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Thymosin beta 10 (TMSB10) overexpression is a general characteristic in human carcinogenesis. It is involved in the malignant process of generating multiple cancers. However, there are only a few reports about TMSB10 in colorectal cancer (CRC) and the mechanism of its carcinogenetic effect is still poorly understood. The present study intends to clarify the biological roles and carcinogenic mechanism of TMSB10 in CRC and to explore the possibility whether TMSB10 might be useful as a non-invasive serum tumor biomarker in detecting CRC. Immunohistochemical results showed that TMSB10 protein expression in CRC tissues was generally higher than that in adjacent tissues, and the TMSB10 contents in serum of CRC patients was significantly elevated compared to that of healthy controls. Knockdown-TMSB10 increased apoptosis and induced S-cell cycle arrest, and finally inhibited cell proliferation in vitro and in vivo. Transcriptome sequencing and western blotting analysis revealed that knockdown-TMSB10 increased phosphorylation of p38 and activated the p38 pathway that blocked cell cycle and promoted apoptosis. Taken together, our study indicated that TMSB10 could serve as a minimally invasive serum tumor marker in detecting CRC. At the same time it demonstrates an effective regulatory capacity of TMSB10 on cell proliferation of CRC, suggesting that TMSB10 and downstream effector molecules regulated by TMSB10 could further be applied as an appealing target in clinical post-surgery chemotherapy., Competing Interests: Declaration of competing interest All authors have participated in the research and/or article preparation and agree with submission of this manuscript to Translational Oncology. The material has not been published previously, and will not be submitted for publication elsewhere. None of the authors have potential conflicts of interest with regard to this manuscript to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Senecavirus A (SVA), a picornavirus, causes vesicular diseases and epidemic transient neonatal losses in swine, resulting in a multifaceted economic impact on the swine industry. SVA counteracts host antiviral response through multiple strategies facilitatng viral infection and transmission. However, the mechanism of how SVA modulates interferon (IFN) response remains elusive. Here, we demonstrate that SVA 3C protease (3C pro ) blocks the transduction of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway to antagonize type I IFN response. Mechanistically, 3C pro selectively cleaves and degrades STAT1 and STAT2 while does not target JAK1, JAK2, and IRF9, through its protease activity. Notably, SVA 3C pro cleaves human and porcine STAT1 on a Leucine (L)-Aspartic acid (D) motif, specifically L693/D694. In the case of STAT2, two cleavage sites were identified: glutamine (Q) 707 was identified in both human and porcine, while the second cleavage pattern differed, with residues 754-757 (Valine-Leucine-Glutamine-Serine motifs) in human STAT2 and Q758 in porcine STAT2. These cleavage patterns by SVA 3C pro partially differ from previously reported classical motifs recognized by other picornaviral 3C pro , highlighting the distinct characteristics of SVA 3C pro . Together, these results reveal a mechanism by which SVA 3C pro antagonizes IFN-induced antiviral response but also expands our knowledge about the substrate recognition patterns for picornaviral 3C pro .IMPORTANCESenecavirus A (SVA), the only member in the Senecavirus genus within the Picornaviridae family, causes vesicular diseases in pigs that are clinically indistinguishable from foot-and-mouth disease (FMD), a highly contagious viral disease listed by the World Organization for Animal Health (WOAH). Interferon (IFN)-mediated antiviral response plays a pivotal role in restricting and controlling viral infection. Picornaviruses evolved numerous strategies to antagonize host antiviral response. However, how SVA modulates the JAK-STAT signaling pathway, influencing the type I IFN response, remains elusive. Here, we identify that 3C pro , a protease of SVA, functions as an antagonist for the IFN response. 3C pro utilizes its protease activity to cleave STAT1 and STAT2, thereby diminishing the host IFN response to promote SVA infection. Our findings underscore the significance of 3C pro as a key virulence factor in the antagonism of the type I signaling pathway during SVA infection., Competing Interests: The authors declare no conflict of interest.

Purpose: mRNA vaccines represent a promising and innovative strategy within the realm of cancer immunotherapy. However, their efficacy in treating lower-grade glioma (LGG) requires evaluation. Ferroptosis exhibits close associations with the initiation, evolution, and suppression of cancer. In this study, we explored the landscape of the ferroptosis-associated tumor microenvironment to facilitate the development of mRNA vaccines for LGG patients., Patients and Methods: Genomic and clinical data of the LGG patients was obtained from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Ferroptosis-related tumor antigens were identified based on differential expression, mutation status, correlation with antigen-presenting cells, and prognosis, relevance to immunogenic cell death (ICD). Antigen expression levels in LGG specimens and cell lines were validated using real time-polymerase chain reaction (RT-PCR). Consensus clustering was employed for patient classification. The immune landscapes of ferroptosis subtypes were further characterized, including immune responses, prognostic ability, tumor microenvironment, and tumor-related signatures., Results: Five tumor antigens, namely, HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified in LGG. RT-PCR demonstrated higher expression of these genes in LGG compared to the control. Twelve gene modules and four ferroptosis subtypes (FS1-FS4) of LGG were defined. FS2 and FS4, characterized as "cold" tumors due to their decreased tumor mutation burden (TMB) and immune checkpoint proteins (ICPs), were deemed appropriate candidates for the mRNA vaccine., Conclusion: HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified as promising candidate antigens for the development of an LGG mRNA vaccine, particularly offering potential benefits to FS2 and FS4 patients., Competing Interests: The authors declare that they have no competing interests in this work., (© 2024 Zhao et al.)

African swine fever, one of the major viral diseases of swine, poses an imminent threat to the global pig industry. The high-efficient replication of the causative agent African swine fever virus (ASFV) in various organs in pigs greatly contributes to the disease. However, how ASFV manipulates the cell population to drive high-efficient replication of the virus in vivo remains unclear. Here, we found that the spleen reveals the most severe pathological manifestation with the highest viral loads among various organs in pigs during ASFV infection. By using single-cell-RNA-sequencing technology and multiple methods, we determined that macrophages and monocytes are the major cell types infected by ASFV in the spleen, showing high viral-load heterogeneity. A rare subpopulation of immature monocytes represents the major population infected at late infection stage. ASFV causes massive death of macrophages, but shifts its infection into these monocytes which significantly arise after the infection. The apoptosis, interferon response, and antigen-presentation capacity are inhibited in these monocytes which benefits prolonged infection of ASFV in vivo. Until now, the role of immature monocytes as an important target by ASFV has been overlooked due to that they do not express classical monocyte marker CD14. The present study indicates that the shift of viral infection from macrophages to the immature monocytes is critical for maintaining prolonged ASFV infection in vivo. This study sheds light on ASFV tropism, replication, and infection dynamics, and elicited immune response, which may instruct future research on antiviral strategies., Competing Interests: Competing interests statement:The authors declare no competing interest.

Nitric oxide (NO) generated within the tumor microenvironment is an established driver of cancer progression and metastasis. Recent efforts have focused on leveraging this feature to target cancer through the development of diagnostic imaging agents and activatable chemotherapeutics. In this context, porphyrins represent an extraordinarily promising class of molecules, owing to their demonstrated use within both modalities. However, the remodeling of a standard porphyrin to afford a responsive chemical that can distinguish elevated NO from physiological levels has remained a significant research challenge. In this study, we employed a photoinduced electron transfer strategy to develop a panel of NO-activatable porphyrin photosensitizers (NOxPorfins) augmented with real-time fluorescence monitoring capabilities. The lead compound, NOxPorfin-1, features an o -phenylenediamine trigger that can effectively capture NO (via N 2 O 3 ) to yield a triazole product that exhibits a 7.5-fold enhancement and a 70-fold turn-on response in the singlet oxygen quantum yield and fluorescence signal, respectively. Beyond demonstrating excellent in vitro responsiveness and selectivity toward NO, we showcase the potent photodynamic therapy (PDT) effect of NOxPorfin-1 in murine breast cancer and human non-small cellular lung cancer cells. Further, to highlight the in vivo efficacy, two key studies were executed. First, we utilized NOxPorfin-1 to ablate murine breast tumors in a site-selective manner without causing substantial collateral damage to healthy tissue. Second, we established a nascent human lung cancer model to demonstrate the unprecedented ability of NOxPorfin-1 to halt tumor growth and progression completely. The results of the latter study have tremendous implications for applying PDT to target metastatic lesions.

