Publications by authors named "Yang Ming-Yu"

71 Publications

MiR-6924-5p-rich exosomes derived from genetically modified Scleraxis-overexpressing PDGFRα(+) BMMSCs as novel nanotherapeutics for treating osteolysis during tendon-bone healing and improving healing strength.

Biomaterials 2021 Nov 5;279:121242. Epub 2021 Nov 5.

Department of Orthopedics/Sports Medicine Center, State Key Laboratory of Trauma, Burn and Combined Injury, First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, 400000, China. Electronic address:

Osteolysis at the tendon-bone interface can impair pullout strength during tendon-bone healing and lead to surgery failure, but the effects of clinical treatments are not satisfactory. Mesenchymal stem cell (MSC)-derived exosomes have been used as potent and feasible natural nanocarriers for drug delivery and have been proven to enhance tendon-bone healing strength, indicating that MSC-derived exosomes could be a promising therapeutic strategy. In this study, we explored Scleraxis (Scx) dynamically expressed in PDGFRα(+) bone marrow-derived mesenchymal stem cells (BMMSCs) during natural tendon-bone healing. Then, we investigated the role of PDGFRα(+) BMMSCs in tendon-bone healing after Scx overexpression as well as the underlying mechanisms. Our data demonstrated that Scx-overexpressing PDGFRα(+) BMMSCs (BMMSC) could efficiently inhibit peritunnel osteolysis and enhance tendon-bone healing strength by preventing osteoclastogenesis in an exosomes-dependent manner. Exosomal RNA-seq revealed that the abundance of a novel miRNA, miR-6924-5p, was highest among miRNAs. miR-6924-5p could directly inhibit osteoclast formation by binding to the 3'-untranslated regions (3'UTRs) of OCSTAMP and CXCL12. Inhibition of miR-6924-5p expression reversed the prevention of osteoclastogenic differentiation by BMMSC derived exosomes (BMMSC-exos). Local injection of BMMSC-exos or miR-6924-5p dramatically reduced osteoclast formation and improved tendon-bone healing strength. Furthermore, delivery of miR-6924-5p efficiently inhibited the osteoclastogenesis of human monocytes. In brief, our study demonstrates that BMMSC-exos or miR-6924-5p could serve as a potential therapy for the treatment of osteolysis during tendon-bone healing and improve the outcome.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121242DOI Listing
November 2021

Systemic toll-like receptor 9 agonist CpG oligodeoxynucleotides exacerbates aminoglycoside ototoxicity.

Hear Res 2021 11 8;411:108368. Epub 2021 Oct 8.

Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan. Electronic address:

The Toll-like receptor (TLR) signaling pathway is the key regulator of the innate immune system in response to systemic infection. Several studies have reported that the systemic TLR4 agonist lipopolysaccharide exacerbates aminoglycoside ototoxicity, but the influence of virus-associated TLR7 and TLR9 signaling cascades on the cochlea is unclear. The present study aimed to investigate the auditory effects of systemic TLR7 and TLR9 agonists during chronic kanamycin treatment. CBA/CaJ mice received the TLR7 agonist gardiquimod or TLR9 agonist CpG oligodeoxynucleotides (ODN) one day before kanamycin injection and on the 5th and 10th days during a 14-day course of kanamycin treatment. We observed that systemic gardiquimod or CpG ODN alone did not affect the baseline auditory brainstem response (ABR) threshold. Three weeks after kanamycin treatment, gardiquimod did not significantly change ABR threshold shifts, whereas CpG ODN significantly increased kanamycin-induced ABR threshold shifts. Furthermore, outer hair cell (OHC) evaluation revealed that CpG ODN reduced distortion product otoacoustic emission amplitudes and increased kanamycin-induced OHC loss. CpG ODN significantly elevated cochlear Irf-7, Tnf-α, Il-1, and Il-6 transcript levels. In addition, an increased number of Iba-1 cells, which represented activated macrophages, was observed in the cochlea treated with CpG ODN. Our results indicated that systemic CpG ODN exacerbated kanamycin-induced ototoxicity and increased cochlear inflammation. This study implies that patients with underlying virus infection may experience more severe aminoglycoside-induced hearing loss if it occurs.
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http://dx.doi.org/10.1016/j.heares.2021.108368DOI Listing
November 2021

Dihydroisotanshinone I as a Treatment Option for Head and Neck Squamous Cell Carcinomas.

Int J Mol Sci 2021 Aug 18;22(16). Epub 2021 Aug 18.

Department of Medical Research and Development, Chiayi Chang Gung Memorial Hospital, Chiayi 61363, Taiwan.

Head and neck squamous cell carcinomas (HNSCCs) are the most common cancers of the head and neck, and their prevalence is rapidly increasing. HNSCCs present a clinical challenge because of their high recurrence rate, therapeutic resistance to radiation and chemotherapy drugs, and adverse effects. Hence, traditional Chinese herbal treatment may be advantageous to therapeutic strategies for HNSCCs. Danshen (), a well-known Chinese herb, has been extensively applied in treatments for various diseases, including cancer, because of its high degree of safety and low rate of adverse effects despite its unclear mechanism. Thus, we aimed to explore the possible anticancer effects and mechanisms of dihydroisotanshinone I (DT), a compound in danshen (extract from danshen), on HNSCCs. Three HNSCCs cell lines were used for in vitro studies, and a Detroit 562 xenograft mouse model was chosen for in vivo studies. Our in vitro results showed that DT could initiate apoptosis, resulting in cell death, and the p38 signaling partially regulated DT-initiated cell apoptosis in the Detroit 562 model. In the xenograft mouse model, DT reduced tumor size with no obvious adverse effect of hepatotoxicity. The present study suggests that DT is a promising novel candidate for anti-HNSCCs therapy.
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http://dx.doi.org/10.3390/ijms22168881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396193PMC
August 2021

Loss of ZNF215 imprinting is associated with poor five-year survival in patients with cytogenetically abnormal-acute myeloid leukemia.

Blood Cells Mol Dis 2021 09 26;90:102577. Epub 2021 May 26.

