Publications by authors named "Jen-Fen Fu"

23 Publications

  • Page 1 of 1

Torus Mandibularis in Patients Receiving Hemodialysis.

Int J Environ Res Public Health 2021 Sep 7;18(18). Epub 2021 Sep 7.

College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.

Reports on the prevalence of torus mandibularis among dialysis patients have been limited and inconclusive. A wide variety of oral manifestations has been found in patients with hyperparathyroidism. Furthermore, uremia-related changes in facial bone structures have been described in the literature. This prospective observational study examined 322 hemodialysis patients treated at the Chang Gung Memorial Hospital from 1 August to 31 December 2016. Two subgroups were identified: patients with torus mandibularis (n = 25) and those without (n = 297). Clinical oral examinations including inspection and palpation were employed. Our study found that most mandibular tori were symmetric (84.0%), nodular (96.0%), less than 2 cm in size (96.0%), and located in the premolar area (92.0%). Poor oral hygiene was observed among these patients, with 49.7% and 24.5% scoring 3 and 4, respectively, on the Quigley-Hein plaque index. More than half (55.0%) of patients lost their first molars. Multivariate logistic regression analysis revealed that blood phosphate level (odds ratio = 1.494, = 0.029) and younger age (odds ratio = 0.954, = 0.009) correlated significantly with torus mandibularis. The prevalence of torus mandibularis in patients receiving hemodialysis in this study was 7.8%. Younger age and a higher blood phosphate level were predictors for torus mandibularis in these patients.
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http://dx.doi.org/10.3390/ijerph18189451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465652PMC
September 2021

plays critical roles in disease progression and response to cytarabine in AML.

Oncol Rep 2021 Jul 3;46(1). Epub 2021 Jun 3.

Department of Nephrology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, R.O.C.

Lysine methyltransferase 2A (, also known as ) translocations (‑t) are frequently associated with mutations in pathway genes in acute myeloid leukemia (AML). Previous findings with a mouse model showed that cooperation of with tyrosine‑protein phosphatase non‑receptor type 11  accelerated leukemia development, but increased cytarabine (Ara‑C) sensitivity of leukemia cells. To identify the genes responsible for reduced survival and Ara‑C resistance, transcriptomic profiling between six pairs of mouse leukemia cells harboring activating and wild‑type or was compared. A total of 23 differentially expressed genes (DEGs) with >1.5‑fold‑change between the paired cell lines were identified. The Gene Ontology (GO) terms overrepresented in these 23 DEGs included 'immune system process', 'actin filament binding', 'cellular response to interferon‑alpha' and 'sequence‑specific DNA'. Among the four genes (, PR domain zinc finger protein 5, Iroquois‑class homeodomain protein IRX‑5 and homeobox protein PKNOX2) mapped to the GO term 'sequence‑specific DNA', upregulation was associated with AML harboring ‑t and signaling mutations based on a meta‑analysis using data deposited in Oncomine™ and analysis of the clinical samples in the present study. Microarray data revealed that only was upregulated in those cells harboring activating . Functional studies of knockdown or overexpression in cells revealed that expression levels were associated with survival and Ara‑C sensitivity/apoptosis . In addition, regulated the expression of the apoptosis‑related genes, NF‑κB inhibitor α, transcription factor p65 and transformation‑related protein p53. Furthermore, the results of a meta‑analysis using Heuser's AML dataset supported the finding that chemotherapy responders have higher expression levels of . These results indicated that the expression of increased cell apoptosis and predicted an improved response to Ara‑C in AML.
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http://dx.doi.org/10.3892/or.2021.8101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185505PMC
July 2021

Outcomes of elderly patients with organophosphate intoxication.

Sci Rep 2021 06 2;11(1):11615. Epub 2021 Jun 2.

Department of Nephrology, Clinical Poison Center, Kidney Research Center, Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, and Chang Gung University, 199 Tung Hwa North Road, Taipei, Taoyuan, 105, Taiwan.

This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.
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http://dx.doi.org/10.1038/s41598-021-91230-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172550PMC
June 2021

Environmental Cadmium Exposure and Dental Indices in Orthodontic Patients.

Healthcare (Basel) 2021 Apr 2;9(4). Epub 2021 Apr 2.

Department of Nephrology, Chang Gung Memorial Hospital, Linkou 333, Taiwan.

Background: Previous studies have shown that environmental cadmium exposure could disrupt salivary gland function and is associated with dental caries and reduced bone density. Therefore, this cross-sectional study attempted to determine whether tooth decay with tooth loss following cadmium exposure is associated with some dental or skeletal traits such as malocclusions, sagittal skeletal pattern, and tooth decay.