Background: Management guidelines for obesity suggest maintaining a minimum of 5% body weight reduction to help prevent or lower the risk of developing conditions such as hypertension and type 2 diabetes. However, achieving long-term weight control is difficult with lifestyle modification alone, making it essential to combine pharmacotherapy with diet and exercise in individual cases. Semaglutide 2.4 mg has demonstrated significant reductions in body weight and cardiometabolic risk factors in clinical trials, but information on outcomes in a real-world setting is limited., Objective: To assess changes in body weight and other clinical outcomes at 6-month follow-up among adults on semaglutide 2.4 mg in a real-world setting in the United States (US)., Methods: Observational and retrospective cohort study of patients initiating treatment between 15 June 2021, and 31 March 2022, using a large US claims-linked electronic health record database., Results: Mean (±SD) body mass index (BMI) of the 343 patients included in the analysis was 37.9 ± 5.5 kg/m 2 . After 6 months, mean body weight change was -10.5 ± 6.8 kg (95% CI: -11.2; -9.8, p  < 0.001) and mean percentage body weight change was -10.0% ± 6.6% (95% CI: -10.7; -9.3, p  < 0.001). Most (79.0%) patients had ≥5% body weight reduction, 48.1% had ≥10% body weight reduction, and 19.0% had ≥15% body weight reduction. Among patients with available data, the mean change in HbA1c ( n  = 30) was -0.6% ± 1.2% (95% CI: -1.0; -0.1, p  = 0.016) and nearly two-thirds of patients with prediabetes or diabetes at baseline reverted to normoglycemia. Mean reductions of -4.4 ± 12.3 mmHg (95% CI: -5.7; -3.0, p  < 0.001) and -1.7 ± 8.4 mmHg (95% CI: -2.6; -0.7, p  < 0.001) were observed in systolic and diastolic blood pressure, respectively ( n  = 307). Statistically significant reductions in mean total cholesterol (-12.2 ± 38.8 mg/dl [95% CI: -24.3 to -0.06, p  < 0.049]) and triglycerides (-18.3 ± 43.6 mg/dl [95% CI: -4.7; -31.9, p  < 0.009]) were also observed ( n  = 42)., Conclusions: This study demonstrated the effectiveness of semaglutide 2.4 mg in reducing body weight and improving cardiometabolic parameters in adults with overweight or obesity in a real-world clinical practice setting, showing a significant mean body weight reduction and improvements in biomarkers like blood pressure and HbA1c over a 6-month period. These findings, aligning with previous clinical trials at comparable time points, highlight the clinical relevance of semaglutide as an effective therapeutic option for obesity., Competing Interests: AR, WM, ZZ, AF, and BO are employees of Novo Nordisk Inc. and are shareholders of Novo Nordisk A/S. DU has served as a consultant for Novo Nordisk Inc., (© 2024 Novo Nordisk Inc. and The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: Brain metastasis (BM) is a clinically relevant cause of death in patients with breast cancer (BRCA). This study was designed to develop a clinical model capable of predicting BRCA patients' prognostic outcomes according to the expression of BM-related genes (BMRGs)., Methods: The public Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases served as data sources. BMRGs of BRCA were selected from previous literature. Differences among BRCA molecular subtypes were compared using R 'limma' package. The impact of BM-related differentially expressed genes (BM&#95;DEGs) on BRCA patients' outcomes was explored with a risk score model, after which the relationship between these risk scores and immune cell infiltration was examined. Risk scores were also used to judge the predicted efficacy of immunotherapeutic interventions. The utility of risk scores in combination with clinicopathological characteristics was evaluated as a predictor of patient's survival through univariate and multivariate analyses., Results: The R limma package was used to explore differential gene expression, after which 12 BM&#95;DEGs were incorporated into a risk scoring model. The resultant risk scores were able to predict immunotherapeutic treatment efficacy. In addition, a nomogram incorporating risk scores, stage, and age was established. The nomogram was able to reliably predict the overall survival (OS) of BRCA patients, yielding predictive outcomes that aligned well with actual observations., Conclusions: In summary, a predictive clinical model for BRCA patients was successfully established in this study, providing a valuable tool that may be particularly helpful for the assessment of patients facing a risk of BM development., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1123/coif). The authors have no conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

Background: Thymidylate synthase (TYMS) is involved in the malignant process of multiple cancers, and has gained much attention as a cancer treatment target. However, the mechanism in carcinogenesis of esophageal squamous cell cancer (ESCC) is little reported. The present study was to clear the biological roles and carcinogenic mechanism of TYMS in ESCC, and explored the possibility to use TYMS as a tumor marker in diagnosis and a drug target for the treatment of ESCC., Methods: Stably TYMS-overexpression cells established by lentivirus transduction were used for the analysis of cell proliferation. RNA sequencing was performed to explore the possible carcinogenic mechanisms., Results: GEPIA databases analysis showed that TYMS expression in esophageal cancer tissues was higher than that in normal tissues. The MTT assay, colony formation assay, and nude mouse subcutaneous tumor model found that the overexpression of TYMS increased cell proliferation. Transcriptome sequencing analysis revealed that the promoted cell proliferation in TYMS-overexpression ESCC cells were mediated through activating genes expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2 dependent antioxidant enzymes to relieve oxidative stress, which was confirmed by increased glutathione (GSH), glutathione peroxidase (GPX) activities, and reduced reactive oxygen species. Nrf2 active inhibitors (ML385) used in TYMS-overexpression cells inhibited the expression of Nrf2-dependent antioxidant enzyme genes, thereby increasing oxidative stress and blocking cell proliferation., Conclusion: Our study indicated a novel and effective regulatory capacity of TYMS in the cell proliferation of ESCC by relieving oxidative stress through activating expression of Nrf2 and Nrf2-dependent antioxidant enzymes genes. These properties make TYMS and Nrf2 as appealing targets for ESCC clinical chemotherapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To study the difference of clinical characteristics and prognostic factors from elderly patients with renal cell carcinoma (RCC), the statistical analysis was carried out based on the surveillance, epidemiology, and end results database. The relevant clinical information of 19,472 RCC patients from 2010 to 2015 were collected, and the differences of clinicopathological characteristics and survival rate was analyzed by log-rank method and Chi square test, respectively. Multivariate Cox regression model was used to explore the independent risk factors affecting the long-term survival of RCC patients. Results showed that the proportion of elderly RCC patients in the 60-64-year group in 2010 was 15.20%, but the value elevated to 18.51% in 2015, and the Chi-square test revealed the significant correlation between elderly RCC patients with gender, race, American Joint Committee on cancer stage, T stage, N stage, and M stage. The difference of survival time between the 60-69 year, 70-79 year, 80-84 year, and 85+ year group was significant, and Kaplan-Meier analysis showed a negative effects of age on survival rate of RCC patients, indicating a worsening trend with increasing age. Cox proportional hazards model analysis further confirmed that age was the important independent prognostic factor. Our study reveals that the onset age of RCC in elderly population is gradually decreasing, and the malignant degree of elderly RCC patients is increasing with age. The female elderly population could be more susceptible to RCC than male elderly population, and 85+ year population could also be cancer susceptible with a higher lymph node metastasis rate, later tumor stage, and poor prognosis, suggesting that these elderly populations should pay more attention to the RCC screening., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The pattern recognition receptors (PRRs) sense exogenous molecular patterns most commonly derived from invading pathogens, to active the interferon (IFN) signalling. In the cytoplasm, the viral double-stranded RNAs (dsRNAs) are sensed by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5), depending on the length and chemical properties. Through the binding and oligomerizing onto the RNAs, they form filament to initiate the signalling cascade. Regulation of these receptors' activities are essential for manipulating the strength of IFN signalling. Here, through the virtual screening of chemical reagents using the published MDA5-dsRNA complex structure (PDB: 4GL2), we identified an antibiotic, gramicidin A as a stimulator that enhanced MDA5-mediated IFN signalling. Cytotoxic assay and IFN signalling assay suggested that disruption of lipid membrane, which is a well-defined mechanism of gramicidin A to perform its action, was dispensable in this process. Sucrose gradient ultracentrifugation assay showed that the gramicidin A treatment enhanced MDA5 oligomerization status in the presence of dsRNA. Our work implicated a new role of gramicidin A in innate immunity and presented a new tool to manipulate MDA5 activity., (© 2023 John Wiley & Sons Ltd.)

