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Angiotensin II receptor blockers (ARBs) are one of the standard treatments for diabetic kidney disease (DKD). Some patients may opt for Chinese herbal medicine (CHM) of their own free will. However, there is no real-world evidence regarding the effectiveness and safety of CHM. We aimed to explore the effectiveness of CHM for DKD in comparison to ARBs. We enrolled 732 DKD patients (72 used only CHM and 661 used ARBs) from 2007 to 2016, and all patients were followed until December 2016 at China Medical University Hospital in Taiwan. A total of 355 ARB users and 71 CHM users were analyzed after propensity score matching. The estimated glomerular filtration rate (eGFR) after treatment was 84.9 ± 28.1 ml/min/1.73 m2 in CHM users, which was higher than that (67.8 ± 35.4 ml/min/1.73 m2) in ARB users (p

Abstract Background Complementary and alternative medicine (CAM) is frequently used in the general population, yet only limited data are available regarding the prevalence of these medications in patients with chronic kidney disease (CKD). Hence, our study aimed to explore the prevalence and types of CAM in Taiwanese patients with CKD. Methods A cross-sectional questionnaire survey was conducted by face-to-face interview of 275 pre-dialysis patients without dialysis treatment or kidney transplant at an outpatient nephrology clinic in Taiwan from March 2021 to June 2023. The study outcomes were the prevalence of CAM, CAM types, reasons for using CAM, and sources of information about CAM. Results Overall, 128 patients (46.5%) were using CAM, but no significant differences from non-CAM users in the various CKD stages (p = 0.156) were found. CAM usage was high in the age range of 20–60 years and duration of CKD ≤ 5 years (p

Myopia is the leading cause of impaired vision, and its prevalence is increasing among Asian populations. This study aimed to develop a polygenic risk score (PRS) followed by replication to predict myopia in the Taiwanese population. In total, 23,688 participants with cycloplegic autorefraction-measured mean spherical equivalent (SE), genetic, and demographic data were included. The myopia PRS was generated based on genome-wide association study (GWAS) outcomes in a Taiwanese population and previously published GWAS reports. The results demonstrated that the inclusion of age and sex in the PRS had an area under the curve (AUC) of 0.80, 0.78, and 0.73 (p < 0.001) for participants aged >18 years with high (SE < −6.0 diopters (D); n = 1089), moderate (−6.0 D < SE ≤ −3.0 D; n = 3929), and mild myopia (−3.0 D < SE ≤ −1.0 D; n = 2241), respectively. Participants in the top PRS quartile had a 1.30-fold greater risk of high myopia (95% confidence interval = 1.09–1.55, p = 0.003) compared with that in the remaining participants. Further, a higher PRS significantly increased the risk of high myopia (SE ≤ −2.0 D) in children ≤6 years of age (p = 0.027). In conclusion, including the PRS, age, and sex improved the prediction of high myopia risk in the Taiwanese population.

Pain within the trigeminal system, particularly dental pain, is poorly understood. This study aimed to determine whether single or multiple dental pulp injuries induce persistent pain, its association with trigeminal central nociceptive pathways and whether electroacupuncture (EA) provides prolonged analgesic and neuroprotective effects in a persistent dental pain model. Models of single dental pulp injury (SDPI) and multiple dental pulp injuries (MDPI) were used to induce trigeminal neuropathic pain. The signs of dental pain-related behavior were assessed using the mechanical head withdrawal threshold (HWT). Immunofluorescence and western blot protocols were used to monitor astrocyte activation, changes in apoptosis-related proteins, and GABAergic interneuron plasticity. SDPI mice exhibited an initial marked decrease in HWT from days one to 14, followed by progressive recovery from days 21 to 42. From days 49 to 70, the HWT increased and returned to the control values. In contrast, MDPI mice showed a persistent decrease in HWT from days one to 70. MDPI increased glial fibrillary acidic protein (GFAP) and decreased glutamine synthetase (GS) and glutamate transporter-1 (GLT1) expression in the Vi/Vc transition zone of the brainstem on day 70, whereas no changes in astrocytic markers were observed on day 70 after SDPI. Increased expression of cleaved cysteine-aspartic protease-3 (cleaved caspase-3) and Bcl-2-associated X protein (Bax), along with decreased B-cell lymphoma/leukemia 2 (Bcl-2), were observed at day 70 after MDPI but not after SDPI. The downregulation of glutamic acid decarboxylase (GAD65) expression was observed on day 70 only after MDPI. The effects of MDPI-induced lower HWT from days one to 70 were attenuated by 12 sessions of EA treatment (days one to 21 after MDPI). Changes in astrocytic GFAP, GS, and GLT-1, along with cleaved caspase-3, Bax, Bcl-2, and GAD65 expression observed 70 days after MDPI, were reversed by EA treatment. The results suggest that persistent dental pain in mice was induced by MDPI but not by SDPI. This effect was associated with trigeminal GABAergic interneuron plasticity along with morphological and functional changes in astrocytes. EA exerts prolonged analgesic and neuroprotective effects that might be associated with the modulation of neuron-glia crosstalk mechanisms.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. The prevalence and phenotypes of AMD differ among populations, including between people in Taiwan and other regions. We performed a genome-wide association study to identify genetic variants and to develop genetic models to predict the risk of AMD development and progression in the Taiwanese population. In total, 4039 patients with AMD and 16,488 non-AMD controls (aged ≥ 65 years) were included. We identified 31 AMD-associated variants (p < 5 × 10−8) on chromosome 10q26, surrounding PLEKHA1-ARMS2-HTRA1. Two genetic models were constructed using the clump and threshold method. Model 1 included the single nucleotide polymorphism rs11200630 and showed a 1.31-fold increase in the risk of AMD per risk allele (95% confidence interval (CI) = 1.20–1.43, p < 0.001). In model 2, 1412 single-nucleotide polymorphisms were selected to construct a polygenic risk score (PRS). Individuals with the top 5% PRS had a 1.40-fold higher AMD risk compared with that of individuals with a PRS in the bottom quartile (95% CI = 1.04–1.89, p = 0.025). Moreover, the PRS in the upper quartile was related to a decreased age at AMD diagnosis by 0.62 years (95% CI = −1.15, −0.09, p = 0.023). Both genetic models provide useful predictive power for populations at high risk of AMD, affording a basis for identifying patients requiring close follow-up and early intervention.

