bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapamycin Modulates the Proinflammatory Memory-Like Response of Microglia Induced by BAFF
Authors: Wang Jianing , Yang Chunshu , Hou Xiaoyu , Xu Jingyi , Yun Yang , Qin Ling , Yang Pingting
Published: May 2021

Background

Recently trained immunity of microglia provided an opportunity to study the chronic effect of microglial activation and its metabolic rewiring in neuroimmunological diseases. Since elevated levels of B cell-activating factor (BAFF) have been proved to be associated with some chronic neuroimmunological disorders. Here, we used the trained innate immunity model to analyze the effect of BAFF, a vital regulator of the adaptive immune system, on long-term microglial activation and metabolic reprogramming in vitro and in vivo.

Methods and results

In vitro, BV2 cells and mouse primary microglial cells were incubated with BAFF for 24 h (BAFF priming). After 5 days of resting, microglia were restimulated with LPS (LPS restimulation) or BAFF (BAFF restimulation). BAFF priming induced a pro-inflammatory trained immunity-phenotype of both BV2 cells and primary microglial cells, which was indicated by morphological change, secretion of pro-inflammatory cytokine and chemokine upon LPS restimulation or BAFF restimulation. The production of lactate and NAD+/NADH ratio were elevated 5 days after BAFF priming. The activation of the Akt/mTOR/HIF-1α pathway was induced by BAFF priming and lasted for 5 days. Pretreating the BV2 cells or mouse primary microglial cells with rapamycin blocked mTOR/HIF-1α activation and cellular metabolic reprogramming induced by BAFF training. Consistently, rapamycin efficiently suppressed the trained immunity-like responses of microglia triggered by BAFF. In vivo, adult male mice were treated with BAFF by intracerebroventricular injection for priming and 7 days later with BAFF for restimulation. BAFF training activated microglia in the cortex and hippocampus. The production of proinflammatory cytokines and chemokines was elevated after BAFF training.

Conclusion

Our current data, for the first time, demonstrate that BAFF priming induces a proinflammatory memory-like response of microglia not only to LPS but also to BAFF itself. Rapamycin inhibits microglial priming triggered by BAFF through targeting the mTOR/HIF-1α signaling pathway. Our data reveal a novel role of BAFF in trained immunity and that rapamycin may be a potential therapeutic target of neuroimmunological diseases.
Dietary Phytogenics and Galactomannan Oligosaccharides in Low Fish Meal and Fish Oil-Based Diets for European Sea Bass (Dicentrarchus labrax) Juveniles: Effects on Gill Structure and Health and Implications on Oxidative Stress Status
Authors: Torrecillas Silvia , Terova Genciana , Makol Alex , Serradell Antonio , Valdenegro-Vega Victoria , Izquierdo Marisol , Acosta Felix , Montero Daniel
Published: May 2021

An effective replacement for fish meal (FM) and fish oil (FO) based on plant-based raw materials in the feed of marine fish species is necessary for the sustainability of the aquaculture sector. However, the use of plant-based raw materials to replace FM and FO has been associated with several negative health effects, some of which are related to oxidative stress processes that can induce functional and morphological alterations in mucosal tissues. This study aimed to evaluate the effects of dietary oligosaccharides of plant origin (5,000 ppm; galactomannan oligosaccharides, GMOS) and a phytogenic feed additive (200 ppm; garlic oil and labiatae plant extract mixture, PHYTO) on the oxidative stress status and mucosal health of the gills of juvenile European sea bass (Dicentrarchus labrax). The experimental diets, low FM and FO diets (10%FM/6%FO) were supplemented with GMOS from plant origin and PHYTO for 63 days. GMOS and PHYTO did not significantly affect feed utilization, fish growth, and survival. GMOS and PHYTO downregulated the expression of β-act, sod, gpx, cat, and gr in the gills of the fish compared with that in fish fed the control diet. The expression of hsp70 and ocln was upregulated and downregulated, respectively, in the GMOS group compared with that in the control group, whereas the expression of zo-1 was downregulated in the PHYTO group compared with that in the GMOS group. The morphological, histopathological, immunohistochemical, and biochemical parameters of the fish gills were mostly unaffected by GMOS and PHYTO. However, the PHYTO group had lower incidence of lamellar fusion than did the control group after 63 days. Although the tissular distribution of goblet cells was unaffected by GMOS and PHYTO, goblet cell size showed a decreasing trend (−11%) in the GMOS group. GMOS and PHYTO significantly reduced the concentration of PCNA+ in the epithelium of the gills. The above findings indicated that GMOS and PHYTO in low FM/FO-based diets protected the gill epithelia of D. labrax from oxidative stress by modulating the expression of oxidative enzyme-related genes and reducing the density of PCNA+ cells in the gills of the fish.
Rituximab Associated Hypogammaglobulinemia in Autoimmune Disease
Authors: Tieu Joanna , Smith Rona M. , Gopaluni Seerapani , Kumararatne Dinakantha S. , McClure Mark , Manson Ania , Houghton Sally , Jayne David R. W.
Published: May 2021

Objective

To evaluate the characteristics of patients with autoimmune disease with hypogammaglobulinemia following rituximab (RTX) and describe their long-term outcomes, including those who commenced immunoglobulin replacement therapy.

