Castration-resistant prostate cancer (CRPC) patients frequently develop neuroendocrine differentiation, with high mortality and no effective treatment. However, the regulatory mechanism that connects ...neuroendocrine differentiation and metabolic adaptation in response to therapeutic resistance of prostate cancer remain to be unravelled.
By unbiased cross-correlation between RNA-sequencing, database signatures, and ChIP analysis, combining in vitro cell lines and in vivo animal models, we identified that PCK1 is a pivotal regulator in therapy-induced neuroendocrine differentiation of prostate cancer through a LIF/ZBTB46-driven glucose metabolism pathway.
Upregulation of PCK1 supports cell proliferation and reciprocally increases ZBTB46 levels to promote the expression of neuroendocrine markers that are conducive to the development of neuroendocrine characteristic CRPC. PCK1 and neuroendocrine marker expressions are regulated by the ZBTB46 transcription factor upon activation of LIF signalling. Targeting PCK1 can reduce the neuroendocrine phenotype and decrease the growth of prostate cancer cells in vitro and in vivo.
Our study uncovers LIF/ZBTB46 signalling activation as a key mechanism for upregulating PCK1-driven glucose metabolism and neuroendocrine differentiation of CRPC, which may yield significant improvements in prostate cancer treatment after ADT using PCK1 inhibitors.
Very few studies have been conducted to assess the potential preventive role of vaccines, particularly mRNA vaccines, in the improvement of survival among moderate and severe hospitalized patients ...with COVID-19. After community-acquired outbreaks of the Omicron variant from 18 March until 31 May 2022, occurred in Taiwan, this retrospective cohort of 4090 moderate and 1378 severe patients admitted to hospital was classified according to whether they were administered an mRNA-based vaccine, and followed up to ascertain rates of death in both the vaccinated (≥2 doses) and unvaccinated (no or 1 dose) groups. The age-adjusted hazard ratio (aHR) of less than 1 was used to assess the preventive role of mRNA vaccines in reducing deaths among moderate and severe Omicron-infected patients. Survival was statistically significantly better for the ≥2 dose jab group (aHR, 0.75, 95% confidence interval CI, 0.60 to 0.94) and even higher among those who had received a booster jab (aHR, 0.71; 95% CI, 0.55 to 0.91) compared with the unvaccinated group among moderate patients, but not among severe patients. In conclusion, unveiling the role of mRNA vaccines in preventing moderate but not severe COVID-19 patients from death provides new insights into how mRNA vaccines play a role in the pathway leading to a severe outcome due to Omicron COVID-19.
Fibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by ...clinical approaches. Also, the aetiology remains largely unknown.
We used a newly developed mouse model and lipidomic approaches to probe the causation and explore the biological plausibility for how perceived stress translates into chronic non-inflammatory pain. Clinical and lipidomic investigations of fibromyalgia were conducted for human validation.
Using non-painful sound stimuli as psychological stressors, we demonstrated that mice developed long-lasting non-inflammatory hyperalgesia after repeated and intermittent sound stress exposure. Elevated serum malondialdehyde level in stressed mice indicated excessive oxidative stress and lipid oxidative damage. Lipidomics revealed upregulation of lysophosphatidylcholine 16:0 (LPC16:0), a product of lipid oxidisation, in stressed mice. Intramuscular LPC16:0 injection triggered nociceptive responses and a hyperalgesic priming-like effect that caused long-lasting hypersensitivity. Pharmacological or genetic inhibition of acid-sensing ion channel 3 impeded the development of LPC16:0-induced chronic hyperalgesia. Darapladib and antioxidants could effectively alleviate the stress-induced hyperalgesia by inhibiting LPC16:0 synthesis. Clinical investigations showed that excessive oxidative stress and LPC16:0 expression also exist in patients with fibromyalgia. Moreover, LPC16:0 expression was correlated with pain symptoms in patients with high oxidative stress and disease severity.
Our study provides experimental evidence for the causal effect of psychological stressors on chronic pain development. The findings identify a possible pathophysiological mechanism of stress-induced chronic non-inflammatory pain at molecular, behavioural and clinical levels that might indicate a new therapeutic approach for fibromyalgia.
