bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of 3′,5′‐cyclic inosine monophosphate in cystathionine γ‐lyase‐dependent regulation of the vascular tone
Authors: Mitidieri Emma , Vellecco Valentina , Brancaleone Vincenzo , Vanacore Domenico , Manzo Onorina L. , Martin Emil , Sharina Iraida , Krutsenko Yekaterina , Monti Maria Chiara , Morretta Elva , Papapetropoulos Andreas , Caliendo Giuseppe , Frecentese Francesco , Cirino Giuseppe , Sorrentino Raffaella , d'Emmanuele di Villa Bianca Roberta , Bucci Mariarosaria
Published: May 2021

Background and Purpose

l‐cysteine or hydrogen sulfide (H2S) donors induce a biphasic effect on precontracted isolated vessels. The contractile effect occurs within a concentration range of 10 nM to 3 μM followed by vasodilatation at 30–100 μM. Here, we have investigated the signalling involved in the H2S‐induced contraction.

Experimental Approach

Vascular response to NaHS or l‐cysteine is evaluated on isolated precontracted with phenylephrine vessel rings harvested from wild type, cystathionine γ‐lyase (CSE−/−), soluble guanylyl cyclase (sGCα1−/−) and endothelial nitric oxide synthase (eNOS−/−) knock‐out mice. The cAMP, cGMP and inosine 3′,5′‐cyclic monophosphate (cIMP) levels are simultaneously quantified using ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) analysis. The involvement of sGC, phosphodiesterase (PDE) 4A and PDE5 are also evaluated.

Key Results

CSE‐derived H2S‐induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H2S contractile effect involves a transient increase of cGMP and cAMP metabolism caused by PDE5 and PDE4A, thus unmasking cIMP contracting action. The stable cell‐permeable analogue of cIMP elicits concentration‐dependent contraction on a stable background tone induced by phenylephrine. The lack of cIMP, coupled to the hypocontractility displayed by vessels harvested from CSE−/− mice, confirms that H2S‐induced contraction involves cIMP.

Conclusion and Implications

The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE‐derived H2S that is mediated by cIMP.
The immunological impact of preoperative chemoradiotherapy on the tumor microenvironment of pancreatic cancer
Authors: Okubo Satoshi , Suzuki Toshihiro , Hioki Masayoshi , Shimizu Yasuhiro , Toyama Hirochika , Morinaga Soichiro , Gotohda Naoto , Uesaka Katsuhiko , Ishii Genichiro , Takahashi Shinichiro , Kojima Motohiro
Published: May 2021

Several therapeutic regimens, including neoadjuvant chemoradiation therapy (NACRT), have been reported to serve as anticancer immune effectors. However, there remain insufficient data regarding the immune response after NACRT in pancreatic ductal adenocarcinoma (PDAC) patients. Data from 40 PDAC patients that underwent surgical resection after NACRT (NACRT group) and 30 PDAC patients that underwent upfront surgery (US group) were analyzed to examine alterations in immune cell counts/distribution using a multiplexed fluorescent immunohistochemistry system. All immune cells were more abundant in the cancer stroma than in the cancer cell nest regardless of preoperative therapy. Although the stromal counts of CD4+ T cells, CD20+ B cells, and Foxp3+ T cells in the NACRT group were drastically decreased in comparison with those of the US group, counts of these cell types in the cancer cell nest were not significantly different between the two groups. In contrast, CD204+ macrophage counts in the cancer stroma were similar between the NACRT and US groups, while those in the cancer cell nests were significantly reduced in the NACRT group. Following multivariate analysis, only a high CD204+ macrophage count in the cancer cell nest remained an independent predictor of shorter relapse‐free survival (odds ratio = 2.37;P = .033). NACRT for PDAC decreased overall immune cell counts, but these changes were heterogeneous within the cancer cell nests and cancer stroma. The CD204+ macrophage count in the cancer cell nest is an independent predictor of early disease recurrence in PDAC patients after NACRT.
Ibrutinib improves the efficacy of anti‐CD19‐CAR T‐cell therapy in patients with refractory non‐Hodgkin lymphoma
Authors: Liu Meijing , Deng Haobin , Mu Juan , Li Qing , Pu Yedi , Jiang Yili , Deng Qi , Qian Zhengzi
Published: May 2021