Methods

Patients received RTX for autoimmune disease between 2003 and 2012 with immunoglobulin G (IgG) <7g/L were included in this retrospective series. Hypogammaglobulinemia was classified by nadir IgG subgroups of 5 to <7g/L (mild), 3 to <5g/L (moderate) and <3g/L (severe). Characteristics of patients were compared across subgroups and examined for factors associated with greater likelihood of long term hypogammaglobulinemia or immunoglobulin replacement.

Results

142 patients were included; 101 (71%) had anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV), 18 (13%) systemic lupus erythematosus (SLE) and 23 (16%) other conditions. Mean follow-up was 97.2 months from first RTX. Hypogammaglobulinemia continued to be identified during long-term follow-up. Median time to IgG <5g/L was 22.5 months. Greater likelihood of moderate hypogammaglobulinemia (IgG <5g/L) and/or use of immunoglobulin replacement therapy at 60 months was observed in patients with prior cyclophosphamide exposure (odds ratio (OR) 3.60 [95% confidence interval (CI) 1.03 – 12.53], glucocorticoid use at 12 months [OR 7.48 (95% CI 1.28 – 43.55], lower nadir IgG within 12 months of RTX commencement [OR 0.68 (95% CI 0.51 – 0.90)] and female sex [OR 8.57 (95% CI 2.07 – 35.43)]. Immunoglobulin replacement was commenced in 29/142 (20%) and associated with reduction in infection rates, but not severe infection rates.

Conclusion

Hypogammaglobulinemia continues to occur in long-term follow-up post-RTX. In patients with recurrent infections, immunoglobulin replacement reduced rates of non-severe infections.
Novel Models for Chronic Intestinal Inflammation in Chickens: Intestinal Inflammation Pattern and Biomarkers
Authors: Dal Pont Gabriela C. , Belote Bruna L. , Lee Annah , Bortoluzzi Cristiano , Eyng Cinthia , Sevastiyanova Milena , Khadem Alireza , Santin Elizabeth , Farnell Yuhua Z. , Gougoulias Christos , Kogut Michael H.
Published: May 2021

For poultry producers, chronic low-grade intestinal inflammation has a negative impact on productivity by impairing nutrient absorption and allocation of nutrients for growth. Understanding the triggers of chronic intestinal inflammation and developing a non-invasive measurement is crucial to managing gut health in poultry. In this study, we developed two novel models of low-grade chronic intestinal inflammation in broiler chickens: a chemical model using dextran sodium sulfate (DSS) and a dietary model using a high non-starch polysaccharide diet (NSP). Further, we evaluated the potential of several proteins as biomarkers of gut inflammation. For these experiments, the chemical induction of inflammation consisted of two 5-day cycles of oral gavage of either 0.25mg DSS/ml or 0.35mg DSS/ml; whereas the NSP diet (30% rice bran) was fed throughout the experiment. At four times (14, 22, 28 and 36-d post-hatch), necropsies were performed to collect intestinal samples for histology, and feces and serum for biomarkers quantification. Neither DSS nor NSP treatments affected feed intake or livability. NSP-fed birds exhibited intestinal inflammation through 14-d, which stabilized by 36-d. On the other hand, the cyclic DSS-treatment produced inflammation throughout the entire experimental period. Histological examination of the intestine revealed that the inflammation induced by both models exhibited similar spatial and temporal patterns with the duodenum and jejunum affected early (at 14-d) whereas the ileum was compromised by 28-d. Calprotectin (CALP) was the only serum protein found to be increased due to inflammation. However, fecal CALP and Lipocalin-2 (LCN-2) concentrations were significantly greater in the induced inflammation groups at 28-d. This experiment demonstrated for the first time, two in vivo models of chronic gut inflammation in chickens, a DSS and a nutritional NSP protocols. Based on these models we observed that intestinal inflammation begins in the upper segments of small intestine and moved to the lower region over time. In the searching for a fecal biomarker for intestinal inflammation, LCN-2 showed promising results. More importantly, calprotectin has a great potential as a novel biomarker for poultry measured both in serum and feces.
Molecular Dynamics Simulation of Zener Pinning by Differently Shaped and Oriented Particles
Authors: Li Yi , Zhou Jian , Li Runjie , Zhang Qingyu
Published: May 2021

Zener pinning between a curved Cu grain boundary (GB) and a differently shaped and oriented Ag particle has been simulated via molecular dynamics. The computed magnitudes of the maximum pinning force agreed with theoretical predictions only when the force was small. As the force increased, discrepancy became obvious. Through careful inspection of the structures of the Cu–Ag interfaces, detailed interaction processes, and variation of the Cu GB during the interaction, the discrepancy is found to correlate with GB faceting, which very likely reduces the maximum pinning force and facilitates boundary passage. GB anisotropy and/or interface characteristics are also found to slightly contribute to the discrepancy. These findings suggest that the assumption of an isotropic GB with constant energy utilized in previous theoretical studies for deriving the maximum pinning force might be inappropriate and that an accurate maximum pinning force could not be predicted without knowing the effects of GB evolution together with detailed properties of both GBs and interfaces.
Influence of Serum Albumin on HbA1c and HbA1c-Defined Glycemic Status: A Retrospective Study
Authors: Feng Xiaojing , Yang Yanyi , Zhuang Siqi , Fang Yiyuan , Dai Yufeng , Fu Yaoyang , Hu Qian , Yuan Qianqin , Tang Haoneng , Tang Lingli
Published: May 2021

Background: Glycated hemoglobin (HbA1c) is commonly used in the diagnosis and evaluation of glycemic control in diabetes, and it may be influenced by several non-glycemic and glycemic factors, including albumin. This retrospective study investigated the influence of albumin on HbA1c and HbA1c-defined glycemic status.