BackgroundDialysis-related myofascial pain in hemodialysis (HD) patients is an important issue that is associated with many other psychosomatic problems. Effective interventions are required to alleviate pain in this group. Chinese herbal medicine (CHM) may be a potential therapeutic treatment for reducing pain. The aim of this study is to evaluate the effects of a classic CHM formula intervention on pain intensity, daily function, quality of life (QOL), and safety in patients receiving HD in a dialysis center within the context of southern Taiwan.MethodsThis will be a randomized, open label, cross-over trial with two parallel groups in a pre- and post-test study. Forty patients reporting myofascial pain related to the arteriovenous (AV) fistula in the arm during regular HD sessions will be recruited. Participants will receive 4 weeks of treatment with Juan Bi Tang (JBT) and 4 weeks of no treatment in a random order, separated by a washout period of 2 weeks. Treatment doses (3 g JBT) will be consumed thrice daily. The primary outcome measure will be the Kidney Disease Quality of Life 36-Item Short-Form Survey. Secondary outcomes will include the Fugl-Meyer Assessment-arm, Visual Analogue Scale (VAS) of pain, and grip strength. Outcomes will be collected before and after each intervention, for a total of four times per participant. The safety evaluation will focus on adverse events (AEs).DiscussionThis study will be the first to use CHM to treat patients receiving HD with dialysis-related myofascial pain in their fistula arm and to perform a complete assessment of the treatment, including records of QOL, arm function and muscle power, severity of pain, and safety. The results of the study will provide convincing evidence on the use of JBT as an adjuvant treatment for dialysis-related myofascial pain.Trial registrationClinicaltrials.gov registry (NCT04417101) registered 30 May 2020.

1-Isothiocyanato-6-(methylsulfinyl)-hexanate (6-MITC) is a natural compound found in Wasabia japonica. The synthetic derivatives 1-Isothiocyanato-6-(methylsulfenyl)-hexane (I7447) and 1-Isothiocyanato-6-(methylsulfonyl)-hexane (I7557) were obtained from 6-MITC by deleting and adding an oxygen atom to the sulfone group, respectively. We previously demonstrated that extensive mitotic arrest, spindle multipolarity, and cytoplasmic vacuole accumulation were induced by 6-MITC and inhibited the viability of human chronic myelogenous leukemia K562 cells. In this study, we examined the anti-cancer effects of 6-MITC derivatives on human chronic myelogenous leukemia (CML) cells. Autophagy was identified as the formation of autophagosomes with double-layered membranes using transmission electron microscopy. Cell cycle and differentiation were analyzed using flow cytometry. Apoptosis was detected by annexin V staining. After treatment with I7447 and I7557, the G2/M phase of cell cycle arrest was revealed. Cell death can be induced by a distinct mechanism (the simultaneous occurrence of autophagy and aberrant mitosis). The expression levels of acridine orange were significantly affected by lysosomal inhibitors. The natural wasabi component, 6-MITC, and its synthetic derivatives have similar effects on human chronic myelogenous leukemia cells and may be developed as novel therapeutic agents against leukemia.

Background: Oral mucositis (OM) is a common side effect of radiotherapy (RT) that can have severe implications in patients with head and neck cancer (HNC). Traditional Chinese medicine (TCM) formula is widely applied in treating OM, but little substantial evidence exists to clarify it effects. The study intends to determine whether the TCM-based prescription in treating HNC with RT can improve the OM when compared with RT alone. Methods: A single-center, randomized, two-arm parallel-group, open-label controlled clinical trial will be conducted to determine whether the Zi-Yin-Liang-Ge-San (ZYLGS), which contains Rx. Scutellariae, Rx. Glycyrrhizae, Hb. Dendrobii, Rx. Ophiopogonis, and Hb. Menthae Haplocalycis, combined with RT can improve the incidence and severity of OM. Two hundred participants will randomly 1:1 to receive at least 6 weeks of RT plus ZYLGS powder or control. The primary outcome measures are onset, gradation of OM (Common Terminology Criteria for Adverse Events v5.0), and oral pain (visual analogue scale). The secondary outcome measures include nutritional status, the EORTC Quality of Life Core Questionnaire and head and neck module. The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, serious adverse events, and blood and biochemical analysis will be recorded to evaluate the safety. Visits will be performed for each week during the RT treatment period and then 2 weeks in the follow-up period. Discussion: The study's result will provide a high-level evidence for TCM-based formulation for HNC patients with RT on the effect of OM prevention and management.

Pain management for traumatic rib fracture is important to prevent complications and reduce associated comorbidities. This trial investigated the analgesic efficacy of acupuncture on traumatic rib fracture. Patients with traumatic rib fracture were randomly assigned to traditional acupuncture (TA), laser acupuncture (LA) or sham laser acupuncture (SLA) groups in a 1:1:1 ratio. The intervention was performed on days 1 to 3 after treatment allocation. The acupoints included bilateral LI4 (Hegu), SJ6 (Zhigou), ST36 (Zusanli) and GB34 (Yanglingquan). The primary outcome was Numeric Rating Scale (NRS) scores for pain after the intervention. Secondary outcomes included sustained maximal inspiration (SMI) lung volume, stress responses, the use of analgesics, and associated complications. Data were analyzed via one-way analysis of variance (ANOVA) with Scheffé’s post hoc testing or chi-squared testing. Of the 120 study participants, 109 completed all interventions and measurements. The primary outcomes, which indicated average pain intensity levels and pain while deep breathing, were both significantly lower in the TA and LA groups than in the SLA group after 2 treatments. No between-group differences were observed in SMI lung volume, stress response, analgesics use or associated complications. These findings suggest that TA and LA are safe and effective analgesic modalities for pain management for traumatic rib fracture.Clinical Trial Registration:[ClinicalTrials.gov], identifier [NCT03822273].

Background: Cancer-related fatigue (CRF) is a common psychosomatic problem in breast cancer patients. Traditional Chinese medicine (TCM) has been used to address symptoms in patients with CRF. Identification of the specific constitution in TCM is essential for personalized care. Aim: To explore the relationship between fatigue and specific constitutions in breast cancer. Experimental procedure: We conducted a cross-sectional study in all breast cancer patients at Kaohsiung Chang Gung Memorial Hospital in Taiwan. The severity of fatigue was determined using the Brief Fatigue Inventory-Taiwanese (BFI-T) form. TCM patterns were determined using the Body Constitution Questionnaire (BCQ). The relationship between constitution and fatigue was analyzed using logistic regression. Results: We recruited 110 breast cancer patients with fatigue (mean age: 55 ± 11 years). The mean duration of breast cancer was 17.4 months. The major constitution among these patients with fatigue was Yang-Qi deficiency (50%). Phlegm-Stasis syndrome was correlated with a duration of breast cancer of more than 18 months (p = 0.02). Out of all participants, 42.7% (n = 47) reported clinically significant fatigue (BFI-T score ≥4). According to logistic regression, the score of Yang-Qi deficiency [odds ratio (OR): 3.5, 95% confidence interval (CI): 1.49–8.21, p

The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT–drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH2PO4)–methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUCcabozantinib) between the control group and the RT2Gy×3 f’x and RT9Gy×3 f’x groups in the concurrent and the sequential regimens. However, compared to those in the control group, the Tmax, T1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT2Gy×3 f’x in the concurrent regimen, respectively. Additionally, the T1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT9Gy×3 f’x group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT2Gy×3 f’x in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT9Gy×3 f’x sequential regimen. Compared to the RT9Gy×3 f’x concurrent regimen, the RT9Gy×3 f’x sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT9Gy×3 f’x is more significant with the sequential regimen than with the concurrent regimen.