The efficacy and side effects of the second‐time humanized CD19 chimeric antigen receptor (CD19‐CAR) T‐cell therapy after unsuccessful first‐time anti‐CD19‐CAR T‐cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B‐cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first‐time humanized anti‐CD19‐CAR T‐cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7‐16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second‐time humanized anti‐CD19‐CAR T‐cell therapy, which was the same as their first‐time anti‐CD19‐CAR T‐cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second‐time anti‐CD19‐CAR T‐cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti‐CD19‐CAR T‐cell therapy. However, the second‐time anti‐CD19‐CAR T‐cell therapy led to higher peaks of anti‐CD19‐CAR T cells and anti‐CD19‐CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second‐time anti‐CD19‐CAR T‐cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti‐CD19‐CAR T cells.
Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer
Authors: Du Wushuang , Gao Aiai , Herman James G. , Wang Lidong , Zhang Lirong , Jiao Shunchang , Guo Mingzhou
Published: May 2021

Wnt, PI3K‐Akt‐mTOR, and NF‐κB pathways were reported to be involved in DNA damage repair (DDR). DDR‐deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K‐Akt‐mTOR, and its role in DDR remains unclear. Methylation‐specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P < .001), tumor size (P < .01), TNM stage (P < .001), differentiation (P < .001) and alcohol consumption (P < .05). We found that NRN1 methylation is an independent prognostic factor for poor 5‐y overall survival (P < .001). NRN1 inhibits colony formation, cell proliferation, migration, and invasion, and induces apoptosis and G1/S arrest in esophageal cancer cells. NRN1 suppresses KYSE150 and KYSE30 cells xenografts growth in nude mice. PI3K signaling is reported to activate ATR signaling by targeting CHK1, the downstream component of ATR. By analyzing the synthetic efficiency of NVP‐BEZ235 (PI3K inhibitor) and VE‐822 (an ATR inhibitor), we found that the combination of NVP‐BEZ235 and VE‐822 increased cytotoxicity in NRN1 methylated esophageal cancer cells, as well as KYSE150 cell xenografts. In conclusion, NRN1 suppresses esophageal cancer growth both in vitro and in vivo by inhibiting PI3K‐Akt‐mTOR signaling. Methylation of NRN1 is a novel synthetic lethal marker for PI3K‐Akt‐mTOR and ATR inhibitors in human esophageal cancer.
Loss of polarity protein Par3, via transcription factor Snail, promotes bladder cancer metastasis
Authors: Wang Shenyi , Cai Jinming , Zhang Si , Dong Mingwei , Zhang Li , Xu Yingying , Shen Bing , Chen She
Published: May 2021

Bladder cancer (BLCA) remains the leading cause of cancer‐related mortality among genitourinary malignancies worldwide. BLCA metastasis represents the primary reason for its poor prognosis. In this study, we report that decreased expression of partitioning defective 3 (Par3), a polarity protein (encoded by PARD3), is associated with tumor aggressive phenotypes and poor prognosis in BLCA patients. Consistently, ablation of Par3 promotes the metastasis and invasion of BLCA cells in vitro and in vivo. Further studies reveal that zinc finger protein Snail represses the expression of Par3 by binding to E2‐box (CAGGTG) of PARD3 promoter‐proximal. Inhibition of GSK‐3β promotes the expression and nuclear localization of Snail and then reduces the expression of Par3, resulting in the metastasis and invasion of BLCA cells. Moreover, we detected the interaction between Par3 (936‐1356 aa) and ZO‐1 (1372‐1748 aa), which is involved in the maintenance of tight junction. Together, our results demonstrate that the GSK‐3β/Snail/Par3/ZO‐1 axis regulates BLCA metastasis, and Snail is a major regulator for Par3 protein expression in BLCA.
NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF‐1α signaling in hepatocellular carcinoma
Authors: Sun Bo , Yu Lei , Xu Cong , Li Yi‐Ming , Zhao Yan‐Rong , Cao Mo‐Mo , Yang Lian‐Yue
Published: May 2021