Well-dispersed PdIn bimetallic alloy nanoparticles (1-4 nm) were immobilized on mesostructured silica by an in situ capture-alloying strategy, and PdIn-In 2 O 3 interfaces were rationally constructed by changing the In 2 O 3 loading and reduction temperature. The catalytic performance for benzyl alcohol partial oxidation was evaluated, and a catalytic synergy was observed. The Pd-rich PdIn-In 2 O 3 interface is prone to be formed on the catalyst with a low In 2 O 3 loading after being reduced at 300 °C. It was demonstrated that the Pd-rich PdIn-In 2 O 3 interface was more active for benzyl alcohol partial oxidation than In-rich Pd 2 In 3 species, which was likely to be formed at a high reduction temperature (400 °C). The high catalytic activity on the Pd-rich PdIn-In 2 O 3 interface was attributed to the exposure of more Pd-enriched active sites, and an optimized PdIn-In 2 O 3 /Pd assemble ratio enhanced the oxygen transfer during partial oxidation. The density functional theory (DFT) calculation confirmed that the Pd-rich Pd 3 In 1 (111)-In 2 O 3 interface facilitated the activation of oxygen molecules, resulting in high catalytic activity.

DELLA gene family plays a key role in regulating plant development and responding to stress. Currently, many DELLA family members have been identified in plants, however, information on DELLA genes in pumpkin ( Cucurbita moschata ) is scarce. In this study, physical and chemical properties, gene structure cis -regulatory elements and expression of CmoDELLA genes were examined in pumpkin. We found that seven CmoDELLA genes were identified in pumpkin, and they were unevenly classified into five chromosomes. CmoDELLA proteins were relatively unstable and their secondary structures were mainly made up α-helix and random coil. All seven CmoDELLA proteins contained typical DELLA domain and GRAS domain, however, motif numbers between CmoDELLA proteins were unevenly distributed, implying the complex evolution and functional diversification of CmoDELLA proteins. Cis -regulatory elements analysis revealed that CmoDELLA genes might play an essential role in regulating plant growth and development, and response to stress in pumpkin. Transcriptome data in the roots, stems, leaves and fruits demonstrated that CmoDELLA2 , CmoDELLA3 and CmoDELLA7 were related to the stems development, CmoDELLA1 , CmoDELLA4 , CmoDELLA5 and CmoDELLA6 were associated with the fruits development. Furthermore, we found that CmoDELLA1 and CmoDELLA5 were up-regulated under NaCl stress. CmoDELLA1 , CmoDELLA2 , CmoDELLA3 , CmoDELLA5 , CmoDELLA6 and CmoDELLA7 were remarkably induced under waterlogging stress. While, all of the 7 CmoDELLA genes showed significantly induced expression under cold stress. The expression patterns under abiotic stress suggested that CmoDELLA genes might mediate the stress response of pumpkin to NaCl, waterlogging and cold, however, the functions of different CmoDELLA genes varied under different stress. Overall, our study provides valuable information for further research about the potential functions and regulatory networks of CmoDELLA genes in pumpkin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luo, Zhao, Chen, Ao, Lu, Liu, Li and Sun.)

Activity-based sensing (ABS) probes equipped with a NIR bioluminescence readout are promising chemical tools to study cancer biomarkers owing to their high sensitivity and deep tissue compatibility. Despite the demand, there is a dearth of such probes because NIR substrates (e.g., BL660 (a NIR luciferin analog)) are not equipped with an appropriate attachment site for ABS trigger installation. For instance, our attempts to mask the carboxylic acid moiety with standard self-immolative benzyl linkers resulted in significant background signals owing to undesirable ester hydrolysis. In this study, we overcame this longstanding challenge by rationally designing a new hydrolysis-resistant ester-based linker featuring an isopropyl shielding arm. Compared to the parent, the new design is 140.5-fold and 67.8-fold more resistant toward spontaneous and esterase-mediated hydrolysis, respectively. Likewise, we observed minimal cleavage of the ester moiety when incubated with a panel of enzymes possessing ester-hydrolyzing activity. These impressive in vitro results were corroborated through a series of key experiments in live cells. Further, we showcased the utility of this technology by developing the first NIR bioluminescent probe for nitroreductase (NTR) activity and applied it to visualize elevated NTR expression in oxygen deficient lung cancer cells and in a murine model of non-small cell lung cancer. The ability to monitor the activity of this key biomarker in a deep tissue context is critical because it is associated with tumor hypoxia, which in turn is linked to drug resistance and aggressive cancer phenotypes.

Obesity is a chronic health condition characterized by the accumulation of excessive body fat which can lead to and exacerbate cardiovascular disease, type-II diabetes, high blood pressure, and cancer through systemic inflammation. Unfortunately, visualizing key mediators of the inflammatory response, such as monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), in a selective manner is a profound challenge owing to an overlapping substrate scope that involves arachidonic acid (AA). Specifically, these enzymes work in concert to generate AA, which in the context of obesity, has been implicated to control appetite and energy metabolism. In this study, we developed the first selective activity-based sensing probes to detect MGL (PA-HD-MGL) and FAAH (PA-HD-FAAH) activity via photoacoustic imaging. Activation of PA-HD-MGL and PA-HD-FAAH by their target enzymes resulted in 1.74-fold and 1.59-fold signal enhancements, respectively. Due to their exceptional selectivity profiles and deep-tissue photoacoustic imaging capabilities, these probes were employed to measure MGL and FAAH activity in a murine model of obesity. Contrary to conflicting reports suggesting levels of MGL can be attenuated or elevated, our results support the latter. Indeed, we discovered a marked increase of both targets in the gastrointestinal tract. These key findings set the stage to uncover the role of the endocannabinoid pathway in obesity-mediated inflammation., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Arylsulfatase A (ARSA), a lysosomal enzyme, has been shown to inhibit the aggregation and propagation of α-synuclein (α-syn) through its molecular chaperone function. The relationship between ARSA levels and Parkinson's disease (PD) in the Chinese Han population remains controversial, and few quantitative research studies have investigated the relationship between plasma ARSA levels and PD., Objectives: The purpose of this study was to investigate the relationships between ARSA levels and cognitive function in PD patients and to evaluate the association of ARSA and α-syn levels with nonmotor symptoms., Methods: Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma ARSA and α-syn levels in 50 healthy controls, 120 PD patients (61 PD patients with no cognitive impairment (PD-NCI) and 59 PD patients with cognitive impairment (PD-CI)). Motor symptoms and nonmotor symptoms (cognitive function, Unified Parkinson's Disease Rating Scale (UPDRS) score, depression, anxiety, constipation, olfactory dysfunction, sleep disruption, and other symptoms) were assessed with the relevant scales. The Kruskal-Wallis H test was used for comparison between groups, and Pearson/Spearman analysis was used for correlation analysis., Results: The plasma ARSA concentrations were lower in the PD-CI group than in the PD-NCI group. The plasma α-syn levels in the PD-CI group were higher than those in the healthy control group, and the plasma ARSA levels were correlated with the Mini-Mental State Examination (MMSE scores) and Hoehn and Yahr (H-Y) stage., Conclusion: We used a quantitative assessment method to show that low plasma ARSA levels and high α-syn levels are related to cognitive impairment in PD patients. Plasma ARSA levels gradually decrease with PD progression., (© 2022. The Author(s).)

Objectives: To explore the associations among activation, physical activity, hemoglobin A1c (HbA1c), and healthy days in older adults with type 2 diabetes (T2D) who participated in wellness programs., Study Design: Observational, longitudinal cohort study utilizing survey, claims, and wellness program data., Methods: From January to May 2018, individuals enrolled in a commercial or Medicare Advantage and prescription drug plan with T2D (aged 55-89 years) and SilverSneakers or step count data were eligible. Three waves of surveys were mailed (n = 5000) to collect information on activation (Consumer Health Activation Index; Influence, Motivation, and Patient Activation for Diabetes) and health-related quality of life (Healthy Days). Generalized linear models and predictive models evaluated the associations of unhealthy days and HbA1c with physical activity and activation factors. Additional models tested the relationship between physical activity and future acute care visits, accounting for potential confounders via inverse probability of treatment weighting., Results: Respondents to all 3 waves (n = 1147) had higher comorbidity indices but lower HbA1c than individuals with T2D without physical activity data (P < .0001). Individuals with moderate and high activation levels had 67.4% to 74.0% and 71.6% to 85.6% fewer unhealthy days, respectively, than those with lower activation (P < .01). Individuals with high (> 8000/day) step counts at baseline were predicted to have 2.04 fewer unhealthy days/month at follow-up (P < .05) and 0.19% (P < .02) lower HbA1c units, respectively, compared with those with less than 4000 steps per day. High SilverSneakers activity (> 2 activities per week) reduced subsequent acute care visits by 49%., Conclusions: Increasing patient activation levels encourages physical activity, which can help improve glycemic control and health-related quality of life, especially among older adults.

