Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer

Purpose Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors. Materials and Methods We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1-mouse model for in vivo experiments to confirm our findings. Results In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3 beta serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion. Conclusion Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken together, our results support further clinical development of DDR-targeting strategies for PC.

Investigating Endocrine Disrupting Impacts of Nine Disinfection Byproducts on Human and Zebrafish Estrogen Receptor Alpha

Background: Disinfection byproducts (DBPs) cause endocrine disruption via estrogenic or anti-estrogenic effects on estrogen receptors. However, most studies have focused on human systems, with little experimental data being presented on aquatic biota. This study aimed to compare the effects of nine DBPs on zebrafish and human estrogen receptor alpha (zERα and hERα). Methods: In vitro enzyme response-based tests, including cytotoxicity and reporter gene assays, were performed. Additionally, statistical analysis and molecular docking studies were employed to compare ERα responses. Results: Iodoacetic acid (IAA), chloroacetonitrile (CAN), and bromoacetonitrile (BAN) showed robust estrogenic activity on hERα (maximal induction ratios of 108.7%, 50.3%, and 54.7%, respectively), while IAA strongly inhibited the estrogenic activity induced by 17β-estradiol (E2) in zERα (59.8% induction at the maximum concentration). Chloroacetamide (CAM) and bromoacetamide (BAM) also showed robust anti-estrogen effects in zERα (48.1% and 50.8% induction at the maximum concentration, respectively). These dissimilar endocrine disruption patterns were thoroughly assessed using Pearson correlation and distance-based analyses. Clear differences between the estrogenic responses of the two ERαs were observed, whereas no pattern of anti-estrogenic activities could be established. Some DBPs strongly induced estrogenic endocrine disruption as agonists of hERα, while others inhibited estrogenic activity as antagonists of zERα. Principal coordinate analysis (PCoA) showed similar correlation coefficients for estrogenic and anti-estrogenic responses. Reproducible results were obtained from computational analysis and the reporter gene assay. Conclusions: Overall, the effects of DBPs on both human and zebrafish highlight the importance of controlling their differences in responsiveness for estrogenic activities including the water quality monitoring and endocrine disruption, as DBPs have species-specific ligand-receptor interactions.Peer reviewe

Acupuncture Enhances the Synaptic Dopamine Availability to Improve Motor Function in a Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the depletion of striatal dopamine (DA). Acupuncture, as an alternative therapy for PD, has beneficial effects in both PD patients and PD animal models, although the underlying mechanisms therein remain uncertain. The present study investigated whether acupuncture treatment affected dopamine neurotransmission in a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that acupuncture treatment at acupoint GB34 improved motor function with accompanying dopaminergic neuron protection against MPTP but did not restore striatal dopamine depletion. Instead, acupuncture treatment increased dopamine release that in turn, may lead to the enhancement of dopamine availability in the synaptic cleft. Moreover, acupuncture treatment mitigated MPTP-induced abnormal postsynaptic changes, suggesting that acupuncture treatment may increase postsynaptic dopamine neurotransmission and facilitate the normalization of basal ganglia activity. These results suggest that the acupuncture-induced enhancement of synaptic dopamine availability may play a critical role in motor function improvement against MPTP

Biomechanical Analysis of Biodegradable Cervical Plates Developed for Anterior Cervical Discectomy and Fusion

Study Design In-vitro biomechanical investigation. Purpose To evaluate the biomechanical effects of the degeneration of the biodegradable cervical plates developed for anterior cervical discectomy and fusion (ACDF) on fusion and adjacent levels. Overview of Literature Biodegradable implants have been recently introduced for cervical spine surgery. However, their effectiveness and safety remains unclear. Methods A linear three-dimensional finite element (FE) model of the lower cervical spine, comprising the C4–C6 vertebrae was developed using computed tomography images of a 46-year-old woman. The model was validated by comparison with previous reports. Four models of ACDF were analyzed and compared: (1) a titanium plate and bone block (Tita), (2) strong biodegradable plate and bone block (PLA-4G) that represents the early state of the biodegradable plate with full strength, (3) weak biodegradable plate and bone block (PLA-1G) that represents the late state of the biodegradable plate with decreased strength, and (4) stand-alone bone block (Bloc). FE analysis was performed to investigate the relative motion and intervertebral disc stress at the surgical (C5–C6 segment) and adjacent (C4–C5 segment) levels. Results The Tita and PLA-4G models were superior to the other models in terms of higher segment stiffness, smaller relative motion, and lower bone stress at the surgical level. However, the maximal von Mises stress at the intervertebral disc at the adjacent level was significantly higher in the Tita and PLA-4G models than in the other models. The relative motion at the adjacent level was significantly lower in the PLA-1G and Bloc models than in the other models. Conclusions The use of biodegradable plates will enhance spinal fusion in the initial stronger period and prevent adjacent segment degeneration in the later, weaker period