Methods: Between August 2019 and June 2020, 60 orthodontic patients with no history of previous orthodontics, functional appliances, or surgical treatment were examined. The patients were stratified into two groups according to their urine cadmium concentrations: high (>1.06 µg/g creatinine, = 28) or low (<1.06 µg/g creatinine, = 32).

Results: The patients were 25.07 ± 4.33 years old, and most were female (female/male: 51/9 or 85%). The skeletal relationship was mainly Class I (48.3%), followed by Class II (35.0%) and Class III (16.7%). Class I molar relationships were found in 46.7% of these patients, Class II molar relationships were found in 15%, and Class III molar relationships were found in 38.3%. The mean decayed, missing, and filled surface (DMFS) score was 8.05 ± 5.54, including 2.03 ± 3.11 for the decayed index, 0.58 ± 1.17 for the missing index, and 5.52 ± 3.92 for the filled index. The mean index of complexity outcome and need (ICON) score was 53.35 ± 9.01. The facial patterns of these patients were within the average low margin (26.65 ± 5.53 for Frankfort-mandibular plane angle (FMA)). There were no significant differences in the above-mentioned dental indices between patients with high urine cadmium concentrations and those with low urine cadmium concentrations. Patients were further stratified into low (<27, = 34), average (27-34, = 23), and high (>34, = 3) FMA groups. There were no statistically significant differences in the urine cadmium concentration among the three groups. Nevertheless, a marginally significant -value of 0.05 for urine cadmium concentration was noted between patients with low FMA and patients with high FMA.

Conclusion: This analysis found no association between environmental cadmium exposure and dental indices in our orthodontic patients.
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http://dx.doi.org/10.3390/healthcare9040413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066373PMC
April 2021

Impact of kidney size on mortality in diabetic patients receiving peritoneal dialysis.

Sci Rep 2021 04 15;11(1):8203. Epub 2021 Apr 15.

Department of Nephrology, Clinical Poison Center, Kidney Research Center, Center for Tissue Engineering, Chang Gung Memorial Hospital, Chang Gung University, 199 Tung Hwa North Road, Linkou, Taoyuan, Taipei, 105, Taiwan.

Although patients with diabetes mellitus mostly present with enlarged or normal-sized kidneys throughout their life, a small proportion of patients have small kidneys. This longitudinal study enrolled 83 diabetic patients treated with peritoneal dialysis (PD) between 2015 and 2019. Patients were stratified into two groups, those with enlarged or normal (n = 67) or small (n = 16) kidneys, based on their kidney sizes before dialysis. Patients with small kidney size were not only older (76.63 ± 10.63 vs. 68.03 ± 11.26 years, P = 0.007), suffered longer duration of diabetes mellitus (272.09 ± 305.09 vs. 151.44 ± 85.31 month, P = 0.006) and predominantly female (75.0 vs. 41.8%, P = 0.017), but also had lower serum levels of creatinine (9.63 ± 2.82 vs. 11.74 ± 3.32 mg/dL, P = 0.022) and albumin (3.23 ± 0.67 vs. 3.60 ± 0.47 g/dL, P = 0.010) than patients with enlarged or normal kidney size. At the end of analysis, 14 (16.9%) patients died. Patients with small kidney size demonstrated higher all-cause (50.0 vs. 9.0%, P < 0.001) and infection-related (43.8 vs. 7.5%, P < 0.001) mortality than patients with enlarged or normal kidney size. In a multivariate-logistic-regression model, small kidney size was a powerful predictor of mortality (odds ratio 6.452, 95% confidence interval 1.220-34.482, P = 0.028). Diabetic patients with small kidney size at the beginning of PD carry a substantial risk for mortality.
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http://dx.doi.org/10.1038/s41598-021-87684-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050039PMC
April 2021

Application of Bone Marrow-Derived Mesenchymal Stem Cells for Muscle Healing After Contusion Injury in Mice.

Am J Sports Med 2020 04 5;48(5):1226-1235. Epub 2020 Mar 5.

Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou.

Background: Skeletal muscle injuries are very common in sports medicine. Conventional therapies have limited clinical efficacy. New treatment methods should be developed to allow athletes to return to play with better function.

Purpose: To evaluate the in vitro differentiation potential of bone marrow-derived mesenchymal stem cells and the in vivo histologic and physiologic effects of mesenchymal stem cell therapy on muscle healing after contusion injury.

Study Design: Controlled laboratory study.