Photoacoustic (PA) imaging has emerged as a powerful technique for the high resolution visualization of biological processes within deep tissue. Through the development and application of exogenous targeted contrast agents and activatable probes that can respond to a given cancer biomarker, researchers can image molecular events in vivo during cancer progression. This information can provide valuable details that can facilitate cancer diagnosis and therapy monitoring. In this tutorial review, we provide a step-by-step guide to select a cancer biomarker and subsequent approaches to design imaging agents for in vivo use. We envision this information will be a useful summary to those in the field, new members to the community, and graduate students taking advanced imaging coursework. We also highlight notable examples from the recent literature, with emphasis on the molecular designs and their in vivo PA imaging performance. To conclude, we provide our outlook and future perspective in this exciting field.

miR160 plays a crucial role in various biological processes by regulating their target gene auxin response factor (ARF) in plants. However, little is known about miR160 and ARF in cucumber fruit expansion. Here, 4 Csa-MIR160 family members and 17 CsARFs were identified through a genome-wide search. Csa-miR160 showed a closer relationship with those in melon. Phylogenetic analysis revealed that CsARFs were divided into four classes and most of CsARFs presented a closer evolutionary relationship with those from tomato. Putative cis-elements analysis predicted that Csa-MIR160 and CsARFs were involved in light, phytohormone and stress response, which proved that they might take part in light, phytohormone and stress signaling pathway by the miR160-ARF module. In addition, CsARF5, CsARF11, CsARF13 and CsARF14 were predicted as the target genes of Csa-miR160. qRT-PCR revealed that Csa-miR160 and their target gene CsARFs were differentially expressed in differential cucumber tissues and developmental stages. Csa-miR160d was only expressed in the expanded cucumber fruit. CsARF5, CsARF11 and CsARF13 exhibited the lower expression in the expanded fruit than those in the ovary, while, CsARF14 showed the reverse trend. Our results suggested that Csa-miR160d might play a crucial role in cucumber fruit expansion by negatively targeting CsARF5, CsARF11 and CsARF13. This is the first genome-wide analysis of miR160 in cucumber. These findings provide useful information and resources for further studying the role of miR160 and ARF in cucumber fruit expansion., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: While Ureaplasma parvum has previously been linked to the incidence of chorioamnionitis, abortion, premature birth, and perinatal complications, there have only been rare reports of invasive infections of the central nervous system (CNS) in adults. Owing to its atypical presentation and the fact that it will yield sterile cultures using conventional techniques, diagnosing U. parvum meningitis can be challenging., Case Presentation: We describe a case of U. parvum meningitis detected in an adult patient following surgical brain tumor ablation. After operation, the patient experienced epilepsy, meningeal irritation, and fever with unconsciousness. Cerebrospinal fluid (CSF) analysis showed leukocytosis (484 * 10 6 /L), elevated protein levels (1.92 g/L), and decreased glucose concentrations (0.02 mmol/L). Evidence suggested that the patient was suffering from bacterial meningitis. However, no bacterial pathogens in either CSF or blood were detected by routine culture or serology. The symptoms did not improve with empirical antibiotics. Therefore, we performed metagenomic next-generation sequencing (mNGS) to identify the etiology of the meningitis. Ureaplasma parvum was detected by mNGS in CSF samples. To the best of our knowledge, this case is the first reported instance of U. parvum meningitis in an adult patient in Asian. After diagnosis, the patient underwent successful moxifloxacin treatment and recovered without complications., Conclusions: As mNGS strategies can enable the simultaneous detection of a diverse array of microbes in a single analysis, they may represent a valuable means of diagnosing the pathogens responsible for CNS infections and other clinical conditions with atypical presentations., (© 2021. The Author(s).)

Objective: Pituitary adenylate-cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuropeptides that exhibit anti-inflammatory and neuroprotective properties, modulating the production of cytokines and chemokines, and the behavior of immune cells. However, the relationship between PACAP and VIP levels and Parkinson's disease (PD) are not clear. The aim of the current study was to evaluate serum PACAP and VIP levels in PD patients and to analysis the correlation between neuropeptide levels and non-motor symptoms. Methods: In this cross-sectional study, we enrolled 72 patients with idiopathic PD and 71 healthy volunteers. Serum PACAP and VIP levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Non-motor symptoms were assessed with the Non-Motor Symptoms Scale (NMSS) for PD, including total and single-item scores. Results: The serum PACAP levels of PD patients were significantly lower than those of healthy controls [(76.02 ± 43.78) pg/ml vs. (154.96 ± 76.54) pg/ml, P < 0.001]; and the serum VIP levels of PD patients were also significantly lower than those of healthy controls [(109.56 ± 15.39) pg/ml vs. (136.46 ± 24.16) pg/ml, P < 0.001]. PACAP levels were inversely correlated only with the score on NMSS item five, assessing Attention/memory ( r = -0.276, P < 0.05) and lower serum PACAP levels were detected in the cognitive dysfunction subgroup than in the cognitively intact subgroup [(61.87 ± 32.66) pg/ml vs. (84.51 ± 47.59) pg/ml, P < 0.05]; meanwhile, VIP levels were inversely correlated with the NMSS total score ( r = -0.285, P < 0.05) and the single-item scores for item one, assessing Cardiovascular ( r = -0.257, P < 0.05) and item three, assessing Mood/cognition ( r = -0.373, P < 0.05), and lower serum VIP levels were detected in the anxiety subgroup and depression subgroup than in the non-anxiety subgroup and non-depression subgroup, respectively [(107.45 ± 15.40) pg/ml vs. (116.41 ± 13.67) pg/ml, P < 0.05]; [(104.45 ± 15.26) pg/ml vs. (113.43 ± 14.52) pg/ml, P < 0.05]. Conclusion: The serum PACAP and VIP levels of PD patients were significantly lower than those of healthy controls. The non-motor symptoms significantly negatively correlated with serum PACAP level was cognitive dysfunction, while mood disorder was significantly correlated with serum VIP level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hu, Huang, Ma, Li, Zhao, Zheng, Li, Wang, Sun and Shi.)

Increasing the concentration of oxygen deficiency in perovskite oxides by suitable cation doping or anion doping can significantly increase the cathode ionic conductivity, thus improving the oxygen reduction reaction activity in solid oxide fuel cells (SOFCs). Herein, pre-calcining the perovskite oxide precursor in N 2 atmosphere is a new strategy to further improve the oxygen non-stoichiometry ( δ ) and electrocatalytic activity of the cathode. The obtained nitrogen-treated Sm 0.5 Sr 0.5 CoO 3- δ (SSC) powder has higher oxygen non-stoichiometry than the untreated one. The δ value is 0.27 for SSC-400 at 800 °C in air. The obtained nitrogen-treated SSC-400 cathodes calcined at 1000 °C show improved electrochemical performance compared to SSC-air, achieving the polarization resistance ( R p ) values to be 0.035, 0.078 and 0.214 Ω cm 2 at 700 °C, 650 °C and 600 °C. The maximum power density of the cell with the SSC-600 cathode reaches 0.87, 1.16 and 1.24 W cm -2 at 600, 650 and 700 °C, which are more excellent than SSC-air. Pre-calcining the perovskite oxide precursor in N 2 at a suitable temperature can remarkably improve the electrochemical capability of the cathode and provide a convenient and useful strategy to alleviate the problem of oxygen deficiency in perovskite oxides., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic porcine enteropathogenic coronavirus causing severe enteritis and lethal watery diarrhea in piglets. PEDV infection suppresses the synthesis of type I IFN, and multiple viral proteins of PEDV have been shown to target the adaptors of innate immune pathways to inhibit type I IFN production. In this study, we identified PEDV membrane (M) protein as a new antagonist of type I IFN production in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells and determined the antagonistic mechanism used by M protein to target IFN regulatory factor 7 (IRF7), an important regulator of type I IFN production. IRF7 is phosphorylated and activated by TBK1 and IKKε in response to viral infection. We found that PEDV M protein interacted with the inhibitory domain of IRF7 and significantly suppressed TBK1/IKKε-induced IRF7 phosphorylation and dimerization of IRF7, leading to the decreased expression of type I IFN, although it did not affect the interaction between TBK1/IKKε and IRF7. As expected, overexpression of M protein significantly increased PEDV replication in porcine cells. The M proteins of both epidemic PEDV strains and vaccine strain showed similar antagonistic effect on type I IFN production, and the 1-55 region of M protein was essential for disruption of IRF7 function by interacting with IRF7. Taken together, our data identified a new, to our knowledge, IFN antagonist of PEDV, as well as a novel, to our knowledge, antagonistic mechanism evolved by PEDV to inhibit type I IFN production., (Copyright © 2021 by The American Association of Immunologists, Inc.)