Department of Otolaryngology Head and Neck Surgery, Chiayi Chang Gung Memorial Hospital, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taiwan. Electronic address:

Genomic imprinting is a form of epigenetic regulation and imprinted genes are silenced in a parental-specific manner. Imprinting is associated with various human diseases and cancers, but its roles in leukemogenesis remains elusive. In this study, the expression of a panel of 16 human imprinted genes was investigated using real-time quantitative polymerase chain reaction and 8 of them were further validated in 114 patients newly diagnosed with cytogenetically abnormal-acute myeloid leukemia (CA-AML) and 85 healthy subjects. Our results demonstrated upregulated expression of 8 imprinted genes (C15orf2, COPG2, H19, IGF2, PEG3-AS1, PRIM2, SLC22A3 and ZNF215) was observed in patients with CA-AML (p < 0.001). Patients' survival days were negatively correlated with the expression levels of H19 (p = 0.024), PGE3-AS1 (p = 0.038), and ZNF215 (p = 0.012). Multivariate logistic regression analysis further revealed the expression level ZNF215 can be used as a predictor for five-year survival for patients with CA-AML (p = 0.009) with a hazard ratio of 0.870 (95.0% confident interval: 0.784-0.965). Our results demonstrated that loss of imprinting of imprinted genes is critical for the leukemogenesis of AML under CA condition, and loss of ZNF215 imprinting is associated with poor five-year survival of patients with CA-AML.
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http://dx.doi.org/10.1016/j.bcmd.2021.102577DOI Listing
September 2021

Circadian Mechanisms in Medicine.

N Engl J Med 2021 05;384(20):e76

E-Da Hospital, Kaohsiung, Taiwan.

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http://dx.doi.org/10.1056/NEJMc2104154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549064PMC
May 2021

Disrupted Expression of Circadian Clock Genes in Patients with Bronchial Asthma.

J Asthma Allergy 2021 16;14:371-380. Epub 2021 Apr 16.

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.

Purpose: Circadian clock is synchronized to the 24-hour day by the daily light-dark cycle and proper function of circadian rhythm is essential for many physiological processes. Disruption of circadian rhythm can affect disease processes and influence disease severity, treatment responses, and even survivorship. In this retrospective case-controlled study, we tried to explore whether expression of circadian clock genes was disturbed in patients with bronchial asthma.

Patients And Methods: We performed real-time quantitative reverse transcriptase-polymerase chain reactions to examine the expression of the nine core circadian clock genes (, , , , , , , , and ) in total leukocytes of peripheral blood collected at chest clinics from 120 patients with asthma and 60 health individuals.

Results: Expression levels of the nine circadian clock genes were significantly different between patients and healthy individuals, but not associated with the asthma control status. We also noted the difference of expression in asthmatic patients with and without nocturnal symptoms. In well-controlled asthmatics, expression of , , , , , and was significantly lower in patients with nocturnal symptoms than those without nocturnal symptoms. However, in not well-controlled asthmatics, expression of only , , , and was significantly different between patients with and without nocturnal symptoms. Binary logistic regression analysis selected , , , and as independent factors for bronchial asthma and ROC curves showed the combined expression of these four genes enhanced the capability of predicting asthma (AUC=0.924; 95% CI=0.875-0.958; <0.001).

Conclusion: Our results showed altered expression of circadian clock genes in patients with bronchial asthma and down-regulated in patients with nocturnal symptoms. Altered expression of circadian clock genes was also observed in asthmatics with or without nocturnal symptoms in well- or not well-controlled subgroups. Combined expression of , , , and could be a potential predictor for bronchial asthma.
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http://dx.doi.org/10.2147/JAA.S302508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057829PMC
April 2021

The Association Between Changes in Plasma Short-Chain Fatty Acid Concentrations and Hypertension in Children With Chronic Kidney Disease.

Front Pediatr 2020 4;8:613641. Epub 2021 Feb 4.

Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung, Taiwan.

Some children with chronic kidney disease (CKD) develop hypertension faster than others. This may be attributable to endothelial dysfunction, among other reasons. Short-chain fatty acids (SCFAs), that is, acetate, butyrate, and propionate, are known for reducing cardiovascular risks preserving endothelial function. This study aimed to investigate the association between changes in plasma SCFA concentrations and in cardiovascular and endothelial parameters in children with CKD. In total, 105 children and adolescents who met the CKD criteria were enrolled in this study, and 65 patients aged >6 years were divided into two groups based on the ambulatory BP measurements. The parameters of plasma SCFAs, endothelial function and morphology, and echocardiography were examined at the index visit and followed up after 1 year. We observed that 27.69% of 65 patients developed hypertension during the study period. Plasma acetate increased by 22.75 μM in the stable group ( < 0.001), whereas there was no change in the worsened BP group. The index higher plasma butyrate was positively correlated with worsened BP (adjusted odd ratio, 1.381; = 0.013). At the follow-up, plasma butyrate decreased by 2.12 and 4.41 μM in the stable and worsened BP groups, respectively ( < 0.001). In 105 subjects, higher index plasma propionate was positively correlated with decreasing ejection fraction (adjusted odd ratio, 1.281; = 0.046). Plasma acetate seemed to play a role in preventing hypertension in children with CKD. However, the index plasma propionate and butyrate concentrations seemed to imply the development of cardiovascular problems in our 1-year study.
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http://dx.doi.org/10.3389/fped.2020.613641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890123PMC
February 2021

Real-world evidence and optimization of vocal dysfunction in end-stage renal disease patients with secondary hyperparathyroidism.

Sci Rep 2021 01 12;11(1):653. Epub 2021 Jan 12.

Department of Otolaryngology - Head and Neck Surgery, Chiayi Chang Gung Memorial Hospital, No 6, Sec. West, Jiapu Rd., Puzi-City, Chiayi County, Taiwan.