Methods: Bone marrow cells were flushed from both femurs of 5-week-old C57BL/6 mice to establish immortalized mesenchymal stem cell lines. A total of 36 mice aged 8 to 10 weeks were used to develop a muscle contusion model and were divided into 6 groups (6 mice/group) on the basis of the different dosages of IM2 cells to be injected (0, 1.25 × 10, and 2.5 × 10 cells with/without F-127 in 100 μL of phosphate-buffered saline). Histological analysis of muscle regeneration was performed, and the fast-twitch and tetanus strength of the muscle contractions was measured 28 days after muscle contusion injury, after injections of different doses of mesenchymal stem cells with or without the F-127 scaffold beginning 14 days after contusion injury.

Results: The mesenchymal stem cell-treated muscles exhibited numerous regenerating myofibers. All the groups treated with mesenchymal stem cells (1.25 × 10 cells, 2.5 × 10 cells, 1.25 × 10 cells plus F-127, and 2.5 × 10 cells plus F-127) exhibited a significantly higher number of regenerating myofibers (mean ± SD: 111.6 ± 14.77, 133.4 ± 21.44, 221.89 ± 32.65, and 241.5 ± 25.95, respectively) as compared with the control group and the control with F-127 (69 ± 18.79 and 63.2 ± 18.98). The physiologic evaluation of fast-twitch and tetanus strength did not reveal differences between the age-matched uninjured group and the groups treated with various doses of mesenchymal stem cells 28 days after contusion. Significant differences were found between the control group and the groups treated with various doses of mesenchymal stem cells after muscle contusion.

Conclusion: Mesenchymal stem cell therapy increased the number of regenerating myofibers and improved fast-twitch and tetanus muscle strength in a mouse model of muscle contusion. However, the rapid decay of transplanted mesenchymal stem cells suggests a paracrine effect of this action. Treatment with mesenchymal stem cells at various doses combined with the F-127 scaffold is a potential therapy for a muscle contusion.

Clinical Relevance: Mesenchymal stem cell therapy has an effect on sports medicine because of its effects on myofiber regeneration and muscle strength after contusion injury.
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http://dx.doi.org/10.1177/0363546520905853DOI Listing
April 2020

Ets1 Plays a Critical Role in MLL/EB1-Mediated Leukemic Transformation in a Mouse Bone Marrow Transplantation Model.

Neoplasia 2019 05 8;21(5):469-481. Epub 2019 Apr 8.

Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Leukemogenic potential of MLL fusion with the coiled-coil domain-containing partner genes and the downstream target genes of this type of MLL fusion have not been clearly investigated. In this study, we demonstrated that the coiled-coil-four-helix bundle structure of EB1 that participated in the MLL/EB1 was required for immortalizing mouse bone marrow (BM) cells and producing myeloid, but not lymphoid, cell lines. Compared to MLL/AF10, MLL/EB1 had low leukemogenic ability. The MLL/EB1 cells grew more slowly owing to increased apoptosis in vitro and induced acute monocytic leukemia with an incomplete penetrance and longer survival in vivo. A comparative analysis of transcriptome profiling between MLL/EB1 and MLL/AF10 cell lines revealed that there was an at least two-fold difference in the induction of 318 genes; overall, 51.3% (163/318) of the genes were known to be bound by MLL, while 15.4% (49/318) were bound by both MLL and MLL/AF9. Analysis of the 318 genes using Gene Ontology-PANTHER overrepresentation test revealed significant differences in several biological processes, including cell differentiation, proliferation/programmed cell death, and cell homing/recruitment. The Ets1 gene, bound by MLL and MLL/AF9, was involved in several biological processes. We demonstrated that Ets1 was selectively upregulated by MLL/EB1. Short hairpin RNA knockdown of Ets1 in MLL/EB1 cells reduced the expression of CD115, apoptosis rate, competitive engraftment to BM and spleen, and incidence of leukemia and prolonged the survival of the diseased mice. Our results demonstrated that MLL/EB1 upregulated Ets1, which controlled the balance of leukemia cells between apoptosis and BM engraftment/clonal expansion. Novelty and impact of this study The leukemogenic potential of MLL fusion with cytoplasmic proteins containing coiled-coil dimerization domains and the downstream target genes of this type of MLL fusion remain largely unknown. Using a retroviral transduction/transplantation mouse model, we demonstrated that MLL fusion with the coiled-coil-four-helix bundle structure of EB1 has low leukemogenic ability; Ets1, which is upregulated by MLL/EB1, plays a critical role in leukemic transformation by balance between apoptosis and BM engraftment/clonal expansion.
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http://dx.doi.org/10.1016/j.neo.2019.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458341PMC
May 2019

Predictors of acute kidney injury after paraquat intoxication.

Oncotarget 2017 Aug 18;8(31):51345-51354. Epub 2017 May 18.

Department of Nephrology and Poison Center, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Linkou, Taiwan.

