Displaying publications 1 - 20 of 50 in total

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  1. Tablit S, Krache R, Amroune S, Jawaid M, Hachaichi A, Ismail AS, et al.
    J Mech Behav Biomed Mater, 2024 Apr;152:106438.
    PMID: 38359736 DOI: 10.1016/j.jmbbm.2024.106438
    Arundo donax L. is investigated in this study as a suitable reinforcing agent for PLA/PP waste blend 3D printing filament. To improve the compatibility of the fibre and polymer, the Arundo fibre was chemically modified using alkali and silane treatment. Untreated and treated fibres were extruded with Polymer blends before being 3D printed. Effect of chemical treatment on thermal, mechanical, and morphological properties of the composites was investigated. The tensile, Izod impact, and water absorption of the 3D printed specimens were also tested. The Alkali treated (ALK) and combination of alkali and silane treatment (SLN) composites displayed good results. Tensile strength and modulus of the materials increased, as well as their maintained stability in the Izod impact test, demonstrating that the incorporation of ArF did not result in a loss in performance. SEM examination supported these findings by confirming the creation of beneficial interfacial contacts between the matrix and fibre components, as demonstrated by the lack of void between the matrix and the fibre surface. Furthermore, the alkali treatment of the ArF resulted in a considerable reduction in water absorption inside the biocomposite, with a 64% reduction seen in ALK composite comparison to the untreated composite (Un). After the 43-day assessment period.
    Matched MeSH terms: Receptor Protein-Tyrosine Kinases
  2. Wan Mohamad Darani WNS, Mat Ruzlin AN, Azhar ZI, Chen XW
    Sci Rep, 2024 Mar 22;14(1):6890.
    PMID: 38519534 DOI: 10.1038/s41598-024-57593-y
    The growing Human Immunodeficiency Virus (HIV) incidences and insufficient HIV knowledge among Malaysian late adolescents necessitate immediate attention to HIV prevention via education. This study aims to develop and validate an Information-Motivation-Behavioural skills (IMB) model-based education kit for adolescents, PREM-Kit, to educate on HIV prevention among Malaysian late adolescents. Utilizing the Analysis, Design, Development, Implementation, and Evaluation model, we conducted the study in three phases: needs assessment, development of PREM-Kit, and validation of PREM-Kit by applying the IMB model to map the PREM-Kit's contents. PREM-Kit, developed in Malay language, consisted of an infographic flip chart and videos. Five multi-disciplinary experts validated the PREM-Kit using the content validity index (CVI), and 13 end-users validated the PREM-Kit using the Malay version of the Patient Education Materials Assessment Tool for Printable and Audiovisual Materials. The infographic flip chart comprised three modules covering 15 topics, and an animated video accompanied each module. PREM-Kit achieved CVI scores of 1.0 and median scores of over 80% for understandability and actionability. Overall, the newly developed IMB model-based HIV education kit has good content validity, is simple to comprehend and apply, and is ready for testing its effectiveness in improving adolescents' knowledge, attitudes, and practices for HIV prevention.
    Matched MeSH terms: Receptor Protein-Tyrosine Kinases
  3. Yahya TSANT, Azmi NC, Yee FS, Chyang PJ, Ting NS, Seng TC
    Int J Med Mushrooms, 2024;26(3):55-66.
    PMID: 38505903 DOI: 10.1615/IntJMedMushrooms.2024052325
    Leukemia can be a result of genetic changes associated with protein tyrosine kinase activity such as in MPL W515L and BCR/ABL genes. However, the current conventional treatment of leukemia produces severe side effects that urge the approach to use natural products. A medicinal mushroom, Lignosus rhinocerus shows potential as an anti-cancer treatment. To investigate the efficacy and mechanism of action of the L. rhinocerus cultivar (TM02®) extract on leukemogenic tyrosine kinase cell lines, a cold-water extract (CWE) was produced by using TM02® sclerotia powder at 4°C. The carbohydrate and protein contents were found to be 77.24% and 1.75% respectively. In comparison to the normal Ba/F3 cell, the CWE TM02® shows significant effects on exhibiting proliferation of Ba/F3 expressed MPL W515L and BCR/ABL, possibly due to the presence of phenolic compounds and antioxidant properties of TM02®, which contribute to act on various signaling pathways, and the reported apoptotic activity of CWE TM02®. In contrast, CWE TM02® significantly exhibited high scavenging activity of both Ba/F3 expressed MPL W515L and BCR/ABL. At concentrations of 125 μg/mL and 500 μg/mL of CWE TM02® decreased 49.5% and 67.5% of cell migration activity of Ba/F3 expressed MPL W515L and BCR/ABL respectively. Therefore, we postulate that CWE TM02® has the capability to mediate the migration route of the leukemogenic tyrosine kinase cell lines.
    Matched MeSH terms: Protein-Tyrosine Kinases
  4. Cho BC, Kim DW, Batra U, Park K, Kim SW, Yang CT, et al.
    Cancer Res Treat, 2023 Jan;55(1):83-93.
    PMID: 35344649 DOI: 10.4143/crt.2021.1571
    PURPOSE: Previous report from the ASCEND-8 trial showed consistent efficacy with less gastrointestinal (GI) toxicity in patients with anaplastic lymphoma kinase-rearranged (ALK+) advanced/metastatic non-small cell lung cancer (NSCLC) treated with ceritinib 450-mg with food compared with 750-mg fasted. In this subgroup analysis, we report outcomes in Asian patients of the ASCEND-8 trial.