Reactive oxygen species (ROS) derived from aberrant tumor metabolism could contribute to tumor invasion and metastasis. NAD(P)HX Epimerase (NAXE), an epimerase that allows the repair of damaged forms of antioxidant NADPH, is a potential cellular ROS scavenger and its role in tumor development is still elusive. Here, we found that NAXE is significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. NAXE downregulation is associated with poor clinicopathological characteristics and is an independent risk factor for overall and disease‐free survival of HCC patients after liver resection. In addition, low NAXE expression could identify worse prognosis of HCC patients before vascular invasion or in early stages of disease. In particularly, low NAXE expression in HCC is markedly associated with microvascular invasion (MVI) and its combination with MVI predicts poorer prognosis of HCC patients after liver resection. Furthermore, in vitro and in vivo experiments both showed that knockdown of NAXE expression in HCC cells promoted migration, invasion, and metastasis by inducing epithelial‐mesenchymal transition (EMT), whereas NAXE overexpression causes the opposite effects. Mechanistically, low NAXE expression reduced NADPH levels and further caused ROS level increase and hypoxia‐inducible factor‐1α (HIF‐1α) activation, thereby promoting invasion and metastasis of HCC by facilitating EMT. What is more, the tumor‐promoting effect of NAXE knockdown in HCC xenograft can be abolished by giving mice N‐acetyl‐l‐cysteine (NAC) in drinking water. Taken together, our findings uncovered a tumor suppressor role for NAXE in HCC by scavenging excessive ROS and inhibiting tumor‐promoting signaling pathways, suggesting a new strategy for HCC therapy by targeting redox signaling.
CIRCULATE‐Japan: Circulating tumor DNA–guided adaptive platform trials to refine adjuvant therapy for colorectal cancer
Authors: Taniguchi Hiroya , Nakamura Yoshiaki , Kotani Daisuke , Yukami Hiroki , Mishima Saori , Sawada Kentaro , Shirasu Hiromichi , Ebi Hiromichi , Yamanaka Takeharu , Aleshin Alexey , Billings Paul R. , Rabinowitz Matthew , Oki Eiji , Takemasa Ichiro , Kato Takeshi , Mori Masaki , Yoshino Takayuki
Published: May 2021

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE‐Japan including three clinical trials. The GALAXY study is a prospectively conducted large‐scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high‐risk stage II or low‐risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double‐blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor–positive status in the GALAXY study. Therefore, CIRCULATE‐Japan encompasses both “de‐escalation” and “escalation” trials for ctDNA‐negative and ‐positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA‐guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.
Clinical use of machine learning‐based pathomics signature for diagnosis and survival prediction of bladder cancer
Authors: Chen Siteng , Jiang Liren , Zheng Xinyi , Shao Jialiang , Wang Tao , Zhang Encheng , Gao Feng , Wang Xiang , Zheng Junhua
Published: May 2021