Paraquat intoxication is characterized by multi-organ failure, causing substantial mortality and morbidity. Many paraquat patients experience acute kidney injury (AKI), sometimes requiring hemodialysis. We observed 222 paraquat-intoxicated patients between 2000 and 2012, and divided them into AKI ( = 103) and non-AKI ( = 119) groups. The mortality rate was higher for AKI than non-AKI patients (70.1% vs. 40.0%, 0.001). Patients with AKI had a longer time to hospital arrival ( = 0.003), lower PaO ( = 0.006) and higher alveolar-arterial O difference ( 0.001) 48 h after admission, higher sequential organ failure assessment 48-h score ( 0.001), higher severity index of paraquat poisoning (SIPP) score ( = 0.016), lower PaCO at admission ( = 0.031), higher PaO at admission ( = 0.015), lower nadir PaCO ( = 0.001) and lower nadir HCO ( = 0.004) than non-AKI patients. Multivariate logistic regression indicated that acute hepatitis ( 0.001), a longer time to hospital arrival ( 0.001), higher SIPP score ( = 0.026) and higher PaO at admission ( = 0.014) were predictors of AKI. The area under the receiver operating characteristic curve confirmed that an Acute Kidney Injury Network 48-hour score ≥ 2 predicted AKI necessitating hemodialysis with a sensitivity of 0.6 and specificity of 0.832. AKI is common (46.4%) following paraquat ingestion, and acute hepatitis, the time to hospital arrival, SIPP score and PaO at admission were powerful predictors of AKI. Larger studies with longer follow-up durations are warranted.
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http://dx.doi.org/10.18632/oncotarget.17975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584253PMC
August 2017

Isolation of Mesenchymal Stem Cells from Human Deciduous Teeth Pulp.

Biomed Res Int 2017 9;2017:2851906. Epub 2017 Mar 9.

Poison Center, Department of Nephrology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Linkou, Taiwan; Kidney Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan; Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou, Taiwan.

This study aimed to identify predictors of success rate of mesenchymal stem cell (MSC) isolation from human deciduous teeth pulp. A total of 161 deciduous teeth were extracted at the dental clinic of Chang Gung Memorial Hospital. The MSCs were isolated from dental pulps using a standard protocol. In total, 128 colonies of MSCs were obtained and the success rate was 79.5%. Compared to teeth not yielding MSCs successfully, those successfully yielding MSCs were found to have less severe dental caries (no/mild-to-moderate/severe: 63.3/24.2/12.5% versus 12.5/42.4/42.4%, < 0.001) and less frequent pulpitis (no/yes: 95.3/4.7% versus 51.5/48.5%, < 0.001). In a multivariate regression model, it was confirmed that the absence of dental caries (OR = 4.741, 95% CI = 1.564-14.371, = 0.006) and pulpitis (OR = 9.111, 95% CI = 2.921-28.420, < 0.001) was significant determinants of the successful procurement of MSCs. MSCs derived from pulps with pulpitis expressed longer colony doubling time than pulps without pulpitis. Furthermore, there were higher expressions of proinflammatory cytokines, interleukin- (IL-) 6 and monocyte chemoattractant protein- (MCP-) 1, < 0.01, and innate immune response [toll-like receptor 1 (TLR1) and TLR8, < 0.05; TLR2, TLR3, and TLR6, < 0.01] in the inflamed than noninflamed pulps. Therefore, a carious deciduous tooth or tooth with pulpitis was relatively unsuitable for MSC processing and isolation.
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http://dx.doi.org/10.1155/2017/2851906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362703PMC
April 2017

Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model.

Int J Cancer 2017 Mar 25;140(5):1159-1172. Epub 2016 Nov 25.

Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11 . To study the impact of PTPN11 cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 , the cells harboring PTPN11 were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11 autonomously differentiated into macrophages (1.8%) in the medium containing IL3. Further studies showed that the cells had an elevated (∼2.9-fold) Csf1 transcription level and secreted more (∼4.5-fold) M-CSF to the medium which can stimulate monocyte/macrophage differentiation of BM cells. Mice transplanted with the cells harboring PTPN11 had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 , the cells harboring PTPN11 had an increased competitive engraftment and clonal expansion in the BM and spleen of recipient mice, although no competitive growth advantage was observed in the in vitro co-culturing assays. The mice transplanted with the MLL/AF10(OM-LZ) cells harboring PTPN11 developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11 -induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11 to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.
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http://dx.doi.org/10.1002/ijc.30515DOI Listing
March 2017

Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model.

Int J Cancer 2017 Mar 25;140(5):1159-1172. Epub 2016 Nov 25.

Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11 . To study the impact of PTPN11 cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 , the cells harboring PTPN11 were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11 autonomously differentiated into macrophages (1.8%) in the medium containing IL3. Further studies showed that the cells had an elevated (∼2.9-fold) Csf1 transcription level and secreted more (∼4.5-fold) M-CSF to the medium which can stimulate monocyte/macrophage differentiation of BM cells. Mice transplanted with the cells harboring PTPN11 had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 , the cells harboring PTPN11 had an increased competitive engraftment and clonal expansion in the BM and spleen of recipient mice, although no competitive growth advantage was observed in the in vitro co-culturing assays. The mice transplanted with the MLL/AF10(OM-LZ) cells harboring PTPN11 developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11 -induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11 to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.
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http://dx.doi.org/10.1002/ijc.30515DOI Listing
March 2017

Tumor-associated macrophages in stage IIIA pN2 non-small cell lung cancer after neoadjuvant chemotherapy and surgery.

Am J Transl Res 2014 11;6(5):593-603. Epub 2014 Oct 11.

Department of Internal Medicine, Chang Gung University College of Medicine Taoyuan, Taiwan.

Purpose: Most of the patients with stage IIIA pN2 non-small cell lung cancer (NSCLC) develop recurrence after surgery. It is not clear whether post neoadjuvant chemotherapy tumor-associated macrophages is associated with recurrence.

Patients And Methods: Stage IIIA pN2 NSCLC patients underwent cisplatin/docetaxel neoadjuvant chemotherapy and surgery were retrospectively enrolled. Immunohistochemical staining of CD68 was used to identify macrophages in surgical resected stored tissues.

Results: The objective response rate of cisplatin/docetaxel was 68%, overall median disease-free survival (DFS) was 13.1 months and median overall survival (OS) 36.8. months. Multiple Cox regression analysis showed low total macrophage numbers and mediastinal lymph nodes downstaging were independent factors for longer DFS, whereas high islet/stromal macrophages ratio was an independent facto for OS. In patients downstaged to pN0, low total macrophage numbers was also associated with longer DFS.

Conclusions: Low total macrophage number is an independent factor for better DFS in pN2 stage IIIA NSCLC patients receiving neoadjuvant chemotherapy and surgical resection, which association was kept in those downstaged to pN0. Further studies are warrant to confirm the predictive role of TAMs and their potential causative role in tumor recurrence.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4212933PMC
October 2014

Outcomes of patients with rodenticide poisoning at a far east poison center.

Springerplus 2013 3;2:505. Epub 2013 Oct 3.

Department of Nephrology and Division of Clinical Toxicology, Chang Gung Memorial Hospital, 199 Tung Hwa North Road, Taipei, 105 Taiwan ; College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Background: Rodenticide poisoning remains a major public health problem in Asian countries. Nevertheless, very few data are available in world literature regarding the outcomes of these patients. Therefore, the purpose of this study was to investigate the clinical outcomes of rodenticide poisonings in our hospital and to compare these data with published reports from other international poison centers.

Findings: We retrospectively examined the records of 20 patients with rodenticide poisoning (8 brodifacoum, 12 bromadiolone) who were referred to Chang Gung Memorial Hospital between 2000 and 2011. It was found that most of the rodenticide patients were middle-aged adults. Both genders were equally affected and many patients had a past history of major depressive disorder or schizophrenia. Nevertheless, patients with bromadiolone were referred significantly sooner than patients with brodifacoum poisoning (0.1 ± 0.1 versus 5.5 ± 10.5, P < 0.001). Furthermore, it was found that patients with brodifacoum suffered higher incidences of ecchymosis (50.0% versus 0%, P = 0.006) and hematuria (50.0% versus 0%, P = 0.006) than patients with bromadiolone poisoning. Laboratory analysis also demonstrated a poorer hemostatic profile of patients with brodifacoum [prothrombin time (PT), international normalized ratio (INR), 4.3 ± 4.8 versus 1.0 ± 0.1, P = 0.032; PT prolongation, 50.0% versus 0%, P = 0.006; activated partial thromboplastin time (aPTT) prolongation, 50.0% versus 0%, P = 0.006] than patients with bromadiolone poisoning. At the end of analysis, no patient died of the poisoning.

Conclusion: The favorable outcome (zero mortality rate) is comparable to the published reports from other international poison centers. Further studies are warranted.
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http://dx.doi.org/10.1186/2193-1801-2-505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795205PMC
October 2013

A repeat sequence causes competition of ColE1-type plasmids.

PLoS One 2013 16;8(4):e61668. Epub 2013 Apr 16.

Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Plasmid pSW200 from Pantoea stewartii contains 41 copies of 15-bp repeats and has a replicon that is homologous to that of ColE1. Although deleting the repeats (pSW207) does not change the copy number and stability of the plasmid. The plasmid becomes unstable and is rapidly lost from the host when a homoplasmid with the repeats (pSW201) is present. Deleting the repeats is found to reduce the transcriptional activity of RNAIp and RNAIIp by about 30%, indicating that the repeats promote the transcription of RNAI and RNAII, and how the RNAI that is synthesized by pSW201 inhibits the replication of pSW207. The immunoblot analysis herein demonstrates that RNA polymerase β subunit and σ(70) in the lysate from Escherichia coli MG1655 bind to a biotin-labeled DNA probe that contains the entire sequence of the repeat region. Electrophoretic mobility shift assay also reveals that purified RNA polymerase shifts a DNA probe that contains four copies of the repeats. These results thus obtained reveal that RNA polymerase holoenzyme binds to the repeats. The repeats also exchange RNA polymerase with RNAIp and RNAIIp in vitro, revealing the mechanism by which the transcription is promoted. This investigation elucidates a mechanism by which a plasmid prevents the invasion of an incompatible plasmid and maintains its stability in the host cell during evolution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061668PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628316PMC
November 2013

Involvement of Gpr125 in the myeloid sarcoma formation induced by cooperating MLL/AF10(OM-LZ) and oncogenic KRAS in a mouse bone marrow transplantation model.

Int J Cancer 2013 Oct 7;133(8):1792-802. Epub 2013 May 7.

Department of Medical Research, Chang Gung Memorial Hospital, and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.

Oncogenic N-/KRAS mutations were frequently associated with MLL/AF10 in acute myeloid leukemia with myeloid sarcoma (MS). To study the cooperating leukemogenesis by MLL/AF10 and KRAS mutation, we retrovirally transduced MLL/AF10(OM-LZ) and KRASG12C into mouse bone marrow cells and generated two immortalized cell lines. The cells carrying cooperating MLL/AF10(OM-LZ) and KRASG12C had immature myelomonocytic phenotypes. Compared to a previously established cell line carrying MLL/AF10(OM-LZ) alone, cooperation of MLL/AF10(OM-LZ) with KRASG12C blocked the cells at a more immature myelomonocytic stage with reduced expression of monocyte/macrophage markers. The mice transplanted with the cells carrying cooperating MLL/AF10(OM-LZ) and KRASG12C, liked those transplanted with the cells carrying MLL/AF10(OM-LZ) alone, induced myeloproliferative disease-like myeloid leukemia, but in a shorter latency and formed multiple MS at the adipose tissues of skin, peritoneum and intraperitoneal cavity. Cooperation of MLL/AF10(OM-LZ) with KRASG12C increased cell adhesion via upregulation of an adhesion G-protein-coupled receptor Gpr125. Knockdown of Gpr125 in the cells by short hairpin RNA reduced cell aggregation and diminished MS formation in the transplanted mice. Our results indicated that upregulation of Gpr125 by cooperating MLL/AF10(OM-LZ) and KRASG12C promoted cell adhesion and contributed to the MS formation.
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http://dx.doi.org/10.1002/ijc.28195DOI Listing
October 2013

MLL/AF10(OM-LZ)-immortalized cells expressed cytokines and induced host cell proliferation in a mouse bone marrow transplantation model.

Int J Cancer 2010 Apr;126(7):1621-9

Department of Medical Research, Chang Gung Memorial Hospital, and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.

Several mouse models studying the MLL fusion-induced leukemic transformation showed that a myeloproliferation stage precedes leukemia or occurred as the only phenotype of hematological disorder in mice. We established 6 MLL/AF10(OM-LZ)-immortalized cell lines by retrovirally transducing the fusion gene into bone marrow cells from B6 or congenic GFP-B6 mice. Immunophenotypic and cytological analyses revealed that the immortalized cell lines could be divided into 2 types. Type I had a high percentage of cells expressing monocytic lineage marker CD115 in the medium containing IL3 and could terminally differentiate into granulocytes and monocytes in response to granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) treatments, respectively. On the other hand, type II had a low percentage of cells expressing CD115. The type II cell lines could not differentiate into granulocytes by G-CSF treatment and died rapidly in response to M-CSF treatment. Transplantation of both types I and II cells induced lethal myeloproliferative disease (MPD)-like myeloid leukemia in most of the sublethally irradiated B6 mice. Flow cytometric analysis of GFP and lineage markers of the peripheral blood cells from MPD mice revealed that the monocytes and granulocytes were generated not only from the donor cells but also from the host cells. RT-PCR analysis revealed that the MLL/AF10(OM-LZ)-immortalized cells expressed mRNAs encoding colony-stimulating factors (CSFs) of M-CSF and GM-CSF and inflammatory cytokines of IL-1alpha, IL-1beta and TNF-alpha. Our results showed that the MLL/AF10(OM-LZ)-immortalized cells could induce host cell proliferation in the transplanted mice, probably through stimulation by CSFs or cytokines produced by the donor cells.
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http://dx.doi.org/10.1002/ijc.24867DOI Listing
April 2010

Analysis of acute leukemias with MLL/ENL fusion transcripts: identification of two novel breakpoints in ENL.