    MATERIALS AND METHODS: Key efficacy endpoints were blinded independent review committee (BIRC)-assessed overall response rate (ORR) and duration of response (DOR) evaluated per Response Evaluation Criteria in Solid Tumors v1.1. Other efficacy endpoints were investigator-assessed ORR and DOR; BIRC- and investigator-assessed progression-free survival (PFS) and disease control rate; overall survival (OS). Safety was evaluated by frequency and severity of adverse events.

    RESULTS: At final data cutoff (6 March 2020), 198 treatment-naïve patients were included in efficacy analysis, of which 74 (37%) comprised the Asian subset; 450-mg fed (n=29), 600-mg fed (n=19), and 750-mg fasted (n=26). Baseline characteristics were mostly comparable across study arms. At baseline, more patients in 450-mg fed arm (44.8%) had brain metastases than in 750-mg fasted arm (26.9%). Per BIRC, patients in the 450-mg fed arm had a numerically higher ORR, 24-month DOR rate and 24-month PFS rate than the 750-mg fasted arm. The 36-month OS rate was 93.1% in 450-mg fed arm and 70.9% in 750-mg fasted arm. Any-grade GI toxicity occurred in 82.8% and 96.2% of patients in the 450-mg fed and 750-mg fasted arms, respectively.

    CONCLUSION: Asian patients with ALK+ advanced/metastatic NSCLC treated with ceritinib 450-mg fed showed numerically higher efficacy and lower GI toxicity than 750-mg fasted patients.

    Matched MeSH terms: Receptor Protein-Tyrosine Kinases
  5. Prasher P, Sharma M, Chan Y, Singh SK, Anand K, Dureja H, et al.
    Curr Med Chem, 2023;30(13):1529-1567.
    PMID: 34766883 DOI: 10.2174/0929867328666211111161811
    Protein kinases modulate the structure and function of proteins by adding phosphate groups to threonine, tyrosine, and serine residues. The phosphorylation process mediated by the kinases regulates several physiological processes, while their overexpression results in the development of chronic diseases, including cancer. Targeting of receptor tyrosine kinase pathways results in the inhibition of angiogenesis and cell proliferation that validates kinases as a key target in the management of aggressive cancers. As such, the identification of protein kinase inhibitors revolutionized the contemporary anticancer therapy by inducing a paradigm shift in the management of disease pathogenesis. Contemporary drug design programs focus on a broad range of kinase targets for the development of novel pharmacophores to manage the overexpression of kinases and their pathophysiology in cancer pathogenesis. In this review, we present the emerging trends in the development of rationally designed molecular inhibitors of kinases over the last five years (2016-2021) and their incipient role in the development of impending anticancer pharmaceuticals.
    Matched MeSH terms: Receptor Protein-Tyrosine Kinases
  6. Chear CT, Ismail IH, Chan KC, Noh LM, Kassim A, Latiff AHA, et al.
    Front Immunol, 2023;14:1252765.
    PMID: 37809070 DOI: 10.3389/fimmu.2023.1252765
    BACKGROUND: Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.

    RESULTS: Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.

    CONCLUSION: This report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.