Patients with end-stage renal disease (ESRD) may demonstrate secondary hyperparathyroidism (SHPT), characterized by parathyroid hormone oversecretion in response to electrolyte imbalance (e.g., hypocalcemia and hyperphosphatemia). Moreover, this electrolyte imbalance may affect vocal cord muscle contraction and lead to voice change. Here, we explored the effects of SHPT on the voices of patients with ESRD. We used data of 147,026 patients with ESRD from the registry for catastrophic illness patients, a sub-database of Taiwan National Health Insurance Research Database. We divided these patients into 2 groups based on whether they had hyperparathyroidism (HPT) and compared vocal dysfunction (VD) incidence among them. We also prospectively included 60 ESRD patients with SHPT; 45 of them underwent parathyroidectomy. Preoperatively and postoperatively, voice analysis was used to investigate changes in vocal parameters. In the real-world database analysis, the presence of HPT significantly increased VD incidence in patients with ESRD (p = 0.003): Cox regression analysis results indicated that patients with ESRD had an approximately 1.6-fold increased VD risk (p = 0.003). In the clinical analysis, the "jitter" and "shimmer" factors improved significantly after operation, whereas the aerodynamic factors remained unchanged. In conclusion, SHPT was an independent risk factor for VD in patients with ESRD, mainly affecting their acoustic factors.
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http://dx.doi.org/10.1038/s41598-020-79810-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804098PMC
January 2021

Altered Expression of Circadian Clock Genes in Patients with Atrial Fibrillation Is Associated with Atrial High-Rate Episodes and Left Atrial Remodeling.

Diagnostics (Basel) 2021 Jan 7;11(1). Epub 2021 Jan 7.

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.

A prominent circadian variation is present in atrial fibrillation (AF) attacks that may be related to the expression of circadian clock genes. Little is known about the expression of circadian clock genes in AF. We prospectively enrolled 73 patients who had received pacemaker implantation, in order to define the burden of atrial high-rate episodes (AHREs) accurately. AF was diagnosed clinically in 43 (59%) patients (15 with persistent AF and 28 with paroxysmal AF). The expression levels of circadian clock genes of peripheral blood leukocytes were checked. There were more males and patients with a larger left atrial (LA) size and lower expression levels of , , , , , , , and genes in persistent AF group than in other groups. There was a significant correlation between higher AHRE burden and larger LA size and between higher AHRE burden and decreased expression of circadian clock genes in patients with AF. LA volume and the expression of , , and are significantly associated with AHRE burden. However, the underlying mechanism needs to be elucidated in further studies.
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http://dx.doi.org/10.3390/diagnostics11010090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828089PMC
January 2021

Angiotensin II receptor blockers valsartan and losartan improve survival rate clinically and suppress tumor growth via apoptosis related to PI3K/AKT signaling in nasopharyngeal carcinoma.

Cancer 2021 May 6;127(10):1606-1619. Epub 2021 Jan 6.

Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Background: Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer in Asia. Adverse effects occur in over 90% of NPC patients treated with radiotherapy or chemoradiation. Angiotensin II receptor blockers (ARBs) are commonly used to treat hypertension without serious adverse effects. However, the anticancer activity of ARBs in NPC remains unclear.

Methods: We investigated the survival impacts of ARBs among NPC patients in a retrospective study. The anticancer effects and related signaling pathways of the ARBs valsartan and losartan were also evaluated in vitro and in vivo.

Result: A total of 927 patients with NPC who had hypertension were enrolled in the study, 272 (29.3%) of whom received ARBs. Kaplan-Meier analysis revealed that patients who used ARBs had higher rates of 5-year overall survival (OS; 87.8% vs 75.1%; P = .002) and disease-specific survival (DSS; 95.4% vs 77.7%; P < .001) than those who did not receive this treatment. Additionally, ARBs inhibited cell proliferation and induced apoptosis by increasing levels of cleaved caspase-3, cleaved caspase-9, and cytochrome C; the cell population in the sub-G1 phase; and caspase-3 activity in NPC-TW01 cells. ARBs inhibited tumor growth and angiogenesis via apoptosis in an NPC xenografts model. Interestingly, ARBs inhibited phosphorylation of PI3K/AKT signaling in vitro and in vivo, which is markedly attributed to their antitumor effects in NPC.

Conclusion: These data indicate that ARBs not only improve 5-year OS and DSS among patients with NPC but also exert antiproliferative and antiangiogenesis effects by inducing apoptosis in NPC, supporting that ARBs may be promising agents for treatment of NPC.
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http://dx.doi.org/10.1002/cncr.33391DOI Listing
May 2021

Patient-Related Factors of Medialization Laryngoplasty with Autologous Thyroid Cartilage.

Healthcare (Basel) 2020 Nov 30;8(4). Epub 2020 Nov 30.

Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan.

(1) Background: Medialization laryngoplasty with autologous thyroid cartilage (MLATC) is a surgical treatment for glottal closure insufficiency (GCI) resulted from unilateral vocal fold paralysis/paresis (UVFP) and vocal fold atrophy. We aimed to survey the influence of patient-related factors on the outcomes after MLATC. (2) Methods: The study enrolled 35 patients with GCI who underwent MLATC. Patient voice data were recorded before and after MLATC by using multiple acoustic parameters and subjective assessment in a computerized speech laboratory. GCI patients were characterized into subgroups based on three factors: age, ≥60 vs. <60 years; sex, men vs. women; and BMI, ≥24 vs. <24. (3) Results: When the subgroups were compared, men did not have better results after surgery than women. Patients ages < 60 years did not exhibit any significantly different outcome compared with those aged ≥ 60 years. Patients with BMI ≥ 24 did not have any significantly different outcome compared with those with BMI < 24. The subgroups of age, sex, and BMI had no significant difference in cumulative voice recovery and summation of GRBAS (G = grade, R = roughness, B = breathiness, A = asthenia, and S = strain). (4) Conclusions: MLATC is a good alternative surgery with long-term improvement in GCI patients. There is no evidence that age, sex, or BMI affect the functional outcome.
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http://dx.doi.org/10.3390/healthcare8040521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711452PMC
November 2020

Constant Light Dysregulates Cochlear Circadian Clock and Exacerbates Noise-Induced Hearing Loss.

Int J Mol Sci 2020 Oct 13;21(20). Epub 2020 Oct 13.

Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

Noise-induced hearing loss is one of the major causes of acquired sensorineural hearing loss in modern society. While people with excessive exposure to noise are frequently the population with a lifestyle of irregular circadian rhythms, the effects of circadian dysregulation on the auditory system are still little known. Here, we disturbed the circadian clock in the cochlea of male CBA/CaJ mice by constant light (LL) or constant dark. LL significantly repressed circadian rhythmicity of circadian clock genes , , , , and in the cochlea, whereas the auditory brainstem response thresholds were unaffected. After exposure to low-intensity (92 dB) noise, mice under LL condition initially showed similar temporary threshold shifts to mice under normal light-dark cycle, and mice under both conditions returned to normal thresholds after 3 weeks. However, LL augmented high-intensity (106 dB) noise-induced permanent threshold shifts, particularly at 32 kHz. The loss of outer hair cells (OHCs) and the reduction of synaptic ribbons were also higher in mice under LL after noise exposure. Additionally, LL enhanced high-intensity noise-induced 4-hydroxynonenal in the OHCs. Our findings convey new insight into the deleterious effect of an irregular biological clock on the auditory system.
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http://dx.doi.org/10.3390/ijms21207535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589695PMC
October 2020

Maximum and Minimum Phonatory Glottal Area before and after Treatment for Vocal Nodules.

Healthcare (Basel) 2020 Sep 7;8(3). Epub 2020 Sep 7.

Department of Otolaryngology-Head and Neck Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan.

: Vocal fold nodules (VFNs) are a challenge for otolaryngologists. Glottal area (GA) waveform analysis is an examination method used for assessing vocal fold vibration and function. However, GA in patients with VFNs has rarely been studied. This study investigated the maximum and minimum GA in VFN patients using modern waveform analysis combining ImageJ software and videostroboscopy. : This study enrolled 42 patients newly diagnosed with VFN, 15 of whom received voice therapy and 27 of whom underwent surgery. Acoustic parameters and maximum phonation time (MPT) were recorded, and patients completed the Chinese Voice Handicap Index-10 (VHI-C10) before and after treatment. After videostroboscopy examination, the maximum and minimum GAs were calculated using ImageJ software. The GAs of patients with VFNs before and after surgery or voice therapy were analyzed. : The MPTs of the patients before and after voice therapy or surgery did not change significantly. VHI-C10 scores decreased after voice therapy but the decrease was nonsignificant (14.0 ± 8.44 vs. 9.40 ± 10.24, = 0.222); VHI-C10 scores were significantly decreased after surgery (22.53 ± 7.17 vs. 12.75 ± 9.84, = 0.038). Voice therapy significantly increased the maximum GA (5.58 ± 2.41 vs. 8.65 ± 3.17, = 0.012) and nonsignificantly decreased the minimum GA (0.60 ± 0.73 vs. 0.21 ± 0.46, = 0.098). Surgery nonsignificantly increased the maximum GA (6.34 ± 3.82 vs. 8.73 ± 5.57, p = 0.118) and significantly decreased the minimum GA (0.30 ± 0.59 vs. 0.00 ± 0.00, = 0.036). This study investigated the GA of patients with VFNs who received voice therapy or surgery. The findings indicated that voice therapy significantly increased maximum GA and surgery significantly decreased minimum GA. GA analysis could be applied to evaluate the efficacy of voice therapy, and it may help physicians to develop precise treatment for VFN patients (either by optimizing voice therapy or by performing surgery directly).
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http://dx.doi.org/10.3390/healthcare8030326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551475PMC
September 2020

Proteomic Analysis of Peri-Wounding Tissue Expressions in Extracorporeal Shock Wave Enhanced Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Model.

Int J Mol Sci 2020 Jul 30;21(15). Epub 2020 Jul 30.

Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan..

Our former studies have demonstrated that extracorporeal shock wave therapy (ESWT) could enhance diabetic wound healing but the bio-mechanisms remain elusive. This study investigated the changes of topical peri-wounding tissue expressions after ESWT in a rodent streptozotocin-induced diabetic wounding model by using the proteomic analysis and elucidated the molecular mechanism. Diabetic rats receiving ESWT, normal control, and diabetic rats receiving no therapy were analyzed. The spots of interest in proteome analysis were subjected to mass spectrometry to elucidate the peptide mass fingerprints. Protein expression was validated using immunohistochemical staining and related expression of genes were analyzed using real-time RT-PCR. The proteomic data showed a significantly higher abundance of hemopexin at day 3 of therapy but down-regulation at day 10 as compared to diabetic control. In contrast, the level of serine proteinase inhibitor (serpin) A3N expression was significantly decreased at day 3 therapy but expression was upregulated at day 10. Using real-time RT-PCR revealed that serpin-related EGFR-MAPK pathway was involved in ESWT enhanced diabetic wound healing. In summary, proteome analyses demonstrated the expression change of hemopexin and serpin with related MAPK signaling involved in ESWT-enhanced diabetic wound healing. Modulation of hemopexin and serpin related pathways are good strategies to promote wound healing.
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http://dx.doi.org/10.3390/ijms21155445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432617PMC
July 2020

Upregulation of miR-941 in Circulating CD14+ Monocytes Enhances Osteoclast Activation via WNT16 Inhibition in Patients with Psoriatic Arthritis.

Int J Mol Sci 2020 Jun 17;21(12). Epub 2020 Jun 17.

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

Psoriatic arthritis (PsA) is a destructive joint disease mediated by osteoclasts. MicroRNAs (miRNAs) regulate several important pathways in osteoclastogenesis. We profiled the expression of miRNAs in CD14+ monocytes from PsA patients and investigated how candidate microRNAs regulate the pathophysiology in osteoclastogenesis. The RNA from circulatory CD14+ monocytes was isolated from PsA patients, psoriasis patients without arthritis (PsO), and healthy controls (HCs). The miRNAs were initially profiled by next-generation sequencing (NGS). The candidate miRNAs revealed by NGS were validated by PCR in 40 PsA patients, 40 PsO patients, and 40 HCs. The osteoclast differentiation and its functional resorption activity were measured with or without RNA interference against the candidate miRNA. The microRNA-941 was selectively upregulated in CD14+ monocytes from PsA patients. Osteoclast development and resorption ability were increased in CD14+ monocytes from PsA patients. Inhibition of miR-941 abrogated the osteoclast development and function while increased the expression of WNT16. After successful treatment, the increased miR-941 expression in CD14+ monocytes from PsA patients was revoked. The expression of miR-941 in CD14+ monocytes is associated with PsA disease activity. MiR-941 enhances osteoclastogenesis in PsA via WNT16 repression. The miR-941 could be a potential biomarker and treatment target for PsA.
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http://dx.doi.org/10.3390/ijms21124301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352857PMC
June 2020

Alternations of Circadian Clock Genes Expression and Oscillation in Obstructive Sleep Apnea.