Am J Clin Pathol 2007 Jan;127(1):24-30

Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

t(11;19)(q23;p13.3); is one of the common chromosomal translocations in acute leukemias involving MLL rearrangements. This translocation generates MLL/ENL fusion transcripts. In a study of acute leukemias, 148 patients were identified to have MLL rearrangements by Southern blot analysis. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay, using primer sets covering the 2 previously described breakpoints at exons 2 and 7 of ENL detected 11 samples harboring MLL/ENL. complementary DNA panhandle PCR further identified 4 additional cases with novel breakpoints in ENL at exon 4 or 6. Sequencing analysis showed that all novel fusion transcripts were in-frame. The conventional cytogenetic analysis failed to detect t(11;19) in 6 of 13 cases. Of 15 patients with MLL/ENL, 7 had precursor B-cell acute lymphoblastic leukemia, 4 had T-cell acute lymphoblastic leukemia, and 4 had acute myeloid leukemia. The present study showed that PCR-based techniques are more sensitive than conventional karyotyping for detecting MLL/ENL fusions and an extra antisense primer at exon 6 of ENL should be included in RT-PCR assay to ensure complete detection of all MLL/ENL fusion transcripts.
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http://dx.doi.org/10.1309/XKQLMPN81LGG3HDLDOI Listing
January 2007

K-Ras mutations and N-Ras mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements.

Cancer 2006 Feb;106(4):950-6

Division of Pediatric Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.

Background: It is believed that Ras mutations drive the proliferation of leukemic cells. The objective of this study was to investigate the association of Ras mutations with childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) with special reference to the presence or absence of mixed-lineage leukemia gene (MLL) rearrangements.

Methods: Bone marrow samples from 313 children with B-precursor ALL and 130 children with de novo AML were studied at diagnosis. Southern blot analysis was used to detect MLL rearrangements, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was used to detect common MLL fusion transcripts. Complementary DNA panhandle PCR was used to identify the infrequent or unknown MLL partner genes. DNA PCR or RT-PCR followed by direct sequencing was performed to detect mutations at codons 12, 13, and 61 of the N-Ras and K-Ras genes.

Results: Twenty of 313 patients with B-precursor ALL and 17 of 130 patients with de novo AML had MLL rearrangements. N-Ras mutations were detected in 2 of 20 patients with MLL-positive ALL and in 27 of 293 patients with MLL-negative ALL (P = 1.000). N-Ras mutations were detected in 2 of 17 patients with MLL-positive AML and in 14 of 113 patients with MLL-negative AML (P = 1.000). K-Ras mutations were present in 8 of 20 patients with MLL-positive ALL compared with 32 of 293 patients with MLL-negative ALL (P = 0.001). K-Ras mutations were detected in 3 of 17 patients with MLL-positive AML compared with 5 of 113 patients with MLL-negative AML (P = 0.069).

Conclusions: Ras mutations were detected in 20.8% of patients with childhood B-precursor ALL and in 17.7% of patients with childhood AML. MLL-positive B-precursor ALL was associated closely with Ras mutations (50%), especially with K-Ras mutations (40%), whereas MLL-positive AML was not associated with Ras mutations.
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http://dx.doi.org/10.1002/cncr.21687DOI Listing
February 2006

MLL is fused to EB1 (MAPRE1), which encodes a microtubule-associated protein, in a patient with acute lymphoblastic leukemia.

Genes Chromosomes Cancer 2005 Jun;43(2):206-10

Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

We have shown that the EB1 (MAPRE1) gene, at 20q11.2, is fused to MLL in an adult patient with pro-B acute lymphoblastic leukemia. Southern blot analysis indicated that a rearrangement of the MLL gene was involved in the chromosomal abnormality. cDNA panhandle polymerase chain reaction (PCR) identified the fusion transcript, in which MLL exon 6 was fused in-frame with EB1 exon 5. The presence of the MLL-EB1 and the reciprocal EB1-MLL fusion transcripts was verified by reverse-transcription PCR. EB1 is the first gene on chromosome 20 found to fuse with MLL. The genomic break junctions of MLL-EB1 and EB1-MLL were amplified by long-distance PCR. Sequencing of the break junctions revealed that multiple DNA breaks had occurred and that the DNA fragments flanked by these breaks had been duplicated, deleted, or inverted. Nontemplate DNA segments of 2 bp also were detected at the breakpoints on derivative chromosomes 11 and 20. These features indicate that this translocation likely resulted from the DNA damage-repair pathway. EB1 is a microtubule-associated protein that interacts with the colorectal adenomatous polyposis coli tumor-suppressor protein and plays important roles in regulating microtubule dynamics, cell polarity, and chromosome stability. Immunofluorescence staining demonstrated that the MLL-EB1 fusion proteins were localized in the nuclei.
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http://dx.doi.org/10.1002/gcc.20174DOI Listing
June 2005

Molecular analysis of t(X;11)(q24;q23) in an infant with AML-M4.