Traditional histopathology performed by pathologists by the naked eye is insufficient for accurate and efficient diagnosis of bladder cancer (BCa). We collected 643 H&E‐stained BCa images from Shanghai General Hospital and The Cancer Genome Atlas (TCGA). We constructed and cross‐verified automatic diagnosis and prognosis models by performing a machine learning algorithm based on pathomics data. Our study indicated that high diagnostic efficiency of the machine learning‐based diagnosis model was observed in patients with BCa, with area under the curve (AUC) values of 96.3%, 89.2%, and 94.1% in the training cohort, test cohort, and external validation cohort, respectively. Our diagnosis model also performed well in distinguishing patients with BCa from patients with glandular cystitis, with an AUC value of 93.4% in the General cohort. Significant differences were found in overall survival in TCGA cohort (hazard ratio (HR) = 2.09, 95% confidence interval (CI): 1.56‐2.81, P < .0001) and the General cohort (HR = 5.32, 95% CI: 2.95‐9.59, P < .0001) comparing patients with BCa of high risk vs low risk stratified by risk score, which was proved to be an independent prognostic factor for BCa. The integration nomogram based on our risk score and clinicopathologic characters displayed higher prediction accuracy than current tumor stage/grade systems, with AUC values of 77.7%, 83.8%, and 81.3% for 1‐, 3‐, and 5‐y overall survival prediction of patients with BCa. However, prospective studies are still needed for further verifications.
Benzo[a]phenazine derivatives: Promising scaffolds to combat resistant Mycobacteriumtuberculosis
Authors: Halicki Priscila Cristina Bartolomeu , da Silva Eufrânio Nunes , Jardim Guilherme Augusto de Melo , Almeida Renata Gomes de , Vicenti Juliano Rosa de Menezes , Gonçalves Bruna Lisboa , da Silva Pedro Eduardo Almeida , Ramos Daniela Fernandes
Published: May 2021

The continuous emergence of resistant Mycobacterium tuberculosis keeps tuberculosis (TB) treatment options still insufficient, and new therapeutic alternatives are urgently needed. Considering the antimycobacterial activity of phenazine derivatives previously reported by our research group, we aimed to explore possible applications to circumvent the resistance in M. tuberculosis. Firstly, we evaluated the antimicrobial activity of seven benzo[a]phenazine derivatives against eleven M. tuberculosis strains: ten resistant and one susceptible (H37Rv). Then, we determined the cytotoxicity of benzo[a]phenazine derivatives and investigated the possible mechanism of action of the most promising compound. Among them, compound 10 was the only one active against all strains evaluated, with a minimum inhibitory concentration between 18.3 and 146.5 µM. For some resistant strains, this compound showed antimicrobial activity higher than rifampicin and it was also active against MDR strains, indicating an absence of cross‐resistance with anti‐TB drugs. Also, 10 showed a pharmacological safety for further in vivo studies and its mechanism of action seems to be related to oxidative stress. Thus, our findings indicate that benzo[a]phenazine derivatives are promising scaffolds for the development of new anti‐TB drugs, mainly focusing on the treatment of resistant TB cases.
Effects of Montessori Education on the Academic, Cognitive, and Social Development of Disadvantaged Preschoolers: A Randomized Controlled Study in the French Public‐School System
Authors: Courtier Philippine , Gardes Marie‐Line , Van der Henst Jean‐Baptiste , Noveck Ira A. , Croset Marie‐Caroline , Epinat‐Duclos Justine , Léone Jessica , Prado Jérôme
Published: May 2021

Previous research on Montessori preschool education is inconsistent and prone to analytic flexibility. In this preregistered study, disadvantaged preschoolers in a French public school were randomly assigned to either conventional or Montessori classrooms, with the latter being adapted to French public education. Adaptations included fewer materials, shorter work periods, and relatively limited Montessori teacher training. Cross‐sectional analyses in kindergarten (N = 176; Mage = 5–6) and longitudinal analyses over the 3 years of preschool (N = 70; Mage = 3–6) showed that the adapted Montessori curriculum was associated with outcomes comparable to the conventional curriculum on math, executive functions, and social skills. However, disadvantaged kindergarteners from Montessori classrooms outperformed their peers on reading (d = 0.68). This performance was comparable to that of advantaged children from an accredited Montessori preschool.
Free thyroxine in early pregnancy is an independent negative predictor of 3rd trimester HbA1c. Odense child cohort
Authors: Andersen Marianne Skovsager , Jensen Tina Kold , Dreyer Anja Fenger , Madsen Jeppe Buur , Christesen Henrik Thybo , Brandslund Ivan , Bilenberg Niels , Glintborg Dorte
Published: May 2021

Background

Lower thyroid function outside pregnancy is associated with an increased risk of type 2 diabetes mellitus. The relationship between thyroid function in early pregnancy and glucose status in 3rd trimester has not been investigated.

Aims

To study the association between 1st trimester thyroid function and 3rd trimester glucose status.