The capability of landing on previously unvisited areas is a fundamental challenge for an unmanned aerial vehicle (UAV). In this paper, we developed a vision-based motion estimation as an aid to ...improve landing performance. As an alternative to the common scenarios accompanying by external infrastructures or well-defined marker, the proposed hybrid framework can successfully land on a new area without any prior information about guiding marks. The implementation was based on the optical flow technique associated with a multi-scale strategy to overcome the decreasing field-of-view during the UAV descending. Compared with a commercial Global Positioning System (GPS) through a sequence of flight trials, the vision-aided scheme can effectively minimize the possible sensing error, thus, leading to a more accurate result. Moreover, this work has potential to integrate the fast-growing image learning process and yields more practical versatility for UAV applications in the future.
Chronic kidney disease (CKD) is associated with bone and mineral metabolism. In this study we evaluated the comparative efficacies and safety of osteoporosis medications in patients with CKD or a ...history of kidney transplantation, and make recommendations for the best choice of osteoporosis treatment among patients with CKD or a history of kidney transplantation.
We systemically searched for randomized controlled trials published in PubMed, Embase, and Cochrane databases up to June 2020. Network-meta analysis was used to compare the relative effectiveness of different treatments. A random-effects model was used when heterogeneity was expected. The safety of different treatments was also evaluated in terms of reported major adverse events.
A total of 17 studies with data from 10,214 patients who had stage 2-5 CKD, were receiving dialysis, or had a history of kidney transplantation were included in the network meta-analysis. Treatment with teriparatide, denosumab, alendronate, and raloxifene were all associated with a significantly reduced risk of fractures compared to treatment with placebos teriparatide: odds ratio (OR) = 0.19, 95% confidence interval (CI): 0.10-0.35; denosumab: OR = 0.40, 95% CI: 0.27-0.58; alendronate: OR = 0.61, 95% CI: 0.40-0.92; raloxifene: OR = 0.52, 95% CI: 0.41-0.67. The rank probability and the surface under the cumulative ranking (SUCRA) values suggested that teriparatide ranked the highest for improvement in vertebral bone mineral density (BMD) (SUCRA = 97.8%), whereas denosumab ranked the highest for improvement in femoral neck BMD (SUCRA = 88.3%).
Teriparatide and denosumab seem to be the most effective treatments for preventing bone loss and reducing the risk of fracture in our network comparison. However, because of the limitations and potential biases in the reviewed studies, there is still some uncertainty about the best treatment options for osteoporosis in patients with CKD or a history of kidney transplantation.
: PROSPERO, identifier CRD42020209830.
The purpose of the study was to explore the levels of and relationships between disaster nursing competence, anticipatory disaster stress, and the motivation for disaster engagement among ...undergraduate nursing students in Taiwan. A cross-sectional research design was applied. Using convenience sampling, 90 nursing students participated with an 86.54% response rate. The Disaster Core Competencies Questionnaire, Anticipatory Disaster Stress Questionnaire, and Motivation for Disaster Engagement Questionnaire were used to collect data. The Pearson correlation and ANOVA were used to analyze the data. Results showed that students' level of disaster nursing competence was low, anticipatory disaster stress was not high, and motivation for disaster engagement was high. Motivation for disaster engagement was positively correlated with anticipatory disaster stress. Students who were more willing to participate in disaster management had a higher level of anticipatory disaster stress and motivation for disaster engagement. It is suggested that healthcare institutions and schools should work together to design disaster education plans using innovative teaching/learning strategies to increase students' willingness and motivation for disaster engagement.
Organotin compounds have been applied as stabilizers for PVCs, fungicides, and pesticides, those can enter water systems through antifouling paints on ships as well as from diverse industrial and ...agricultural processes. This study aims to monitor the background levels of six organotins in 200 fishery products. In the current study, the high organotin levels are over tolerable average residue levels in Taiwan. Phenyltins (PTs) levels in fish and seafood are higher than butyltins (BTs). Risk assessment showed that 95% upper confidence limits of the hazard index (HI) of organotins were almost all over 1, indicating that there are probability of health impacts for organotin consumption in Taiwanese consumers. Those who consume higher amounts of seafood and fishery may be at a higher risk of health issues, but the data indicate that organotin levels have become controlled in recent years as compared with health risk data published in 2006.
•Organotin enter water systems through antifouling paints on ships.•Build up background levels of six organotins in 200 fishery products.•The high organotin levels are over tolerable average residue levels in Taiwan.•PTs level in seafood is obviously higher than BTs.•There are still health impacts for organotin consumption in Taiwanese.