Methods: The demographic, hematological, and biochemical data were collected for 11,922 patients undergoing routine physical examination. Univariate and multivariate linear regression analyses, stratified analyses and interaction analyses, and multiple logistic regression were conducted to identify the association between albumin and HbA1c in people with different glycemic status.

Results: HbA1c levels were inversely associated with serum albumin level (P < 0.0001) in all participants. Risk factors leading to the association included age > 45 years, high fasting plasma glucose (≥7.0 mmol/L), and anemia. The negative association between HbA1c and albumin was curved (P < 0.0001) and had a threshold effect in the HbA1c-defined diabetic population; the association was significantly stronger when the albumin level fell below 41.4 g/L (β: −0.31, 95% CI: −0.45 to −0.17, P < 0.0001). A 2 g/L increase in albumin reduced the odds of HbA1c-defined dysglycemia, diabetes, and poor glycemia control by 12% to 36%, after adjustment for all possible confounders.

Conclusions: HbA1c was inversely associated with albumin level in all participants, and the association was significantly stronger in people with diabetes (defined by HbA1c criteria). For diabetic patients with lower albumin level, there was an increased risk of an erroneous HbA1c-based identification and management of glycemic status.
The Association of Hypertension With the Severity of and Mortality From the COVID-19 in the Early Stage of the Epidemic in Wuhan, China: A Multicenter Retrospective Cohort Study
Authors: Mubarik Sumaira , Liu Xiaoxue , Eshak Ehab S. , Liu Keyang , Liu Qing , Wang Fang , Shi Fang , Wen Haoyu , Bai Jianjun , Yu Chuanhua , Cao Jinhong
Published: May 2021

Background: Hypertension may affect the prognosis of COVID-19 illness. We analyzed the epidemiological and clinical characteristics associated with the disease severity and mortality in hypertensive vs. non-hypertensive deceased COVID-19 patients.

Methods: We included all the deceased patients with laboratory-confirmed COVID-19 admitted to >200 health facilities in Wuhan between December 1 and February 24, 2020. The median survival time in COVID-19 patients with and without hypertension, the association of hypertension with the disease severity, and the risk factors associated with the COVID-19 mortality stratified by the hypertension status were assessed using the Kaplan-Meier survival analysis, logistic regression, and Cox proportional regression, respectively before and after the propensity score-matching (PS) for age and sex.

Results: The prevalence of hypertension in the studied 1,833 COVID-19 patients was 40.5%. Patients with hypertension were more likely to have severe COVID-19 illness than patients without hypertension; the PS-matched multivariable-adjusted odds ratio (95% CI) was 2.44 (1.77–3.08). Moreover, the median survival time in the hypertension group was 3–5 days shorter than the non-hypertension group. There was a 2-fold increased risk of COVID-19 mortality in the hypertension group compared with the non-hypertension group; the PS-matched multivariable-adjusted hazard ratio (HR) = 2.04 (1.61–2.72), and the significant increased risk of COVID-19 mortality in the moderate vs. mild COVID-19 illness was confined to patients with hypertension. Additionally, the history and the number of underlying chronic diseases, occupation, and residential location showed stronger associations with the COVID-19 mortality among patients with hypertension than patients without hypertension.

Conclusion: Hypertension was associated with the severity and mortality of COVID-19 illness.
Biochemical Characterization of a Novel Bacterial Laccase and Improvement of Its Efficiency by Directed Evolution on Dye Degradation
Authors: Dai Shuang , Yao Qian , Yu Gen , Liu Shan , Yun Jeonyun , Xiao Xiong , Deng Zujun , Li He
Published: May 2021

Laccase is a copper-containing polyphenol oxidase with a wide range of substrates, possessing a good application prospect in wastewater treatment and dye degradation. The purpose of this research is to study the degradation of various industrial dyes by recombinant laccase rlac1338 and the mutant enzyme lac2-9 with the highest enzyme activity after modification by error-prone PCR. Four enzyme activities improved mutant enzymes were obtained through preliminary screening and rescreening, of which lac2-9 has the highest enzyme activity. There are four mutation sites, including V281A, V281A, P309L, S318G, and D232V. The results showed that the expression of the optimized mutant enzyme also increased by 22 ± 2% compared to the unoptimized enzyme and the optimal reaction temperature of the mutant enzyme lac2-9 was 5°C higher than that of the rlac1338, and the optimal pH increased by 0.5 units. The thermal stability and pH stability of mutant enzyme lac2-9 were also improved. With ABTS as the substrate, the kcat/Km of rlac1338 and mutant strain lac2-9 are the largest than other substrates, 0.1638 and 0.618 s–1M–1, respectively, indicating that ABTS is the most suitable substrate for the recombinant enzyme and mutant enzyme. In addition, the Km of the mutant strain lac2-9 (76 μM) was significantly lower, but the kcat/Km (0.618 s–1M–1) was significantly higher, and the specific enzyme activity (79.8 U/mg) increased by 3.5 times compared with the recombinant laccase (22.8 U/mg). The dye degradation results showed that the use of rlac1338 and lac2-9 alone had no degradation effect on the industrial dyes [indigo, amaranth, bromophenol blue, acid violet 7, Congo red, coomassie brilliant blue (G250)], however, adding small molecular mediators Ca2+ and ABTS at the same time can significantly improve the degradation ability. Compared to the rlac1338, the degradation rates with the simultaneous addition of Ca2+ and ABTS of mutant enzyme lac2-9 for acid violet 7, bromophenol blue and coomassie brilliant blue significantly improved by 8.3; 3.4 and 3.4 times. Therefore, the results indicated that the error-prone PCR was a feasible method to improve the degradation activity of laccase for environmental pollutants, which provided a basis for the application of laccase on dye degradation and other environmental pollutants.
Oxidative Modifications of RNA and Its Potential Roles in Biosystem
Authors: Tanaka Mikiei , Chock P. Boon
Published: May 2021