A photoredox-mediated δ-C(sp 3 )-H fluorination of sulfonyl-protected primary alkylamines with Selectfluor is developed. The reaction can proceed in excellent monofluorination selectivity for amine substrates without α substituent. For α-substituted substrates, a slightly modified reaction conditions with two rounds of operation gives the δ,δ-difluorination products in good yield. Mechanistic studies suggest SET oxidation of sulfonamide group directly generates the key sulfonamide N radical intermediate, which triggers a 1,5-HAT process to form the δ alkyl radical.

Introduction : Heme oxygenase-1 (HO-1) is a 32 kDa stress-response protein implicated in the pathogenesis of Parkinson's disease (PD). Biliverdin is derived from heme through a reaction mediated by HO-1 and protects cells from oxidative stress. However, iron and carbon monoxide produced by the catabolism of HO-1 exert detrimental effects on patients with PD. The purpose of this study was to determine whether plasma HO-1 levels represent a biomarker of PD and to further explore the underlying mechanism of increased HO-1 levels by applying voxel-based morphometry (VBM). Methods : We measured plasma HO-1 levels using an enzyme-linked immunosorbent assay (ELISA) in 156 subjects, including 81 patients with early- and advanced-stage PD and 75 subjects without PD. The analyses were adjusted to control for confounders such as age, sex, and medication. We analyzed T1-weighted magnetic resonance imaging (MRI) data from 74 patients with PD using VBM to elucidate the association between altered brain volumes and HO-1 levels. Then, we compared performance on MMSE sub-items between PD patients with low and high levels of HO-1 using Mann-Whitney U tests. Results : Plasma HO-1 levels were significantly elevated in PD patients, predominantly those with early-stage PD, compared with controls ( p < 0.05). The optimal cutoff value for patients with early PD was 2.245 ng/ml HO-1 [area under the curve (AUC) = 0.654]. Plasma HO-1 levels were unaffected by sex, age, and medications ( p > 0.05). The right hippocampal volume was decreased in the subset of PD patients with high HO-1 levels ( p < 0.05). A weak correlation was observed between right hippocampal volume and plasma HO-1 levels ( r = -0.273, p = 0.018). There was no difference in total MMSE scores between the low- and high-HO-1 groups ( p > 0.05), but the high-HO-1 group had higher language scores than the low-HO-1 group ( p < 0.05). Conclusions : Plasma HO-1 levels may be a promising biomarker of early PD. Moreover, a high plasma concentration of the HO-1 protein is associated with a reduction in right hippocampal volume., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Zheng, Ma, Wang, Shi, Li, Huang, Hu, Zhao and Li.)

Background: Orexin, a neuropeptide primarily secreted by neurons in the lateral hypothalamus, has been implicated in Parkinson's disease (PD). Studies on the relationship between plasma orexin-A levels and PD are rare., Objectives: This study aimed to assess levels of plasma orexin-A in the progression of PD and to evaluate the correlation between orexin-A levels and non-motor symptoms., Methods: Enzyme-linked immunosorbent assay was used to determine plasma orexin-A levels in 117 healthy controls and 121 PD patients, including those with early (n = 68), medium (n = 40) and advanced (n = 13) stages of the disease. Evaluation of motor symptoms and non-motor symptoms in PD patients, such as sleep disorders, cognitive dysfunction, neuropsychiatric symptoms, autonomic nervous dysfunction, hyposmia and PD-related pain, were assessed by the associated scales., Results: Plasma orexin-A levels were significantly higher in PD patients compared to healthy controls. Orexin-A levels were elevated in early-stage and medium-stage PD compared to healthy controls, but were decreased in advanced-stage PD. Orexin-A levels were negatively correlated with the Unified Parkinson's Disease Rating Scale Part III scores, disease duration, and dopamine receptor agonist doses, and were positively correlated with the Pittsburgh Sleep Quality Index, REM-sleep Behavior Disorder Questionnaire, 14-item Hamilton Anxiety Scale, Mini-Mental State Examination, and Non-motor Symptom Scale items 22-24 scores., Conclusions: We found for the first time that plasma orexin-A levels were increased in early-stage and medium-stage PD and were decreased in advanced-stage PD. Furthermore, orexin-A levels were correlated with the non-motor symptoms of insomnia, REM-sleep behavior disorder, anxiety, cognitive dysfunction, and renal dysfunction., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Evidence suggests that insulin therapy of patients with type 2 diabetes mellitus (T2DM) is frequently discontinued. However, the reasons for discontinuing insulin and factors associated with insulin discontinuation in this patient population are not well understood., Methods: We conducted a retrospective cohort study of adults with T2DM prescribed insulin between 2010 and 2017 at Partners HealthCare. Reasons for discontinuing insulin and factors associated with insulin discontinuation were studied using electronic medical records (EMR) data. Natural language processing (NLP) was applied to identify reasons from unstructured clinical notes. Factors associated with insulin discontinuation were extracted from structured EMR data and evaluated using multivariable logistic regression., Results: Among 7009 study patients, 2957 (42.2%) discontinued insulin within 12 months after study entry. Most patients who discontinued insulin (2121 / 71.7%) had reasons for discontinuation documented. The most common reasons were improving blood glucose control (33.2%), achieved weight loss (18.5%) and initiation of non-insulin diabetes medications (16.7%). In multivariable analysis adjusted for demographics and comorbidities, patients were more likely to discontinue either basal or bolus insulin if they were on a basal-bolus regimen (OR 1.6, 95% CI 1.3 to 1.8; p <  0.001) or were being seen by an endocrinologist (OR 2.6; 95% CI 2.2 to 3.0; p <  0.001)., Conclusions: In this large real-world evidence study conducted in an area with a high penetration of health insurance, insulin discontinuation countenanced by healthcare providers was common. In most cases it was linked to achievement of glycemic control, achieved weight loss and initiation of other diabetes medications. Factors associated with and stated reasons for insulin discontinuation were different from those previously described for non-adherence to insulin therapy, identifying it as a distinct clinical phenomenon.

Coronaviruses (CoVs) are a group of related enveloped RNA viruses that have severe consequences in a wide variety of animals by causing respiratory, enteric or systemic diseases. Porcine epidemic diarrhea virus (PEDV) is an economically important CoV distributed worldwide that causes diarrhea in pigs. nsp14 is a nonstructural protein of PEDV that is involved in regulation of innate immunity and viral replication. However, the function and mechanism by which nsp14 modulates and manipulates host immune responses remain largely unknown. Here, we report that PEDV nsp14 is an NF-κB pathway antagonist. Overexpression PEDV nsp14 protein remarkably decreases SeV-, poly (I:C)- and TNF-α-induced NF-κB activation. Meanwhile, expression of proinflammatory cytokines is suppressed by nsp14. nsp14 inhibits the phosphorylation of IKKs by interacting with IKKs and p65. Furthermore, nsp14 suppresses TNF-α-induced phosphorylation and nuclear import of p65. Overexpression nsp14 considerably increases PEDV replication. These results suggest a novel mechanism employed by PEDV to suppress the host antiviral response, providing insights that can guide the development of antivirals against CoVs., Competing Interests: Competing interestsAuthor Haixue Zheng was not involved in the journal’s review or decisions related to this manuscript. The authors declare no competing interests., (© The Author(s) 2021.)

The expression of tumor stem cell markers musashi1 (msi1) and numb in brain metastases were detected to explore their roles in the development of brain metastases.A total of 51 cases of brain metastasis, 29 cases of primary tumor and 15 cases of normal brain tissue were selected. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were used to detect msi1 and numb expression at the protein and mRNA levels. Correlation between msi1 and numb in brain metastases were evaluated.Immunohistochemistry and RT-PCR showed that no significant difference in the expression of msi1 and numb between brain metastases and primary tumors was observed (P > .05); the expression of msi1 and numb in brain metastases was significantly higher than that in normal brain tissues (P < .05); and the expression of msi1 and numb in primary tumors was significantly higher than that in normal brain tissues (P < .05). In general, the expression of msi1 gene was negatively correlated with the expression of numb at mRNA level by Pearson correlation analysis (r = -0.345, P < .05). Additionally, the expression of msi1 and numb in brain metastases was not related to gender, age, and tissue origin (P > .05).Msi1 is highly expressed in brain metastases and primary tumors, while numb is lowly expressed in brain metastases and primary tumors; msi1 and numb are negatively correlated in brain metastases, suggesting that msi1 and numb may have regulatory mechanisms in the development of brain metastases.