    Matched MeSH terms: Protein-Tyrosine Kinases/genetics
  7. Abdullah MN, Ali Y, Abd Hamid S
    Chem Biol Drug Des, 2022 Dec;100(6):921-934.
    PMID: 34651438 DOI: 10.1111/cbdd.13974
    Tyrosine kinase overexpression could result in an unfavourable consequence of cancer progression in the body. A number of kinase inhibitor drugs targeting various cancer-related protein kinases have been developed and proven successful in clinical therapy. Benzimidazole is one of the most studied scaffolds in the search for effective anticancer drugs. The association of various functional groups and the structural design of the compounds may influence the binding towards the receptor. Despite numerous publications on the design, synthesis and biological assays of benzimidazole derivatives, their inhibitory activities against epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), have not been specifically analysed. This review covers recent research reports on the anticancer activity of benzimidazole derivatives focusing on EGFR expression cell lines, based on their structure-activity relationship study. We believe it would aid researchers to envision the challenges and explore benzimidazole's potentials as tyrosine kinase inhibitors.
    Matched MeSH terms: Protein-Tyrosine Kinases
  8. Soo R, Mery L, Bardot A, Kanesvaran R, Keong TC, Pongnikorn D, et al.
    ESMO Open, 2022 Oct;7(5):100560.
    PMID: 35988454 DOI: 10.1016/j.esmoop.2022.100560
    BACKGROUND: Lung cancer is the second most common cancer and leading cause of cancer mortality worldwide. Recent advances in molecular testing and targeted therapy have improved survival among patients with metastatic non-small-cell lung cancer (NSCLC). We sought to quantify and describe molecular testing among metastatic non-squamous NSCLC cases in selected Southeast Asian countries and describe first-line therapy chosen.

    PATIENTS AND METHODS: A retrospective study was conducted based on incident lung cancer cases diagnosed between 2017 and 2019 in Lampang (Thailand), Penang (Malaysia), Singapore and Yogyakarta (Indonesia). Cases (n = 3413) were defined using the International Classification of Diseases for Oncology third edition. In Singapore, a clinical series obtained from the National Cancer Centre was used to identify patients, while corresponding population-based cancer registries were used elsewhere. Tumor and clinical information were abstracted by chart review according to a predefined study protocol. Molecular testing of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) gene rearrangement, ROS1 gene rearrangement and BRAF V600 mutation was recorded.

    RESULTS: Among 2962 cases with a specified pathological diagnosis (86.8%), most patients had non-squamous NSCLC (75.8%). For cases with staging information (92.1%), the majority presented with metastatic disease (71.3%). Overall, molecular testing rates in the 1528 patients with stage IV non-squamous NSCLC were 67.0% for EGFR, 42.3% for ALK, 39.1% for ROS1, 7.8% for BRAF and 36.1% for PD-L1. Among these patients, first-line systemic treatment included chemotherapy (25.9%), targeted therapy (35.6%) and immunotherapy (5.9%), with 31% of patients having no record of antitumor treatment. Molecular testing and the proportion of patients receiving treatment were highly heterogenous between the regions.

    CONCLUSIONS: This first analysis of data from a clinically annotated registry for lung cancer from four settings in Southeast Asia has demonstrated the feasibility of integrating clinical data within population-based cancer registries. Our study results identify areas where further development could improve patient access to optimal treatment.

    Matched MeSH terms: Protein-Tyrosine Kinases/genetics; Protein-Tyrosine Kinases/therapeutic use
  9. Liew K, Yu GQS, Wei Pua LJ, Wong LZ, Tham SY, Hii LW, et al.
    Cancer Lett, 2021 Apr 28;504:81-90.
    PMID: 33587980 DOI: 10.1016/j.canlet.2021.02.006
    Despite recent in advances in the management of nasopharyngeal carcinoma (NPC), development of targeted therapy remains challenging particularly in patients with recurrent or metastatic disease. To search for clinically relevant targets for the treatment of NPC, we carried out parallel genome-wide functional screens to identified essential genes that are required for NPC cells proliferation and cisplatin resistance. We identified lymphocyte-specific protein tyrosine kinase (LCK) as a key vulnerability of both proliferation and cisplatin resistance. Depletion of endogenous LCK or treatment of cells with LCK inhibitor induced tumor-specific cell death and synergized cisplatin sensitivity in EBV-positive C666-1 and EBV-negative SUNE1 cells. Further analyses demonstrated that LCK is regulating the proliferation and cisplatin resistance through activation of signal transducer and activator of transcription 5 (STAT5). Taken together, our study provides a molecular basis for targeting LCK and STAT5 signaling as potential druggable targets for the management of NPC.
    Matched MeSH terms: Protein-Tyrosine Kinases/genetics*
  10. Verusingam ND, Chen YC, Lin HF, Liu CY, Lee MC, Lu KH, et al.
    J Chin Med Assoc, 2021 03 01;84(3):248-254.
    PMID: 33009209 DOI: 10.1097/JCMA.0000000000000438
    BACKGROUND: Lung cancer contributes to high cancer mortality worldwide with 80% of total cases diagnosed as non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain serves as a druggable target in NSCLC patients with exon 19 deletion and L858R mutation. However, patients eventually succumbed to resistance to first- and second-generation EGFR-TK inhibitors through activation of T790M mutation. Third-generation EGFR-TKI, Osimertinib exhibits high efficacy in patients with exon 19 deletion/L858R/T790M mutation but they experienced acquired resistance thereafter. Available treatment options in NSCLC patients remains a challenge due to unknown molecular heterogeneity responsible for acquired resistance to EGFR-TKI. In this study, we aim to generate Osimertinib-resistant (OR) cells from H1975 carrying L858R/T790M double mutation which can be used as a model to elucidate mechanism of resistance.