Elevated level of oxidized RNA was detected in vulnerable neurons in Alzheimer patients. Subsequently, several diseases and pathological conditions were reported to be associated with RNA oxidation. In addition to several oxidized derivatives, cross-linking and unique strand breaks are generated by RNA oxidation. With a premise that dysfunctional RNA mediated by oxidation is the pathogenetic molecular mechanism, intensive investigations have revealed the mechanism for translation errors, including premature termination, which gives rise to aberrant polypeptides. To this end, we and others revealed that mRNA oxidation could compromise its translational activity and fidelity. Under certain conditions, oxidized RNA can also induce several signaling pathways, to mediate inflammatory response and induce apoptosis. In this review, we focus on the oxidative modification of RNA and its resulting effect on protein synthesis as well as cell signaling. In addition, we will also discuss the potential roles of enzymatic oxidative modification of RNA in mediating cellular effects.
Does Parkinson's Disease Increase the Risk of Atrial Fibrillation? Insights From Electrocardiogram and Risk Scores From a Case-Control Study
Authors: Alves Mariana , Abrantes Ana Mafalda , Portugal Gonçalo , Cruz M. Manuela , Reimão Sofia , Caldeira Daniel , Ferro José M. , Ferreira Joaquim J.
Published: May 2021

Background: Previous studies suggested that Parkinson's Disease (PD) patients could have an increased risk of atrial fibrillation. However, data supporting this association is not robust. We aimed to compare the potential risk of atrial fibrillation associated with PD in an age and gender matched case-control study, comparing the p-wave indexes from electrocardiograms and clinical risk scores among groups.

Methods: A cross-sectional case-control study was performed. All subjects included in the analysis were clinically evaluated and subjected to a 12-lead electrocardiogram. Two blinded independent raters measured the p-wave duration. Subjects were classified as having normal P-wave duration (<120 ms), partial IAB (P-wave duration ≥ 120 ms, positive in inferior leads), and advanced IAB (p-wave duration ≥ 120 ms with biphasic morphology in inferior leads). Atrial fibrillation risk scores (CHARGE-AF, HATCH, and HAVOC) were calculated.

Results: From 194 potential participants, three were excluded from the control group due to a previous diagnosis of atrial fibrillation. Comparing the PD patients (n = 97) with controls (n = 95), there were no statistically significant differences regarding the mean p-wave duration (121 ms vs. 122 ms, p = 0.64) and proportion of advanced interatrial block (OR = 1.4, 95%CI = 0.37–5.80, p = 0.58). All patients had a low or medium risk of developing atrial fibrillation based on the clinical scores. There were no differences between the PD patients and controls regarding the mean values of CHARGE-AF, HATCH, and HAVOC.

Conclusions: Our results do not support the hypothesis that PD patients have an increased risk of atrial fibrillation based on the p-wave predictors and atrial fibrillation clinical scores.
Evaluation of Effect of Ninjin'yoeito on Regional Brain Glucose Metabolism by 18F-FDG Autoradiography With Insulin Loading in Aged Mice
Authors: Zhao Jingmin , Imai Ryota , Ukon Naoyuki , Shimoyama Saki , Tan Chengbo , Maejima Yuko , Omiya Yuji , Takahashi Kazuhiro , Nan Guangxian , Zhao Songji , Ito Hiroshi , Shimomura Kenju
Published: May 2021

Introduction: A recent clinical study revealed that Ninjin'yoeito (NYT) may potentially improve cognitive outcome. However, the mechanism by which NYT exerts its effect on elderly patients remains unclear. The aim of this study is to evaluate the effect of Ninjin'yoeito on regional brain glucose metabolism by 18F-FDG autoradiography with insulin loading in aged wild-type mice.

Materials and Methods: After 12 weeks of feeding NYT, mice were assigned to the control and insulin-loaded groups and received an intraperitoneal injection of human insulin (2 U/kg body weight) 30 min prior to 18F-FDG injection. Ninety minutes after the injection, brain autoradiography was performed.

Results: After insulin loading, the 18F-FDG accumulation showed negative changes in the cortex, striatum, thalamus, and hippocampus in the control group, whereas positive changes were observed in the NYT-treated group.

Conclusions: Ninjin'yoeito may potentially reduce insulin resistance in the brain regions in aged mice, thereby preventing age-related brain diseases.
Analysing EU Treaty-Making and Litigation With Network Analysis and Natural Language Processing
Authors: Ovádek Michal , Dyevre Arthur , Wigard Kyra
Published: May 2021

We apply network analysis and topic modeling techniques to explore the evolution of the European Union's treaty making activity and the patterns of litigation they have given rise to. Our analysis reveals that, despite the expansion of the bloc's policy remit, its treaty-making activity retains a strong economic focus. Among the many agreements negotiated by EU institutions, the European Economic Agreement, the Ankara Agreement with Turkey and the World Trade Organization Agreement form the largest clusters of litigated cases. EU international agreements are disproportionately litigated in cases pertaining to residence rights and competition law.
Observations of Magnetic Flux Ropes Opened or Disconnected From the Sun by Magnetic Reconnection in Interplanetary Space
Authors: Feng Hengqiang , Zhao Yan , Wang Jiemin , Liu Qiang , Zhao Guoqing
Published: May 2021

During solar eruptions, many closed magnetic flux ropes are ejected into interplanetary space, which contribute to the heliospheric magnetic field and have important space weather effect because of their coherent magnetic field. Therefore, understanding the evolution of these closed flux ropes in the interplanetary space is important. In this paper, we examined all the magnetic and plasma data measured in 1997 by the Wind spacecraft and identified 621 reconnection exhausts. Of the 621 reconnection events, 31 were observed at the boundaries of magnetic flux ropes and were thought to cause the opening or disconnection magnetic field lines of the adjacent ropes. Of the 31 magnetic reconnection events, 29 were interchange reconnections and the closed field lines of these related flux ropes were opened by them. Only 2 of the 31 magnetic reconnection events disconnected the opened field lines of the original flux ropes. These observations indicate that interchange reconnection and disconnection may be two important mechanisms changing the magnetic topology of the magnetic flux ropes during their propagation during the interplanetary space.
Reevaluating the Influence of Leaders Under Proportional Representation: Quantitative Analysis of Text in an Electoral Experiment
Authors: Fredén Annika , Sikström Sverker
Published: May 2021

We propose that leaders play a more important role in voters’ party sympathy in proportional representation systems (PR) than previous research has suggested. Voters, from the 2018 Swedish General Election, were in an experiment asked to describe leaders and parties with three indicative keywords. Statistical models were conducted on these text data to predict their vote choice. The results show that despite that the voters vote for a party, the descriptions of leaders predicted vote choice to a similar extent as descriptions of parties. However, the order of the questions mattered, so that the first questions were more predictive than the second question. These analyses indicate that voters tend to conflate characteristics of leaders with their parties during election campaigns, and that leaders are a more important aspect of voting under PR than previous literature has suggested. Overall, this suggests that statistical analysis of words sheds new light of underlying sympathies related to voting.
Do You Get What I Mean?!? The Undesirable Outcomes of (Ab)Using Paralinguistic Cues in Computer-Mediated Communication
Authors: Sidi Yael , Glikson Ella , Cheshin Arik
Published: May 2021

The shift to working from home, which has intensified due to Covid-19, increased our reliance on communication technology and the need to communicate effectively via computer-mediated communication and especially via text. Paralinguistic cues, such as repeated punctuation, are used to compensate for the lack of non-verbal cues in text-based formats. However, it is unclear whether these cues indeed bridge the potential gap between the writer’s intentions and the reader’s interpretations. A pilot study and two experiments investigated the effect of using repeated punctuation on behavioral intention to assist an email writer in a work-related situation. Findings demonstrate that while the intentions behind using repeated punctuation relate to signaling situational importance or affective state, behavioral intentions are driven by dispositional rather than situational attributions. Specifically, the use of repeated punctuation reduces perceived competence of the message writer and consequently decreases positive behavioral intentions. Overall, the study challenges the simplified view of paralinguistic cues as communication facilitators, highlighting their potential harmful effects on impression formation and behavioral intentions in the digital age.
Recognition of Depression and Help-Seeking Preference Among University Students in Singapore: An Evaluation of the Impact of Advancing Research to Eliminate Mental Illness Stigma an Education and Contact Intervention
Authors: Tan Gregory Tee Hng , Shahwan Shazana , Abdin Edimansyah , Lau Jue Hua , Goh Chong Min Janrius , Ong Wei Jie , Samari Ellaisha , Kwok Kian Woon , Chong Siow Ann , Subramaniam Mythily
Published: May 2021

Background: The SMHS 2016 revealed that young adults in Singapore had the highest 12-month prevalence of mental disorders, with depression being the most prevalent condition. Additionally, the study found that those with higher education were less likely to seek treatment. The recognition of mental illness and knowledge of where to seek help has been found to influence one's ability to seek timely psychological help. This study thus aims to evaluate the effects of ARTEMIS, an education and contact intervention on university students' recognition of depression and help-seeking preference.

Methods: A total of 390 university students were recruited over a period of 6-months (October 2018 to April 2019). Students had to attend a one-off intervention which comprised a lecture on depression and personal contact with a person with lived experience of mental illness. Recognition of depression and help-seeking preference were assessed using a vignette approach, at pre- and post-intervention as well as at 3-month follow-up.

Results: The intervention was effective at improving student's recognition of depression and this effect was sustained at 3-months follow-up. The intervention was also effective in shifting student's help-seeking preference, although the effects were not sustained at 3-month follow-up. Having a close friend or family with mental illness was associated with better recognition, and being able to correctly recognize depression was linked to a preference to seek psychiatric over non-psychiatric help.