Design

In the prospective study Odense Child Cohort (OCC), 1,041 women had 1st trimester blood samples analysed for thyroid‐stimulating hormone (TSH), free T4 (FT4), thyroid peroxidase antibody and HbA1c. Third trimester (week 28) fasting blood samples included plasma glucose, insulin and HbA1c. Oral glucose tolerance test (OGTT, 75 g glucose) was performed in 509 women. First trimester FT4 was dichotomized >vs. ≤ the 25th percentile (25p = 12.9 pmol/L). Homeostatic model assessment‐insulin resistance (HOMA)‐IR and HOMA‐β were calculated.

Results

Women with FT4 ≤25p had significantly higher HbA1c in 1st and 3rd trimesters and higher 3rd trimester fasting glucose, insulin, HOMA‐IR and HOMA‐β compared to women with FT4 >25p. In multiple regression analyses, FT4 was an independent negative predictor of 3rd trimester HbA1c. FT4 levels in 3rd and 4th quartiles (high‐normal FT4 levels) showed closest inverse associations with HbA1c (p‐trend <.001). TSH was not associated with 3rd trimester HbA1c.

Conclusion

Women with lower levels of FT4 in early pregnancy had higher HbA1c in 3rd trimester and FT4 was an independent negative predictor of 3rd trimester HbA1c.
Mental health, adverse life events and health service use among Norwegian youth in the child welfare system: Results from a population‐based study
Authors: Nilsen Sondre Aasen , Askeland Kristin Gärtner , Loro Dora Poni Joseph , Iversen Anette Christine , Havnen Karen J. Skaale , Bøe Tormod , Heradstveit Ove
Published: May 2021

Youth within the child welfare system (CWS) have often experienced adverse life events, and many need support from health services. This study aimed to compare mental health problems and health service use among adolescents receiving in‐home services (IHS), living in foster care (FC) and general population youth (GP). Data stem from the youth@hordaland survey, a population‐based study of adolescents (N = 10,257, age 16–19) conducted in 2012 in Hordaland County, Norway. The adolescents provided self‐reported data on CWS contact, health service use, adverse life events and multiple instruments assessing mental health problems. The IHS and FC groups had significantly higher symptom scores across most mental health measures than peers from the GP. Youth receiving IHS had significantly higher scores on measures of general internalizing and externalizing problems, attention deficit hyperactivity disorder (ADHD) and depression compared with peers in FC. Those receiving IHS reported the highest health service use. Adverse life events accounted for a substantial part of the differences between the groups. Mental health problems are frequent among older adolescents within the CWS, especially among youth receiving IHS. Service providers and policymakers should be aware of the present and likely continued challenges faced by many of these youth.
Juvenile idiopathic inflammatory myopathies with anti‐3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase antibodies in a Chinese cohort
Authors: Hou Ying , Shao Kai , Zhao Bing , Dai Tingjun , Wang Qinzhou , Zhao Yuying , Yan Chuanzhu , Yan Yaping , Ma Xiaotian , Li Wei
Published: May 2021

Aims

To characterize the clinical and histopathological characteristics and treatment outcomes of juvenile idiopathic inflammatory myopathies (JIIMs) with anti‐3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) antibodies in a Chinese cohort.

Methods

We detected anti‐HMGCR antibodies in a series of Chinese JIIM by ELISA and indirect immunofluorescence assay on HEK293 cells, and summarized the clinical findings of these anti‐HMGCR antibody‐positive patients.

Results

Of 32 JIIM patients, 5 (15.63%) were found to be anti‐HMGCR antibody‐positive. The disease duration was 1.20 ± 0.45 months. Statin exposure was not found. Four patients had skin lesions, while typical pathological features of dermatomyositis such as perifascicular atrophy or myxovirus resistance protein A expression were not found. The mean creatine kinase level was 16771.60 U/L. Among the four patients who received long‐term (10.46 ± 1.42 years) follow‐up, three exhibited favorable outcomes with prednisone and additional immunosuppressants.