A method for the construction of cyclophane-braced peptide macrocycles via Pd-catalyzed aminoquinoline-directed intramolecular C(sp 3 )-H arylation with aryl iodides is developed. Unlike our previous AQ-directed exo-type intramolecular C-H arylation of long alkyl tails, this endo-type C-H cyclization reaction takes places on the β-methyl group of N -methyl alanine at the C-termini of peptides. Unusual C-N cleavage side products of Ala were observed and attributed to intramolecular deprotonation-assisted α,β-elimination of the palladacycle intermediate.

The present study aimed to identify the gene expression changes conferred by capsaicin in the cell model of 6-OHDA-induced Parkinson's disease, to disclose the molecular mechanism of action of capsaicin. We used capsaicin-treated and paraffin-embedded wax blocks containing substantia nigra tissue from 6-OHDA-induced Parkinson's disease rats to analyze transcriptional changes using Affymetrix GeneChip Whole Transcript Expression Arrays. A total of 108 genes were differentially expressed in response to capsaicin treatment, and seven of these genes were selected for further analysis: Olr724, COX1, Gsta2, Rab5a, Potef, Actg1, and Acadsb, of which Actg1 (actin gamma 1) was down-regulated and Gsta2 (Glutathione S-transferase alpha 2) was up-regulated. We successfully overexpressed Actg1 and Gsta2 in vitro. CCK-8 detection and flow cytometry demonstrated that overexpression of Actg1 and Gsta2 increased apoptosis in the 6-OHDA-induced Parkinson's disease cell model. The imbalance between Actg1 and Gsta2 may be one of the mechanisms of cell damage in Parkinson's disease (PD). Capsaicin can protect the cells and reduce the apoptosis rate by regulating Actg1 and Gsta2., (© 2020 The Author(s).)

Objective: Melatonin is the major hormone produced and secreted at night by the pineal gland into the cerebrospinal fluid (CSF) and circulation. The relationship between plasma melatonin levels and Parkinson's disease is not clear. The aim of the current study was to assess plasma melatonin levels in Parkinson's disease (PD) patients and to analysis the relationship between plasma melatonin levels and non-motor symptoms., Participants and Methods: In this cross-sectional study, we evaluated 61 patients with idiopathic PD [males n = 30 (49.2%), average age 62.4 years (range: 46-73 years)] and a total of 58 healthy volunteers [males n = 30 (51.7%), average age 64.3 years (range: 45-70 years)] who participated in the study. Plasma melatonin levels were measured using an enzyme-linked immunosorbent assay. The severity of disease in PD patients was scored by the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Staging scale. The quality of life in PD patients was assessed by the 39-item Parkinson's Disease Questionnaire. The non-motor symptoms were assessed by the 14-item Hamilton Anxiety Rating Scale, the 24-item Hamilton Depression Rating Scale, the Parkinson Disease Sleep Scale, the Epworth Sleepiness Scale and the Non-Motor Symptoms Scale for PD., Results: Compared with the healthy controls, the plasma melatonin levels were significantly higher in PD patients (12.82 ± 4.85 vs. 19.40 ± 4.23, P < 0.001). Plasma melatonin levels were significantly associated with the levodopa equivalent daily dose ( r = - 0.262, P < 0.05, n = 61). Higher plasma melatonin concentrations were detected in the negative cardiovascular symptom group than in the cardiovascular symptom group (20.13 ± 3.74 vs. 16.93 ± 3.74, P < 0.05). Higher plasma melatonin concentrations were detected in the non-sleep-disorders group than in the sleep disorders group (22.12 ± 5.93 vs. 18.86 ± 3.66, P < 0.05). In addition, the plasma melatonin concentration was higher in the group without gastrointestinal dysfunction than in the gastrointestinal dysfunction group (21.71 ± 4.44 vs. 18.35 ± 3.74, P < 0.05)., Conclusion: This study revealed that the plasma melatonin levels in PD patients were significantly higher than those in healthy controls. Non-motor symptoms that were significantly negatively correlated with plasma melatonin levels were cardiovascular symptoms, sleep disorders, and gastrointestinal dysfunction. Plasma melatonin levels have the closest relationship with sleep disorders. There was a correlation between plasma melatonin levels and sleep quality in patients with PD. The remaining non-motor symptoms were not related to plasma melatonin levels., (Copyright © 2020 Li, Zhao, Ma, Zheng, Huang, Hu, Gu and Chen.)

DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C-S, C-P and N-S linkages into DELs, which are underrepresented in the canonical methods., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Abnormal immune responses are involved in the development of Parkinson's disease (PD), and also affect peripheral blood lymphocytes. The profile of lymphocyte subsets in peripheral blood and whether it is relevant to the clinical features of PD patients remains controversial., Methods: To explore the role of peripheral blood lymphocytes (NK cells, B cells, CD3 + T cells, CD3 + CD4 + T cells and CD3 + CD8 + T cells) in the development of PD, a case-control study including 127 patients and 148 healthy controls was conducted, and peripheral blood lymphocyte subpopulations of participants were analysed by a FACSCalibur flow cytometer., Results: PD patients had a significantly higher percentage of NK cells and a lower percentage of CD3 + T cells and CD3 + CD4 + T cells than controls [16.4% (12.3%) vs. 12.6% (6.2%), 63.7% (14.2%) vs. 69.0% (6.6%), 33.1% (13.1%) vs. 38.9% (7.6%), P<0.05, respectively]. Through a binary logistic regression model adjusted for gender and age, we found that those who were outside of the reference range of peripheral blood lymphocytes (NK cell, B cell, CD3 + T cell and CD3 + CD4 + T cell) had an increased risk of PD [odds ratio (OR): 2.3, 5.1, 3.1 and 4.1, P<0.05, respectively]. Through a multivariable linear regression model adjusted for gender, age and levodopa equivalent daily dose, we found that deviation from the reference range of CD3 + CD8 + T cells (regression coefficient =3.474, P=0.015), course of disease (regression coefficient =0.411, P=0.004) and the Non-Motor Symptoms Scale (NMSS) scores (regression coefficient =0.553, P=5.92E-11) had a positive association with the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III score (adjusted R 2 =0.364, F=13.004)., Conclusions: Abnormal peripheral blood lymphocyte subpopulations have clinical relevance for PD., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: Non-motor symptoms are common in Parkinson's disease (PD) and can even be used as part of the supportive criteria for diagnosis. Chronic inflammation is involved in every stage of PD. Disorders of the immune system affect the peripheral blood. Whether the humoral immune response is associated with the non-motor symptoms of PD remains unknown., Methods: Mann-Whitney tests and Bonferroni correction were used to compare the serum levels of IgG, IgA, IgM, C3, and C4 between 180 sporadic PD patients and 187 healthy controls. Multiple regression models were conducted to assess the associations among these indicators of humoral immunity and the clinical features of PD patients., Results: Male PD patients had lower levels of C3 and C4 than healthy controls [0.87 (0.22) vs. 0.96 (0.19); 0.19 (0.06) vs. 0.22 (0.07), respectively, Pc < 0.01] and lower levels of C3 than female PD patients [0.87 (0.22) vs. 1.02 (0.23), Pc < 0.01]. Patients suffering from attention/memory problems had significantly lower levels of IgA and C3 than those without these problems [1.92 (1.21) vs. 2.57 (0.76); 0.89 (0.24) vs. 0.97 (0.24), respectively, Pc < 0.04]. In addition, serum IgG levels were negatively associated with mood/cognition problem scores and were positively associated with gastrointestinal tract problem scores (adjusted R 2 = 0.063, F = 1.805, p = 0.038). Serum C3 levels were negatively associated with being male, age, and sleep/fatigue problem scores (adjusted R 2 = 0.123, F = 2.678, p = 0.001)., Conclusion: The peripheral humoral immune response might be correlated with the non-motor symptoms of PD., (Copyright © 2019 Sun, Yu, Zhao, Song, Liu, Jia, Wang and Liu.)