    METHODS: OR cells were established via stepwise-dose escalation and limiting single-cell dilution method. We then evaluated Osimertinib resistance potential via cell viability assay. Proteins expression related to EGFR-signalling, epithelial to mesenchymal transition (EMT), and autophagy were analyzed via western blot.

    RESULTS: OR cell lines exhibited increased drug resistance potential compared to H1975. Distinguishable mesenchymal-like features were observed in OR cells. Protein expression analysis revealed EGFR-independent signaling involved in the derived OR cells as well as EMT and autophagy activity.

    CONCLUSION: We generated OR cell lines in-vitro as evidenced by increased drug resistance potential, increased mesenchymal features, and enhanced autophagy activity. Development of Osimertinib resistance cells may serve as in-vitro model facilitating discovery of molecular aberration present during acquired mechanism of resistance.

    Matched MeSH terms: Protein-Tyrosine Kinases/drug effects*
  11. Ankathil R, Ismail SM, Mohd Yunus N, Sulong S, Husin A, Abdullah AD, et al.
    Malays J Pathol, 2020 Dec;42(3):307-321.
    PMID: 33361712
    Chronic myeloid leukaemia (CML) provides an illustrative disease model for both molecular pathogenesis of cancer and rational drug therapy. Imatinib mesylate (IM), a BCR-ABL1 targeted tyrosine kinase inhibitor (TKI) drug, is the first line gold standard drug for CML treatment. Conventional cytogenetic analysis (CCA) can identify the standard and variant Philadelphia (Ph) chromosome, and any additional complex chromosome abnormalities at diagnosis as well as during treatment course. Fluorescence in situ hybridization (FISH) is especially important for cells of CML patients with inadequate or inferior quality metaphases or those with variant Ph translocations. CCA in conjunction with FISH can serve as powerful tools in all phases of CML including the diagnosis, prognosis, risk stratification and monitoring of cytogenetic responses to treatment. Molecular techniques such as reverse transcriptase-polymerase chain reaction (RT-PCR) is used for the detection of BCR-ABL1 transcripts at diagnosis whereas quantitative reverse transcriptase-polymerase chain reaction (qRTPCR) is used at the time of diagnosis as well as during TKI therapy for the quantitation of BCR-ABL1 transcripts to evaluate the molecular response and minimal residual disease (MRD). Despite the excellent treatment results obtained after the introduction of TKI drugs, especially Imatinib mesylate (IM), resistance to TKIs develops in approximately 35% - 40% of CML patients on TKI therapy. Since point mutations in BCR-ABL1 are a common cause of IM resistance, mutation analysis is important in IM resistant patients. Mutations are reliably detected by nested PCR amplification of the translocated ABL1 kinase domain followed by direct sequencing of the entire amplified kinase domain. The objective of this review is to highlight the importance of regular and timely CCA, FISH analysis and molecular testing in the diagnosis, prognosis, assessment of therapeutic efficacy, evaluation of MRD and in the detection of BCR-ABL1 kinase mutations which cause therapeutic resistance in adult CML patients.
    Matched MeSH terms: Protein-Tyrosine Kinases/antagonists & inhibitors
  12. Issac PK, Guru A, Chandrakumar SS, Lite C, Saraswathi NT, Arasu MV, et al.
    Mol Biol Rep, 2020 Sep;47(9):6727-6740.
    PMID: 32809102 DOI: 10.1007/s11033-020-05728-5
    Understanding the mechanism by which the exogenous biomolecule modulates the GLUT-4 signalling cascade along with the information on glucose metabolism is essential for finding solutions to increasing cases of diabetes and metabolic disease. This study aimed at investigating the effect of hamamelitannin on glycogen synthesis in an insulin resistance model using L6 myotubes. Glucose uptake was determined using 2-deoxy-D-[1-3H] glucose and glycogen synthesis were also estimated in L6 myotubes. The expression levels of key genes and proteins involved in the insulin-signaling pathway were determined using real-time PCR and western blot techniques. The cells treated with various concentrations of hamamelitannin (20 µM to 100 µM) for 24 h showed that, the exposure of hamamelitannin was not cytotoxic to L6 myotubes. Further the 2-deoxy-D-[1-3H] glucose uptake assay was carried out in the presence of wortmannin and Genistein inhibitor for studying the GLUT-4 dependent cell surface recruitment. Hamamelitannin exhibited anti-diabetic activity by displaying a significant increase in glucose uptake (125.1%) and glycogen storage (8.7 mM) in a dose-dependent manner. The optimum concentration evincing maximum activity was found to be 100 µm. In addition, the expression of key genes and proteins involved in the insulin signaling pathway was studied to be upregulated by hamamelitannin treatment. Western blot analysis confirmed the translocation of GLUT-4 protein from an intracellular pool to the plasma membrane. Therefore, it can be conceived that hamamelitannin exhibited an insulinomimetic effect by enhancing the glucose uptake and its further conversion into glycogen by regulating glucose metabolism.
