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  1. Article ; Online: ULK2 Is a Key Pro-Autophagy Protein That Contributes to the High Chemoresistance and Disease Relapse in FLT3-Mutated Acute Myeloid Leukemia

    Justine Lai / Claire Yang / Chuquan Shang / Will Chen / Michael P. Chu / Joseph Brandwein / Raymond Lai / Peng Wang

    International Journal of Molecular Sciences, Vol 25, Iss 1, p

    2024  Volume 646

    Abstract: We recently demonstrated that a small subset of cells in FLT3-mutated acute myeloid leukemia (AML) cell lines exhibit SORE6 reporter activity and cancer stem-like features including chemoresistance. To study why SORE6 + cells are more chemoresistant than ...

    Abstract We recently demonstrated that a small subset of cells in FLT3-mutated acute myeloid leukemia (AML) cell lines exhibit SORE6 reporter activity and cancer stem-like features including chemoresistance. To study why SORE6 + cells are more chemoresistant than SORE6 − cells, we hypothesized that these cells carry higher autophagy, a mechanism linked to chemoresistance. We found that cytarabine (Ara-C) induced a substantially higher protein level of LC3B-II in SORE6 + compared to SORE6 − cells. Similar observations were made using a fluorescence signal-based autophagy assay. Furthermore, chloroquine (an autophagy inhibitor) sensitized SORE6 + but not SORE6 − cells to Ara-C. To decipher the molecular mechanisms underlying the high autophagic flux in SORE6 + cells, we employed an autophagy oligonucleotide array comparing gene expression between SORE6 + and SORE6 − cells before and after Ara-C treatment. ULK2 was the most differentially expressed gene between the two cell subsets. To demonstrate the role of ULK2 in conferring higher chemoresistance in SORE6 + cells, we treated the two cell subsets with a ULK1/2 inhibitor, MRT68921. MRT68921 significantly sensitized SORE6 + but not SORE6 − cells to Ara-C. Using our in vitro model for AML relapse, we found that regenerated AML cells contained higher ULK2 expression compared to pretreated cells. Importantly, inhibition of ULK2 using MRT68921 prevented in vitro AML relapse. Lastly, using pretreatment and relapsed AML patient bone marrow samples, we found that ULK2 expression was higher in relapsed AML. To conclude, our results supported the importance of autophagy in the relapse of FLT3-mutated AML and highlighted ULK2 in this context.
    Keywords acute myeloid leukemia ; cancer stemness ; relapse ; autophagy ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 333
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: An In Vitro Model for Acute Myeloid Leukemia Relapse Using the SORE6 Reporter

    Justine Lai / Chuquan Shang / Will Chen / Iyare Izevbaye / Michael P. Chu / Irwindeep Sandhu / Joseph Brandwein / Raymond Lai / Peng Wang

    International Journal of Molecular Sciences, Vol 25, Iss 1, p

    2023  Volume 496

    Abstract: Many patients diagnosed with acute myeloid leukemia (AML) relapse within two years of the initial remission. The biology of AML relapse is incompletely understood, although cancer stem-like (CSL) cells have been hypothesized to be important. To test this ...

    Abstract Many patients diagnosed with acute myeloid leukemia (AML) relapse within two years of the initial remission. The biology of AML relapse is incompletely understood, although cancer stem-like (CSL) cells have been hypothesized to be important. To test this hypothesis, we employed SORE6, a reporter designed to detect the transcriptional activity of the embryonic stem cell proteins Oct4 and Sox2, to identify/purify CSL cells in two FLT3-mutated AML cell lines. Both cell lines contained ~10% of SORE6 + cells in the steady state. Compared to SORE6 − cells, SORE6 + cells exhibited more characteristics of CSL cells, with significantly higher chemoresistance and rates of spheroid formation. SORE6 + cells had substantially higher expression of Myc and FLT3 proteins, which are drivers of SORE6 activity. Using a mixture of SORE6 − /SORE6 + cells that were molecularly barcoded, we generated an in vitro study model for AML relapse. Specifically, after ‘in vitro remission’ induced by Ara-C, both cell lines regenerated after 13 ± 3 days. Barcode analysis revealed that most of the regenerated cells were derived from the original SORE6 + cells. Regenerated cells exhibited more CSL features than did the original SORE6 + cells, even though a proportion of them lost SORE6 activity. In bone marrow samples from a patient cohort, we found that relapsed blasts expressed significantly higher levels of Myc, a surrogate marker of SORE6 activity, compared to pre-treatment blasts. To conclude, using our in vitro model, we have provided evidence that CSL cells contribute to AML relapse.
    Keywords acute myeloid leukemia ; relapse ; cancer stem-like cell ; SORE6 reporter ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 333
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Gene Methylation and Silencing of WIF1 Is a Frequent Genetic Abnormality in Mantle Cell Lymphoma

    Abdulraheem Alshareef / Anthea C. Peters / Pascal Gélébart / Will Chen / Raymond Lai

    International Journal of Molecular Sciences, Vol 22, Iss 2, p

    2021  Volume 893

    Abstract: We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/ ...