J Clin Med 2019 Oct 6;8(10). Epub 2019 Oct 6.

Division of Hematology and Oncology, Department of Internal Medicine, E-Da Hospital, Kaohsiung 84001, Taiwan.

Circadian misalignment plays an important role in disease processes and can affect disease severity, treatment outcomes, and even survivorship. In this study, we aim to investigate whether expression and daily oscillation patterns of core circadian clock genes were disturbed in patients with obstructive sleep apnea/hypopnea (OSA) syndrome. We performed real-time quantitative reverse transcriptase-polymerase chain reactions to examine the expression of the nine core circadian clock genes in leukocytes of peripheral blood collected at 12 AM, 6 AM, 12 PM, and 6 PM from 133 patients with OSA and 11 normal controls. Daily expression patterns of the nine circadian clock genes were observed in normal controls, but three of these genes (BMAL1, CLOCK, CRY2) were disrupted in patients with OSA. The expressions of eight circadian clock genes (except PER1) at midnight were significantly downregulated in patients with severe OSA. Binary logistic regression analysis selected and as independent factors for severe OSA and showed that the combined expressions of and enhanced the capability of predicting severe OSA (Odds ratio, 5.800; 95% CI, 1.978 to 17.004; = 0.001). Our results show that combined expressions of and at midnight could be a potential predictor for severe OSA.
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http://dx.doi.org/10.3390/jcm8101634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832256PMC
October 2019

Standing genetic variation as the predominant source for adaptation of a songbird.

Proc Natl Acad Sci U S A 2019 02 18;116(6):2152-2157. Epub 2019 Jan 18.

School of Life Science, National Taiwan Normal University, 11677 Taipei, Taiwan;

What kind of genetic variation contributes the most to adaptation is a fundamental question in evolutionary biology. By resequencing genomes of 80 individuals, we inferred the origin of genomic variants associated with a complex adaptive syndrome involving multiple quantitative traits, namely, adaptation between high and low altitudes, in the vinous-throated parrotbill () in Taiwan. By comparing these variants with those in the Asian mainland population, we revealed standing variation in 24 noncoding genomic regions to be the predominant genetic source of adaptation. Parrotbills at both high and low altitudes exhibited signatures of recent selection, suggesting that not only the front but also the trailing edges of postglacial expanding populations could be subjected to environmental stresses. This study verifies and quantifies the importance of standing variation in adaptation in a cohort of genes, illustrating that the evolutionary potential of a population depends significantly on its preexisting genetic diversity. These findings provide important context for understanding adaptation and conservation of species in the Anthropocene.
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http://dx.doi.org/10.1073/pnas.1813597116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369788PMC
February 2019

NVP-BEZ235 Attenuated Cell Proliferation and Migration in the Squamous Cell Carcinoma of Oral Cavities and p70S6K Inhibition Mimics its Effect.

Int J Mol Sci 2018 Nov 10;19(11). Epub 2018 Nov 10.

Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

NVP-BEZ235 or BEZ235 is a dual inhibitor of adenosine triphosphate (ATP)-competitive phosphoinositide 3-kinase (PI3K)/mammalian-target-of-rapamycin (mTOR) and is promising for cancer treatment. Because it targets more than one downstream effector, a dual approach is promising for cancer treatment. The aim of this study was to evaluate the efficacy of NVP-BEZ235 in treating oral cavity squamous cell carcinoma (OSCC). Two human OSCC cell lines, SCC-4 and SCC-25, were used in this study. PI3K-AKT signaling, proliferation, and cell migratory and invasion capabilities of OSCC cells were examined. In NVP-BEZ235-treated SCC-4 and SCC-25 cells, the phosphorylation of 70-kDa ribosomal S6 kinase (p70S6K), but not mTOR, decreased within 24 h. NVP-BEZ235 inhibited OSCC-cell proliferation, migration, and invasion possibly by directly deregulating the phosphorylation of p70S6K. The phospho-p70S6K inhibitor mimicked the effects of NVP-BEZ235 for preventing proliferation and weakening the migratory and invasion abilities of SCC-4 and SCC-25 cells. This study further confirmed the effect of NVP-BEZ235 on OSCC cells and provided a new strategy for controlling the proliferation, migration, and invasion of OSCC cells using the phopho-p70S6K inhibitor.
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http://dx.doi.org/10.3390/ijms19113546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274880PMC
November 2018

Modulation of vascular endothelial growth factor and mitogen-activated protein kinase-related pathway involved in extracorporeal shockwave therapy accelerate diabetic wound healing.

Wound Repair Regen 2019 01 7;27(1):69-79. Epub 2018 Dec 7.