The efficacy of chemotherapeutic drugs for the treatment of brain metastasis may be compromised by the blood–brain barrier (BBB) and blood–tumor barrier (BTB). P-glycoprotein (P-gp) is a multidrug resistance protein that potentially limits the penetration of chemotherapeutics through the BBB and BTB. 5-Fluorouracil (5-FU) is widely used to treat cancer. Bioactive constituents of medicinal herbs, such as borneol and tetrandrine, potentially improve drug penetration through the BBB and BTB. We hypothesized that borneol and tetrandrine might modulate the BBB and BTB to enhance 5-FU penetration into the brain. To investigate this, in vitro and in vivo models were developed to explore the modulatory effects of borneol and tetrandrine on 5-FU penetration through the BBB and BTB. In the in vitro models, barrier integrity, cell viability, barrier penetration, P-gp activity, and NF-κB expression were assessed. In the in vivo brain metastasis models, cancer cells were injected into the internal carotid artery to evaluate tumor growth. The experimental results demonstrated that borneol and borneol + tetrandrine reduced BBB integrity. The efflux pump function of P-gp was partially inhibited by tetrandrine and borneol + tetrandrine. In the in vivo experiment, borneol + tetrandrine effectively prolonged survival without compromising body weight. In conclusion, BBB and BTB integrity was modulated by borneol and borneol + tetrandrine. The combination of borneol and tetrandrine could be used to improve the chemotherapeutic control of brain metastasis.

Abstract Background Chemotherapy after surgery for breast cancer plays a fundamental role in reducing the risk of distant and local recurrence. An increasing number of patients seek traditional Chinese medicine (TCM) during adjuvant chemotherapy to relieve symptom discomfort and side effects as well as to strengthen the body’s defenses. However, evidence on how concurrent TCM treatment affects prognosis is scarce. This trial aims to evaluate the association between TCM treatment and disease-free survival outcomes for patients with early breast cancer who are undergoing adjuvant chemotherapy. Methods/design This is a non-randomized, single center, prospective cohort study begun in November 2018 in Kaohsiung, Taiwan. A sample of 310 participants diagnosed with early breast cancer was recruited from the Breast Cancer Research Team and will be followed up every 3 to 6 months until October 2023. Detailed information of the participants, including general information, history of cancer, quality of life, side effects and safety of treatment, TCM body constitution, and meridian energy analysis, was collected face to face at baseline. Discussion This is the first prospective observational cohort study on TCM in patients with early breast cancer who are receiving adjuvant chemotherapy to evaluate the prognosis. Through this trial, we hope to assess the feasibility of a larger-scale clinical trial in the future and formulate an integrated TCM care program. Trial registration ClinicalTrials.gov, NCT03797248. Registered on 5 January 2019.

Daphnoretin extracted from the stem and roots of Wikstroemia indica (L.) C.A. Mey has been shown to possess antiviral and antitumor activities. Herein, we hypothesized that daphnoretin might induce megakaryocytic differentiation, thereby inhibiting the proliferation of cells and serving as a differentiation therapy agent for chronic myeloid leukemia (CML). Daphnoretin-treated K562 and HEL cells were examined for growth inhibition, cell morphology, and megakaryocyte-specific markers. Potential mechanisms of megakaryocytic differentiation of daphnoretin-treated K562 cells were evaluated. The results showed that daphnoretin inhibited the growth of K562 and HEL cells in a dose- and time-dependent manner. Flow cytometry analyses revealed that daphnoretin treatment slightly increased the proportion of sub-G1 and polyploid cells compared to that of dimethyl sulfoxide (DMSO)-treated control cells. Morphological examination showed that daphnoretin-treated K562 and HEL cells exhibited enlarged contours and multinucleation as megakaryocytic characteristics compared to DMSO-treated control cells. Daphnoretin treatment also dramatically enhanced the expression of megakaryocytic markers CD61 and CD41. Under optimal megakaryocytic differentiation conditions, daphnoretin increased the phosphorylation of STAT3 but not STAT5. In summary, daphnoretin inhibited cell growth and induced megakaryocytic differentiation in K562 and HEL cells. The efficacy of daphnoretin in vivo and in patients with CML may need further investigations for validation.

Esophageal cancer is a common malignancy worldwide and a leading cause of cancer-related mortality. Definitive concurrent chemoradiotherapy (CCRT) has been widely used to treat locally advanced esophageal squamous cell carcinoma (ESCC). In this study, we evaluated the predictive power of a 35-gene mutation profile and radiation parameters in patients with ESCC. Data from 44 patients with ESCC who underwent definitive CCRT were retrospectively reviewed. A 35-gene mutation profile, derived from reported ESCC-specific next-generation sequencing results, and radiation dosimetry parameters were examined using the Kaplan–Meier curve and Cox proportional hazards model. All patients were native Chinese and underwent CCRT with a median follow-up time of 22.0 months. Significant prognostic factors affecting progression-free survival in the multivariable Cox regression model were clinical nodal staging ≥2 (hazard ratio, HR: 2.52, 95% CI: 1.15–5.54, p = 0.022), ≥10% lung volume receiving ≥30 Gy (V30) (HR: 2.36, 95% CI: 1.08–5.17, p = 0.032), and mutation of fibrous sheath interacting protein 2 (FSIP2) (HR: 0.08, 95% CI: 0.01–0.58, p = 0.013). For overall survival, significant prognostic factors in the multivariable Cox regression model were lung V30 ≥10% (HR: 3.71, 95% CI: 1.48–9.35, p = 0.005) and mutation of spectrin repeat containing nuclear envelope protein 1 (SYNE1) (HR: 2.95, 95% CI: 1.25–6.97, p = 0.014). Our cohort showed higher MUC17 (79.5% vs. 5.7%), FSIP2 (18.2% vs. 6.2%), and SYNE1 (38.6% vs. 11.0%) mutation rates and lower TP53 (38.6% vs. 68.7%) mutation rates than the ESCC cohorts from The Cancer Genome Atlas. In conclusion, by using a combination of a 35-gene mutation profile and radiotherapy dosimetry, mutations in FSIP2 and SYNE1 as well as lung V30 were identified as potential predictors for developing a prediction model for clinical outcomes in patients with ESCC administered definitive CCRT.