Aims: Many new mobile technologies are available to assist people in managing chronic conditions, but data on the association between the use of these technologies and medical spending remains limited. As the available digital technology offerings to aid in diabetes management increase, it is important to understand their impact on medical spending. The aim of this study was to investigate the financial impact of a remote digital diabetes management program using medical claims and real-time blood glucose data. Materials and methods: A retrospective analysis of multivariate difference-in-difference and instrumental variables regression modeling was performed using data collected from a remote digital diabetes management program. All employees with diabetes were invited, in a phased introduction, to join the program. Data included blood glucose (BG) values captured remotely from members via connected BG meters and medical spending claims. Participants included members (those who accepted the invitation, n  = 2,261) and non-members ( n  = 8,741) who received health insurance benefits from three self-insured employers. Medical spending was compared between people with well-controlled (BG ≤ 154 mg/dL) and poorly controlled (BG > 154 mg/dL) diabetes. Results: Program access was associated with a 21.9% ( p  < 0.01) decrease in medical spending, which translates into a $88 saving per member per month at 1 year. Compared to non-members, members experienced a 10.7% ( p  < 0.01) reduction in diabetes-related medical spending and a 24.6% ( p  < 0.01) reduction in spending on office-based services. Well-controlled BG values were associated with 21.4% ( p  = 0.03) lower medical spending. Limitations and conclusions: Remote digital diabetes management is associated with decreased medical spending at 1 year. Reductions in spending increased with active utilization. It will be beneficial for future studies to analyze the long-term effects of the remote diabetes management program and assess impacts on patient health and well-being.

The anti-senescence activity of genistein is associated with inducing autophagy; however, the underlying mechanisms are not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were pretreated with genistein (1000 nM) for 30 min and then exposed to ox-LDL (50 mg/L) for another 12 h. The study found that genistein inhibited the ox-LDL-induced senescence (reducing the levels of P16 and P21 protein, and the activity of SA-β-gal); meanwhile, the effect of genistein was bound up with enhancing autophagic flux (increasing LC3-II, and decreasing the level of P62, p-mTOR and p-P70S6K). Moreover, SIRT1/LKB1/AMPK pathway was involved in genistein accelerating autophagic flux and mitigating senescence in HUVECs. The present study illustrated that genistein was a promising therapeutic agent to delay aging process and extend longevity.

Aims: To describe global patterns of insulin treatment and to assess the impact of patient, provider, health system and economic influences on treatment decisions for patients with insulin-treated type 2 diabetes (T2D)., Methods: This prospective cohort study of insulin-treated patients with T2D was conducted across 18 countries categorized as high, upper-middle or lower-middle income regions. Information collected from patients included knowledge of diabetes, experiences and interactions with their healthcare provider. Physician information included specialty, practice size, availability of diabetes support services, volume of diabetes patients treated and time spent per patient. Physicians determined an individualized haemoglobin A1c (HbA1c) target for each patient by the start of the study. Changes in T2D therapies and HbA1c were recorded for 2 years., Results: Complete treatment data were available for 2528 patients. Median age was 61 years and median duration of diabetes was 11.4 years. Changes to treatment regimen occurred in 90.0% of patients, but changes were less common in countries with a higher economic status (P < 0.001). Most treatment changes involved insulin, with changes in dose the most common. Overall predictors of change in insulin therapy included younger age, use of any insulin regimen other than basal only, higher mean baseline HbA1c and longer duration of T2D. HbA1c levels remained constant regardless of regional economic status. At baseline, 20.6% of patients were at their HbA1c target; at 2 years this was 26.8%., Conclusions: Among insulin-treated patients with T2D, treatment changes were common; however, only approximately one-fourth of individuals achieved their HbA1c target., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to investigate real-world patient characteristics, medication use, and health care resource utilization (HCRU) and costs among patients with clinical atherosclerotic cardiovascular disease (ASCVD) as defined by 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, to examine burden of disease and unmet needs, such as potential undertreatment., Patients and Methods: This retrospective cohort study utilized a nationally representative managed care database to identify newly diagnosed ASCVD patients between January 1, 2007, and November 30, 2012 (index = first ASCVD diagnosis date) in the USA. Patients had ≥12-month pre-index (baseline) and ≥12-month post-index (follow-up) health plan enrollment and no baseline lipid-lowering medication (LLM). Patient characteristics, LLM utilization patterns, HCRU, and costs were examined for all patients and by subgroups based on LLM use pattern and/or follow-up low-density lipoprotein cholesterol (LDL-C) levels., Results: A total of 128,017 ASCVD patients were identified with a mean (SD) age of 59 (13) years, 43.1% female, and 48.8% with ≥36-month follow-up. Within 12-month follow-up, 10.6% had high-intensity statins and 56.9% had no LLM fills. Baseline mean (SD) all-cause costs were $8,852 ($25,608). At 12-month follow-up, mean (SD) all-cause and ASCVD-related costs were $31,443 ($54,040) and $20,289 ($45,159), respectively. The 36-month analyses showed similar distributions. Multivariable analyses showed that age, gender, region, health insurance type, baseline comorbidities, baseline use of specific medications, baseline lipid profiles, and index ASCVD type were significantly associated with all-cause and ASCVD-related health care costs., Conclusion: Patients have nonoptimal treatment for ASCVD and substantial HCRU and costs associated with residual risk. Unmet needs and cost burdens of ASCVD patients merit additional investigation., Competing Interests: Disclosure Thomas P Power is an employee of AIM Specialty Health, a wholly owned subsidiary of Anthem, Inc. Xuehua Ke, Mark J Cziraky, Michael Grabner, John J Barron, and Ralph Quimbo are employees of HealthCore, Inc., a wholly owned subsidiary of Anthem, Inc., under contract with Eli Lilly and Company for the conduct of this study. Nicole Gidaya Bonine was an employee of HealthCore, Inc., under contract with Eli Lilly and Company for the conduct of this study at the time of the study. Zhenxiang Zhao and Burkhard Vangerow are employees and stock/shareholders of Eli Lilly and Company. Peter P Toth is an employee of CGH Medical Center and an adjunct associate professor at Johns Hopkins University School of Medicine, under contract with HealthCore, Inc.; has relationships for the following: speakers bureau – Amarin Corporation, AstraZeneca Plc, Genzyme Corporation, GlaxoSmithKline Plc, Kowa Pharmaceuticals America, Inc., and Merck & Co., Inc.; consultant – Amgen, AstraZeneca Plc, Atherotech Diagnostics Lab, Kowa Pharmaceuticals America, Inc., Liposcience, Inc., Merck & Co., Inc., and Novartis Pharmaceuticals Corporation. The authors report no other conflicts of interest in this work.

Increasing evidence suggests that capsaicin may play a role in modulating neuronal function and controlling motor behavior. However, the underlying mechanism is still unclear and the activation of transient receptor potential vanilloid 1 (TRPV1) might be involved in. This study investigated the potential neuroprotective role of capsaicin in a rat model of 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD). Capsaicin was treated intraperitoneally for the 6-OHDA induced PD rats and the locomotor activity and abnormal involuntary movements were found alleviated. Besides, brain oxidative stress (lipid peroxidation, superoxide dismutase and catalase) was also assessed, and oxidative insults were investigated relieved. Both the expression of tyrosine hydroxylase and TRPV1 were increased in the striatal and substantia nigra areas of 6-OHDA induced rats after the treatment of capsaicin by the semi-quantitative analysis of Western Blot. And the immunostaining of substantia nigra further suggested that capsaicin might protect against dopaminergic neuronal loss. Our results showed that TRPV1 might be a novel therapeutic target for PD.