Genes Chromosomes Cancer 2003 Nov;38(3):253-9

Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

t(X;11)(q24;q23) is a recurring chromosomal translocation in pediatric acute myeloid leukemia. The rearrangement results in fusion of MLL at 11q23 with SEPT6 at Xq24. Here, we report the identification of an MLL-SEPT6 fusion transcript in an infant with acute myeloid leukemia (AML)-M4. Reverse transcription-polymerase chain reaction confirmed the presence of an MLL-SEPT6 fusion transcript composed of exon 8 of MLL and exon 2 of SEPT6, but the absence of the reciprocal SEPT6-MLL fusion transcript. Sequence analysis of the genomic break junctions in MLL and SEPT6 suggested that the rearrangement in this case was the result of an insertion of the inverted Xq24 segment, which contained the 3' region of SEPT6 intron 1 and up to 950 kb centromeric to SEPT6, into MLL intron 8. This is a novel type of chromosomal rearrangement leading to the MLL-SEPT6 fusion. The presence of deletions, duplications, and non-template DNA sequence at the break junctions suggested that the DNA damage-repair machinery is likely to be involved in the translocation events.
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http://dx.doi.org/10.1002/gcc.10272DOI Listing
November 2003

Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia.

Genes Chromosomes Cancer 2003 Jun;37(2):214-9

Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

We have shown that the CBL gene at 11q23.3, telomeric to MLL, was fused to MLL in an adult patient with de novo acute myeloid leukemia (FAB-M1). Southern blot analysis indicated that the MLL rearrangement was involved in the chromosomal abnormality. cDNA panhandle polymerase chain reaction identified the fusion transcript, in which MLL exon 6 was fused in-frame with CBL exon 8. Long-distance PCR amplified the genomic junction region, which involved the fusion of the 3' portion of an Alu element in intron 6 of MLL with the 5' portion of an Alu element in intron 7 of CBL. The absence of extensive sequence similarity at both breakpoints of MLL and CBL indicated that the recombination was not generated through homologous recombination. MLL and CBL are located between STS markers D11S939 and D11S924. Analysis of the sequence demonstrated that the transcriptional orientation of both genes at 11q23.3 is from centromere to telomere. The results of Southern blotting in conjunction with fluorescence in situ hybridization suggest that the MLL-CBL fusion was the result of an interstitial deletion. CBL, a proto-oncogene, functions as a negative regulator of several receptor protein-tyrosine-kinase signaling pathways and as an adaptor protein in tyrosine phosphorylation-dependent signaling. CBL is the second gene at 11q23.3 found to fuse with MLL.
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http://dx.doi.org/10.1002/gcc.10204DOI Listing
June 2003

The replicon of pSW800 from Pantoea stewartii.

Microbiology (Reading) 2001 Oct;147(Pt 10):2757-2767

Department of Microbiology and Immunology, Chang-Gung University, Kwei-Shan, 333, Taiwan2.

A 2019 bp DNA fragment containing the replicon of pSW800 from Pantoea stewartii SW2 was cloned and characterized. This replicon contains two genes--repA and repB, which encode a 36.5 kDa replication initiation protein (RepA) and a peptide of 18 aa, respectively. These two genes overlap by 8 bases with repB situated upstream. The replicon also transcribes an antisense RNA (RNAI) that inhibits the expression of repA and repB. The ribosome-binding sequence (RBS) of repA is likely to be hidden in a stem-loop structure, inhibiting the translation of repA. Furthermore, translation of repB is likely to disrupt the stem-loop structure, which is one of the criteria allowing the translation of repA to begin. A mutagenesis study revealed that a sequence (5'-GCACGGG-3') located 111 nt upstream from repA is crucial; mutation of this sequence prevented the translation of repA. Additionally, this region and the stem-loop structure containing the RBS of repA may form an RNA pseudoknot. Results in this study demonstrate that a mechanism similar to that regulating plasmid replication in the IncB, IncIalpha and IncL/M groups also regulates pSW800 replication.
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http://dx.doi.org/10.1099/00221287-147-10-2757DOI Listing
October 2001
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