Background and Objectives: Activation of NRF2, a key transcription factor of cytoprotectant against oxidative stress, and its target genes are associated with aggressive tumor progression, metastasis and poor survival. In addition, NRF2 signaling mediates cancer stem cell (CSC)-like properties in hepatocellular carcinoma (HCC) cells. Moreover, CSCs have been associated with HCC onset and unfavorable prognosis. Transcatheter arterial embolization (TAE) and/or transcatheter arterial chemoembolization (TACE), which attempt to restrict blood supply to diminish tumor growth, can create a hypoxic environment. However, its effect on NRF2 signaling and CSC marker CD133 in the context of prognosis of HCCs have not been investigated. Therefore, we studied the possible role of the expressions of NRF2, its target genes and CSC markers CD133 and EpCAM on the survival of HCC patients after TAE/TACE. Materials and Methods: RT-qPCR was performed with 120 tumor (T) and adjacent tumor (N) tissue pairs. Expression of a single marker or combination was assessed for associations with survival of HCC patients after TAE/TACE. Results: The result of multivariate Cox regression showed that vascular invasion (HR, 1.821; p = 0.015), metastasis (HR, 2.033; p = 0.049) and CD133 overexpression (HR, 2.013; p = 0.006) were associated with poor survival. In a Kaplan–Meier survival analysis, patients with high expression of CD133 had shorter overall survival (OS) than those with low expression of CD133 in post-TAE/TACE HCC (p < 0.001). In contrast, neither NRF2 nor components of its signaling pathway correlated with survival. Combination marker analysis showed that co-expression of NQO1 and CD133 was associated with poor outcome. Conclusions: This study suggests that analyzing the expression status of CD133 alone and co-expression of NQO1 and CD133 may have additional value in predicting the outcome of TAE/TACE-treated HCC patients.

ObjectiveDiabetic nephropathy (DN) and diabetic retinopathy (DR) comprise major microvascular complications of diabetes that occur with a high concordance rate in patients and are considered to potentially share pathogeneses. In this case-control study, we sought to investigate whether DR-related single nucleotide polymorphisms (SNPs) exert pleiotropic effects on renal function outcomes among patients with diabetes.Research design and methodsA total of 33 DR-related SNPs were identified by replicating published SNPs and via a genome-wide association study. Furthermore, we assessed the cumulative effects by creating a weighted genetic risk score and evaluated the discriminatory and prediction ability of these genetic variants using DN cases according to estimated glomerular filtration rate (eGFR) status along with a cohort with early renal functional decline (ERFD).ResultsMultivariate logistic regression models revealed that the DR-related SNPs afforded no individual or cumulative genetic effect on the nephropathy risk, eGFR status or ERFD outcome among patients with type two diabetes in Taiwan.ConclusionOur findings indicate that larger studies would be necessary to clearly ascertain the effects of individual genetic variants and further investigation is also required to identify other genetic pathways underlying DN.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect caused by neurotoxic chemotherapy. This randomized controlled trial aimed to evaluate the effect of manual acupuncture on CIPN. Twenty eligible breast cancer patients receiving taxane chemotherapy treatment were recruited and randomly divided into verum acupuncture and sham acupuncture groups. Each group received 15 treatments over 9 weeks. Quantitative tactile detection thresholds were measured using Semmes–Weinstein monofilament testing (SWM). The World Health Organization Quality of Life scale (WHOQOL-BREF), the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), and the Brief Pain Inventory-Short Form (BPI-SF) were measured before and after treatment. The between-group comparison of SWM revealed that the verum acupuncture group had more improvement of touch perception thresholds compared to the sham acupuncture group. The average pain severity in the BPI-SF of the verum acupuncture group was significantly lower than that of the sham acupuncture group. There were no significant differences in the FACT/GOG-Ntx trial outcome index and WHOQOL-BREF scores between the acupuncture and sham groups. The results suggest that acupuncture can alleviate the neuropathic pain of CIPN and improve touch perception thresholds.

The epicardial adipose tissue (EAT), mainly composed of brown adipose tissue, is a metabolically active tissue releasing various bioactive factors with a critical role in metabolic diseases. The EAT is often irradiated during radiotherapy in patients with esophageal cancer due to its proximity to the target region. We aimed to evaluate the effect of radiation to the EAT on survival outcomes in patients with esophageal cancer receiving neoadjuvant chemoradiotherapy followed by esophagectomy. We analyzed data on 36 patients with esophageal cancer treated with trimodal therapy between 2012 and 2017. The median follow-up period was 22.0 months. The 3-year overall survival and progression-free survival rates were 39.7% and 32.5%, respectively. Multivariate analysis revealed that higher EAT-REI was independently associated with worse overall survival (hazard ratio: 1.002, p = 0.028) and progression-free survival (hazard ratio: 1.002, p = 0.03). The cutoff value with the highest accuracy for avoiding mortality was EAT-REI = 68.8 cGy/mL (area under the curve, 0.78, p = 0.006). The 3-year overall survival rate in patients with EAT-REI ≥68.8 and p = 0.003). The EAT should be considered an organ at risk during radiotherapy in patients with esophageal cancer. EAT-REI might serve as a biomarker of survival outcomes in these patients.

Adiponectin (APN) is suggested to be a potential biomarker for predicting diabetic retinopathy (DR) risk, but the association between APN and DR has been inconsistent in observational studies. We used a Mendelian randomization (MR) analysis to evaluate if circulating APN levels result in DR. We applied three different genetic risk scores (GRS): GRSAll combined all 47 single nucleotide polymorphisms (SNPs), which from a genome-wide association study (GWAS) database-catalog reach significance level; GRSLimited comprised 16 GRSAll-SNPs with a rigorous threshold (p < 5.0 × 10−8 for GWAS), and GRSAPN combined 5 SNPs significantly associated with APN level. The MR-inverse-variance weighted method analysis showed that for each 1-SD increase in genetically induced increase in plasma APN, the OR of having DR was β = 0.20 (95% CI: −0.46–0.85, p = 0.553) for GRSAPN, 0.61 (95% CI: 0.10–1.13, p = 0.020) for GRSAll, and 0.57 (95% CI: −0.06 to 1.20, p = 0.078) for GRSLimited. Sensitivity analysis, including MR-egger regression and the weighted-median approach, did not provide evidence of the pleiotropic effect of IVs. Limited evidence for the causal role of APN in DR risk among Taiwanese diabetic patients was shown based on MR analysis in the present study.