Conclusions

Our study indicates that anti‐HMGCR antibodies may not be rare in Chinese JIIM. These anti‐HMGCR‐positive JIIMs were characterized by acute onset, substantially elevated creatine kinase level, and skin lesions without perifascicular changes in muscle pathology. The treatment outcome is generally favorable with the combination of steroid and immunosuppressant.
Patch testing of budesonide in Italy: The SIDAPA baseline series experience, 2018–2019
Authors: Stingeni Luca , Marietti Rossella , Bianchi Leonardo , Guarneri Fabrizio , Ferrucci Silvia Mariel , Faraci Andrea Giuseppe , Foti Caterina , Romita Paolo , Patruno Cataldo , Napolitano Maddalena , Gallo Rosella , Corazza Monica , Schena Donatella , Milanesi Nicola , Bruni Francesca , Pigatto Paolo , Musumeci Maria Letizia , Martina Emanuela , Piras Viviana , Tramontana Marta , Hansel Katharina
Published: May 2021

Background

Budesonide was included in the European Baseline Series in 2000 as the most suitable marker forcorticosteroid hypersensitivity. In the last two decades, a decreasing trend of budesonide allergy has been observed.

Objectives

To estimate the prevalence of positive patch test reactions to budesonide in a large, Italian patch test population, characterizing patients according to MOAHLFA index and evaluating the benefit with extended readings of budesonide patch test.

Methods

Retrospective analysis of patient demographics and patch test results over a 2‐year period (2018–2019) was performed at 14 patch test clinics in Italy.

Results

Ninety out of 14 544 (0.6%) patients reacted to budesonide 0.01% pet.. Positive reactions were mild in 54.4% and late readings at day 7 showed new positive reactions in 37.8% of patients. The MOAHLFA index showed a significant positive association with male gender, atopic dermatitis, and age >40 years and a significant negative association with hand and face dermatitis.

Conclusions

We documented a low prevalence of budesonide allergy in Italy, confirming its decreasing trend recently reported in the literature. Nevertheless, budesonide needs to be maintained in the baseline series for its good ability to detect corticosteroid sensitization.
Prevalence and trend of allergen sensitization in patients referred for patch testing with a final diagnosis of psoriasis: North American Contact Dermatitis Group data, 2001‐2016
Authors: Silverberg Jonathan I. , Hou Alexander , DeKoven Joel G. , Warshaw Erin M. , Maibach Howard I. , Atwater Amber R. , Belsito Donald V. , Zug Kathryn A. , Taylor James S. , Sasseville Denis , Fransway Anthony F. , DeLeo Vincent A. , Pratt Melanie D. , Reeder Margo J. , Fowler Joseph F. , Zirwas Matthew J. , Marks James G. , Dunnick Cory A. , Houle Marie‐Claude
Published: May 2021

Background

Little is known about the relationship between psoriasis and allergic contact dermatitis (ACD).

Objective

To examine the associations with ACD, related clinical characteristics, and common positive and clinically relevant allergens of patients with a final diagnosis of psoriasis who were referred for patch testing.

Methods

Retrospective analysis of 38 723 patients from the North American Contact Dermatitis Group.

Results

Patients with a final diagnosis of psoriasis had lower proportions of ACD than those without psoriasis (32.7% vs 57.8%). In multivariable logistic regression models, psoriasis was inversely associated with female sex, Black or Asian race, and history of atopic dermatitis and hay fever. Patients with a final diagnosis of psoriasis were less likely to have one or more positive allergic patch‐test reactions or to have a current clinically relevant patch‐test reaction to the majority of the most commonly positive and/or relevant allergens. The most clinically relevant allergens included nickel sulfate, methylisothiazolinone, and fragrance mix I.

Conclusion

Approximately one‐third of patients who were referred for patch testing with a final diagnosis of psoriasis were also diagnosed with ACD. In select patients with suspected psoriasis who also have a clinical presentation suggestive of ACD, patch testing may be helpful.
All that glitters is not gold! Independent directors' attributes and earnings quality: Beyond formal independence
Authors: Marra Antonio
Published: May 2021

Research Question/Issue

This paper examines the effect of additional independent directors' attributes, beyond formal independence, on earnings management practices.

Research Findings/Insights

I find that being non‐busy, having accounting expertise, and being appointed by non‐controlling shareholders are relevant directors' attributes—beyond formal independence—in their earnings management monitoring task, among the directors' attributes I have tested. Additionally, the paper shows that independent directors who possess such features simultaneously outclass all other directors—included the touted effective formally independent directors—in mitigating earnings management activities.

Theoretical/Academic Implications

I respond to calls for dismantling common wisdom on board independence, investigating factors leading to better monitoring, showing that independent directors are not all‐alike. With specific reference to directors' monitoring task, when controlling for additional directors' attributes, formal independence becomes uninfluential in constraining earnings management activities. I also show that the co‐existence of attributes makes independent directors more effective relative to board mates not sharing such attributes.

Practitioner/Policy Implications

Findings of this work might be useful for practitioners in attempting to design corporate governance mechanisms better able to monitor earnings management practices through independent directors and may serve as a stimulus for regulators when re‐thinking regulations on board composition and structure.
The basic route of nuclear‐targeted transport of IGF‐1/IGF‐1R and potential biological functions in intestinal epithelial cells
Authors: Xiu Ming , Huan Xia , Ou Yang , Ying Sha , Wang Jianmeng
Published: May 2021

Objectives

Insulin‐like growth factor (IGF‐1) plays an important role in many biological processes in the intestinal tract. However, the cellular behaviour and characteristics of IGF‐1/IGF‐1R in intestinal cells remain unclear.

Materials and Methods

A series of techniques (such as indirect immunofluorescence, co‐localization and Western blot) have been used to systematically study the cellular behaviour of IGF‐1/IGF‐1R on intestinal cells.

Results

We found that IGF‐1 can not only internalize into the cytoplasm, but also transport into the cell nuclei. We systematically studied the detailed molecular pathways of IGF‐1/IGF‐1R’s nuclear translocation. We found that IGF‐1R underwent clathrin‐mediated endocytosis into cells and then entered into Rab‐5‐positive endosomes. Dynein/dynactin were used as motors to drive Rab‐5‐positive endosomes carrying IGF‐1R (cargo molecule) to Golgi apparatus (transit station) along the surface of the microtubule. IGF‐1 and/or IGF‐1R entered the cell nuclei through NPC (nuclear pore complex), a process mediated by NUP358. Further study indicated that nuclear localization of IGF‐1 and/or IGF‐1R promoted cell proliferation and increased the nuclear residence time of signalling molecules activated by IGF‐1. Further experiments showed that IGF‐1R may regulate the transcription of genes in the cell nuclei, indicating that nuclear‐localized IGF‐1R plays an important in cell proliferation.

Conclusions

In short, we revealed the molecular mechanism by which IGF‐1/IGF‐1R transports into the cell nuclei of intestinal cells. More importantly, the current work showed that the nuclear‐localized IGF‐1R has important biological functions.
PINK1‐mediated mitophagy maintains pluripotency through optineurin
Authors: Wang Chaoqun , Liu Kun , Cao Jiani , Wang Liang , Zhao Qian , Li Zheng , Zhang Honghai , Chen Quan , Zhao Tongbiao
Published: May 2021

Objectives

Dysfunction of autophagy results in accumulation of depolarized mitochondria and breakdown of self‐renewal and pluripotency in ESCs. However, the regulators that control how mitochondria are degraded by autophagy for pluripotency regulation remains largely unknown. This study aims to dissect the molecular mechanisms that regulate mitochondrial homeostasis for pluripotency regulation in mouse ESCs.

Materials and methods

Parkin+/+ and parkin−/− ESCs were established from E3.5 blastocysts of parkin+/− x parkin+/− mating mice. The pink1−/−, optn−/− and ndp52−/− ESCs were generated by CRISPR‐Cas9. shRNAs were used for function loss assay of target genes. Mito‐Keima, ROS and ATP detection were used to investigate the mitophagy and mitochondrial function. Western blot, Q‐PCR, AP staining and teratoma formation assay were performed to evaluate the PSC stemness.