Conclusion: This study elucidated the efficacy of a knowledge-contact-based intervention in improving university students' recognition of depression and help-seeking preference. However, while the benefits on recognition of depression is more enduring, it is more transient for help-seeking beliefs, and booster sessions may be needed to improve the long-term effectiveness of the intervention on help-seeking preference. Lastly, to investigate the generalizability of this study's findings, future studies could replicate the current one across other non-self-selected samples, such as by integrating the intervention as part of student's orientation.
Comparisons of Characteristics Between Psychological Support Hotline Callers With and Without COVID-19 Related Psychological Problems in China
Authors: Zhao Liting , Li Ziyang , Tong Yongsheng , Wu Mengjie , Wang Cuiling , Wang Yuehua , Liu Nancy H.
Published: May 2021

Background: To compare the characteristics between hotline callers with and without the Coronavirus Disease 2019 (COVID-19) related psychological problems.

Methods: From January 25 to March 31, 2020, 581 callers with COVID-19 related psychological problems (COVID-19 callers) and 695 callers without COVID-19 related psychological problems (non-COVID-19 callers) to the Beijing Psychological Support Hotline were recruited. The demographic characteristics, primary concerns, suicidal ideation, depression and other psychological problems were compared between the two groups of callers.

Results: Both groups of the callers were predominantly female and highly educated. The primary concerns reported by the COVID-19 callers were depression (38.4%) and family relationship problems (26.0%). As compared to the non-COVID-19 callers, COVID-19 callers reported more financial (7.4%) and work related problems (4.1%), but revealed lower prevalence of suicidal ideation (47.9% v 71.3%), lower degrees of psychological distress (74.3 v 79.1), intensity of suicidal ideation (0 v 50), severity of depression (57.9 v 65.1), and higher degree of hopefulness (41.1 v 33.6) (all p values < 0.01). Additionally, a lower proportion of COVID-19 callers met the criteria of depressed mood (51.6% v 61.4%) and other 4 symptoms than the non-COVID-19 callers (p values < 0.01).

Conclusions: Based on the content of the primary concerns and the relatively low level of depression of the COVID-19 callers, the psychological intervention for them during the pandemic should focus on “psychological supports.” Coping strategies for daily life stressors and promotion of scientific knowledge about the pandemic should also be included in the hotline-related interventions.
Digital Analysis of Subtrochlear Sclerosis in Elbows Submitted for Dysplasia Screening
Authors: Válega Ana , Alves-Pimenta Sofia , McEvoy Fintan J. , Nielsen Dorte H. , Ginja Mário
Published: May 2021

Ulnar trochlear notch (UTN) subchondral bone sclerosis is observed in elbow dysplasia (ED) associated with the medial coronoid disease. However, its evaluation is based on a simple visual examiner assessment of bone radio-opacity level and is considered subjective. The purpose of this study was to objectively characterize the radiographic opacity of the ulnar trochlear notch (UTN) subchondral bone in mediolateral elbow projections classified, using the International Elbow Working Group guidelines. Records and mediolateral flexed elbow images from the Danish Kennel Club database for the ED screening scheme between 2012 and 2018 were available. Of the dogs in the database, those with an ED-negative status in the left limb were identified. From these, 20 dogs each having a status free from ED, or with Grade 1, 2, or 3 in the right limb, were randomly chosen. Joints with primary ununited anconeal process were excluded from the sample. A template was developed using the ImageJ software, for computer UTN sclerosis analysis. It was overlaid onto each image to define five regions of interest (ROIs): ROI-1, distal UTN; ROI-2, middle UTN; ROI-3, caudal UTN; ROI-4, cortical bone; and ROI-5, bone marrow. Mean pixel intensity for each UTN ROI was divided by the mean pixel intensity of ROI-4 to normalize the data. The mean ± standard deviation (SD) of the normalized pixel intensity in the disease joints (ED Grades 1, 2, and 3) was 1.18 ± 0.17, 1.03 ± 0.12, and 0.92 ± 0.09 for ROIs 1, 2, and 3, respectively. The corresponding values for the contralateral normal left joints were 1.16 ± 0.17, 1.01 ± 0.1, and 0.91 ± 0.08. There was a significant difference (P< 0.05) in the normalized mean pixel intensity in dysplastic vs. non-dysplastic elbow joints for ROIs 1 and 2. The raw mean pixel intensity from right and left cortical and marrow bone ROIs sometimes showed relatively large differences. Digital radiography is associated with exposure and post-processing variabilities. Differences in apparent radio-opacity (as indicated by pixel intensity) though statistically significant in dysplastic joints compared with contralateral normal joints are slight and are thus problematic for computer-aided assessments of UTN sclerosis.
Bovine Intelectin 2 Expression as a Biomarker of Paratuberculosis Disease Progression
Authors: Blanco Vázquez Cristina , Balseiro Ana , Alonso-Hearn Marta , Juste Ramón A. , Iglesias Natalia , Canive Maria , Casais Rosa
Published: May 2021