Background: Patients with terminal cancer frequently suffer from sleep sweats, which occur while sleeping and cease after waking; the cause of these sweats is unknown. The aim of this study was to evaluate the efficacy of a modified Dang Gui Liu Huang Tang in managing sleep sweats, as well as to identify any associated adverse effects. Methods: We enrolled 41 patients with terminal cancer who were receiving hospice care. We excluded patients whose sweating had known causes, as well as those taking drugs that can affect the sweating threshold. Patients received a modified Dang Gui Liu Huang Tang twice a day for 10 consecutive days. Results: The quantitative assessment revealed that sleep sweating was completely relieved in 29 (70.7%) patients, and that the average time required for a 50% decrease in sweating was 5.3 days. Using a visual analog sweating scale that ranged from 0 to 10, patients and caregivers estimated that the mean decrease in sweating was 7.6 and 8.0, respectively. Furthermore, 78.0% of patients experienced an increased appetite after treatment. The most common adverse events were diarrhea (14.6%), nausea (12.1%), and allergy (2.4%), although the severity of these symptoms was never greater than Grade 2, and they resolved after the treatment was stopped. Conclusion: The results suggest that the modified Dang Gui Liu Huang Tang is safe and effective in treating sleep sweats of an unknown cause in elderly patients with terminal cancer.

Purpose : Radiotherapy with concurrent chemotherapy has been recommended as standard treatment for locally advanced cervical cancer. To validate the main tumor location before each high-precision helical tomotherapy (HT) fraction, the development of a more reliable marker or indicator is of clinical importance to avoid inadequate coverage of the main tumor. Material and methods: A 61-year-old woman with cervical cancer, TMN stage cT2b2N1M1, FIGO stage IVB was presented. Extended field external beam radiotherapy (EBRT) with concurrent chemotherapy and the interdigitated delivery of intracavitary brachytherapy was performed. Helical tomotherapy equipped with megavoltage cone beam computed tomography (MV-CBCT) was used for image-guided radiotherapy. For the insertion of tandem of brachytherapy applicator, a silicone sleeve with a central hollow canal was placed into the endocervical canal with the caudal end stopping at the outer surface of the cervical os, and making contact with the distal boundary of the cervical tumor during the entire brachytherapy course. Results : In the remaining EBRT fractions, we found that the air cavity inside the central hollow canal of the sleeve could be clearly identified in daily CBCT images. The radiation oncologists matched the bony markers to adjust the daily setup errors because the megavoltage of the CBCT images could not provide a precise boundary between the soft tissue and the tumor, but the sleeve air cavity, with a clear boundary, could be used as a surrogate and reliable marker to guide the daily setup errors, and to demonstrate the primary tumor location before delivery of each HT fraction. Conclusions : The application of the sleeve during the interdigitated course of HT and brachytherapy in this patient provided information for the feasibility of using the sleeve air cavity as a surrogate marker for the localization of the main primary tumor before the daily delivery of image-guided HT.

The eyes require a rich oxygen and nutrient supply; hence, the high-energy demand of the visual system makes it sensitive to oxidative stress. Excessive free radicals result in mitochondrial dysfunction and lead to retinal neurodegeneration, as an early stage of retinal metabolic disorders. Retinal cells are vulnerable because of their coordinated interaction and intricate neural networks. Nutraceuticals are believed to target multiple pathways and have shown neuroprotective benefits by scavenging free radicals and promoting mitochondrial gene expression. Furthermore, encouraging results demonstrate that nutraceuticals improve the organization of retinal cells and visual functions. This review discusses the mitochondrial impairments of retinal cells and the mechanisms underlying the neuroprotective effects of nutraceuticals. However, some unsolved problems still exist between laboratory study and clinical therapy. Poor bioavailability and bioaccessibility strongly limit their development. A new delivery system and improved formulation may offer promise for health care applications.

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Low levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of type 2 diabetes (T2D). This study investigated CETP gene variants to assess the risk of T2D and specific complications of diabetic kidney disease (DKD) and diabetic retinopathy. Towards this, a total of 3023 Taiwanese individuals (1383 without T2D, 1640 with T2D) were enrolled in this study. T2D mice (+Leprdb/+Leprdb, db/db) were used to determine CETP expression in tissues. The A-alleles of rs3764261, rs4783961, and rs1800775 variants were found to be independently associated with 2.86, 1.71, and 0.91 mg/dL increase in HDL-C per allele, respectively. In addition, the A-allele of rs4783961 was significantly associated with a reduced T2D risk (odds ratio (OR), 0.82; 95% confidence interval (CI), 0.71−0.96)), and the A-allele of rs1800775 was significantly related to a lowered DKD risk (OR, 0.78; 95% CI, 0.64−0.96). CETP expression was significantly decreased in the T2D mice kidney compared to that in the control mice (T2D mice, 0.16 ± 0.01 vs. control mice, 0.21 ± 0.02; p = 0.02). These collective findings indicate that CETP variants in the promoter region may affect HDL-C levels. Taiwanese individuals possessing an allele associated with higher HDL-C levels had a lower risk of T2D and DKD.

Parkinson’s disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose-derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n -Butylidenephthalide (BP), which is extracted from Angelica sinensis , has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies.

Background and purposeThe blood–brain barrier (BBB) not only provides a physical obstruction but also recruits and activates neutrophils in cases of infection. Hemorrhagic or ischemic stroke reportedly induces the disruption of the BBB. However, few studies have reported a correlation between the incidence of meningitis in patients with a history of stroke. This study tested the hypothesis that patients with a history of stroke may be more vulnerable to meningitis.MethodsStroke and age-matched comparison (n = 29,436 and 87,951, respectively) cohorts were recruited from the Taiwan National Health Insurance database (2000–2011). Correlations between the two cohorts were evaluated by Cox proportional hazard regression model, Kaplan–Meier curve, and log-rank tests.ResultsThe incidence of meningitis was higher in the stroke cohort compared to that in the comparison cohort [hazard ratio (HR), 2.89; 95% confidence interval (CI), 2.23–3.74, p

We have previously described the association of rheumatoid arthritis (RA) prevalence and two epidermal growth factor receptor (EGFR) SNPs (rs17337023 and rs2227983) among the Taiwanese population. This present study aimed to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA.The cohort study included 366 Taiwan's Han Chinese RA patients and 326 age and gender matched healthy controls. Blood samples collected from the participants were analyzed to determine their serum EGFR levels and to identify EGFR SNPs from their genomic DNA. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. The relationship between EGFR SNP and the clinical manifestations of RA was evaluated.Our results showed that a statistically significant difference in genotype frequency distributions at rs17337023 SNP for RA patients and controls (p ˂ 0.05). In addition, compared with the haplotype frequencies between case and control groups, the RA patient with the GT haplotype appeared to be a significant "protective" haplotype compared with other haplotypes (OR: 0.73, 95% CI: 0.59-0.91; p = 0.005). Furthermore, the increased serum level of EGFR was also observed in RA patients (p ˂ 0.001).Our study showed that RA is associated with rs17337023 SNP in EGFR gene and increased serum level of the EGFR protein. These findings suggest EGFR is worthy of further investigation as a therapeutic target for RA.