Background: Whereas composite end points are often used in clinical trials of percutaneous coronary interventions (PCI), the impact of individual components on subsequent survival is incompletely defined. We evaluated the association of subsequent acute coronary syndromes (ACS) and unplanned coronary revascularization post-PCI with long-term survival., Methods and Results: From 2009 to 2011, the KiCS-PCI (Keio interhospital Cardiovascular Studies) consecutively enrolled patients undergoing PCI in 14 Japanese teaching hospitals. We identified patients who experienced ACS or unplanned coronary revascularization following their index PCI and compared subsequent survival during the 2-year follow-up period using propensity-matched cohorts of patients who did and did not experience these events. Cox proportional hazard models were used to assess 2-year all-cause mortality. Because unstable angina is less severe than acute myocardial infarction, we also generated a separate propensity-matched cohort for UA post-PCI. Among 3348 PCI patients (mean age, 67.5±10.7 years; 79.7% male), 214 (6.4%) experienced a subsequent ACS (168 events [78.5%] were unstable angina), and 198 (5.9%) underwent unplanned revascularization. In the propensity-matched cohorts, patients with a subsequent ACS admission had an increased risk of mortality as compared with those without (hazard ratio, 4.73; 95% confidence interval=1.35-16.6; P =0.015), whereas those with an unplanned revascularization did not have significantly higher risk (hazard ratio, 2.97; 95% confidence interval=0.57-14.3; P =0.19). Among unstable angina events, no association with mortality was observed (hazard ratio, 1.39; 95% confidence interval=0.48-4.00; P =0.54)., Conclusions: In the KiCS-PCI registry, the incidence of a subsequent ACS was associated with higher mortality, but this association was less apparent after unplanned coronary revascularization or unstable angina. The prognostic implications of different outcomes in a composite end point should be considered when interpreting the results of clinical trials in PCI., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The antioxidant activity of genistein is associated with preventing atherosclerosis; however, the underlying mechanisms are not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were pretreated with genistein at different concentrations (10nM, 100nM and 1000nM) for 6h and then exposed to ox-LDL (50mg/L) for another 24h. Results showed that genistein restrained reactive oxygen species (ROS) and malondialdehyde (MDA) production, and ameliorated the inhibitory effect on superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx) activity elicited by ox-LDL stimulation. The effects of genistein were correlated with the upregulation of sirtuin-1 via inhibiting miR-34a, and were abolished by sirtuin-1 siRNA or miR-34a mimic. Moreover, the antioxidation of genistein was associated with miR-34a/sirtuin-1-mediated nuclear translocation and deacetylation of foxo3a, accompanying with the enhanced expressions of MnSOD and CAT. The present study suggests that miR-34a/sirtuin-1/foxo3a might play an important role in genistein reversing ox-LDL-induced oxidative damage in HUVECs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Genistein plays an important role in the prevention of atherosclerosis. However, the underlying mechanisms have not been fully investigated. In this study, human umbilical vein endothelial cells (HUVECs) were pretreated with genistein (10, 100, and 1000 nM) for 6 h and then exposed to ox-LDL (50 mg/L) for another 24 h. Results showed that ox-LDL induced the expressions of E-selectin, P-selectin, monocyte chemotactic protein-1, interleukin-8, vascular adhesion molecule-1, and intercellular adhesion molecule-1, which were counteracted by genistein. The inhibitory effect was further enhanced with the augment of genistein (10, 100, and 1000 nM). Further analyses demonstrated the effect of genistein was associated with reducing miR-155 and elevating SOCS1, and miR-155 mimics or SOCS1 siRNA acted similarly in genistein ameliorating inflammation. Moreover, the effect of genistein was accompanied with the inhibition of the NF-ĸB signaling pathway. The present study indicates that genistein could reverse ox-LDL-induced inflammation through miR-155/SOCS1-mediated repression of the NF-ĸB signaling pathway in HUVECs.

Background: Growth differentiation factor 15 (GDF15) has been shown to be protective for dopaminergic neurons in animal and ex vivo experiments. However, little is known about its effect on the human body., Objective: This study investigated associations between serum GDF15 levels and clinical parameters in patients with Parkinson disease (PD)., Methods: Idiopathic PD patients (n = 104) and age-matched controls (n = 88) were enrolled. Serum GDF15 levels were measured by human enzyme-linked immunosorbent assay. Univariate and multivariate analyses investigated correlations between GDF15 and clinical characteristics, including disease severity by the Unified PD Rating Scale (UPDRS)-III. The diagnostic value of GDF15 was evaluated by receiver-operating characteristic curve (ROC) analysis., Results: The serum GDF15 levels of the PD patients were significantly higher than those of the healthy controls. In PD patients, serum GDF15 levels in men were significantly higher than in women. GDF15 levels correlated with age, gender, disease duration, and UPDRS-III score. After adjusting for confounding factors, multiple linear regression analysis showed that the serum GDF15 level (β = 0.015, p = 0.001) was an independent risk factor for UPDRS-III score. In ROC analysis, GDF15 achieved an area under the curve of 0.86 for the identification of PD, with a sensitivity of 71.15% and a specificity of 87.50%., Conclusion: GDF15 may be a potential biomarker for the diagnosis and monitoring of motor severity in PD., (© 2017 S. Karger AG, Basel.)

Background: Rehospitalizations after acute myocardial infarction for unplanned coronary revascularization and unstable angina (UA) are common. However, despite the inclusion of these events in composite end points of many clinical trials, their association with health status has not been studied., Methods and Results: We included 3283 patients with acute myocardial infarction enrolled in a prospective, 24-center US study who had rehospitalizations independently classified by experienced cardiologists. Health status was assessed using Seattle Angina Questionnaire and EuroQol-5D Visual Analog Scale. In the propensity-matched cohorts, 1-year health status was compared between those who did and did not experience rehospitalization for UA or revascularization using a hierarchical linear model. Overall, mean age was 59 years, 33% were women, and 70% were white. Rehospitalization rates for UA and unplanned revascularization at 1 year were 4.3% and 4.7%. One-year Seattle Angina Questionnaire summary scores were worse in patients with rehospitalizations for UA (mean difference, -10.1; 95% confidence interval, -12.4 to -7.9) and unplanned revascularization (mean difference, -5.7; 95% confidence interval, -8.8 to -2.5) when compared with patients without such rehospitalizations. Similarly, EuroQol-5D Visual Analog Scale scores were worse among patients with such readmissions. Individual Seattle Angina Questionnaire domains indicated worse 1-year angina and quality of life outcomes among patients rehospitalized for UA or unplanned revascularization., Conclusions: Within the first year after acute myocardial infarction, rehospitalizations for UA and unplanned revascularization are associated with worse health status. These findings highlight the impact of such events from a patient's perspective, beyond their economic impact and support the use of UA and unplanned revascularization as elements of composite end points., (© 2016 American Heart Association, Inc.)

Background: Rehospitalizations following acute myocardial infarction for unplanned coronary revascularization and unstable angina (UA) are often included as parts of composite end points in clinical trials. Although clearly costly, the clinical relevance of these individual components has not been described., Methods and Results: Patients enrolled in a prospective, 24-center, US acute myocardial infarction registry were followed for 1 year after an acute myocardial infarction for rehospitalizations, that were independently adjudicated by experienced cardiologists. Patients who did and did not experience UA or revascularization rehospitalization were propensity matched using greedy matching. Among 3283 patients with acute myocardial infarction who were included, mean age was 59 years, 33% were female, and 70% were white. Rehospitalization rates for UA and unplanned revascularization at 1 year were 5.0% and 4.1%, respectively. After propensity matching, we included 2433 patients in the UA rehospitalization group and 2410 in the unplanned revascularization group. Using weighted proportional hazards Cox regression, there was no significant association between a rehospitalization for UA and 5-year all-cause mortality (9.6% versus 13.8%; adjusted hazard ratio 0.87, 95% CI 0.60-1.16). Patients rehospitalized for unplanned revascularization had a lower 5-year mortality risk (7.0% versus 15.1%; hazard ratio 0.68, 95% CI 0.50-0.92) compared with those without such rehospitalizations. Nevertheless, patients with UA and unplanned revascularization had a substantially greater hazard of subsequent rehospitalizations compared with patients without such events (UA: hazard ratio 4.36, 95% CI 3.48-5.47; revascularization: hazard ratio 4.38, 95% CI 3.53-5.44)., Conclusions: Rehospitalizations for UA and unplanned revascularization in the year after an acute myocardial infarction are associated with higher risks of subsequent rehospitalizations but not with mortality., (© 2016 The Authors and Eli Lilly and Company. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Purpose: Results of a study of bleeding events and other inhospital outcomes with the use of clopidogrel versus prasugrel in patients with acute coronary syndrome (ACS) managed with percutaneous coronary intervention (PCI) are reported., Methods: Demographic and clinical data on adults hospitalized for ACS, managed with PCI, and treated with clopidogrel or prasugrel during a two-year period were extracted from a large hospital claims database. Bleeding rates, hospital length of stay (LOS), and total hospital costs during the index hospitalization were evaluated., Results: The study sample consisted of 75,297 patients who received clopidogrel and 9,477 who received prasugrel. The unadjusted bleeding rates were 5.7% with clopidogrel use and 3.2% with prasugrel use (p < 0.0001). After propensity score stratification to adjust for selection bias, rates of bleeding events were not significantly different between clopidogrel- and prasugrel-treated patients (odds ratio, 0.90; 95% confidence interval [CI], 0.80-1.02; p = 0.0949). The adjusted mean ± S.D. hospital LOS was 0.22 day lower (95% CI, 0.15-0.28; p < 0.001) with the use of prasugrel versus clopidogrel, and adjusted total mean hospital costs were $375 less for prasugrel-treated patients (p = 0.003)., Conclusion: After adjustments for demographic and clinical characteristics, rates of inhospital bleeding in patients who received prasugrel and those who received clopidogrel were not significantly different. The adjusted analyses showed that the mean hospital LOS was shorter and total mean hospital costs were lower for patients treated with prasugrel., (Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)