Department of Surgery, Division of Plastic Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Extracorporeal shockwave therapy (ESWT) has a significant positive effect to accelerate chronic wound healing. This study investigated whether the vascular endothelial growth factor (VEGF)-related pathway has involved in ESWT enhancement of diabetic wound healing. A dorsal skin defect (area, 6 × 5 cm) in a streptozotocin-induced diabetes rodent model was used. Thirty-two male Wistar rats were divided into four groups. Group I consisted of nondiabetic control; group II, diabetic control without treatment; group III, diabetic rats received ESWT; and group IV, rats received Avastin (a VEGF monoclonal antibody) on day 0 (post-wounding immediately) to day 7 and ESWT on day 3 and day 7. The wound healing was assessed clinically. The VEGF, endothelial nitric oxide synthase (eNOS), and Ki-67 were analyzed with immunohistochemical staining. The mRNA expression of mitogen-activated protein kinase-related genes was measured by real-time quantitative real-time polymerase chain reaction. The results revealed wound size was significantly reduced in the ESWT-treated rats as compared to the diabetic control (p < 0.01). The positive effect of ESWT-increasing wound healing was significantly suppressed in pretreatment of the Avastin group. Histological findings revealed significant increase in neo-vessels in the ESWT group as compared to the control. In immunohistochemical stain, significant increases in VEGF, eNOS, and Ki-67 expressions were noted in the ESWT group as compared to that in controls. However, Avastin suppressed the shockwave effect and down-regulation of VEGF, eNOS, and Ki-67 expressions in the Avastin-ESWT group as compared to that in the ESWT alone group. We found that highly mRNA expression of Kras, Raf1, Mek1, Jnkk, Jnk, and Jun at early stage in the ESWT group, as compared to the diabetic control. These evidences indicated treatment with multiple sessions of ESWT significantly enhanced diabetic wound healing associated with increased neovascularization and tissue regeneration. The bio-mechanism of ESWT-enhanced wound healing is correlated with VEGF and mitogen-activated protein kinase-mediated pathway.
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http://dx.doi.org/10.1111/wrr.12686DOI Listing
January 2019

Pre-treatment with angiotensin-(1-7) inhibits tumor growth via autophagy by downregulating PI3K/Akt/mTOR signaling in human nasopharyngeal carcinoma xenografts.

J Mol Med (Berl) 2018 12 29;96(12):1407-1418. Epub 2018 Oct 29.

Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Song District, Kaohsiung, 833, Taiwan.

The highest incidence of nasopharyngeal carcinoma (NPC) is in southeast China, including Taiwan. Many side effects have been observed following radiation therapy with chemotherapy; hence, exploring new treatment modalities for NPC is an important future direction. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone and important component of the renin-angiotensin system that acts through both the Mas receptor and AT2 receptor, exhibiting anti-proliferative and anti-angiogenic properties in cancer cells. However, the anti-cancer activity of Ang-(1-7) related to autophagy in NPC remains largely debated. The effects and signaling pathway(s) involved in the Ang-(1-7)/Mas receptor axis in NPC were investigated both in vitro and in vivo. Ang-(1-7) inhibited cell proliferation, migration, and invasion in NPC-TW01 cells. Ang-(1-7) induced autophagy by increasing the levels of the autophagy marker LC3-II and by enhancing p62 degradation via activation of the Beclin-1/Bcl-2 signaling pathway with involvement of the PI3K/Akt/mTOR and p38 pathways in vitro study. In addition, pre-treatment with Ang-(1-7) inhibited tumor growth in NPC xenografts by inducing autophagy, suggesting a correlation between PI3K/Akt/mTOR pathway inhibition and the abovementioned anti-cancer activities. However, no autophagy was observed following Ang-(1-7) post-treatment. Taken together, these data indicate that Ang-(1-7) plays a novel role in autophagy downstream signaling pathways in NPC, supporting its potential as a therapeutic agent for alleviation the incidence of NPC and preventive treatment of recurrent NPC. KEY MESSAGES: Ang-(1-7) inhibits cell proliferation, migration, and invasion by activating autophagy Ang-(1-7)pre-treatment inhibits tumor growth via autophagy by suppressing PI3K/Akt/mTOR pathway. Ang-(1-7) may provide a novel preventative treatment for NPC and recurrent NPC.
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http://dx.doi.org/10.1007/s00109-018-1704-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095977PMC
December 2018

BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor.

Cancer Sci 2018 Nov 21;109(11):3591-3601. Epub 2018 Sep 21.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Gastrointestinal stromal tumor (GIST) is a type of KIT-driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first-line treatment for advanced GIST, with a significant improvement in progression-free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second- and third-line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT-driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT-mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT-null COS-1 cell-based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor-grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.
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http://dx.doi.org/10.1111/cas.13773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215875PMC
November 2018

Interleukin-15 facilitates muscle regeneration through modulation of fibro/adipogenic progenitors.

Cell Commun Signal 2018 07 20;16(1):42. Epub 2018 Jul 20.

Department of Orthopedic Surgery, Southwest Hospital, Third Military Medical University, Gaotanyan Str. 30, Chongqing city, 400038, People's Republic of China.

Background: Chronic muscle injury is characteristics of fatty infiltration and fibrosis. Recently, fibro/adipogenic progenitors (FAPs) were found to be indispensable for muscular regeneration while were also responsible for fibrosis and fatty infiltration in muscle injury. Many myokines have been proven to regulate the adipose or cell proliferation. Because the fate of FAPs is largely dependent on microenvironment and the regulation of myokines on FAPs is still unclear. We screened the potential myokines and found Interleukin-15 (IL-15) may regulate the fatty infiltration in muscle injury. In this study, we investigated how IL-15 regulated FAPs in muscle injury and the effect on muscle regeneration.

Methods: Cell proliferation assay, western blots, qRT-PCR, immunohistochemistry, flow cytometric analysis were performed to investigate the effect of IL-15 on proliferation and adipogensis of FAPs. Acute muscle injury was induced by injection of glycerol or cardiotoxin to analyze how IL-15 effected on FAPs in vivo and its function on fatty infiltration or muscle regeneration.

Results: We identified that the expression of IL-15 in injured muscle was negatively associated with fatty infiltration. IL-15 can stimulate the proliferation of FAPs and prevent the adipogenesis of FAPs in vitro and in vivo. The growth of FAPs caused by IL-15 was mediated through JAK-STAT pathway. In addition, desert hedgehog pathway may participate in IL-15 inhibiting adipogenesis of FAPs. Our study showed IL-15 can cause the fibrosis after muscle damage and promote the myofiber regeneration. Finally, the expression of IL-15 was positively associated with severity of fibrosis and number of FAPs in patients with chronic rotator cuff tear.

Conclusions: These findings supported the potential role of IL-15 as a modulator on fate of FAPs in injured muscle and as a novel therapy for chronic muscle injury.
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http://dx.doi.org/10.1186/s12964-018-0251-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053744PMC
July 2018

[Plant anti-herbivore defense priming: Concept, mechanisms and application.]