Diabetic retinopathy (DR) is a severe and recurrent microvascular complication in diabetes. The multifunctional response gene to complement 32 (RGC-32) is involved in the regulation of cell cycle, proliferation, and apoptosis. To investigate the role of RGC-32 in the development of DR, we used human retinal microvascular endothelial cells under high-glucose conditions and type 2 diabetes (T2D) mice (+Leprdb/ + Leprdb, db/db). The results showed that RGC-32 expression increased moderately in human retinal endothelial cells under hyperglycemic conditions. Histopathology and RGC-32 expression showed no significant changes between T2D and control mice retina at 16 and 24 weeks of age. However, RGC-32 expression was significantly decreased in T2D mouse retina compared to the control group at 32 weeks of age, which develop features of the early clinical stages of DR, namely reduced retinal thickness and increased ganglion cell death. Moreover, immunohistochemistry showed that RGC-32 was predominantly expressed in the photoreceptor inner segments of control mice, while the expression was dramatically lowered in the T2D retinas. Furthermore, we found that the level of anti-apoptotic protein Bcl-2 was decreased (approximately 2-fold) with a concomitant increase in cleaved caspase-3 (approximately 3-fold) in T2D retina compared to control. In summary, RGC-32 may lose its expression in T2D retina with features of DR, suggesting that it plays a critical role in DR pathogenesis.

Stroke is a result of cerebral ischemia that triggers a cascade of both physiological and biochemical events. No effective treatment is available for stroke; however, stem cells have the potential to rescue tissue from the effects of stroke. Adipose-derived stem cells (ADSCs) are an abundant source of adult stem cells; therefore, ADSC therapy can be considered as a future strategy for regenerative medicine. However, more research is required to improve the effectiveness of transplanted ADSCs as a treatment for stroke in the mouse stroke model. Ligustilide, isolated from the herb Angelica sinensis , exhibits a protective effect on neurons and inhibits inflammation. We also demonstrated that ligustilide treatment increases the expression levels of homing factors such as SDF-1 and CXCR4. In the present study, we evaluated the therapeutic effects of ADSC transplantation and ligustilide treatment in a mouse thromboembolic stroke model by behavioral tests, including beam walking, locomotor activity, and rotarod analysis. ADSCs pretreated with ligustilide were transplanted into the brains of stroke mice. The results showed that the therapeutic effect of ADSCs pretreated with ligustilide was better than that of ADSCs without ligustilide pretreatment. There was no difference between the recovery of mice treated by ADSC transplantation combined with subcutaneous ligustilide injection and that of mice treated only with ADSCs. The TUNEL assay showed fewer apoptotic cells in the brains of mice transplanted with ADSCs pretreated with ligustilide as well as in those without pretreatment. In summary, pretreatment of ADSCs with ligustilide improves the therapeutic efficacy of ADSC transplantation. The results of this study will help improve stem cell therapies being developed for future clinical applications.

Large-cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a very rare malignancy. We aimed to investigate the role of human papillomavirus (HPV) on the survival of patients, and its correlation with clinical parameters of HPV status or survival outcomes. Only seven cases of LCNEC were retrospectively collected among 8018 (0.087%) invasive cervical carcinomas from the cancer registry systems at Mackay Memorial Hospital and Veterans General Hospital over a period of 17 years. The median survival time was 17.2 months, including only one long-term survivor (> 5 years). The 2-year and 5-year survival rates after diagnosis were 42% and 30%, respectively. The results indicated that the majority of LCNEC cases were dominated by high-risk HPV-18. No clinical parameters appeared to be associated with HPV-18 or survival outcomes of LCNEC patients. Pelvic lymph node metastasis positivity could also be considered as a prognostic factor for this disease.

Cardiovascular diseases are related to many risk factors, such as diabetes, high blood pressure, smoking, and obesity. Myocardial infarction (MI), a cardiovascular disease, is the most common cause of cardiomyocyte death. In MI, hypoxia induces cardiomyocyte apoptosis; in particular, diabetes combined with MI has a synergistic effect that exacerbates cardiomyocyte death. The hypoxia-inducible factor-1α (HIF1α) transcriptional factor and a BH-3 only protein, Bcl-2 adenovirus E1B 19-kDa interacting protein 3 (BNIP3), are known to play fundamental roles in both adaptive and cell death processes in response to hypoxia. In addition, most cardioprotective studies used H9c2 cells that were not beating, so H9c2 cells may not be the best model for testing cardioprotective effects. Embryonic stem cells (ESCs) are pluripotent stem cells that are able to differentiate into several types of cells, including cardiomyocytes. In this study, we reveal a simple method to differentiate ESCs into cardiomyocytes by using poly-d-lysine-coated plates combined with ITS and N2-containing medium and characterized the ESC-derived cardiomyocytes by cardiomyocyte marker staining. The ESC-derived cardiomyocytes were used to investigate the protective effect of salvianolic acid B (Sal-B) in high glucose combined with hypoxic conditions to mimic diabetes patients with ischemia. The results of MTT and TUNEL assays indicate that Sal-B suppresses the apoptotic effect of treatment with high glucose combined with hypoxia in ESC-derived cardiomyocytes. In particular, Sal-B inhibited HIF1α, BNIP3, and cleavage caspase 3 expression levels, thereby suppressing apoptosis. This is the first study to mention the correlation between BNIP3 and Sal-B for cardioprotective effects. In conclusion, we suggest that Sal-B may be suitable for use as a future cardioprotective medicine.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are considered the most powerful in terms of differentiating into three-germ-layer cells. However, maintaining self-renewing ESCs and iPSCs in vitro requires leukemia-induced factor (LIF), an expensive reagent. Here we describe a less expensive compound that may serve as a LIF substitute—salvianolic acid B (Sal B), a Salvia miltiorrhiza extract. We found that Sal B is capable of upregulating Oct4 and Sox2, two genes considered important for the maintenance of ESC pluripotency. Our MTT data indicate that instead of triggering cell death, Sal B induced cell proliferation, especially at optimum concentrations of 0.01 nM and 0.1 nM. Other results indicate that compared to non-LIF controls, Sal B-treated ESCs expressed higher levels of several stem cell markers while still maintaining differentiation into three-germ-layer cells after six passages. Further, we found that Sal B triggers the Jak2–Stat3 and EGFR–ERK1/2 signaling pathways. Following Sal B treatment, (a) levels of phosphorylated (p)-Jak2, p-Stat3, p-EGFR, and p-ERK proteins all increased; (b) these increases were suppressed by AG490 (a Jak2 inhibitor) and ZD1839 (an EGFR inhibitor); and (c) cytokines associated with the Jak2–Stat3 signaling pathway were upregulated. Our findings suggest that Sal B can be used as a LIF replacement for maintaining ESC pluripotency while increasing cell proliferation.