Paratuberculosis (PTB), a chronic granulomatous enteritis caused by Mycobacterium avium subsp. paratuberculosis (MAP), is responsible for important economic losses in the dairy industry. Our previous RNA-sequencing (RNA-Seq) analysis showed that bovine intelectin 2 (ITLN2) precursor gene was overexpressed in ileocecal valve (ICV) samples of animals with focal (log2 fold-change = 10.6) and diffuse (log2 fold-change = 6.8) PTB-associated lesions compared to animals without lesions. This study analyzes the potential use of ITLN2, a protein that has been described as fundamental in the innate immune response to infections, as a biomarker of MAP infection. The presence of ITLN2 was investigated by quantitative immunohistochemical analysis of ICV samples of 20 Holstein Friesian cows showing focal (n = 5), multifocal (n = 5), diffuse (n = 5) and no histological lesions (n = 5). Significant differences were observed in the mean number of ITLN2 immunostained goblet and Paneth cells between the three histopathological types and the control. The number of immunolabelled cells was higher in the focal histopathological type (116.9 ± 113.9) followed by the multifocal (108.7 ± 140.5), diffuse (76.5 ± 97.8) and control types (41.0 ± 81.3). These results validate ITLN2 as a post-mortem biomarker of disease progression.
Evaluation of Potential Sustainable Bedding Substrates Focusing on Preference, Behavior, and Stress Physiology in Rats—A Pilot Study
Authors: Vogt Miriam Annika , Geiger Lisa Marie Joy , Härtel Talia , Follert Philipp , Palme Rupert , Chourbaji Sabine
Published: May 2021

Ensuring optimal housing conditions for laboratory animals is a crucial prerequisite for high-quality and ethically justifiable in vivo science. In addition to guaranteeing animal welfare and promoting scientific validity, environmental sustainability is also increasingly gaining attention in laboratory animal facilities. Consequently, comprehensive management of such aspects is one of the core tasks of any research vivarium. Hygienic monitoring and adhering to standardized experimental protocols have been highlighted in the past; nevertheless, various environmental aspects of housing animals still need to be evaluated in greater depth. In this pilot study, we aimed at assessing the suitability of spelt and corncob as economical and ecologically friendly bedding substrates as compared with commonly used aspen wood chips. Therefore, following a descriptive study design, we examined the preferences of male and female Wistar rats for corncob and spelt under specific conditions. In addition, we evaluated potential effects on behavior, metabolism, and stress physiology. The type of bedding did not seem to influence behavior in the observed parameters but did have time- and sex-dependent effects on blood glucose. Furthermore, housing animals on spelt led to a significant reduction in food consumption, probably compensated for by the intake of spelt, and although it did not influence glucose levels, it may have certainly impacted the nutrient supply. Our descriptive pilot study, therefore, highlights the importance of a thorough condition-associated evaluation of even seemingly marginal environmental factors, when balancing potential cost-benefit advances in sustainability and questions of standardization and reproducibility of experimental protocols.
Mediterranean Edible Plants: An Assessment of Their Antioxidant, Radical Scavenger Properties and Their Use as Super Foods, Nutraceuticals, Functional Foods
Authors: Stefanucci Azzurra , Mollica Adriano
Published: May 2021

The Mediterranean diet comprises a set of foods that commonly feature in the diet of inhabitants from countries bordering the Mediterranean Sea [...]
Recruitment, Infiltration, and Cytotoxicity of HLA-Independent Killer Lymphocytes in Three-Dimensional Melanoma Models
Authors: Iaia Ilenia , Gammaitoni Loretta , Cattaneo Giulia , Giraudo Lidia , Donini Chiara , Fiorino Erika , Primo Luca , Carnevale-Schianca Fabrizio , Aglietta Massimo , Puliafito Alberto , Sangiolo Dario
Published: May 2021

Cancer adoptive cell therapy (ACT) with HLA-independent tumor killer lymphocytes is a promising approach, with intrinsic features potentially addressing crucial tumor-escape mechanisms of checkpoint inhibitors. Cytokine-induced Killer (CIK) and Natural Killer (NK) lymphocytes share similar tumor-killing mechanisms, with preclinical evidence of intense activity against multiple solid tumors and currently testing in clinical studies. To improve the effective clinical translation of such ACT approaches, several fundamental questions still need to be addressed within appropriate preclinical contexts, capable of overcoming limitations imposed by most traditional two-dimensional assays. Here, we developed a novel experimental approach to explore, dissect, and visualize the interactions of CIK and NK lymphocytes with melanoma tumors in vitro in 3D. Primary melanoma cells were assembled into small tumors that were dispersed in a 3D matrix and challenged with patient-derived CIK or the NK-92 cell line. By means of imaging-based methods, we reported, visualized, and quantitatively measured the recruitment of CIK and NK on the 3D targets, their infiltration, and cytotoxic activity. Our results support the effective tumor recruitment and tumor infiltration by CIK and NK. Such features appeared dependent on the specific geometric aspects of the environment but can be explained in terms of directional migration toward the tumor, without invoking major feedback components. Overall, our 3D platform allows us to monitor the processes of tumor recruitment, infiltration, and killing by means of live measurements, revealing important kinetic aspects of ACT with CIK and NK against melanoma.
Factors Influencing the Adjuvant Therapy Decision: Results of a Real-World Multicenter Data Analysis of 904 Melanoma Patients
Authors: Lodde Georg , Forschner Andrea , Hassel Jessica , Wulfken Lena M. , Meier Friedegund , Mohr Peter , Kähler Katharina , Schilling Bastian , Loquai Carmen , Berking Carola , Hüning Svea , Schatton Kerstin , Gebhardt Christoffer , Eckardt Julia , Gutzmer Ralf , Reinhardt Lydia , Glutsch Valerie , Nikfarjam Ulrike , Erdmann Michael , Stang Andreas , Kowall Bernd , Roesch Alexander , Ugurel Selma , Zimmer Lisa , Schadendorf Dirk , Livingstone Elisabeth
Published: May 2021

Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.
CXCR2 Levels Correlate with Immune Infiltration and a Better Prognosis of Triple-Negative Breast Cancers
Authors: Boissière-Michot Florence , Jacot William , Massol Océane , Mollevi Caroline , Lazennec Gwendal
Published: May 2021

Chemokines and their receptors are key players in breast cancer progression and outcome. Previous studies have shown that the chemokine receptor CXCR2 was expressed at higher levels by cells of the tumor microenvironment in triple-negative breast cancers (TNBCs). The aim of this study was to focus our attention on a retrospective cohort of 290 TNBC cases and analyze the involvement of CXCR2, CD11b (a marker of granulocytes) and CD66b (a marker of neutrophils) and their link with immune infiltration and immune checkpoint markers. We report that high densities of CXCR2-, CD11b- and CD66b-positive cells were associated with high-grade tumors. Moreover, molecular apocrine TNBCs, defined here as tumors that express both AR and FOXA1 biomarkers, exhibited low levels of CXCR2 and CD11b. High CXCR2 and CD11b levels were correlated with elevated density of tumor-infiltrating lymphocytes (TILs), CD8+ cytotoxic lymphocytes, expression of PD-L1 by tumor and stromal cells and of PD-1 by stromal cells. On the other hand, CD66b levels were associated only with CD8+, stromal PD-L1 and PD-1 expression. In univariate analysis, low levels of CXCR2 were correlated with poor OS and RFS. In multivariate analysis, low levels of CXCR2 were associated with poor OS. Finally, in TNBC treated with adjuvant chemotherapy, CXCR2 density was associated with longer RFS. Overall, our data highlight the potential beneficial association of high levels of CXCR2 with a subgroup of TNBC patients characterized by a better prognosis.
Value of Early Circulating Tumor Cells Dynamics to Estimate Docetaxel Benefit in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients
Authors: Lozano Rebeca , Lorente David , Aragon Isabel M. , Romero-Laorden Nuria , Nombela Paz , Mateo Joaquim , Reid Alison H. M. , Cendón Ylenia , Bianchini Diletta , Llacer Casilda , Sandhu Shahneen K. , Sharp Adam , Rescigno Pasquale , Garcés Teresa , Pacheco Maria I. , Flohr Penelope , Massard Christophe , López-Casas Pedro P. , Castro Elena , de Bono Johann S. , Olmos David
Published: May 2021

Circulating tumor cell (CTC) enumeration and changes following treatment have been demonstrated to be superior to PSA response in determining mCRPC outcome in patients receiving AR signaling inhibitors but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC patients treated with docetaxel. CTCs were measured at baseline and 3–6 weeks post treatment initiation. Cox regression models were constructed to compare 6-month radiographical progression-free survival (rPFS), CTCs and PSA changes predicting outcome. Among the subjects, 80 and 52 patients had evaluable baseline and post-treatment CTC counts, respectively. A significant association of higher baseline CTC count with worse overall survival (OS), PFS and time to PSA progression (TTPP) was observed. While CTC response at 3–6 weeks (CTC conversion (from ≥5 to <5 CTCs), CTC30 (≥30% decline in CTC) or CTC0 (decline to 0 CTC)) and 6-month rPFS were significantly associated with OS (all p < 0.005), the association was not significant for PSA30 or PSA50 response. CTC and PSA response were discordant in over 50% of cases, with outcome driven by CTC response in these patients. The c-index values for OS were superior for early CTC changes compared to PSA response endpoints, and similar to 6-month rPFS. Early CTC declines were good predictors of improved outcomes in mCRPC patients treated with docetaxel in this small study, offering a superior and/or earlier estimation of docetaxel benefit in comparison to PSA or rPFS that merits further confirmation in larger studies.
A Classification Approach for Cancer Survivors from Those Cancer-Free, Based on Health Behaviors: Analysis of the Lifelines Cohort
Authors: Cortés-Ibañez Francisco O. , Belur Nagaraj Sunil , Cornelissen Ludo , Sidorenkov Grigory , de Bock Geertruida H.
Published: May 2021

Health behaviors affect health status in cancer survivors. We hypothesized that nonlinear algorithms would identify distinct key health behaviors compared to a linear algorithm and better classify cancer survivors. We aimed to use three nonlinear algorithms to identify such key health behaviors and compare their performances with that of a logistic regression for distinguishing cancer survivors from those without cancer in a population-based cohort study. We used six health behaviors and three socioeconomic factors for analysis. Participants from the Lifelines population-based cohort were binary classified into a cancer-survivors group and a cancer-free group using either nonlinear algorithms or logistic regression, and their performances were compared by the area under the curve (AUC). In addition, we performed case–control analyses (matched by age, sex, and education level) to evaluate classification performance only by health behaviors. Data were collected for 107,624 cancer free participants and 2760 cancer survivors. Using all variables resulted an AUC of 0.75 ± 0.01, using only six health behaviors, the logistic regression and nonlinear algorithms differentiated cancer survivors from cancer-free participants with AUCs of 0.62 ± 0.01 and 0.60 ± 0.01, respectively. The main distinctive classifier was age. Though not relevant to classification, the main distinctive health behaviors were body mass index and alcohol consumption. In the case–control analyses, algorithms produced AUCs of 0.52 ± 0.01. No key health behaviors were identified by linear and nonlinear algorithms to differentiate cancer survivors from cancer-free participants in this population-based cohort.