Identification of Genetic Variants for Risk Prediction and Early Diagnosis of Age-Related Macular Degeneration in the Taiwanese Population.

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.

Effectiveness of Chinese herbal medicine compared with angiotensin II receptor blockers in patients with diabetic kidney disease: A hospital-based matched cohort study.

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 < 0.001). The change in the eGFR was -6.0 ± 21.4 ml/min/1.73 m2 in CHM users and -12.9 ± 24.8 ml/min/1.73 m2 in ARB users (p = 0.029). The blood urea nitrogen (BUN) and creatinine levels of patients taking CHM were 22 ± 16 mg/dl and 0.9 ± 0.4 mg/dl, respectively, and were lower than those (30 ± 28 mg/dl and 1.7 ± 2.0 mg/dl) of patients taking ARBs (p = 0.025 and p = 0.003). Using linear regression with adjustments for age, sex, BMI, baseline eGFR, and HbA1c levels, we found that the declines in the eGFR/baseline eGFR and changes in the urine albumin-creatinine ratio (ACR) were comparable between the two groups (p = 0.86 and 0.73). This study suggests that CHM may have comparable effectiveness to ARBs, which provides insights for further investigations.

Impact of the trans-ancestry polygenic risk score on type 2 diabetes risk, onset age and progression among population in Taiwan.

Type 2 diabetes (T2D) prevalence in adults at a younger age has increased but the disease status may go unnoticed. This study aimed to determine whether the onset age and subsequent diabetic complications can be attributed to the polygenic architecture of T2D in the Taiwan Han population. A total of 9,627 cases with T2D and 85,606 controls from the Taiwan Biobank were enrolled. Three diabetic polygenic risk scores (PRSs), PRS_EAS and PRS_EUR, and a trans-ancestry PRS (PRS_META), calculated using summary statistic from East Asian and European populations. The onset age was identified by linking to the National Taiwan Insurance Research Database, and the incidence of different diabetic complications during follow-up was recorded. PRS_META (7.4%) explained a higher variation for T2D status. And the higher percentile of PRS is also correlated with higher percentage of T2D family history and prediabetes status. More, the PRS was negatively associated with onset age (ß = -0.91 yr), and this was more evident among males (ß = -1.11 vs. -0.76 for males and females, respectively). The hazard ratio of diabetic retinopathy (DR) and diabetic foot were significantly associated with PRS_EAS and PRS_META, respectively. However, the PRS was not associated with other diabetic complications, including diabetic nephropathy, cardiovascular disease, and hypertension. Our findings indicated that diabetic PRS which combined susceptibility variants from cross-population could be used as a tool for early screening of T2D, especially for high-risk populations, such as individuals with high genetic risk, and may be associated with the risk of complications in subjects with T2D. NEW & NOTEWORTHY Our findings indicated that diabetic polygenic risk score (PRS) which combined susceptibility variants from Asian and European population affect the onset age of type 2 diabetes (T2D) and could be used as a tool for early screening of T2D, especially for individuals with high genetic risk, and may be associated with the risk of diabetic complications among people in Taiwan.

Prevalence and varieties of complementary and alternative medicine usage among individuals with pre-dialysis chronic kidney disease in Taiwan: an investigative cross-sectional analysis.

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 < 0.05). The most commonly used type of CAM was nutritional approaches (79.7%), followed by other complementary health approaches (26.6%). The most commonly utilized modalities of CAM were vitamins and minerals (38.3%), and only 27.1% of patients disclosed their CAM use to their physicians. The most common sources of information about CAM were family and friends, cited by 66% of the participants. Health promotion and a proactive attitude were reported by 40% of users as the reasons for using CAM. CONCLUSIONS: The present study provides data on the CAM usage among CKD patients and adds to the increasing evidence on CAM use. Because some of these practices have safety concerns, better education from healthcare providers on the risks and benefits of CAM therapy is needed by CKD patients.

Electroacupuncture exerts prolonged analgesic and neuroprotective effects in a persistent dental pain model induced by multiple dental pulp injuries: GABAergic interneurons-astrocytes interaction.

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.

Anti-Cancer Effects of Oxygen-Atom-Modified Derivatives of Wasabi Components on Human Leukemia Cells.

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.

Diosgenin, a Natural Steroidal Sapogenin, Alleviates the Progression of Diabetic Retinopathy in Diabetic Mice.

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 phosphate-buffered 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 DG- and 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 DG-treated 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.

Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats.

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.

Sodium-Glucose Transport Protein 2 Inhibitor Use for Type 2 Diabetes and the Incidence of Acute Kidney Injury in Taiwan.

Importance: The association between sodium-glucose transport protein 2 inhibitor (SGLT2i) use and the incidence of acute kidney injury (AKI) remains controversial. The benefits of SGLT2i use in patients to reduce AKI requiring dialysis (AKI-D) and concomitant diseases with AKI as well as improve AKI prognosis have not yet been established. Objective: To investigate the association between SGLT2i use and AKI incidence in patients with type 2 diabetes (T2D). Design, Setting, and Participants: This nationwide retrospective cohort study used the National Health Insurance Research Database in Taiwan. The study analyzed a propensity score-matched population of 104 462 patients with T2D treated with SGLT2is or dipeptidyl peptidase 4 inhibitors (DPP4is) between May 2016 and December 2018. All participants were followed up from the index date until the occurrence of outcomes of interest, death, or the end of the study, whichever was earliest. Analysis was conducted between October 15, 2021, and January 30, 2022. Main Outcomes and Measures: The primary outcome was the incidence of AKI and AKI-D during the study period. AKI was diagnosed using International Classification of Diseases diagnostic codes, and AKI-D was determined using the diagnostic codes and dialysis treatment during the same hospitalization. Conditional Cox proportional hazard models assessed the associations between SGLT2i use and the risks of AKI and AKI-D. The concomitant diseases with AKI and its 90-day prognosis, ie, the occurrence of advanced chronic kidney disease (CKD stage 4 and 5), end-stage kidney disease, or death, were considered when exploring the outcomes of SGLT2i use. Results: In a total of 104 462 patients, 46 065 (44.1%) were female patients, and the mean (SD) age was 58 (12) years. After a follow-up of approximately 2.50 years, 856 participants (0.8%) had AKI and 102 (<0.1%) had AKI-D. SGLT2i users had a 0.66-fold risk for AKI (95% CI, 0.57-0.75; P < .001) and 0.56-fold risk of AKI-D (95% CI, 0.37-0.84; P = .005) compared with DPP4i users. The numbers of patients with AKI with heart disease, sepsis, respiratory failure, and shock were 80 (22.73%), 83 (23.58%), 23 (6.53%), and 10 (2.84%), respectively. SGLT2i use was associated with lower risk of AKI with respiratory failure (hazard ratio [HR], 0.42; 95% CI, 0.26-0.69; P < .001) and shock (HR, 0.48; 95% CI, 0.23-0.99; P = .048) but not AKI with heart disease (HR, 0.79; 95% CI, 0.58-1.07; P = .13) and sepsis (HR, 0.77; 95% CI, 0.58-1.03; P = .08). The 90-day AKI prognosis for the risk of advanced CKD indicated a 6.53% (23 of 352 patients) lower incidence in SGLT2i users than in DPP4i users (P = .045). Conclusions and Relevance: The study findings suggest that patients with T2D who receive SGLT2i may have lower risk of AKI and AKI-D compared with those who receive DPP4i.

Naturally Occurring Bicoumarin Compound Daphnoretin Inhibits Growth and Induces Megakaryocytic Differentiation in Human Chronic Myeloid Leukemia Cells.

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.

Assessing the efficacy and safety of Juan Bi Tang for dialysis-related myofascial pain in the fistula arm: Study protocol for a randomized cross-over trial.

Background: Dialysis-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. Methods: This 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). Discussion: This 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 registration: Clinicaltrials.gov registry (NCT04417101) registered 30 May 2020.

Acupuncture Analgesia in Patients With Traumatic Rib Fractures: A Randomized-Controlled Trial.

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].

Preventive effect and safety of Chinese herbal medicine for oral mucositis during radiotherapy in patients with head and neck cancer: Study protocol for a randomized trial.

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.

The Expression and Prognostic Value of Cancer Stem Cell Markers, NRF2, and Its Target Genes in TAE/TACE-Treated Hepatocellular Carcinoma.

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.

Borneol and Tetrandrine Modulate the Blood-Brain Barrier and Blood-Tumor Barrier to Improve the Therapeutic Efficacy of 5-Fluorouracil in Brain Metastasis.

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.

Combination of 35-Gene Mutation Profile and Radiotherapy Dosimetry Predicts the Therapeutic Outcome of Definitive Chemoradiation in Patients With Esophageal Squamous Cell Carcinoma.

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.

Acupuncture Relieved Chemotherapy-Induced Peripheral Neuropathy in Patients with Breast Cancer: A Pilot Randomized Sham-Controlled Trial.

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.

Association between cancer-related fatigue and traditional Chinese medicine body constitution in female patients with breast cancer.

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 < 0.01] was also associated with clinically significant fatigue. CONCLUSION: Yang-Qi deficiency is associated with clinically significant fatigue in breast cancer patients. However, the association of Phlegm-Stasis syndrome and fatigue as disease duration increases cannot be ignored. Further studies are needed to determine whether treating both constitutions integrating TCM treatment can alleviate patients' fatigue symptoms.

Genome-Wide and Candidate Gene Association Analyses Identify a 14-SNP Combination for Hypertension in Patients With Type 2 Diabetes.

BACKGROUND: High blood pressure is common and comorbid with type 2 diabetes (T2D). Almost 50% of patients with T2D have high blood pressure. Patients with both conditions of hypertension (HTN) and T2D are at risk for cardiovascular diseases and mortality. The study aim was to investigate genetic risk factors for HTN in T2D patients. METHODS: This study included 999 T2D (cohort 1) patients for the first genome scan stage and 922 T2D (cohort 2) patients for the replication stage. Here, we investigated the genetic susceptibility and cumulative weighted genetic risk score for HTN in T2D patients of Han Chinese descent in Taiwan. RESULTS: Thirty novel genetic single nucleotide polymorphisms (SNPs) were associated with HTN in T2D after adjusting for age and body mass index (P value <1 × 10-4). Eight blood pressure-related and/or HTN-related genetic SNPs were associated with HTN in T2D after adjusting for age and body mass index (P value <0.05). Linkage disequilibrium and cumulative weighted genetic risk score analyses showed that 14 of the 38 SNPs were associated with risk of HTN in a dose-dependent manner in T2D (Cochran-Armitage trend test: P value <0.0001). The 14-SNP cumulative weighted genetic risk score was also associated with increased regression tendency of systolic blood pressure in T2D (SBP = 122.05 + 0.8 × weighted genetic risk score; P value = 0.0001). CONCLUSIONS: A cumulative weighted genetic risk score composed of 14 SNPs is important for HTN, increased tendency of systolic blood pressure, and may contribute to HTN risk in T2D in Taiwan.

Causal Relationship between Adiponectin and Diabetic Retinopathy: A Mendelian Randomization Study in an Asian Population.

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 ß = 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.