Ying Yong Sheng Tai Xue Bao 2018 Jun;29(6):2068-2078

Ministry of Education Key Laboratory for Genetics, Breeding and Multiple Utilization of Crop, College of Crop Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

Plant anti-herbivore defense priming refers to the increased readiness of anti-herbivore defense after the initial exposure to a series of biotic or abiotic factors. The primed plants can respond to herbivory more quickly and strongly and thereby show enhanced resistance to insect herbivory. It is a newly recognized strategy of plant defense against insect herbivores. Insect feeding, secretion, oviposition, herbivore-inducible plant volatiles (HIPVs), beneficial microorgani-sms, certain plant nutrient elements, heavy metals and some chemical compounds have been found to be able to prime plant defense. The defense priming is highly efficient, durable, environmental friendly, and even trans-generational. This review summarized current research progress on the plant anti-herbivore defense priming in recent years, and analyzed general characteristics, priming agents and potential mechanisms involved, and proposed the future development and the perspective of practical application in the field. Moreover, the unresolved questions and the research directions in this field were also discussed. Appropriate management of plant defense priming would minimize use of insecticide and serve as an important approach of integrated pest management.
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http://dx.doi.org/10.13287/j.1001-9332.201806.034DOI Listing
June 2018

NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin.

Cell Death Discov 2018 10;4:57. Epub 2018 May 10.

6Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.

NVP-BEZ235 is a dual phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor. A dual approach targeting more than one downstream effector is a promising strategy for treating cancers. The aim of this study was to evaluate the effect of NVP-BEZ235 in treating FaDu hypopharyngeal squamous cell carcinoma (HSCC), either alone or in combination with cisplatin. We found expression was higher in patients with HSCC. In the in vitro study, treatment with NVP-BEZ235 alone attenuated cell proliferation and suppressed p-p70S6K and p-4E-BP1 expression in FaDu cells. When NVP-BEZ235 was combined with Cisplatin, apoptosis was induced more effectively than with either drug alone. In mice with a FaDu xenograft, cotreatment with NVP-BEZ235 and Cisplatin engendered synergistic effects and produced a greater antitumor response than did treatment with either drug alone. Resected tumor samples also showed decreased p-p70S6K expression. Collectively, these data demonstrate that NVP-BEZ235 inhibits HSCC growth through phospho-p70S6K suppression and has a synergistic effect with Cisplatin in treating HSCC. The data also provide a strategy for more effective HSCC treatment.
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http://dx.doi.org/10.1038/s41420-018-0060-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945618PMC
May 2018

Upregulated SLC22A3 has a potential for improving survival of patients with head and neck squamous cell carcinoma receiving cisplatin treatment.

Oncotarget 2017 Sep 4;8(43):74348-74358. Epub 2017 Sep 4.

Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Solute carrier family 22 member 3 (SLC22A3), also called organic cation transporter 3 (OCT3), is responsible for organic cation transport, which can eliminate many endogenous small organic cations, drugs, and toxins. This study investigated whether SLC22A3 expression is related to cisplatin uptake and the survival of patients with head and neck squamous cell carcinoma (HNSCC). Using immunohistochemical staining and digital image analysis, SLC22A3 expression was examined in 42 HNSCC patients who were postoperatively treated with or without adjuvant chemotherapy. SLC22A3-overexpressing SCC-4 cells and SLC22A3-knocked down SCC-25 cells were used to investigate the function of SLC22A3 in cisplatin uptake. We found that patients with higher SLC22A3 expression had longer survival times than those with lower SLC22A3 expression ( = 0.051). Moreover, among advanced T-stage patients receiving adjuvant cisplatin therapy, those with higher SLC22A3 expression had longer survival times than those with lower SLC22A3 expression ( = 0.006). An study demonstrated that SCC-25 cells with upregulated SLC22A3 expression were more sensitive to cisplatin than were SCC-4 cells with downregulated SLC22A3 expression. An increased uptake of cisplatin and an enhanced cytotoxic effect were observed in SLC22A3-overexpressing SCC-4 cells, and decreased uptake was found in SLC22A3-knocked down SCC-25 cells. Our results demonstrated that upregulated SLC22A3 expression can increase the cisplatin uptake and subsequently improve the survival of patients with HNSCC.
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http://dx.doi.org/10.18632/oncotarget.20637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650346PMC
September 2017

Phe354Leu Polymorphism of Is a Potential Prognostic Factor for Cytogenetically Normal Acute Myeloid Leukemia.

In Vivo 2017 Sep-Oct;31(5):841-847

Department of Nursing, I-Shou University, Kaohsiung, Taiwan, R.O.C.

Background/aim: Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established. This study aimed to examine mutation of LKB1 in AML and its clinical and pathological implications.

Patients And Methods: Eighty-five patients newly diagnosed with cytogenetically normal AML were analyzed using polymerase chain reaction followed by direct sequencing.

Results: A silent mutation (837C>T) of LKB1 was detected in one patient and a pathogenic polymorphism Phe354Leu which diminishes LKB1 ability to maintain cell polarity was detected in six (7%) patients. The Phe354Leu polymorphism occurred concurrently with mutations of nucleophosmin 1 (NPM1), fms-related tyrosine kinase 3 (FLT3) and CCAAT/enhancer binding protein alpha (CEBPA), but not with metabolism-related genes, isocitrate dehydrogenase [nicotinamide adenine dinucleotide phosphate (+)]1 (IDH1) and IDH2. Patients with Phe354Leu polymorphism diagnosed at younger ages had a worse overall survival.

Conclusion: LKB1 may be involved in the leukemogenesis and progression of cytogenetically normal AML.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656856PMC
http://dx.doi.org/10.21873/invivo.11137DOI Listing
May 2018

Autologous thyroid cartilage graft implantation in medialization laryngoplasty: a modified approach for treating unilateral vocal fold paralysis.

Sci Rep 2017 07 6;7(1):4790. Epub 2017 Jul 6.