    Matched MeSH terms: Protein-Tyrosine Kinases/genetics; Protein-Tyrosine Kinases/metabolism
  13. Lachhi Reddy V, Avula VKR, Zyryanov GV, Vallela S, Anireddy JS, Pasupuleti VR, et al.
    Bioorg Chem, 2020 01;95:103558.
    PMID: 31911311 DOI: 10.1016/j.bioorg.2019.103558
    A series of 1-(2,3-dihydro-1H-indan-1-yl)-3-aryl urea/thiourea derivatives (4a-j) have been synthesized from the reaction of 2,3-dihydro-1H-inden-1-amine (2) with various aryl isocyanates/isothiocyanates (3a-j) by using N,N-DIPEA base (Hunig's base) catalyst in THF at reflux conditions. All of them are structurally confirmed by spectral (IR, 1H &13C NMR and MASS) and elemental analysis and screened for their in-vitro antioxidant activity against DPPH and NO free radicals and found that compounds 4b, 4i, 4h &4g are potential antioxidants. The obtained in vitro results were compared with the molecular docking, ADMET, QSAR and bioactivity study results performed for them and identified that the recorded in silico binding affinities were observed in good correlation with the in vitro antioxidant results. The Molecular docking analysis had unveiled the strong hydrogen bonding interactions of synthesized ligands with ARG 160 residue of protein tyrosine kinase (2HCK) enzyme and plays an effective role in its inhibition. Toxicology studies have assessed the potential risks of 4a-j and inferred that all of them were in the limits of potential drugs. The conformational analysis of 4a-j inferred that the urea/thiourea spacer linking 2,3-dihydro-1H-inden-1-amino and substituted aryl units has facilitated all these molecules to effectively bind with ARG 160 amino acid residue present on the α-helix of the protein tyrosine kinase (2HCK) enzyme specifically on chain A of hemopoetic cell kinase. Collectively this study has established a relationship between the antioxidant potentiality and ligands binding with ARG 160 amino acid residue of chain A of 2HCK enzyme to inhibit its growth as well as proliferation of reactive oxygen species in vivo.
    Matched MeSH terms: Protein-Tyrosine Kinases/antagonists & inhibitors*; Protein-Tyrosine Kinases/chemistry
  14. Arafath MA, Al-Suede FSR, Adam F, Al-Juaid S, Khadeer Ahamed MB, Majid AMSA
    Drug Dev Res, 2019 09;80(6):778-790.
    PMID: 31215682 DOI: 10.1002/ddr.21559
    The bidentate N-cyclohexyl-2-(3-hydroxy-4-methoxybenzylidene)hydrazine-1-carbothioamide Schiff base ligand (HL) was coordinated to divalent nickel, palladium and platinum ions to form square planar complexes. The nickel and palladium complexes, [NiL2 ], [PdL2 ] form square planar complexes with 2:1 ligand to metal ratio. The platinum complex, [PtL(dmso)Cl] formed a square planar complex with 1:1 ligand to metal ratio. Platinum undergoes in situ reaction with DMSO before complexing with the ligand in solution. The cytotoxicity of HL, [NiL2 ], [PdL2 ], and [PtL(dmso)Cl] were evaluated against human colon cancer cell line (HCT-116), human cervical cancer (Hela) cell line, melanoma (B16F10) cells, and human normal endothelial cell lines (Eahy926) by MTT assay. The [NiL2 ] complex displayed selective cytotoxic effect against the HCT 116 cancer cell line with IC50 of 7.9 ± 0.2 μM. However, HL, [PdL2 ], and [PtL(dmso)Cl] only exhibited moderate cytotoxic activity with IC50 = 75.9 ± 2.4, 100.0 ± 1.8, and 101.0 ± 3.6 μM, respectively. The potent cytotoxicity of [NiL2 ] was characterized using Hoechst and Rhodamine assays. The nickel complex, [NiL2 ], caused remarkable nuclear condensation and reduction in mitochondrial membrane potential. In addition, molecular docking studies confirms that [NiL2 ] possesses significant binding efficiency with Tyrosine kinase. Altogether, the results revealed that [NiL2 ] exhibits cytotoxicity against the cancer cells via Tyrosine kinase-induced proapoptosis pathway. This study demonstrates that the [NiL2 ] complex could be a promising therapeutic agent against colorectal carcinoma.
    Matched MeSH terms: Protein-Tyrosine Kinases/chemistry
  15. Lee JS, Choi SJ, Kim L, Park IS, Han JY, Kim JM, et al.
    Malays J Pathol, 2019 Aug;41(2):213-222.
    PMID: 31427559
    INTRODUCTION: Anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) with a non-common pattern can be diagnostic challenging. Pathologists can be unavoidably and unintentionally blind to non-descript tumor cells in a lymphohistiocytic- (LH) or small-cell (SC)-pattern. We report a case of primary systemic ALK+ ALCL with a SC pattern that presented as secondary gastric lesions with a mixed LH and SC pattern that was masqueraded as inflammatory lesions.