Enhancing the immune response to vaccines and minimizing the need for repeated inoculations remain a challenge in clinical vaccination. This study developed a composite microneedle (MN), composed of ...a sodium hyaluronate (HA) tip and a chitosan base, for biphasic antigen release and evaluated the potential of using this MN formulation as an intradermal delivery system for single-dose vaccination. Upon skin insertion, the dissolvable HA tip dissolved within the skin for rapid release of the encapsulated antigens, thus priming the immune system, while the biodegradable chitosan base remained in the dermis for prolonged antigen release for 4 weeks, thus further boosting the stimulated immunity. Our results showed that a single immunization with the HA/chitosan MN containing ovalbumin (OVA) (100 μg × 1) stimulated both T helper type 1 (Th1) and Th2 immune responses in rats and induced considerably higher and more durable antibody responses than a traditional two-dose (100 μg OVA × 2) or double-dose (200 μg OVA × 1) subcutaneous vaccination. Thus, the proposed MN exerts strong adjuvanticity to greatly augment the antigen’s immunogenicity. Moreover, given its unique rapid and sustained release properties, the HA/chitosan MN formulation has the potential to replace the conventional prime–boost regimen to serve as an effective single-dose vaccine formulation.
Objective
To investigate the risk for second primary cancer in the hypopharynx and esophagus (SPC‐HE) among individuals with an initial oral/oropharyngeal cancer.
Materials and Methods
Mass screening ...data from Taiwan (2004–2009) included individuals who were ≥18 years old and smoked cigarettes and/or chewed betel quid. Occurrence of SPC‐HE was monitored until December 31, 2014. Results were expressed as adjusted relative risk (aRR) and 95% confidence interval (CI).
Results
One hundred and fifty‐eight out of 4,494 subjects with oral cancer developed SPC‐HE (incidence rate: 6.47 per 1,000 person‐years). Relative to patients with primary cancers in the lip, the risk of an SPC‐HE was higher in patients with primary cancers in oropharynx (aRR: 19.98, 95% CI: 4.72–84.55), floor of mouth (aRR: 12.13, 95% CI: 2.67–55.15), and hard palate (aRR: 7.31, 95% CI: 1.65–32.37), but not in patients with cancers in tongue (aRR: 3.67, 95% CI: 0.89–15.17) or gum (aRR: 3.99, 95% CI: 0.92–17.35). Regression analyses also showed the risk of an SPC‐HE was greater in alcohol drinkers than those who did not (aRR: 1.65, 95% CI: 1.10–2.48).
Conclusions
Compared with the initial cancer in the lip, patients with a cancer in the oropharynx, floor of mouth, and hard palate had a higher risk for the SPC‐HE.
Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to ...metastasis, which is difficult to remove using surgery. Doxorubicin (Dox) is the most commonly used chemotherapy drug in the clinical setting; however, drug resistance is a major obstacle to effective treatment. In the present study, we compared Dox-resistant SW1353 cells to their parental cells using RNA sequencing (RNA-Seq). We found that the apelin (APLN) pathway was highly activated in resistant cells. In addition, tissue array analysis also showed that APLN was higher in high-grade tissues compared to low-grade tissues. APLN is a member of the adipokine family, which is a novel secreted peptide with multifunctional and biological activities. Previously, studies have shown that inhibition of the APLN axis may have a therapeutic benefit in cancers. However, the role of APLN in chondrosarcoma is completely unclear, and no related studies have been reported. During in vitro experiments, APLN was also observed to be highly expressed and secreted in Dox-resistant cells. Once APLN was knocked down, it could effectively improve its sensitivity to Dox. We also explored possible upstream regulatory microRNAs (miRNAs) of APLN through bioinformatics tools and the results disclosed that miR-631 was the most likely regulator of APLN. Furthermore, the expression of miR-631 was lower in the resistant cells, but overexpression of miR-631 in the Dox-resistant cell lines significantly increased the Dox sensitivity. These results were also observed in another chondrosarcoma cell line, JJ012 cells. Taken together, these findings will provide rationale for the development of drug resistance biomarkers and therapeutic strategies for APLN pathway inhibitors to improve the survival of patients with chondrosarcoma.
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