Department of Otolaryngology - Head and Neck Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.

Medialization laryngoplasty is the standard surgical treatment for unilateral vocal fold paralysis. This study presents a modified approach in which a thyroid cartilage graft is implanted in medialization laryngoplasty. 22 patients who underwent this approach were included in the study. The results revealed that glottal incompetence and vocal performance were markedly improved following surgery, and the follow-up period ranged from 6 to 74 months (mean, 21.4 months). Acoustic analysis revealed significant improvements in the maximum phonation time (from 3.51 to 7.89 seconds, p < 0.001), F0 (from 221.7 to 171.0 Hertz, p = 0.025), and jitter (from 7.68 to 3.19, p < 0.001). Perceptual assessment revealed a significant decrease in voice grading (from 2.59 to 1.41, p < 0.001), roughness (from 1.82 to 1.23, p = 0.004), and voice breathiness (from 2.55 to 1.23, p < 0.001). None of the patients exhibited severe wound infection, tissue rejection, or other complications attributed to the surgical procedure. In conclusion, autologous thyroid cartilage implantation in medialization laryngoplasty medializes the vocal cord, minimizes the glottal gap, and improves the voice of patients with vocal fold paralysis. This procedure is characterized by simplicity, safety, and acceptable results.
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http://dx.doi.org/10.1038/s41598-017-05024-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500551PMC
July 2017

Capsaicin Induces Autophagy and Apoptosis in Human Nasopharyngeal Carcinoma Cells by Downregulating the PI3K/AKT/mTOR Pathway.

Int J Mol Sci 2017 Jun 23;18(7). Epub 2017 Jun 23.

Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.

Capsaicin is a potential chemotherapeutic agent for different human cancers. In Southeast China, nasopharyngeal carcinoma (NPC) has the highest incidence of all cancers, but final treatment outcomes are unsatisfactory. However, there is a lack of information regarding the anticancer activity of capsaicin in NPC cells, and its effects on the signaling transduction pathways related to apoptosis and autophagy remain unclear. In the present study, the precise mechanisms by which capsaicin exerts anti-proliferative effects, cell cycle arrest, autophagy and apoptosis were investigated in NPC-TW01 cells. Exposure to capsaicin inhibited cancer cell growth and increased G1 phase cell cycle arrest. Western blotting and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) were used to measure capsaicin-induced autophagy via involvement of the class III PI3K/Beclin-1/Bcl-2 signaling pathway. Capsaicin induced autophagy by increasing levels of the autophagy markers LC3-II and Atg5, enhancing p62 and Fap-1 degradation and increasing caspase-3 activity to induce apoptosis, suggesting a correlation of blocking the PI3K/Akt/mTOR pathway with the above-mentioned anticancer activities. Taken together, these data confirm that capsaicin inhibited the growth of human NPC cells and induced autophagy, supporting its potential as a therapeutic agent for cancer.
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http://dx.doi.org/10.3390/ijms18071343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535836PMC
June 2017

The effect of FcγRIIA and FcγRIIB on coronary artery lesion formation and intravenous immunoglobulin treatment responses in children with Kawasaki disease.

Oncotarget 2017 Jan;8(2):2044-2052

Kawasaki Disease Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Previous research has found patients with the FcγRIIIB NA1 variant having increased risk of intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD). Our previous studies revealed that elevated FcγRIIA expression correlated with the susceptibility of KD patients. We conducted this research to determine whether and how Fcγ receptors affect the susceptibility, IVIG treatment response, and coronary artery lesions (CAL) of KD patients. The activating FcγRIIA and inhibitory FcγRIIB methylation levels of seven patients with KD and four control subjects were examined using HumanMethylation27 BeadChip. We enrolled a total of 44 KD patients and 10 control subjects with fevers. We performed real-time RT-PCR to determine the FcγRIIA and FcγRIIB expression levels, as well as a luciferase assay of FcγRIIA. We found a considerable increase in methylation of both FcγRIIA and FcγRIIB in KD patients undergoing IVIG treatment. Promoter methylation of FcγRIIA inhibited reporter activity in K562 cells using luciferase assay. The FcγRIIB mRNA expression levels were not found to increase susceptibility, CAL formation, or IVIG resistance. FcγRIIA mRNA expression levels were significantly higher in IVIG-resistant patients than in those that responded to IVIG during the pre-treatment period. Furthermore, the FcγRIIA/IIB mRNA expression ratio was considerably higher in KD patients with CAL than in those without CAL. FcγRIIA and FcγRIIB both demonstrated increased methylation levels in KD patients that underwent IVIG treatment. FcγRIIA expression influenced the IVIG treatment response of KD patients. The FcγRIIA/IIB mRNA expression ratio was greater in KD patients with CAL formation.
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http://dx.doi.org/10.18632/oncotarget.13489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356778PMC
January 2017

MicroRNA-17 induces epithelial-mesenchymal transition consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer.

Int J Mol Med 2016 Aug 6;38(2):499-506. Epub 2016 Jun 6.

Department of Gastrointestinal Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China.

MicroRNA-17 (miRNA-17/miR‑17) expression has been confirmed to be significantly higher in colorectal cancer tissues than in normal tissues. However, its exact role in colorectal cancer has not yet been fully elucidated. In this study, we found that miR-17 not only promoted epithelial-mesenchymal transition (EMT), but also promoted the formation of a stem cell-like population in colon cancer DLD1 cells. We also wished to determine the role of cytochrome P450, family 7, subfamily B, polypeptide 1 (CYP7B1) in CRC. miR-17 was overexpressed using a recombinant plasmid and CYP7B1 was silenced by transfection with shRNA. Western blot analysis was used to determine protein expression in the DLD1 cells and in tumor tissues obtained from patients with colon cancer. Our results revealed that miR‑17 overexpression led to the degradation of CYP7B1 mRNA expression in DLD1 cells. In addition, we found that the silencing of CYB7B1 promoted EMT and the formation of a stem cell-like population in the cells. Thus, our findings demonstrate that miR‑17 induces EMT consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer.
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http://dx.doi.org/10.3892/ijmm.2016.2624DOI Listing
August 2016
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