A systemic review and meta-analysis on the antihypertensive effect of aromatherapy essential oils

Purpose: This study is a systemic review of experimental results on the effects of aromatherapy on blood pressure. Materials and Methods: Journal articles published to December, 2017, were retrieved from twelve databases. Randomized controlled trials in which were evaluated for changes in blood pressure following aromatherapy were selected. Risks of bias were assessed using the risk-of-bias (ROB) tool of the Cochrane Collaboration. Meta-analysis were dine using RevMan. Results: Of the 2545 articles retrieved from the electronic databases, 580 duplicate articles and 1891 articles that were unrelated to the PICO (patient/problem, intervention, comparison, outcome) elements or did not satisfy the inclusion criteria excluded. Of the remaining 74 articles, 15 found to satisfy the inclusion criteria after full-text review and therefore selected for analysis. The findings of meta-analysis of 11 of these 15 articles revealed that essential oil inhalation and massage effectively decreased both systolic (n = 379; mean difference [MD], -4.72; 95% confidence interval [CI], -8.38 to -1.07) and diastolic (n = 379; MD, -2.42; 95% CI, -4.46 to -0.38) pressure. Conclusions: Essential oil inhalation and massage therapy can effectively decrease systolic and diastolic pressure in health adults as well as in patients with hypertension

The Expression of Adipophilin Is Frequently Found in Solid Subtype Adenocarcinoma and Is Associated with Adverse Outcomes in Lung Adenocarcinoma

Background The up-regulation of the lipogenic pathway has been reported in many types of malignant tumors. However, its pathogenic role or clinical significance is not fully understood. The objective of this study was to examine the expression levels of adipophilin and related hypoxic signaling proteins and to determine their prognostic impacts and associations with the pathologic characteristics of lung adenocarcinoma. Methods Expression levels of adipophilin, heat shock protein 27 (HSP27), carbonic anhydrase IX, and hypoxia-inducible factor 1α were examined by immunohistochemical staining using tissue microarray blocks. Correlations between protein expression levels and various clinicopathologic features were analyzed. Results A total of 230 cases of primary adenocarcinoma of the lung were enrolled in this study. Adipophilin expression was more frequent in males and with the solid histologic type. It was correlated with HSP27 expression. Patients with adipophilin-positive adenocarcinoma showed a shorter progression-free survival (PFS) (median PFS, 17.2 months vs 18.4 months) in a univariable survival analysis, whereas HSP27 positivity correlated with favorable overall survival (OS) and PFS. In a multivariable analysis, adipophilin and HSP27 were independent prognostic markers of both OS and PFS. Conclusions Activated lipid metabolism and the hypoxic signaling pathway might play a major role in the progression of lung adenocarcinoma, especially in the solid histologic type

Cardiovascular outcomes with glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes: A meta-analysis

Background: According to available research, there have been no head-to-head studies comparing the effect of glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors on cardiovascular outcomes among patients with type 2 diabetes not reaching glycemic goal with metformin. Methods: Relevant studies were identified through electronic searches of PubMed and EMBASE published up to January 15, 2020. Efficacy outcomes of interest included the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, its individual components, all-cause death, and hospitalization for heart failure (HF). Safety outcomes included all suggested side effects of both agents previously reported. Results: Eleven studies, including 94,727 patients were used for the analysis. The risk of composite end point was significantly lower in both groups compared to the control group (hazard ratio [HR], 0.88, 95% confidence interval [CI] 0.85–0.92, p < 0.001). The risk of hospitalization for HF was significantly lower in both groups but the magnitude of the effect was more pronounced in the SGLT-2 inhibitors group (HR 0.68, 95% CI 0.60–0.76, p < 0.001) than the GLP-1 agonists group (HR 0.92, 95% CI 0.84–0.99, p = 0.03). Patients treated with GLP-1 agonists discontinued trial medications more frequently compared to conventionally treated patients because of serious side effects. Conclusions: Both GLP-1 agonists and SGLT-2 inhibitors showed comparable cardiovascular outcomes in patients with type 2 diabetes. However, the SGLT-2 inhibitors were associated with more pronounced reduction of hospitalization for HF and lower risk of treatment discontinuation than GLP-1 agonists

From Peripheral to Central: The Role of ERK Signaling Pathway in Acupuncture Analgesia

Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal–regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 μg/μL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia