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Despite epidemiological evidence that suggests diabetes mellitus is a risk factor for cancer, the link between diabetes mellitus and primary bone cancer is rarely discussed. Chondrosarcomas are primary malignant cartilage tumors with poor prognosis and high metastatic potential. It remains unclear whether hyperglycemia affects the stemness and malignancy of chondrosarcoma cells. Nε-(1-Carboxymethyl)-L-lysine (CML), an advanced glycation end product (AGE), is a major immunological epitope detected in the tissue proteins of diabetic patients. We hypothesized that CML could enhance cancer stemness in chondrosarcoma cells. CML enhanced tumor-sphere formation and the expression of cancer stem cell markers in human chondrosarcoma cell lines. Migration and invasion ability and the epithelial–mesenchymal transition (EMT) process were also induced by CML treatment. Moreover, CML increased the protein expression levels of the receptor for AGE (RAGE), phosphorylated NFκB-p65, and decreased the phosphorylation of AKT and GSK-3. We also found that hyperglycemia with high CML levels facilitated tumor metastasis, whereas tumor growth was not affected in the streptozotocin (STZ)-induced diabetic NOD/SCID tumor xenograft mouse models. Our results indicate that CML enhances chondrosarcoma stemness and metastasis, which may reveal the relationship between AGE and bone cancer metastasis. [ABSTRACT FROM AUTHOR]

In this study, we comprehensively investigate the constant voltage stress (CVS) time-dependent breakdown and cycle-to-breakdown while considering metal-ferroelectric-metal (MFM) memory, which has distinct domain sizes induced by different doping species, i.e., Yttrium (Y) (Sample A) and Silicon (Si) (Sample B). Firstly, Y-doped and Si-doped HfO2 MFM devices exhibit domain sizes of 5.64 nm and 12.47 nm, respectively. Secondly, Si-doped HfO2 MFM devices (Sample B) have better CVS time-dependent breakdown and cycle-to-breakdown stability than Y-doped HfO2 MFM devices (Sample A). Therefore, a larger domain size showing higher extrapolated voltage under CVS time-dependent breakdown and cycle-to-breakdown evaluations was observed, indicating that the domain size crucially impacts the stability of MFM memory. [ABSTRACT FROM AUTHOR]

This study presents a clinical treatment decision support system (CTDSS) through which clinicians can simplify the shared-decision making (SDM) process for treating knee osteoarthritis (OA). This system enables patients to participate in selecting the optimum treatment. There has been broad international acceptance of SDM, but its practical implementation in clinical setting has posed challenges. The proposed method incorporates analytic hierarchy process and fuzzy multi-choice goal programming (AHP-FMCGP) into CTDSS to determine treatment standards, beginning with a literature review and expert surveys. The method provides patients with flexibility to modify treatment goals and constraints during the decision-making (DM) process to achieve their preferred treatment and simplifying the traditional SDM. A total of 240 knee OA patients participated in this pilot study, and the results indicated a significant improvement in patient satisfaction (F = 4.104; P < 0.05) with the implementation of CTDSS. This study demonstrates the effectiveness of CTDSS by resolving several challenges in clinical implementation: (1) Improved efficiency of implementing SDM, promoting better clinician-patient communication and higher healthcare quality. (2) Eliminating the need for extensive health literacy and disease knowledge in patients during the DM process. (3) Saving time for physicians, by allowing them to better understand the patients' preferences and select the most appropriate treatment option. (4) This method can be extended to primary clinics to benefit other patients. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) are implicated in the age-related decline of renal function, exacerbated by conditions, such as hyperglycemia and oxidative stress. The accumulation of AGEs in the kidneys contributes to the progressive decline in renal function observed with aging. However, the precise role and mechanisms of AGEs in the age-related decline of renal function remain unclear. In this study, we investigated the impact and potential mechanisms of AGEs on aging kidneys in naturally aging mice. Male C57BL/6 mice were divided into three groups: 6-, 57-, and 107-week-old. First, the 6- and 107-week-old mice were euthanized. The remaining mice were divided into young (6 weeks) and old (57 weeks) groups. The 57-week-old mice were orally administered aminoguanidine (100 mg/kg/day), an AGEs inhibitor, or vehicle for 13 weeks, resulting in a final age of 70 weeks. The serum and kidney tissues were collected for biochemical measurement, histological examination, immunohistochemistry staining, and immunoblotting analysis. Our findings revealed a notable accumulation of AGEs in both serum and kidney tissue specimens and renal dysfunction in naturally aging mice. Aminoguanidine not only reversed AGEs accumulation but also ameliorated renal dysfunction. Additionally, aminoguanidine attenuated the upregulation of fibrosis markers (phosphorylated p38/α-SMA and C/EBP homologous protein, CHOP), senescence markers (p53 and p21), and oxidative stress marker (4-HNE) in the aging kidneys. These findings underscore the critical role of AGEs in age-related renal dysfunction and highlight the therapeutic potential of aminoguanidine in mitigating fibrosis and senescence, offering prospective avenues for combating age-associated renal ailments. [Display omitted] [ABSTRACT FROM AUTHOR]

The abnormal proliferation, migration, and inflammation of vascular smooth muscle cells (VSMCs) play crucial roles in the development of neointimal hyperplasia and restenosis. Exposure to inflammatory cytokines such as platelet-derived growth factor (PDGF)-BB and tumour necrosis factor-alpha (TNF-α) induces the transformation of contractile VSMCs into abnormal synthetic VSMCs. Isoxanthohumol (IXN) has significant anti-inflammatory, antiproliferative, and antimigratory effects. This study aimed to explore the therapeutic impact and regulatory mechanism of IXN in treating neointimal hyperplasia. The present findings indicate that IXN effectively hinders the abnormal proliferation, migration, and inflammation of VSMCs triggered by PDGF or TNF-α. This inhibition is primarily achieved through the modulation of the apelin/AKT or AKT pathway, respectively. In an in vivo model, IXN effectively reduced neointimal hyperplasia in denuded femoral arteries. These results suggest that IXN holds promise as a potential and innovative therapeutic candidate for the treatment of restenosis. [Display omitted] • IXN is a natural product with anti-inflammatory, antitumour, antiproliferative, antioxidative, antimigratory and immunomodulatory effects. • IXN decreases PDGF-BB- or TNF-α-induced abnormal proliferation, migration and inflammation in VSMCs through apelin/AKT inhibition. • IXN is a potential therapeutic candidate for intimal hyperplasia and restenosis. [ABSTRACT FROM AUTHOR]

Background: Stroke is prevalent in patients with chronic kidney disease (CKD) and is associated with high mortality, but the causes of death after stroke among different CKD stages are not well known. Aims: We aimed to investigate whether the severity of CKD would impact on the causes of death after first-ever stroke. Methods: This retrospective multicenter cohort study included stoke patients with CKD between 2007 and 2012. The cause of death and date of death were ascertained by linking the National Death Registry Database of Taiwan. Clinical outcomes, 1-month, and 1-year mortality rates, and major causes of death were compared according to five CKD stages (G1 to G5) in the ischemic and hemorrhagic stroke separately. Results: Of these patients, 9,878 were first-ever ischemic stroke (IS) patients, and 1,387 were first-ever hemorrhagic stroke (HS) patients. Patients with CKD G5 had the highest one-year mortality rate with hazard ratio 5.28 [95%CI, 3.94–7.08] in IS and 3.03 [95%CI, 2.03–4.54] in HS when compared to G1 patients. Leading causes of one-year death after IS were stroke, cancer, and pneumonia in early (G1-3) CKD patients, while diabetes mellitus, CKD, and stroke itself contributed to the major mortality in CKD G5 patients. An inverse association between eGFR decrement and the proportion of deaths caused by stroke itself was observed in CKD G2-5 patients after IS. Stroke was the leading cause of one-year death among all CKD patients after HS. Conclusions: Asides from high mortality, late-stage CKD patients had different causes of death from early CKD patients after stroke. This study highlights the need to imply different treatment strategies in late-stage CKD post-stroke patients to improve their prognosis. [ABSTRACT FROM AUTHOR]

The Developmental Origins of Health and Disease (DOHaD) concept has gained prominence in maternal and child health (MCH), emphasizing how early-life factors impact later-life non-communicable diseases. However, a knowledge–practice gap exists in applying DOHaD principles among healthcare professionals. Healthy Early Life Moments in Singapore (HELMS) introduced webinars to bridge this gap and empower healthcare professionals. We aimed to conduct a preliminary assessment to gain early insights into the outreach and effectiveness of the educational initiative offered with the HELMS webinars. We employed a pragmatic serial cross-sectional study approach and targeted healthcare professionals involved in MCH care. We also collected and analyzed data on webinar registration and attendance, participants' profession and organizational affiliations, and post-webinar survey responses. The median webinar attendance rate was 59.6 % (25th–75th percentile: 58.4–60.8 %). Nurses represented 68.6 % of attendees (n=2,589 out of 3,774). Post-webinar surveys revealed over 75 % of the participants providing positive responses to 14 out of 15 survey questions concerning content, delivery, applicability to work, and organization. Assessment of the HELMS webinars provided insight into the outreach and early effectiveness in enhancing healthcare professionals' knowledge and confidence in delivering DOHaD education. Bridging the knowledge–practice gap remains a crucial goal. [ABSTRACT FROM AUTHOR]

Background: The differential risk of pneumonia among inhaled corticosteroid (ICS) use in patients with COPD requires more investigation, especially regarding beclomethasone-containing inhalers. The goal of this study was to compare the risk and benefit profile of different ICS/long-acting β2-agonist (LABA) combinations in patients with COPD.Methods: This retrospective cohort study was conducted by using national health insurance claims data from the years 2009 to 2015 in Taiwan and included patients with COPD with new ICS/LABA use. Propensity score matching and Cox regression models were used to estimate the hazard ratios of severe pneumonia and acute exacerbation for different ICS/LABA users.Results: Both budesonide/formoterol (BUD/FOR) dry-powder inhalers and beclomethasone/formoterol (BEC/FOR) metered-dose inhalers, compared with fluticasone propionate/salmeterol (FLU/SAL) delivered via the same device type, were associated with a lower risk of severe pneumonia (BUD/FOR hazard ratio [HR], 0.83 [95% CI, 0.70-0.98]; BEC/FOR HR, 0.69 [95% CI, 0.58-0.81]) and severe acute exacerbation (BUD/FOR HR, 0.88 [95% CI, 0.78-0.99]; BEC/FOR HR, 0.82 [95% CI, 0.72-0.93]). After additionally adjusting for the average daily ICS dose, BUD/FOR dry-powder inhaler users continued to have a significantly decreased risk of severe pneumonia (18%), although BEC/FOR metered-dose inhaler users did not. The results were consistent in most of the prespecified subgroups and across all the sensitivity analyses.Conclusions: This study augments the existing evidence concerning the different safety and effectiveness outcomes of ICS/LABA combinations in patients with COPD, which may be considered when making clinical treatment decisions. [ABSTRACT FROM AUTHOR]

[Display omitted] • ZnGa 2 O 4 has shown promising results as a material for NO gas sensing applications. • Plasma surface treatment improves the performance of ZnGa 2 O 4 based NO gas sensors. • The limit of detection is found to be 2.4 ppb. • ZnGa 2 O 4 gas sensor possess highly selectivity for NO gas. • Ar surface modification techniques can enhance the performance of gas sensors. Gas sensors are essential devices in various industrial and environmental monitoring applications. Nitric oxide (NO) is a harmful gas that is produced in various combustion processes and is associated with air pollution and respiratory diseases. Zinc gallate (ZnGa 2 O 4) has shown promising results as a material for NO gas sensing applications. Previously, the performance of NO gas sensors based on ZnGa 2 O 4 epilayers was not substantial. However, there is potential for further improvement by optimizing their surface properties. Plasma surface treatment has been widely utilized to modify the surface characteristics of materials, including semiconductors, for various applications. We have investigated the impact of plasma surface treatment on the performance of metal–organic chemical vapor deposition grown ZnGa 2 O 4 based NO gas sensors in this work. An inductive coupled plasma reactive ion etching was used to apply Ar plasma to successfully optimize the sensing response of the ZnGa 2 O 4 based gas sensor for NO gas. The sensor response for ZnGa 2 O 4 -based NO gas sensors is 159.5%, which is enhanced by 8 times and reached 1276.1% under 5 ppm NO gas concentration after 10 min Ar plasma treatment. The limit of detection is found to be 2.4 ppb. These results demonstrate that Ar plasma treatment significantly improved the ZnGa 2 O 4 -based NO gas sensor's response. The cross-selectivity of this sensor is tested among NO, CO 2 , CO, and SO 2 gases, which indicated that ZnGa 2 O 4 gas sensor possess highly selectivity towards NO gas. This study provides valuable insights into the surface modification techniques for enhancing the performance of gas sensors, which can have a significant impact on the development of advanced sensing technologies for environmental and industrial applications. [ABSTRACT FROM AUTHOR]

Aim: Frailty results from age‐associated declines in physiological reserve and function and is prevalent in older people. Our aim is to examine the association of the Hospital Frailty Risk Score (HFRS) with adverse events in older patients hospitalized with community‐acquired pneumonia (CAP) and hypothesise that frailty is a comparable predictor of outcomes in CAP versus traditional severity indices such as CURB‐65. Methods: Retrospective review of electronic medical records in patients ≥65 years with CAP admitted to a tertiary hospital from 1 January to 30 April 2021. Patients were identified using ICD codes for CAP and categorized as high risk (>15), intermediate risk (5–15) and low risk (<5) of frailty using the HFRS. Results: Of 429 patients with CAP, 53.8% male, mean age of 82.9 years, older patients (85 vs. 79.7 years, P < 0.001) were at higher risk of frailty. Using the HFRS, 47.6% were deemed at high risk, 35.9% at intermediate risk, and 16.6% at low risk of frailty. Multivariate logistic regression shows that HFRS was more strongly associated (≥7 days, OR 1.042, CI 1.017–1.069) than CURB‐65 (OR 0.995, CI 0.810–1.222) with long hospital length of stay (LOS), while CURB‐65 (Confusion, Urea >7mmol/L, Respiratory rate >30, Blood pressure, age => 65 years old) was more strongly associated with mortality at 30, 90 and 365 days, compared with the HFRS. Comparing the values for the area under the receiver operator characteristic curve, the HFRS was found to be a better predictor of long LOS, while CURB‐65 remains a better predictor of mortality. Conclusions: Patients with high risk of frailty have higher healthcare utilization and HFRS is a better predictor of long LOS than CURB‐65 but CURB‐65 was a better predictor of mortality. Geriatr Gerontol Int 2024; 24: 135–141. [ABSTRACT FROM AUTHOR]

Improving technological innovation (TI) capabilities is an integral component of government policies aimed at improving the competitiveness of small and medium enterprises (SMEs). This study aims to address implementation challenges arising from the use of Qualitative Forecasting Method (QFM) in new product development programs and proposes a novel method to aid decision makers (DMs) in their decision-making process. To tackle this issue, a hybrid method is proposed, incorporating Fuzzy Delphi method (FDM), Fuzzy Analytic Hierarchy Process (FAHP), Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS), and Multi-Choice Goal Programming with utility function (MCGP-U), while introducing prospect theory as a novel approach. is proposed. The proposed method offers several advantages, including effective early planning, accurate identification of key success factors (KSFs), selection of the most suitable project leader, and estimation of the most reasonable resource investment, all of which are critical factors for success in TI for enterprises. The research results show that (1) the proposed method reduces project execution time by 20% compared to the original manual planning, (2) it facilitates the acquisition of KSFs using a rational approach to ensure project success, and (3) it increases the financial returns of the company by 17% compared to the company's forecast. In summary, this paper makes a significant contribution to practical applications and additionally contributes to decision-making field by introducing prospect theory into the proposed hybrid method. [ABSTRACT FROM AUTHOR]

Functional impairment of endothelial colony-forming cells (ECFCs), a specific cell lineage of endothelial progenitor cells (EPCs) is highly associated with the severity of coronary artery disease (CAD), the most common type of cardiovascular disease (CVD). Emerging evidence show that circulating microRNAs (miRNAs) in CAD patients’ body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq), we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson’s correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis-related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b-5p up-regulation compared to healthy control. Knockdown of miR-146a-5p or miR-146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3’-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases. [ABSTRACT FROM AUTHOR]

The analysis described in this article shows that a high static stiffness of the bearing is attainable as two design parameters of membrane-type restrictor are properly chosen. The first one is the dimensionless stiffness of the membrane and the other one is the design restriction ratio of the bearing system. When the deformation-load relationship of the restrictor is compliance with the ideal trend, the stiffness of the bearing should theoretically approach infinite in most application range. It was derived that a dimensionless membrane stiffness of 1.33 and a design restriction ratio of 0.25 is the solution for such condition. The film thickness for the bearing will be maintained at designed levels over a loading range. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT), an attractive strategy for cancer treatment, can kill tumor cells and avoid injury to surrounding healthy cells. 4-Borono-2-[18F]fluorophenylalanine ([18F]FBPA) positron emission tomography (PET) is a reliable tool for patient screening. Due to the relatively low radiochemical yield when employing the electrophilic route, this study was able to develop a new method to produce no-carrier-added (NCA) [18F]FBPA and compare the biological characteristics with carrier-added (CA) characteristics. By starting from 4-bromo-2-nitrobenzaldehyde, NCA [18F]FBPA was prepared using radiofluorination, alkylation, borylation, and hydrolysis. Cellular uptake analyses, microPET imaging, and biodistribution analyses were conducted to characterize the biological properties of NCA and CA [18F]FBPA. The radiochemical yield of NCA [18F]FBPA was 20 % ± 6 % (decay corrected) with a radiochemical purity of >98 % and molar activity of 56 ± 15 GBq/μmol in a 100-min synthesis. The in vitro accumulation was significantly higher for NCA [18F]FBPA than for CA [18F]FBPA in both SAS and CT-26 cells. However, no apparent differences in tumor uptake were observed between NCA and CA [18F]FBPA-injected tumor-bearing mice. We successfully prepared NCA [18F]FBPA through nucleophilic substitution and achieved improved radiochemical yield and purity. We also demonstrated the effects of the amount of nonradioactive FBPA on in vitro cellular uptake and in vivo imaging studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Background: Cerebral hypoperfusion is responsible for cognitive impairment in patients with severe carotid artery stenosis (CAS). The manifestation of reversed ophthalmic artery flow (ROAF) is not uncommon in patients with CAS, suggesting a state of intensified cerebral hypoperfusion. This study aimed to examine whether the presence of ROAF can exacerbate cognitive impairment in patients with severe unilateral CAS. Methods: One-hundred-and-two patients with CAS and 37 age-matched volunteers participated in this case–control study. Depending on the side of CAS and occurrences of ROAF, the patients were allocated to four groups: left CAS groups with ROAF (n =28) or without ROAF (n =22), and right CAS groups with ROAF (n =26) or without ROAF (n =26). All subjects underwent a battery of neuropsychological tests. Results: All patients performed worse than the control group on most tests. No significant differences were observed between patient groups (ps>0.05), except for inferior performance on psychomotor speed and visuospatial tests in the right ROAF group (ps<0.03). Hierarchical regression analyses indicated strong contributions of estimated premorbid intelligence to performance on most tests (ps<0.05). The severity of left and right CAS was distinctively associated with different functions. To a lesser extent, the severity of infarcts was also associated with impairment of psychomotor speed and some executive functions (ps<0.05). The contributions of ROAF to performance on most tests were negligible. Conclusion: Patients with unilateral CAS may present with specific cognitive impairment relevant to the ipsilateral hemispheric functions. However, the manifestation of ROAF does not necessarily imply more extensive or severe cognitive impairment. [Copyright &y& Elsevier]

This study presents the design, synthesis, and characterization of bisindole molecules as anti-cancer agents against Tousled-like kinases (TLKs). We show that compound 2 composed of an indirubin-3′-oxime group linked with a (N -methylpiperidin-2-yl)ethyl moiety possessed inhibitory activity toward both TLK1 and TLK2 in vitro and diminished the phosphorylation level of the downstream substrate anti-silencing function 1 (ASF1) in replicating cells. The treatment of compound 2 impaired DNA replication, slowed S-phase progression, and triggered DNA damage response in replicating cells. Structure optimization further discovered six derivatives exhibiting potent TLK inhibitory activity and revealed the importance of the tertiary amine-containing moiety of the side chain. Moreover, the derivatives 6 , 17 , 19 , and 20 strongly suppressed the growth of triple-negative breast cancer MDA-MB-231 cells, non-small cell lung cancer A549 cells, and colorectal cancer HCT-116 cells, while normal lung fibroblast MRC5 and IMR90 cells showed a lower response to these compounds. Taken together, this study identifies tertiary amine-linked indirubin-3′-oximes as potent anticancer agents that inhibit TLK activity. [Display omitted] • Compound 2 is identified as a lead compound for development of TLK inhibitors. • The derivatives with a tertiary amine-containing side chain potently inhibit TLKs. • The derivatives impair chromatin replication and induce DNA damage response. • The derivatives are highly toxic to cancer cell lines. [ABSTRACT FROM AUTHOR]

Simple Summary: CARMA3 is overexpressed in most cancers, and its expression is positively associated with poor prognosis. In this study, we evaluated the detailed mechanisms of CARMA3-mediated CRC metastasis. We found that overexpression of CARMA3 induced the expression of YAP and NF-κB activation, then elicited EMT induction to enhance cell migration and invasion. We demonstrate for the first time that YAP is a critical downstream regulator of CARMA3 in CRC. Our findings reveal a regulation axis between CARMA3 and Hippo oncoprotein YAP and further support the potential role of CARMA3 in the metastasis and cancer stemness of CRC. CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment. [ABSTRACT FROM AUTHOR]

The influence of surface additives, iodine and indium, on copper chemical vapor deposition (CVD) in its initial growth period is studied. The Cu CVD has been carried out on TaN/SiO2 and Cu(sputtered)/TaN/SiO2 substrates using Cu–hexafluoroacetylacetonate–vinyltrimethylsilane (Cu(hfac)(vtms)) precursor. Addition of iodine enhances the horizontal growth and reduces the vertical growth of Cu nuclei on the TaN surface. Addition of indium increases the number density of copper nuclei significantly on TaN. Both effects accelerate the initial growth rate and shorten the initial period. The X-ray photoelectron spectra confirm that iodine floats out to the growing copper surface, but indium does not. Since iodine is floating on the copper surface, it is a surfactant and its influences persist throughout the deposition. On the other hand, the influences of extranucleation sites provided by indium cease at the end of initial growth. Hence, Cu CVD on the In-added TaN surface develops a continuous film quickly, but its growth afterwards is similar to that without indium. On the Cu(sputtered)/TaN/SiO2 substrate, the surface is featured with faceted and protruded Cu grains in the initial growth. The iodine adsorption on sputtered copper worsens the initial morphology and leads to a porous and less conductive film. After 1-h deposition at 145 °C, the sheet resistivity of Cu film on iodine-adsorbed TaN/SiO2 substrate is 1.8 ± 0.1 μΩ-cm. [Copyright &y& Elsevier]

Objective: To compare the real‐world effectiveness and tolerability of calcitonin gene‐related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients. Methods: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult‐to‐treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS). Results: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (−13.0 vs. −8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (−13.0 vs. −9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication‐overuse headache (MOH) (−13.3 vs. −9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (−42.2 vs. −11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs. Conclusions: In this multicenter, real‐world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings. [ABSTRACT FROM AUTHOR]

Introduction Design Methods Results Conclusion Clinical Relevance The effectiveness of health interventions delivered via a combination of in‐person and electronic social networking services for caregivers of stroke survivors remains uncertain. This study evaluates the feasibility of implementing educational and peer support programs for these caregivers through such platforms.Quasi‐experimental design.This study included 105 caregiver–survivor dyads, with 54 dyads allocated to the intervention group and the remaining 51 to the control group. The LINE intervention comprised a combination of in‐person and electronic social networking services including stroke and rehabilitation education, problem‐solving skills training, long‐term care information support, and 24‐h peer and professional support for caregivers. The outcomes were assessed at baseline, after 1 month, and after 3 months, and encompassed caregivers' care burden, depressive symptoms, perceived social support, and quality of life, as well as the rehabilitation adherence and depressive symptoms of stroke survivors. Generalized estimating equations were used to examine group differences. The data were collected between August 2021 and October 2022.The average age of the caregivers was 48.3 years. Caregivers in the intervention group reported reduced care burdens and enhanced perceptions of social support and quality of life as compared to those in the control group. Additionally, stroke survivors in the intervention group were less likely to exhibit high‐risk depressive symptoms.Delivering a stroke caregiver support intervention via in‐person and electronic social networking services, such as LINE, effectively reduced the care burden for caregivers of stroke survivors. Additionally, it enhanced caregivers' perceived social support and quality of life.This study demonstrated that caregiver education and peer support programs administered through a combination of in‐person and electronic social networking services can serve as an effective support system for the psychosocial health of stroke caregivers. These findings support the integration of such interventions into standard clinical practice by healthcare providers or governmental bodies. [ABSTRACT FROM AUTHOR]

Owing to the lack of a suitable tool for detecting the unmet needs of young stroke survivors, this study aims to develop a validated questionnaire for evaluating these unmet needs.A cross-sectional, observational research design.Chang Gung Memorial Hospital Linkou and Taoyuan branches in Taiwan.A total of 211 participants (average age 53 years; within 6 months post-stroke) completed the questionnaire.A qualitative approach was used to create an item pool. Experts verified item suitability, and content validity was evaluated using the item content validity index. Item analysis was applied to determine item quality, and factor analysis was used to explore construct validity. In addition, parallel analysis was employed to ascertain the optimal number of factors.The scale development procedure resulted in a 27-item questionnaire that assesses the unmet needs of young stroke survivors after a stroke. The item content validity index was 1.0. The Unmet Needs Questionnaire has five factors: restoring prestroke abilities and life, rehabilitation-related resources, social support and self-adjustment, economic and post-stroke life adjustment, and stroke-related information. These five factors accounted for 54% of the variance. Cronbach's alpha for the total scale was 0.91, while the alpha for the subscales ranged from 0.74 to 0.88.The Unmet Needs Questionnaire showed acceptable reliability and validity. It can help clinical professionals and government agencies identify stroke survivors’ unmet needs and develop tailored care plans. Future research should explore the trajectory of post-stroke unmet needs using this tool. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles that play a role in intercellular communication through the transportation of their cargo including mRNAs, microRNAs, proteins, and nucleic acids. Exosomes can also regulate glucose homeostasis and insulin secretion under diabetic conditions. However, the role of exosomes in insulin secretion in islet β-cells under physiological conditions remains to be clarified. The aim of this study was to investigate whether exosomes derived from pancreatic islet β-cells could affect insulin secretion in naïve β-cells. We first confirmed that exosomes derived from the RIN-m5f β-cell line interfered with the glucose-stimulated insulin secretion (GSIS) of recipient β-cells without affecting cell viability. The exosomes significantly reduced the protein expression levels of phosphorylated Akt, phosphorylated GSK3α/β, CaMKII, and GLUT2 (insulin-related signaling molecules), and they increased the protein expression levels of phosphorylated NFκB-p65 and Cox-2 (inflammation-related signaling molecules), as determined by a Western blot analysis. A bioinformatics analysis of Next-Generation Sequencing data suggested that exosome-carried microRNAs, such as miR-1224, -122-5p, -133a-3p, -10b-5p, and -423-5p, may affect GSIS in recipient β-cells. Taken together, these findings suggest that β-cell-derived exosomes may upregulate exosomal microRNA-associated signals to dysregulate glucose-stimulated insulin secretion in naïve β-cells. [ABSTRACT FROM AUTHOR]

Regarding the increased incidence and high mortality rate of malignant melanoma, practical early-detection methods are essential to improve patients' clinical outcomes. In this study, we successfully prepared novel picolinamide–benzamide (18F-FPABZA) and nicotinamide–benzamide (18F-FNABZA) conjugates and determined their biological characteristics. The radiochemical yields of 18F-FPABZA and 18F-FNABZA were 26 ± 5% and 1 ± 0.5%, respectively. 18F-FPABZA was more lipophilic (log P = 1.48) than 18F-FNABZA (log P = 0.68). The cellular uptake of 18F-FPABZA in melanotic B16F10 cells was relatively higher than that of 18F-FNABZA at 15 min post-incubation. However, both radiotracers did not retain in amelanotic A375 cells. The tumor-to-muscle ratios of 18F-FPABZA-injected B16F10 tumor-bearing mice increased from 7.6 ± 0.4 at 15 min post-injection (p.i.) to 27.5 ± 16.6 at 3 h p.i., while those administered with 18F-FNABZA did not show a similarly dramatic increase throughout the experimental period. The results obtained from biodistribution studies were consistent with those derived from microPET imaging. This study demonstrated that 18F-FPABZA is a promising melanin-targeting positron emission tomography (PET) probe for melanotic melanoma. [ABSTRACT FROM AUTHOR]

Aberrant alteration of epigenetic information disturbs chromatin structure and gene function, thereby facilitating cancer development. Several drugs targeting histone deacetylases (HDACs), a group of epigenetic enzymes, have been approved for treating hematologic malignancies in the clinic. However, patients who suffer from solid tumors often respond poorly to these drugs. In this study, we report a selective entinostat derivative, MPT0L184, with potent cancer-killing activity in both cell-based and mouse xenograft models. A time-course analysis of cell-cycle progression revealed that MPT0L184 treatment elicited an early onset of mitosis but prevented the division of cells with duplicated chromosomes. We show that MPT0L184 possessed potent inhibitory activity toward HDAC1 and 2, and its HDAC-inhibitory activity was required for initiating premature mitotic signaling. HDAC inhibition by MPT0L184 reduced WEE1 expression at the transcription level. In addition, MPT0L184 treatment also downregulated ATR-mediated CHK1 phosphorylation independent of HDAC inhibition. Furthermore, gastric cancer cells resistant to HDAC inhibitors were vulnerable to MPT0L184. Taken together, our study discovers MPT0L184 as a novel HDAC inhibitor that can trigger premature mitosis and potentially counteract drug resistance of cancers. [Display omitted] • MPT0L184 exhibits high toxicity in various cancer cell lines including gastric cancer cells resistant to HDAC inhibitors. • MPT0L184 shows tumor-suppressing activity in a tumor xenograft mouse model. • MPT0L184 possesses strong inhibitory activity toward HDAC1 and 2. • MPT0L184 treatment leads to an early onset of mitosis. • MPT0L184 treatment downregulates WEE1 expression and ATR/CHK1 signaling. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is a leading cause of cancer mortality among women but unfortunately is usually not diagnosed until advanced stage. Early detection of EOC is of paramount importance to improve outcomes. Liquid biopsy of circulating tumor cells (CTCs) is emerging as one of the promising biomarkers for early detection of solid tumors. However, discrepancies in terms of oncogenomics (i.e., different genetic defects detected) between the germline, primary tumor, and liquid biopsy are a serious concern and may adversely affect downstream cancer management. Here, we illustrate the potential and pitfalls of CTCs by presenting two patients of Stage I EOC. We successfully isolated and recovered CTCs by a silicon-based nanostructured microfluidics system, the automated Cell RevealTM. We examined the genomics of CTCs as well as the primary tumor and germline control (peripheral blood mononuclear cells) by whole exome sequencing. Different signatures were then investigated by comparisons of identified mutation loci distinguishing those that may only arise in the primary tumor or CTCs. A novel model is proposed to test if the highly variable allele frequencies, between primary tumor and CTCs results, are due to allele dropout in plural CTCs or tumor heterogeneity. This proof-of-principle study provides a strategy to elucidate the possible cause of genomic discrepancy between the germline, primary tumor, and CTCs, which is helpful for further large-scale use of such technology to be integrated into clinical management protocols. [ABSTRACT FROM AUTHOR]

The study focuses on the prudent design and synthesis of anilide type class I HDAC inhibitors employing a functionalized pyrrolo[2,3- d ]pyrimidine skeleton as the surface recognition part. Utilization of the bicyclic aromatic ring to fabricate the target compounds was envisioned to confer rigidity to the chemical architecture of MS-275 and chidamide. In-vitro enzymatic and cellular assays led to the identification of compound 7 as a potent inhibitor of HDAC1 and 2 isoform that exerted substantial cell growth inhibitory effects against human breast MDA-MB-231, cervical HeLa, breast MDA-MB-468, colorectal DLD1, and colorectal HCT116 cell lines with an IC 50 values of 0.05–0.47 μM, better than MS-275 and chidamide. In addition, the anilide 7 was also endowed with a superior antiproliferative profile than MS275 and chidamide towards the human cutaneous T cell lymphoma (HH and HuT78), leukemia (HL60 and KG-1), and HDACi sensitive/resistant gastric cell lines (YCC11 and YCC3/7). Exhaustive exploration of the construct 7 confirmed it to be a microtubule-targeting agent that could trigger the cell-cycle arrest in mitosis. In pursuit of extracting the benefits of evidenced microtubule-destabilizing activity of the anilide 7 , it was further evaluated against non-small-cell lung cancer cell lines as well as the multiple-drug resistant uterine cancer cell line (MES-SA/Dx5) and overwhelmingly positive results in context of inhibitory effects were attained. Furthermore, molecular modelling studies were performed and some key interactions of the anilide 7 with the amino acid residues of the active site of HDAC1 isoform and tubulin were figured out. [Display omitted] [ABSTRACT FROM AUTHOR]

Analyzes the magnetic characteristics of brushless permanent-magnet (BPM) motors with embedded magnets. Applications of BPM; Information on rare earth permanent magnets; Considerations of magnet design.

Carotid blowout syndrome (CBS) is a rare yet life-threatening complication that occurs after radiation therapy (RT). This study aimed to determine the incidence of CBS in patients with head and neck cancer (HNC) undergoing contemporary RT and to explore potential discrepancies in the risk of CBS between nasopharyngeal cancer (NPC) and non-NPC patients. A total of 1084 patients with HNC who underwent RT between 2013 and 2023 were included in the study. All patients were under regular follow-ups at the radio-oncology department, and underwent annual contrast-enhanced computed tomography and/or magnetic resonance imaging for cancer recurrence surveillance. Experienced neuroradiologists and vascular neurologists reviewed the recruited patients' images. Patients were further referred to the neurology department for radiation vasculopathy evaluation. The primary outcome of this study was CBS. Patients were categorized into NPC and non-NPC groups and survival analysis was employed to compare the CBS risk between the two groups. A review of the literature on CBS incidence was also conducted. Among the enrolled patients, the incidence of CBS in the HNC, NPC, and non-NPC groups was 0.8%, 0.9%, and 0.7%, respectively. Kaplan–Meier analysis revealed no significant difference between the NPC and non-NPC groups (p = 0.34). Combining the findings for our cohort with those of previous studies revealed that the cumulative incidence of CBS in patients with HNC is 5% (95% CI = 3–7%) after both surgery and RT, 4% (95% CI = 2–6%) after surgery alone, and 5% (95% CI = 3–7%) after RT alone. Our findings indicate a low incidence of CBS in patients with HNC undergoing contemporary RT. Patients with NPC may have a CBS risk close to that of non-NPC patients. However, the low incidence of CBS could be a potentially cause of selection bias and underestimation bias. [ABSTRACT FROM AUTHOR]

Neurons in sensory and motor cortices tend to aggregate in clusters with similar functional properties. Within the primate dorsal ("where") pathway, an important interface between three-dimensional (3-D) visual processing and motor-related functions consists of two hierarchically organized areas: V3A and the caudal intraparietal (CIP) area. In these areas, 3-D visual information, choice-related activity, and saccade-related activity converge, often at the single-neuron level. Characterizing the clustering of functional properties in areas with mixed selectivity, such as these, may help reveal organizational principles that support sensorimotor transformations. Here we quantified the clustering of visual feature selectivity, choice-related activity, and saccade-related activity by performing correlational and parametric comparisons of the responses of well-isolated, simultaneously recorded neurons in macaque monkeys. Each functional domain showed statistically significant clustering in both areas. However, there were also domain-specific differences in the strength of clustering across the areas. Visual feature selectivity and saccade-related activity were more strongly clustered in V3A than in CIP. In contrast, choice-related activity was more strongly clustered in CIP than in V3A. These differences in clustering may reflect the areas' roles in sensorimotor processing. Stronger clustering of visual and saccade-related activity in V3A may reflect a greater role in within-domain processing, as opposed to cross-domain synthesis. In contrast, stronger clustering of choice-related activity in CIP may reflect a greater role in synthesizing information across functional domains to bridge perception and action. NEW & NOTEWORTHY: The occipital and parietal cortices of macaque monkeys are bridged by hierarchically organized areas V3A and CIP. These areas support 3-D visual transformations, carry choice-related activity during 3-D perceptual tasks, and possess saccade-related activity. This study quantifies the functional clustering of neuronal response properties within V3A and CIP for each of these domains. The findings reveal domain-specific cross-area differences in clustering that may reflect the areas' roles in sensorimotor processing. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To analyze the Gly2385Arg (G2385R) mutation in Taiwanese Alzheimer''s disease (AD) patients. Background: The leucine-rich repeat kinase 2 (LRRK2) gene is well known to predispose subjects to Parkinson''s disease (PD). The Gly2385Arg (G2385R) variant of LRRK2 is believed to be “East Asian”-specific, particularly in the Han Chinese population; however, whether the LRRK2 G2385R is associated with a risk of AD in pure Han-Chinese patients has not often been studied. Methods: A total of 209 AD patients (87 men, 122 women) and 180 age- and gender-matched controls were recruited and the demographic data of the AD patients were analyzed. Genotyping of the Gly2385Arg variant was studied using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Results: Subjects with the Gly2385Arg variant were all heterozygous carriers. The frequency of Gly2385Arg carriers did not differ significantly between the AD patients and controls (4.78% versus 4.44%, odds ratio=1.04, 95% CI=0.62–1.77, P =0.87). In the AD patient group, the age of symptom onset, the length of education, or the MMSE score showed no significant differences between wild-type carriers and heterozygous variant carriers (P =0.51, 0.43, and 0.09). Conclusion: The Gly2385Arg variant of LRRK2 may not be a major risk factor for AD in pure Han Chinese patient. Among the AD patients, Gly2385Arg carriers were not clinically different from wild-type carriers. [Copyright &y& Elsevier]

This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC 50 = 1.48 μM), MDA-MB-468 (IC 50 = 0.65 μM), and liver cancer cells HepG2 (IC 50 = 2.44 μM), better than MS-275 (5) and Chidamide (6). Compared to the well-known HDAC inhibitor SAHA, 14 showed a higher toxicity (IC 50 = 0.33 μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, 14 was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, respectively, indicating the potential of 14 to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 (5) and Chidamide (6) were displayed by 14 towards HDAC1, 2 and 3 isoforms with IC 50 values of 0.108, 0.585 and 0.563 μM respectively. Compound 14 also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents. Image 1 • A series of benzamides containing purine/purine isoster as capping group has been synthesized. • Compound 14 remarkably suppressed the growth of triple negative breast cancer cell lines. • Benzamide 14 displayed striking inhibitory effects towards HDAC 1, 2 and 3 isoforms. • Benzamide 14 was found to be virulent in YCC3/7 cell line (HDAC resistant gastric cell line). • Benzamide 14 also exerts a dose-dependent upregulation of ac-H3K9 in MDA-MB-231 cells. [ABSTRACT FROM AUTHOR]

Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (FGFR3), collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), diastrophic dysplasia sulfate transporter (DTDST), and SRY-box 9 (SOX9). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G>A(p.G170D) mutation in peptidylprolyl isomerase B (PPIB) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical PPIB mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population. [ABSTRACT FROM AUTHOR]

A series of thiochromeno[2,3- c ]quinolin-12-one derivatives with various substitutions were synthesized and evaluated as topoisomerase (Topo) inhibitors. Six (8 , 10 , 12 , 14 , 19 , and 26) of 23 compounds showed strong inhibitory activities against Topo-mediated DNA relaxation and proliferation of five human cell lines including breast (MDA-MB-231, MDA-MB-468 and MCF7), colorectal (HCT116) and non-small cell lung (H1299) cancers. Among these, compounds 14 and 26 exhibited full inhibitory activities against Topo I at 3 μM and Topo IIα at 1 μM. Cancer cells treated with 26 accumulated DNA damage and were arrested at the G 2 /M phase. With time, cells proceeded to apoptosis, as revealed by increased amounts of cells with fragmented DNA and cleavage of caspase-8 and -9. In contrast, normal breast epithelial cells showed low sensitivity to 26. Taken together, our study identifies 26 as a potent Topo dual-inhibitor with low toxicity to normal cells, and elucidates that the terminal amino group of N -2-aminoethylamino or N -3-aminopropylamino at the 6th position and 8,10-di-halogen substituents on thiochromeno[2,3- c ]quinolin-12-one are critical for the Topo-inhibiting and cancer-killing activities. Image 1 • Six compounds identified as dual Topo inhibitors. • 26 exhibits the highest toxicity in five cancer cell lines but is less toxic in normal breast epithelial cells. • 26 traps Topo I and IIα on chromatin and suppresses their activities. • 26 triggers DNA damage, cell-cycle arrest at the G 2 /M phase, followed by apoptosis. [ABSTRACT FROM AUTHOR]

Introduction: Frailty has an important impact on the health outcomes of older patients, and frailty screening is recommended as part of perioperative evaluation. The Hospital Frailty Risk Score (HFRS) is a validated tool that highlights frailty risk using 109 International Classification of Diseases, 10th revision (ICD-10) codes. In this study, we aim to compare HFRS to the Charlson Comorbidity Index (CCI) and validate HFRS as a predictor of adverse outcomes in Asian patients admitted to surgical services. Method: A retrospective study of electronic health records (EHR) was undertaken in patients aged 65 years and above who were discharged from surgical services between 1 April 2022 to 31 July 2022. Patients were stratified into low (HFRS <5), intermediate (HFRS 5--15) and high (HFRS >15) risk of frailty. Results: Those at high risk of frailty were older and more likely to be men. They were also likely to have more comorbidities and a higher CCI than those at low risk of frailty. High HFRS scores were associated with an increased risk of adverse outcomes, such as mortality, hospital length of stay (LOS) and 30-day readmission. When used in combination with CCI, there was better prediction of mortality at 90 and 270 days, and 30-day readmission. Conclusion: To our knowledge, this is the first validation of HFRS in Singapore in surgical patients and confirms that high-risk HFRS predicts long LOS (≥7days), increased unplanned hospital readmissions (both 30-day and 270-day) and increased mortality (inpatient, 10-day, 30-day, 90-day, 270-day) compared with those at low risk of frailty. [ABSTRACT FROM AUTHOR]

Background: To investigate the frequency of temporal lobe necrosis (TLN) soon after radiotherapy (RT) and identify differences among patients with various types of head and neck cancer (HNC) and between different RT methods. Methods: We retrospectively reviewed 483 patients with HNC who had completed RT in our hospital after January, 2015. These patients were followed-up at the radio-oncology department and received contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) to identify metastases or recurrence of cancer at regular intervals. Meanwhile, the occurrence of TLN, graded according to the Common Terminology Criteria for Adverse Events V5.0, was recorded. We categorized the patients into nasopharyngeal carcinoma (NPC) and non-NPC groups and compared the cumulative occurrence of TLN between the groups using Kaplan–Meier and Cox regression analyses. We further compared the cumulative occurrence of TLN between proton beam therapy (PBT) and volumetric modulated arc therapy (VMAT) in patients with any HNC, NPC, and non-NPC HNC. Results: Compared with the non-NPC group, the NPC group had a higher frequency of TLN (5.6% vs. 0.4%, p < 0.01) and were more commonly associated with TLN in the Kaplan–Meier analysis (p < 0.01) and the Cox regression model after covariates were adjusted for (adjusted hazard ratio: 13.35, 95% confidence interval: 1.37–130.61) during the follow-up period. Furthermore, the frequency of TLN was similar between patients receiving PBT and those receiving VMAT (PBT vs. VMAT: 4.7% vs. 6.3%, p = 0.76). Kaplan–Meier analysis revealed that the accumulated risks of TLN were similar between PBT and VMAT in patients with any HNC (p = 0.44), NPC (p = 0.84), and non-NPC HNC (p = 0.70). Conclusion: Our study demonstrated that patients with NPC are susceptible to TLN during the early period after RT. In addition, PBT may be associated with an equivalent risk of TLN when compared with VMAT in patients with NPC or other HNCs. [ABSTRACT FROM AUTHOR]

Background: To investigate the frequency of temporal lobe necrosis (TLN) soon after radiotherapy (RT) and identify differences among patients with various types of head and neck cancer (HNC) and between different RT methods. Methods: We retrospectively reviewed 483 patients with HNC who had completed RT in our hospital after January, 2015. These patients were followed-up at the radio-oncology department and received contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) to identify metastases or recurrence of cancer at regular intervals. Meanwhile, the occurrence of TLN, graded according to the Common Terminology Criteria for Adverse Events V5.0, was recorded. We categorized the patients into nasopharyngeal carcinoma (NPC) and non-NPC groups and compared the cumulative occurrence of TLN between the groups using Kaplan–Meier and Cox regression analyses. We further compared the cumulative occurrence of TLN between proton beam therapy (PBT) and volumetric modulated arc therapy (VMAT) in patients with any HNC, NPC, and non-NPC HNC. Results: Compared with the non-NPC group, the NPC group had a higher frequency of TLN (5.6% vs. 0.4%, p < 0.01) and were more commonly associated with TLN in the Kaplan–Meier analysis (p < 0.01) and the Cox regression model after covariates were adjusted for (adjusted hazard ratio: 13.35, 95% confidence interval: 1.37–130.61) during the follow-up period. Furthermore, the frequency of TLN was similar between patients receiving PBT and those receiving VMAT (PBT vs. VMAT: 4.7% vs. 6.3%, p = 0.76). Kaplan–Meier analysis revealed that the accumulated risks of TLN were similar between PBT and VMAT in patients with any HNC (p = 0.44), NPC (p = 0.84), and non-NPC HNC (p = 0.70). Conclusion: Our study demonstrated that patients with NPC are susceptible to TLN during the early period after RT. In addition, PBT may be associated with an equivalent risk of TLN when compared with VMAT in patients with NPC or other HNCs. [ABSTRACT FROM AUTHOR]

Developing sensitive diagnostic methods for a longitudinal evaluation of the status of liver fibrosis is a priority. This study is aimed at assessing the significance of longitudinal positron emission tomography (PET) imaging with 18F-labeling tracers for assessing liver fibrosis in a rat model with bile duct ligation (BDL). Twenty-one 6-week-old Sprague-Dawley male rats were used in this study. Longitudinal PET images using [18F]N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) (n = 3), [18F]fluoroacetate ([18F]FAc) (n = 3), and 18F-fluoro-2-deoxy-D-glucose ([18F]FDG) (n = 3) were obtained at 0, 1, and 2 weeks after BDL. Biochemical assays, histological assays, immunohistochemical staining assays, and next generation sequencing analyses were also performed at 0 (n = 3), 1 (n = 3), 2 (n = 3), and 3 (n = 3) weeks after BDL, which demonstrated the severe damage in rat livers after BDL. Regarding [18F]FEPPA and [18F]FDG, there was a significantly higher uptake in the liver after BDL (both P < 0.05), which lasted until week 2. However, the uptake of [18F]FAc in the liver was not significantly different before and after BDL (P = 0.28). Collectively, both [18F]FEPPA and [18F]FDG can serve as sensitive probes for detecting the liver fibrosis. However, [18F]FAc is not recommended to diagnose liver fibrosis. [ABSTRACT FROM AUTHOR]

Cerebral vasoreactivity (CVR) can be assessed by functional MRI (fMRI) using hypercapnia challenges. In normal subjects, studies have shown temporal variability of CVR blood oxygenation level-dependent responses among different brain regions. In the current study, we analyzed the variability of BOLD CVR dynamics by fMRI with a breath-holding task in 17 subjects with unilateral carotid stenosis before they received carotid stenting. Great heterogeneity of CVR dynamics was observed when comparing BOLD responses between ipsilateral and contralateral hemispheres in each patient, especially in middle cerebral artery (MCA) territories. While some subjects (n=12) had similar CVR responses between either hemisphere, the others (n=5) had a poorly correlated pattern of BOLD changes between ipsilateral and contralateral hemispheres. In the latter group, defined as impaired CVR, post-stenting perfusion tended to be more significantly increased. Our data provides the first observation of divergent temporal BOLD responses during breath holding in patients with carotid stenosis. The development of collateral circulation and the derangement of cerebral hemodynamics can be detected through this novel analysis of the different patterns of BOLD changes. The results also help in prediction of robust increase of perfusion or hyperperfusion after carotid stenting. [ABSTRACT FROM AUTHOR]

Early ischemic lesion on non-contrast computed tomogram (NCCT) in acute stroke can be subtle and need confirmation with magnetic resonance (MR) image for treatment decision-making. We retrospectively included the NCCT slices of 129 normal subjects and 546 ischemic stroke patients (onset < 12 h) with corresponding MR slices as reference standard from a prospective registry of Chang Gung Research Databank. In model selection, NCCT slices were preprocessed and fed into five different pre-trained convolutional neural network (CNN) models including Visual Geometry Group 16 (VGG16), Residual Networks 50, Inception-ResNet-v2, Inception-v3, and Inception-v4. In model derivation, the customized-VGG16 model could achieve an accuracy of 0.83, sensitivity 0.85, F-score 0.80, specificity 0.82, and AP 0.82 after using a tenfold cross-validation method, outperforming the pre-trained VGG16 model. In model evaluation, the customized-VGG16 model could correctly identify 53 in 58 subjects (91.37%) including 29 ischemic stroke patients and 24 normal subjects and reached the sensitivity of 86.95% in identifying ischemic NCCT slices (200/230), irrespective of supratentorial or infratentorial lesions. The customized-VGG16 CNN model can successfully identify the presence of early ischemic lesions on NCCT slices using the concept of automatic feature learning. Further study will be proceeded to detect the location of ischemic lesion. [ABSTRACT FROM AUTHOR]

In this work, the relaxation analysis is performed to understand the V TH instability in FeFETs with two different dopants, i.e., Si and Gd. The FeFETs with different dopants show the different delay-after-write characteristics, i.e., Gd:HfO 2 FeFETs show a better delay-after-write stability compared to the case of Si:HfO 2 FeFETs. With the relaxation analysis, Si:HfO 2 FeFETs exhibit an obvious V TH recovery during the relaxation phases. Furthermore, the power law fitting is used to analyze the V TH shift under the positive program bias, indicating that a wide and easily accessible defects can exist in the IL and/or Si:HfO 2 since the smaller overdrive voltage dependence exponent (γ) is obtained in Si:HfO 2. Last, the smaller V TH shift/recovery in Gd:HfO 2 FeFETs can be attributed to a relatively tighter defect distribution, indicating that the dopants in the ferroelectric layer and the defects in IL and/or ferroelectric dielectric have to be carefully optimized to achieve the better V TH stability. • Si:HfO 2 FeFETs exhibit an obvious V TH recovery during the relaxation phases. • The power law fitting is used to analyze the V TH shift, indicating that a wide and easily accessible defects can exist in the IL and/or Si:HfO 2. • The smaller V TH shift/recovery in Gd:HfO 2 FeFETs indicates that the dopants and the defects have to be carefully optimized to achieve the better V TH stability. [ABSTRACT FROM AUTHOR]

Background and purpose: to investigate the frequency of cervical–cranial vascular complications soon after radiation therapy (RT) and identify differences among patients with various types of head and neck cancer (HNC). Methods: We enrolled 496 patients with HNC who had received their final RT dose in our hospital. These patients underwent carotid duplex ultrasound (CDU) for monitoring significant carotid artery stenosis (CAS). Brain imaging were reviewed to detect vertebral, intracranial artery stenosis, or preexisted CAS before RT. Primary outcome was significant CAS at the internal or common carotid artery within first 5 years after RT. We categorized the patients into nasopharyngeal carcinoma (NPC) and non-NPC groups and compared the cumulative occurrence of significant CAS between the groups using Kaplan–Meier and Cox-regression analyses. Results: Compared to the NPC group, the non-NPC group had a higher frequency of significant CAS (12.7% vs. 2.0%) and were more commonly associated with significant CAS after adjusting the covariates (Adjusted hazard ratio: 0.17, 95% confident interval: 0.05–0.57) during the follow-up period. All the non-NPC subtypes (oral cancer/oropharyngeal, hypopharyngeal, and laryngeal cancers) were associated with higher risks of significant CAS than the NPC group (p < 0.001 respectively). Conclusion: Significant CAS was more frequently noted within 5 years of RT among the patients with non-NPC HNC than among the patients with NPC. Scheduled carotid artery surveillance and vascular risk monitoring should be commenced earlier for patients with non-NPC HNC. By contrast, vascular surveillance could be deferred to 5 years after RT completion in NPC patients. [ABSTRACT FROM AUTHOR]

We enrolled 221 patients with elective carotid artery stenting (CAS). Patients with contralateral carotid stenosis exceeding 50%, insufficient vertebral artery (VA) flows, or angioplasty at subclavian artery were excluded. All patients underwent serial cerebral ultrasound studies. Of the 116 included patients, the direction of ophthalmic artery (OA) flow was forward in 74 patients while reversed in 42. The reversed flow group had worse ipsilateral stenosis, higher hemoglobin, and cardiac output. After CAS, the reversed flow group had an immediate recovery of ipsilateral internal carotid artery flow volume (FV; P < .0001), time average velocity (TAV) of middle cerebral artery (P = .02), and normalization of OA flow. The forward flow group had gradual decrement in TAV of contralateral anterior cerebral artery (P = .01) and total FV of VA (P = .001). Our results suggest CAS improves cerebral hemodynamics through different ways regardless of the direction of OA flow. [ABSTRACT FROM AUTHOR]

Objectives: Flow cytometry (FC) is critical for the diagnosis and monitoring of hematologic malignancies. Machine learning (ML) methods rapidly classify multidimensional data and should dramatically improve the efficiency of FC data analysis. We aimed to build a model to classify acute leukemias, including acute promyelocytic leukemia (APL), and distinguish them from nonneoplastic cytopenias. We also sought to illustrate a method to identify key FC parameters that contribute to the model's performance.Methods: Using data from 531 patients who underwent evaluation for cytopenias and/or acute leukemia, we developed an ML model to rapidly distinguish among APL, acute myeloid leukemia/not APL, acute lymphoblastic leukemia, and nonneoplastic cytopenias. Unsupervised learning using gaussian mixture model and Fisher kernel methods were applied to FC listmode data, followed by supervised support vector machine classification.Results: High accuracy (ACC, 94.2%; area under the curve [AUC], 99.5%) was achieved based on the 37-parameter FC panel. Using only 3 parameters, however, yielded similar performance (ACC, 91.7%; AUC, 98.3%) and highlighted the significant contribution of light scatter properties.Conclusions: Our findings underscore the potential for ML to automatically identify and prioritize FC specimens that have critical results, including APL and other acute leukemias. [ABSTRACT FROM AUTHOR]

Highlights: [•] Little is known about how tactile information is integrated across digits. [•] We describe a tactile motion stimulator that can stimulate multiple digits independently. [•] We use the stimulator to probe subjects’ ability to discriminate tactile motion. [•] We replicate previous findings with single digit stimulation. [•] Stimulation of multiple digits reveals biases in the perception of tactile motion. [ABSTRACT FROM AUTHOR]

Developing sensitive diagnostic methods for a longitudinal evaluation of the status of liver fibrosis is a priority. This study is aimed at assessing the significance of longitudinal positron emission tomography (PET) imaging with 18F-labeling tracers for assessing liver fibrosis in a rat model with bile duct ligation (BDL). Twenty-one 6-week-old Sprague-Dawley male rats were used in this study. Longitudinal PET images using [18F]N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA) (n = 3), [18F]fluoroacetate ([18F]FAc) (n = 3), and 18F-fluoro-2-deoxy-D-glucose ([18F]FDG) (n = 3) were obtained at 0, 1, and 2 weeks after BDL. Biochemical assays, histological assays, immunohistochemical staining assays, and next generation sequencing analyses were also performed at 0 (n = 3), 1 (n = 3), 2 (n = 3), and 3 (n = 3) weeks after BDL, which demonstrated the severe damage in rat livers after BDL. Regarding [18F]FEPPA and [18F]FDG, there was a significantly higher uptake in the liver after BDL (both P < 0.05), which lasted until week 2. However, the uptake of [18F]FAc in the liver was not significantly different before and after BDL (P = 0.28). Collectively, both [18F]FEPPA and [18F]FDG can serve as sensitive probes for detecting the liver fibrosis. However, [18F]FAc is not recommended to diagnose liver fibrosis. [ABSTRACT FROM AUTHOR]

Electronegative LDL (LDL(-)) and free fatty acids (FFAs) are circulating risk factors for cardiovascular diseases (CVDs) and have been associated with inflammation. Interleukin-1 beta (IL-1β) represents a key cytokine in the development of CVD; however, the initial trigger of IL-1β in CVD remains to be explored. In this study, we investigated the combined effects of LDL(-) from the plasma of ST-segment elevation myocardial infarction (STEMI) patients or diet-induced hypercholesterolemic rabbits and bovine serum albumin bound palmitic acid (PA-BSA) on IL-1β production in macrophages. Macrophages derived from THP-1 cells or human peripheral blood mononuclear cells were independently treated with LDL(-), PA-BSA or cotreated with LDL(-) and PA-BSA. The results showed that nLDL and/or PA-BSA had no effect on IL-1β, and LDL(-) slightly increased IL-1β; however, cotreatment with LDL(-) and PA-BSA resulted in abundant secretion of IL-1β in macrophages. Rabbit LDL(-) induced the elevation of cellular pro-IL-1β and p-Iκ-Bα, but PA-BSA had no effect on pro-IL-1β or p-Iκ-Bα. In potassium-free buffer, LDL(-)-induced IL-1β reached a level similar to that induced by cotreatment with LDL(-) and PA-BSA. Moreover, LDL(-) and PA-BSA-induced IL-1β was inhibited in lectin-type oxidized LDL receptor-1 (LOX-1) knockdown cells and by blockers of voltage-gated potassium (Kv) channels. LDL(-) from diet-induced hypercholesterolemic rabbit had a similar effect as STEMI LDL(-) on IL-1β in macrophages. These results show that PA-BSA cooperates with LDL(-) to trigger IL-1β production in macrophages via a mechanism involving the LOX-1 and Kv channel pathways, which may play crucial roles in the regulation of inflammation in CVD. [ABSTRACT FROM AUTHOR]

This study aimed to develop a novel magnetic resonance imaging (MRI)-detectable boron (B)-containing nanoassemblies and evaluate their potential for boron neutron capture therapy (BNCT). Starting from the citrate-coated gold nanoparticles (AuNPs) (23.9 ± 10.2 nm), the diameter of poly (D, L-lactide-co-glycolide) AuNPs (PLGA-AuNPs) increased approximately 110 nm after the encapsulation of the PLGA polymer. Among various B drugs, the self-produced B cages had the highest loading efficiency. The average diameter of gadolinium (Gd)- and B-loaded NPs (PLGA-Gd/B-AuNPs) was 160.6 ± 50.6 nm with a B encapsulation efficiency of 28.7 ± 2.3%. In vitro MR images showed that the signal intensity of PLGA-Gd/B-AuNPs in T1-weighted images was proportional to its Gd concentration, and there exists a significantly positive relationship between Gd and B concentrations (R2 = 0.74, p < 0.005). The hyperintensity of either 250 ± 50 mm3 (larger) or 100 ± 50 mm3 (smaller) N87 xenograft was clearly visualized at 1 h after intravenous injection of PLGA-Gd/B-AuNPs. However, PLGA-Gd/B-AuNPs stayed at the periphery of the larger xenograft while located near the center of the smaller one. The tumor-to-muscle ratios of B content, determined by inductively coupled plasma mass spectrometry, in smaller- and larger-sized tumors were 4.17 ± 1.42 and 1.99 ± 0.55, respectively. In summary, we successfully developed theranostic B- and Gd-containing AuNPs for BNCT in this study. [ABSTRACT FROM AUTHOR]