    CASE REPORT: A 34-year-old woman with intractable epigastric pain was referred to have repeated endoscopy with biopsy. She was found to multiple gastric erosions and nodules that were diagnosed as inflammatory lesions both endoscopically and histologically. Meanwhile, she developed an acute onset of severe back pain associated with a pathologic compression fracture in the T3 thoracic vertebral body. Imaging studies disclosed a disseminated systemic disease involving abdominopelvic lymph nodes and cervical and thoracic vertebral bodies. The needle biopsy of the pelvic lymph node disclosed diffuse proliferation of monomorphic small round cells that were diffusely positive for CD30 and ALK. A diagnosis of ALK+ ALCL with a monomorphic SC pattern was rendered.

    DISCUSSION: A retrospective review of the gastric biopsies with the aid of immunohistochemistry enabled us to recognise the presence of lymphomatous infiltrates with a mixed LH and SC pattern in every piece of gastric biopsies that were repeatedly misdiagnosed as inflammatory lesions. This case illustrates a significant diagnostic pitfall of the LH- and SC-patterns in ALK+ ALCL, in which the tumour cells featuring lymphoid, plasmacytoid or histiocytoid appearance can be masqueraded as inflammatory cells.

    Matched MeSH terms: Receptor Protein-Tyrosine Kinases
  16. Awang-Kechik NH, Ahmad R, Doustjalali SR, Sabet NS, Abd-Rahman AN
    J Clin Exp Dent, 2019 Mar;11(3):e269-e274.
    PMID: 31001398 DOI: 10.4317/jced.55546
    Background: The biological responses involved during retention phase have been studied for many years but little is known about the effect of saliva proteome during retention phase of post-orthodontic treatment. This study aims to identify the protein profiles during retention phase in relation to biological processes involved by Liquid Chromatography Mass Spectrometry (LC-MS) approach.

    Material and Methods: A total of 5 ml of unstimulated saliva was collected from each subject (10 non-orthodontic patients and 15 post-orthodontic patients with 6-months retention phase). Samples were then subjected to LC-MS analysis. The expressed proteins were identified and compared between groups. Incisor irregularity for both maxilla and mandible were determined with Little's Irregularity Index at 6-months retention phase.

    Results: 146 proteins and 135 proteins were expressed in control and 6-months retention phase group respectively. 15 proteins were identified to be co-expressed between groups. Immune system process was only detected in 6-months retention phase group. Detected protein in immune system process was identified as Tyrosine-protein kinase Tec. Statistical significant of incisor irregularity was only found in mandible at 6-months retention phase.

    Conclusions: Our study suggests that immune system process protein which is Tyrosine-protein kinase Tec could be used as biomarker for prediction of stability during retention phase of post-orthodontic treatment. Key words:Orthodontics, proteomics, retention, LC-MS, saliva.

    Matched MeSH terms: Protein-Tyrosine Kinases
  17. Karim ME, Shetty J, Islam RA, Kaiser A, Bakhtiar A, Chowdhury EH
    Pharmaceutics, 2019 Feb 20;11(2).
    PMID: 30791612 DOI: 10.3390/pharmaceutics11020089
    Inorganic nanoparticles hold great potential in the area of precision medicine, particularly for treating cancer owing to their unique physicochemical properties, biocompatibility and improved pharmacokinetics properties compared to their organic counterparts. Here we introduce strontium sulfite nanoparticles as new pH-responsive inorganic nanocarriers for efficient transport of siRNAs into breast cancer cells. We employed the simplest nanoprecipitation method to generate the strontium sulfite nanoparticles (SSNs) and demonstrated the dramatic roles of NaCl and d-glucose in particle growth stabilization in order to produce even smaller nanosize particles (Na-Glc-SSN) with high affinity towards negatively charged siRNA, enabling it to efficiently enter the cancer cells. Moreover, the nanoparticles were found to be degraded with a small drop in pH, suggesting their potential capability to undergo rapid dissolution at endosomal pH so as to release the payload. While these particles were found to be nontoxic to the cells, they showed higher potency in facilitating cancer cell death through intracellular delivery and release of oncogene-specific siRNAs targeting ros1 and egfr1 mRNA transcripts, than the strontium sulfite particles prepared in absence of NaCl and d-glucose, as confirmed by growth inhibition assay. The mouse plasma binding analysis by Q-TOF LC-MS/MS demonstrated less protein binding to smaller particles of Na-Glc-SSNs. The biodistribution studies of the particles after 4 h of treatment showed Na-Glc-SSNs had less off-target distribution than SSNs, and after 24 h, all siRNAs were cleared from all major organs except the tumors. ROS1 siRNA with its potential therapeutic role in treating 4T1-induced breast tumor was selected for subsequent in vivo tumor regression study, revealing that ROS1 siRNA-loaded SSNs exerted more significant anti-tumor effects than Na-Glc-SSNs carrying the same siRNA following intravenous administration, without any systemic toxicity. Thus, strontium sulfite emerged as a powerful siRNA delivery tool with potential applications in cancer gene therapy.
    Matched MeSH terms: Protein-Tyrosine Kinases
  18. Hooi Yeen Yap, Jack Bee Chook, Sin Yeang Teow
    MyJurnal
    ntroduction: Nasopharyngeal carcinoma (NPC) is a prevalent cancer among human population in Southern China, Hong Kong and Southeast Asia. In Malaysia, NPC is the fourth most common cancer in both sexes, predominantly in the Chinese. Epstein-Barr virus (EBV) infection is known to be highly associated with NPC. Fibroblast growth factor receptor-4 (FGFR4) is part of the family of tyrosine kinase receptors that regulate cell survival, differentiation and pro-liferation. The binding of FGFR4 ligands such as fibroblasts growth factors (FGFs) has been shown to activate various oncogenic signalling pathway including MAPK, Ras and PI3K-Akt pathways. In the past, FGFR4 has been shown to promote tumorigenesis and tumour progression in various cancers such as liver, colon, breast and pancreatic and gastric cancers. However, its role in NPC establishment and pathogenesis is under-explored. This study aimed to evaluate the FGFR4 expression in NPC using various cell lines and its potential as a therapeutic target for NPC treat-ment by gene silencing. Methods: The basal FGFR4 level of NPC (EBV-positive: C666-1 and EBV-negative: HONE1 and HK1) and nasopharyngeal epithelial (NPE) normal (NP69 and NP460) cell lines was determined by western blot analysis and RT-qPCR. FGFR4 level at different time points (0, 24, 48, and 72 hours) in HONE1 and C666-1 cell lines were determined by western blot analysis. Luminescence-based assay was performed to determine the cell prolifer-ation of NPC cells in correlation with the FGFR4 expression. NPC cells were then treated with the optimised FGFR4 siRNA or FGFR inhibitor, BLU-9931 and the silencing/ inhibition of FGFR4 expression was confirmed by western blot analysis. The effect of FGFR4 inhibition on the cell proliferation and aggressiveness of NPC cells was then investigat-ed through wound healing assay and invasion marker analysis. Results: Out of the five tested cell lines, HONE1 and C666-1 highly expressed FGFR4, NP69 showed very low expression while HK1 and NP460 did not express FGFR4. In the time-point study, the FGFR4 level of HONE1 and C666-1 peaked at 24-48 hours which is the exponential phase of cells. Following that, the FGFR4 level decreased corresponding to the decreased cell growth rate due to the nutrient deprivation. siRNA experiments showed that 6.25nM of four siRNAs (5, 6, 9 and 10) could effectively target and silence the FGFR4 expression of HONE1, but not in C666-1 even up to 250nM was tested. When BLU-9931 was used, only modest inhibition was observed in both cells at 3uM. Compared to the untreated control, FGFR4-inhibited HONE1 exhibited decreased cell proliferation rate. Cell migration and invasion capabilities of HONE1 were also significantly reduced following the FGFR4 silencing, suggesting the potential of utilising FGFR4 as the therapeutic target. Conclusion: FGFR4 is highly expressed in C666-1 (EBV-positive) and HONE1 (initially EBV-positive, but lost EBV genome in subsequent in vitro passage) NPC cells, but not in EBV-negative HK1 NPC cell and normal NPE cells. FGFR4 gene silencing effectively inhibited the cell proliferation, migration and invasive potentials of NPC cell line. These findings highlight the therapeutic value of targeting FGFR4 for NPC treatment. Further investigations are war-ranted to reveal the molecular mechanism and the possible role of EBV in regulating FGFR4 pathway.
    Matched MeSH terms: Receptor Protein-Tyrosine Kinases
  19. Caunter G, Faeez Md Noh MS, Safri LS, Kumar K, Md Idris MA, Harunarashid H, et al.
    EJVES Short Rep, 2019;44:19-22.
    PMID: 31453386 DOI: 10.1016/j.ejvssr.2019.06.003
    Introduction: The development of metastatic renal cell carcinoma (RCC) many years after a nephrectomy is not common but has been reported. A metastasis appearing as a hypervascular tumour, mimicking an arteriovenous malformation (AVM), is a highly unusual phenomenon, with a biopsy required for diagnostic confirmation. Surgery is an option for a solitary metastatic lesion amenable to complete excision, with proven survival benefits. However, widespread metastatic disease carries a very poor prognosis, and is best treated with systemic agents such as anti-angiogenic drugs or tyrosine kinase inhibitors.