Glycine N-methyltransferase (GNMT) affects genetic stability by regulating the ratio of S-adenosylmethionine to S-adenosylhomocysteine, by binding to folate, and by interacting with environmental carcinogens. In Taiwanese men, GNMT was found to be a tumor susceptibility gene for prostate cancer. However, the association of GNMT with prostate cancer risk in other ethnicities has not been studied. It was recently reported that sarcosine, which is regulated by GNMT, increased markedly in metastatic prostate cancer. We hereby explored the association of GNMT polymorphisms with prostate cancer risk in individuals of European descent from the Health Professionals Follow-up Study (HPFS).A total of 661 incident prostate cancer cases and 656 controls were identified from HPFS. The GNMT short tandem repeat polymorphism 1 (STRP1), 4-bp insertion/deletion polymorphisms (INS/DEL) and the single nucleotide polymorphism rs10948059 were genotyped to test for their association with prostate cancer risk.The rs10948059 T/T genotype was associated with a 1.62-fold increase in prostate cancer risk (95% confidence interval (CI): 1.18, 2.22) when compared with the C/C genotype. The STRP1 ≥ 16GAs/≥ 16GAs genotype was associated with decreased risk of prostate cancer when compared with the < 16GAs/< 16GAs genotype (odds ratio (OR) = 0.68; 95% CI: 0.46, 1.01). INS/DEL was not associated with prostate cancer risk. Haplotypes containing the rs10948059 T allele were significantly associated with increased prostate cancer risk.In men of European descent, the GNMT rs10948059 and STRP1 were associated with prostate cancer risk. Compared to the study conducted in Taiwanese men, the susceptibility GNMT alleles for prostate cancer had a reverse relationship. This study highlights the differences in allelic frequencies and prostate cancer susceptibility in different ethnicities.

Stem cells are capable of self-renewal and differentiation into a wide range of cell types with multiple clinical and therapeutic applications. Stem cells are providing hope for many diseases that currently lack effective therapeutic methods, including stroke, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Embryonic stem (ES) cells were originally targeted for differentiation into functional dopamine neurons for cell therapy. Today, induced pluripotent stem (iPS) cells are being tested for such purposes as generating functional dopamine neurons and treating a rat model of Parkinson's disease. In addition, neural stem cell and mesenchymal stem cells are also being used in neurodegenerative disorder therapies for stroke and Parkinson's disease. Although stem cell therapy is still in its infancy, it will likely become a powerful tool for many diseases that currently do not have effective therapeutic approaches. In this article, we discuss current research on the potential application of neural stem cells, mesenchymal stem cells, ES cells, and iPS cells to neurodegenerative disorders.

Urinary nucleosides are associated with many types of cancer. In this study, six targeted urinary nucleosides, namely adenosine, cytidine, 3-methylcytidine, 1-methyladenosine, inosine, and 2-deoxyguanosine, were chosen to evaluate their role as biomarkers of four different types of cancer: lung cancer, gastric cancer, colon cancer, and breast cancer. Urine samples were purified using solid-phase extraction (SPE) and then analyzed using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The Mann-Whitney U test and Principal Component Analysis (PCA) were used to compare differences in urinary nucleosides between patients with one of four types of cancer and healthy controls. The diagnostic sensitivity of single nucleosides for different types of cancer ranged from 14% to 69%. In contrast, the diagnostic sensitivity of a set of six nucleosides ranged from 37% to 69%. The false-positive identification rate associated with the set of six nucleosides in urine was less than 2% compared with that of less than 5% for a single nucleoside. Furthermore, combining the set of six urinary nucleosides with carcinoembryonic antigen improved the diagnostic sensitivity for colon cancer. In summary, the study show that a set of six targeted nucleosides is a good diagnostic marker for breast and colon cancers but not for lung and gastric cancers.

Kawasaki disease (KD) is pediatric systemic vasculitis with the classic complication of coronary artery aneurysm (CAA). It is the leading cause of acquired cardiovascular diseases in children. Some severe cases present with multi-organ involvement or neurological dysfunction. To identify the role of the glutamate receptor, ionotropic, N-methyl-d-aspartate 3A (GRIN3A) in KD, we investigated genetic variations in GRIN3A in a Taiwanese cohort of 262 KD patients (76 with and 186 without CAA complications). We used univariate and multivariate regression analyses to identify the associations between clinical characteristics and GRIN3A genetic variations in KD. According to univariate regression analysis, CAA formation in KD was significantly associated with fever duration (p < 0.0001), first Intravenous immunoglobulin (IVIG) used (days after day one of fever) (p < 0.0001), and the GRIN3A (rs7849782) genetic variant (p < 0.001). KD patients with GG+GC genotype showed a lower rate of developing CAA (GG+GC genotype: odds ratio = 0.26; 95% CI = 0.14-0.46). Significant associations were identified between KD with CAA complication and the GRIN3A (rs7849782) genetic variant by using multivariate regression analysis. Specifically, significant correlations were observed between KD with CAA complications and the presence of GG+GC genotypes for the GRIN3A rs7849782 single-nucleotide polymorphism (full model: odds ratio = 0.25; 95% CI = 0.14-0.46). Our results suggest that a polymorphism of the GRIN3A gene may play a role in KD pathogenesis.

In 2006, induced pluripotent stem (iPS) cells were generated from somatic cells by introducing Oct4, Sox2, c-Myc and Klf4. The original process was inefficient; maintaining the pluripotency of embryonic stem (ES) and iPS cell cultures required an expensive reagent-leukemia induced factor (LIF). Our goal is to find a pure compound that not only maintains ES and iPS cell pluripotency, but also increases iPS cell generation efficiency. From 15 candidate compounds we determined that 10 µg/ml n-Butylidenephthalide (BP), an Angelica sinensis extract, triggers the up-regulation of Oct4 and Sox2 gene expression levels in MEF cells. We used ES and iPS cells treated with different concentrations of BP to test its usefulness for maintaining stem cell pluripotency. Results indicate higher expression levels of several stem cell markers in BP-treated ES and iPS cells compared to controls that did not contain LIF, including alkaline phosphatase, SSEA1, and Nanog. Embryoid body formation and differentiation results confirm that BP containing medium culture was capable of maintaining ES cell pluripotency after six time passage. Microarray analysis data identified PPAR, ECM, and Jak-Stat signaling as the top three deregulated pathways. We subsequently determined that phosphorylated Jak2 and phosphorylated Stat3 protein levels increased following BP treatment and suppressed with the Jak2 inhibitor, AG490. The gene expression levels of cytokines associated with the Jak2-Stat3 pathway were also up-regulated. Last, we used pou5f1-GFP MEF cells to test iPS generation efficiency following BP treatment. Our data demonstrate the ability of BP to maintain stem cell pluripotency via the Jak2-Stat3 pathway by inducing cytokine expression levels, at the same time improving iPS generation efficiency.

