compete with TRIP-Br for binding to PHD zinc finger- and/or bromodomain-containing proteins elicit an anti-proliferative effect and induces caspase-3-independent sub-diploidization in cancer cells in vitro.

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The G1 D-type cyclins, in conjunction with cyclin-dependent kinases Cdk4 and Cdk6, play key roles in the execution of mitogen-induced cellular proliferation. TRIP-Br1, a member of the TRIP-Br family of transcriptional regulators, has been implicated in the regulation of Cdk4/cyclin D activity. To further elucidate the functional role(s) of the TRIP-Br proteins in mitogenic signaling, we have developed the synthetic DNA enzymes E-Br1 and E-Br2 to specifically knock down the serum-inducible expression of TRIP-Br1 and TRIP-Br2, respectively, in WI-38 human fibroblasts in culture, as well as generated TRIP-Br2 null primary embryonic fibroblasts from a novel TRIP-Br2 knockout mouse model.

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