    Report: A 58 year old man developed an AVM mimicking a vascular tumour within his left brachioradialis muscle 10 years after a nephrectomy for RCC. Ultrasound and magnetic resonance imaging did not reveal any suspicious features of the vascular lesion.The lesion was successfully removed surgically, and was later proven histopathologically to be metastatic RCC. Further imaging showed widespread metastatic disease, and the patient survived only 15 months after receiving tyrosine kinase inhibitor therapy.

    Discussion: This case report aims to highlight a few important points: RCC metastases may be hypervascular, mimicking an AVM. A long disease free interval does not necessarily exclude recurrence or metastasis, as in this case, therefore long term surveillance is recommended. A high index of suspicion must be maintained to avoid delay in treatment, and biopsy of any suspicious lesion for histological examination is mandatory, albeit after many years of cancer remission. Whole body imaging with computed tomography or positron emission tomography computed tomography may detect clinically occult recurrence or metastases, and is important to guide further treatment.

    Matched MeSH terms: Protein-Tyrosine Kinases
  20. Zakaria Z, Zulkifle MF, Wan Hasan WAN, Azhari AK, Abdul Raub SH, Eswaran J, et al.
    Onco Targets Ther, 2019;12:7749-7756.
    PMID: 31571924 DOI: 10.2147/OTT.S214611
    Background: Epidermal growth factor receptor (EGFR) is a member of the ErbB family of tyrosine kinase receptor proteins that plays important roles in tumour cell survival and proliferation. EGFR has been reported to be overexpressed in up to 78% of triple-negative breast cancer (TNBC) cases suggesting it as a potential therapeutic target. The clinical trials of anti-EGFR agents in breast cancer showed low response rates. However, a subgroup of patients demonstrated response to EGFR inhibitors highlighting the necessity to stratify patients, who might benefit from effective combination therapy that could include anti EGFR-agents. Population variability in EGFR expression warrants systematic evaluation in specific populations.

    Purpose: To study EGFR alterations and expressions in a multi ethnic Malaysian TNBC patient cohort to determine the possibility of using anti-EGFR combinatorial therapy for this population.

    Patients and methods: In this study, we evaluated 58 cases of Malaysian TNBC patient samples for EGFR gene copy number alteration and EGFR protein overexpression using fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) methods, respectively.

    Results: EGFR protein overexpression was observed in about 30% while 15.5% displayed high EGFR copy number including 5.17% gene amplification and over 10% high polysomy. There is a positive correlation between EGFR protein overexpression and gene copy number and over expression of EGFR is observed in ten out of the 48 low copy number cases (20.9%) without gene amplification.

    Conclusion: This study provides the first glimpse of EGFR alterations and expressions in a multi ethnic Malaysian TNBC patient cohort emphasising the need for the nationwide large scale EGFR expression evaluation in Malaysia.

    Matched MeSH terms: Receptor Protein-Tyrosine Kinases
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