Stem cells are capable of self-renewal and differentiation into a wide range of cell types with multiple clinical therapeutic applications. The two most important issues associated with embryonic stem (ES) cells are immune rejection and medical ethics. In 2006, induced pluripotent (iPS) cells were generated from somatic cells via the introduction of four transcriptional factors: OCT4, SOX2, c-MYC, and KLF4. Researchers found that iPS cell morphology, proliferation, surface antigens, gene expression, telomerase activity, and the epigenetic status of pluripotent cell-specific genes were similar to the same characteristics in ES cells. iPS cells are capable of overcoming hurdles associated with ES cells due to their generation from mature somatic cells (e.g., fibroblasts). For this reason, iPS cells are considered an increasingly important cell therapy technology. iPS cell production entails the use of retroviruses, lentiviruses, adenoviruses, plasmid transfections, transposons, or recombinant proteins. In this article we discuss the advantages and limitations of each strategy and address issues associated with clinical trials, including the potential for liver tumor formation and low generation efficiency.

For many years, cancer research has focused on the adult stem cells present in malignant tumors. It is believed that current cancer treatments sometimes fail because they do not target these cells. According to classic models of carcinogenesis, these events can occur in any cell. In contrast, the cancer stem cell (CSC) hypothesis states that the preferential targets of oncogenic transformation are tissue stem cells or early progenitor cells that have acquired the potential for self-renewal. These tumor-initiating cells, or CSCs, in turn, are characterized by their ability to undergo self-renewal, a process that drives tumorigenesis and differentiation, which contributes to the cellular heterogeneity of tumors. Herein, we discuss the definitions and properties of CSCs in the major human cancers.

Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.

Pain within the trigeminal system, particularly dental pain, is poorly understood. This study aimed to determine whether single or multiple dental pulp injuries induce persistent pain, its association with trigeminal central nociceptive pathways and whether electroacupuncture (EA) provides prolonged analgesic and neuroprotective effects in a persistent dental pain model. Models of single dental pulp injury (SDPI) and multiple dental pulp injuries (MDPI) were used to induce trigeminal neuropathic pain. The signs of dental pain-related behavior were assessed using the mechanical head withdrawal threshold (HWT). Immunofluorescence and western blot protocols were used to monitor astrocyte activation, changes in apoptosis-related proteins, and GABAergic interneuron plasticity. SDPI mice exhibited an initial marked decrease in HWT from days one to 14, followed by progressive recovery from days 21 to 42. From days 49 to 70, the HWT increased and returned to the control values. In contrast, MDPI mice showed a persistent decrease in HWT from days one to 70. MDPI increased glial fibrillary acidic protein (GFAP) and decreased glutamine synthetase (GS) and glutamate transporter-1 (GLT1) expression in the Vi/Vc transition zone of the brainstem on day 70, whereas no changes in astrocytic markers were observed on day 70 after SDPI. Increased expression of cleaved cysteine-aspartic protease-3 (cleaved caspase-3) and Bcl-2-associated X protein (Bax), along with decreased B-cell lymphoma/leukemia 2 (Bcl-2), were observed at day 70 after MDPI but not after SDPI. The downregulation of glutamic acid decarboxylase (GAD65) expression was observed on day 70 only after MDPI. The effects of MDPI-induced lower HWT from days one to 70 were attenuated by 12 sessions of EA treatment (days one to 21 after MDPI). Changes in astrocytic GFAP, GS, and GLT-1, along with cleaved caspase-3, Bax, Bcl-2, and GAD65 expression observed 70 days after MDPI, were reversed by EA treatment. The results suggest that persistent dental pain in mice was induced by MDPI but not by SDPI. This effect was associated with trigeminal GABAergic interneuron plasticity along with morphological and functional changes in astrocytes. EA exerts prolonged analgesic and neuroprotective effects that might be associated with the modulation of neuron-glia crosstalk mechanisms. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical and radiological outcomes between an anterior to psoas (ATP) approach combined with cortical bone trajectory (CBT) fixation (ATP group) and minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) combined with CBT fixation (MI-TLIF group) for treating patients with lumbar degenerative disc disease and instability. Methods: This retrospective study included patients who underwent interbody fusion and internal fixation between May 1, 2019, and September 30, 2020, using the ATP or MI-TLIF approach to treat degenerative lumbar disc disease and instability. The visual analog scale (VAS) score, Oswestry Disability Index (ODI) results, blood loss, operation time, complications, and bony fusion were analyzed and compared to understand clinical outcomes. Clinical and radiologic follow-up for all patients was at least 12 months. Results: The ATP approach combined with CBT fixation resulted in less blood loss, earlier reduced VAS scores, better ODI scores, but longer operation time. At 12 months, the fusion rates in the ATP and MITLIF groups were 90% (18/20) and 72% (13/18), respectively. Conclusion: Our results show that the ATP approach combined with CBT fixation had the advantage of less blood loss, earlier recovery in VAS scores, and better ODI than in MI-TLIF. Indirect and direct decompression could be successfully integrated by the ATP approach combined with CBT fixation and laminectomy. [ABSTRACT FROM AUTHOR]

Background/Aim: Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a major cause of blindness in working-age adults. Diosgenin (DG), a natural steroidal sapogenin extracted from fenugreek seeds and wild yam roots, has hypolipidemic, hypoglycemic, anticancer, and anti-inflammatory properties. Given its pharmacological effects, we speculated that DG may be a promising treatment for DR. Therefore, this study was aimed at evaluating the effectiveness of DG in preventing or slowing DR progression in a mouse model (+Leprdb/+Leprdb strain) of type 2 diabetes (T2D). Materials and Methods: DG (5.0 mg/kg body weight) or phosphatebuffered saline (PBS) was administered to 8-week-old T2D mice via oral gavage daily for 24 weeks. Paraffin-embedded eye tissues from the mice were collected and stained with hematoxylin and eosin to evaluate retinal histopathology. Apoptosis-related proteins BCL2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 were evaluated by western blotting of mouse retinas. Results: Body weight was slightly reduced in the DG-treated group; however, glucose levels were not markedly different between the DGand PBS-treated groups. Total retinal thickness, thickness of the photoreceptor and outer nuclear layers, and loss of ganglion cells significantly improved in the retina of the DGtreated T2D mice compared with those in the PBS-treated T2D mice. Cleaved caspase-3 level significantly decreased in the retina of the DG-treated T2D mice. Conclusion: DG alleviates DR pathology and exerts a protective effect on the T2D mouse retina. The inhibitory effects of DG on DR may involve mechanisms of the anti-apoptotic pathway. [ABSTRACT FROM AUTHOR]