    Abstract We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/silencing of WIF1 (Wnt inhibitory factor-1), a physiologic inhibitor of WCP, contributes to the deregulation of WCP and promotes cell growth in MCL. In support of this hypothesis, we found that the expression of WIF1 was detectable in none of the 4 MCL cell lines, and in only 2 of 5 tumors (40%) examined. Using methylation-specific PCR, we found evidence of gene methylation of WIF1 in 4 of 5 cell lines (80%) and in 24 of 29 (82%) tumors. The addition of the demethylation agent 5-aza-2′-deoxycytidine to Mino and JeKo-1, two WIF1-negative cell lines, restored the expression of WIF1 mRNA in these cells. Gene transfection of WIF1 into JeKo-1 and Mino cells significantly reduced cell growth, and this finding correlated with substantial downregulations of various proteins in WCP, such as β-catenin and pGSK-3β. In conclusion, our results support the concept that gene methylation/silencing of WIF1 is a frequent event in MCL, and this abnormality contributes to the aberrant activation of WCP. These results have provided further evidence that aberrant Wnt signaling is pathogenetically important in MCL and it may represent a potential therapeutic target.
    Keywords mantle cell lymphoma ; Wnt canonical pathway ; Wnt inhibitory factor-1 ; gene methylation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 570
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Web-based oil immersion whole slide imaging increases efficiency and clinical team satisfaction in hematopathology tumor board

    Zhongchuan Will Chen / Jessica Kohan / Sherrie L Perkins / Jerry W Hussong / Mohamed E Salama

    Journal of Pathology Informatics, Vol 5, Iss 1, Pp 41-

    2014  Volume 41

    Abstract: Background: Whole slide imaging (WSI) is widely used for education and research, but is increasingly being used to streamline clinical workflow. We present our experience with regard to satisfaction and time utilization using oil immersion WSI for ... ...

    Abstract Background: Whole slide imaging (WSI) is widely used for education and research, but is increasingly being used to streamline clinical workflow. We present our experience with regard to satisfaction and time utilization using oil immersion WSI for presentation of blood/marrow aspirate smears, core biopsies, and tissue sections in hematology/oncology tumor board/treatment planning conferences (TPC). Methods: Lymph nodes and bone marrow core biopsies were scanned at ×20 magnification and blood/marrow smears at 83X under oil immersion and uploaded to an online library with areas of interest to be displayed annotated digitally via web browser. Pathologist time required to prepare slides for scanning was compared to that required to prepare for microscope projection (MP). Time required to present cases during TPC was also compared. A 10-point evaluation survey was used to assess clinician satisfaction with each presentation method. Results: There was no significant difference in hematopathologist preparation time between WSI and MP. However, presentation time was significantly less for WSI compared to MP as selection and annotation of slides was done prior to TPC with WSI, enabling more efficient use of TPC presentation time. Survey results showed a significant increase in satisfaction by clinical attendees with regard to image quality, efficiency of presentation of pertinent findings, aid in clinical decision-making, and overall satisfaction regarding pathology presentation. A majority of respondents also noted decreased motion sickness with WSI. Conclusions: Whole slide imaging, particularly with the ability to use oil scanning, provides higher quality images compared to MP and significantly increases clinician satisfaction. WSI streamlines preparation for TPC by permitting prior slide selection, resulting in greater efficiency during TPC presentation.
    Keywords Hematopathology ; microscope projection ; oil immersion ; tumor board ; whole slide imaging ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Pathology ; RB1-214
    Subject code 302
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: A technology developed from concept of acupuncture and meridian system, the clinical effect of BIOCERAMIC resonance on psychological related sleep disturbance with findings on questionnaire, EEG and fMRI

    Lei Zhang / Paul Chan / Zhong Min Liu / Yi Li Tseng / C. Will Chen / Ming Tse Lin / Wing P. Chan / Ting-Kai Leung

    Journal of Traditional and Complementary Medicine, Vol 8, Iss 2, Pp 289-

    2018  Volume 295

    Abstract: Under the concept of meridian channels that belongs to traditional Chinese medicine, BIOCERAMIC Resonance (BR) has already been applied to many clinical medical research projects with functions mimicking of traditional acupuncture. Forty-five patients ... ...

    Abstract Under the concept of meridian channels that belongs to traditional Chinese medicine, BIOCERAMIC Resonance (BR) has already been applied to many clinical medical research projects with functions mimicking of traditional acupuncture. Forty-five patients were recruited with chronic sleep disorders; 36 patients were given, applied to the device with BIOCERAMIC material and sound rhythm on chest skin surface; 9 patients were included as controls. All study participants completed a sleep pattern and quality of life questionnaire (assessment on psychological and physical causes of sleep disturbances), which was repeated before, during and after treatment. Electroencephalograph (EEG) recordings were analyzed before, during and after treatment. Functional MRI (fMRI) was also used for demonstration of BR effect for another 8 candidates. During the first 3 days of treatment, sleep quality improved in all 36 patients especially to psychological reasons; in 91.7% (33/36) treatment was associated with an elevation in the beta spectrum of the EEG (at 15–27 Hz). The result of fMRI found corresponding cerebral and cerebellar areas of activation and deactivation. BIOCERAMIC Resonance can improve sleep disorder due to psychological causes, with transient alter brain wave activity and functional activation on specific locations of brain. Keywords: EEG, BIOCERAMIC, Sound rhythm, Sleep disturbance, fMRI
    Keywords Medicine ; R
    Subject code 610 ; 150
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Wave-Induced Flow in Meridians Demonstrated Using Photoluminescent Bioceramic Material on Acupuncture Points

    C. Will Chen / Chen-Jei Tai / Cheuk-Sing Choy / Chau-Yun Hsu / Shoei-Loong Lin / Wing P. Chan / Han-Sun Chiang / Chang-An Chen / Ting-Kai Leung

    Evidence-Based Complementary and Alternative Medicine, Vol

    2013  Volume 2013

    Abstract: The mechanisms of acupuncture remain poorly understood, but it is generally assumed that measuring the electrical conductivity at various meridians provides data representing various meridian energies. In the past, noninvasive methods have been used to ... ...

    Abstract The mechanisms of acupuncture remain poorly understood, but it is generally assumed that measuring the electrical conductivity at various meridians provides data representing various meridian energies. In the past, noninvasive methods have been used to stimulate the acupuncture points at meridians, such as heat, electricity, magnets, and lasers. Photoluminescent bioceramic (PLB) material has been proven to weaken hydrogen bonds and alter the characteristics of liquid water. In this study, we applied the noninvasive PLB technique to acupuncture point irradiation, attempting to detect its effects by using electrical conductivity measurements. We reviewed relevant literature, searching for information on meridians including their wave-induced flow characteristics.
    Keywords Other systems of medicine ; RZ201-999
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: Mass production of C50 carotenoids by Haloferax mediterranei in using extruded rice bran and starch under optimal conductivity of brined medium

    Will Chen, C. / Hsu, Shu-hui / Lin, Ming-Tse / Hsu, Yi-hui

    Bioprocess and biosystems engineering

    Volume v. 38,, Issue no. 1

    Abstract: Microbial carotenoids have potentially healthcare or medical applications. Haloferax mediterranei was difficult to economically grow into a large quantities as well as producing a valuable pigment of carotenoids. This study reports a novel investigation ... ...

    Abstract Microbial carotenoids have potentially healthcare or medical applications. Haloferax mediterranei was difficult to economically grow into a large quantities as well as producing a valuable pigment of carotenoids. This study reports a novel investigation into the optimal conductivity on the mass production of carotenoids from H. mediterranei. The major component at about 52.4 % in the extracted red pigment has been confirmed as bacterioruberin, a C₅₀ carotenoids, by liquid chromatography separation and mass spectrometry analysis. By maintaining higher conductivity of 40 S/m in the brined medium, the cell concentration attained to 7.73 × 10⁹ cells/L with low pigments concentration of 125 mg/L. When the conductivity was controlled at about 30 S/m, we obtained the highest cell concentration to 1.29 × 10¹⁰ cells/L with pigments of 361.4 mg/L. When the conductivity was maintained at optimal 25 S/m, the pigments can be increased to maximum value of 555.6 mg/L at lower cell concentration of 9.22 × 10⁹ cells/L. But conductivity below 20 S/m will cause the significant decrease in cell concentration as well as pigments due to the osmotic stress around the cells. Red pigment of carotenoids from an extremely halophilic archaebacterium could be efficiently produced to a high concentration by applying optimal conductivity control in the brined medium with extruded low-cost rice bran and corn starch.
    Keywords liquid chromatography ; rice bran ; mass spectrometry ; health services ; pigments ; carotenoids ; Haloferax mediterranei ; osmotic stress ; corn starch ; starch
    Language English
    Document type Article
    ISSN 1615-7591
    Database AGRIS - International Information System for the Agricultural Sciences and Technology

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