Results

PINK1 or OPTN depletion impairs the degradation of dysfunctional mitochondria during reprogramming, and reduces the reprogramming efficiency and quality. In ESCs, PINK1 or OPTN deficiency leads to accumulation of dysfunctional mitochondria and compromised pluripotency. The defective mitochondrial homeostasis and pluripotency in pink1−/− ESCs can be compensated by gain expression of phosphomimetic Ubiquitin (Ub‐S65D) together with WT or a constitutively active phosphomimetic OPTN mutant (S187D, S476D, S517D), rather than constitutively inactive OPTN (S187A, S476A, S517A) or a Ub‐binding dead OPTN mutant (D477N).

Conclusions

The mitophagy receptor OPTN guards ESC mitochondrial homeostasis and pluripotency by scavenging damaged mitochondria through TBK1‐activated OPTN binding of PINK1‐phosphorylated Ubiquitin.
The case for reintroduction: The jaguar (Panthera onca) in the United States as a model
Authors: Sanderson Eric W. , Beckmann Jon P. , Beier Paul , Bird Bryan , Bravo Juan Carlos , Fisher Kim , Grigione Melissa M. , López González Carlos A. , Miller Jennifer R. B. , Mormorunni Cristina , Paulson Laura , Peters Rob , Polisar John , Povilitis Tony , Robinson Michael J. , Wilcox Sharon
Published: May 2021

Reintroduction—defined here as the return of a species to a part of its range where it has been extirpated—is a critical pathway to conservation in the 21st century. As late as the 1960s, jaguars (Panthera onca) inhabited an expansive region in the central mountain ranges of Arizona and New Mexico in the United States, a habitat unique in all of jaguar range. Here, we make the case for reintroduction, building a rhetorical bridge between conservation science and practice. First, we present a rationale rooted in the philosophy of wildlife conservation. Second, we show that the species once occupied this territory and was extirpated by human actions that should no longer pose a threat. Third, we demonstrate that the proposed recovery area provides suitable ecological conditions. Fourth, we discuss how return of the species could be a net benefit to people, explicitly recognizing a diversity of values and concerns. Fifth, we show that reintroduction is practical and feasible over a realistic time horizon. Returning the jaguar to this area will enhance the recovery of an endangered species in the United States, further its range‐wide conservation, and restore an essential part of North America's cultural and natural heritage.
Oxypurinol pharmacokinetics and pharmacodynamics in healthy volunteers: Influence of BCRP Q141K polymorphism and patient characteristics
Authors: Vora Bianca , Brackman Deanna J. , Zou Ling , Garcia‐Cremades Maria , Sirota Marina , Savic Radojka M. , Giacomini Kathleen M.
Published: May 2021

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300 mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half‐life (34.2 ± 12.2 h vs. 19.1 ± 1.42 h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1 mg/dl difference in serum creatinine. Real‐world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.
Immune response profiling in patients with traumatic injuries associated with alcohol ingestion
Authors: Breslin Adam W. , Limkakeng Alexander T. , Silvius Elizabeth , Staton Catherine A. , Almond Chandra , Joshi Mary‐Beth , Adams Bartley , Johnston Bria , McGowan Lauren , Kirk Allan D. , Elster Eric
Published: May 2021

Traumatic injuries afflict more than 5 million people globally every year. Current and past animal research has demonstrated association among alcohol, trauma, and impaired immune function, whereas human registries have shown association between alcohol and morbidity as well as mortality. The purpose of this study is to elucidate the immune interactions with alcohol in traumatically injured patients. We prospectively enrolled 379 patients after trauma at three medical centers in the Surgical Critical Care Initiative. Plasma was analyzed using Luminex for up to 35 different cytokines. Collected samples were grouped by patients with detectable plasma alcohol levels versus those without. Univariate testing determined differences in analytes between groups. We built Bayesian belief networks with multiple minimum descriptive lengths to compare the two groups. All 379 patient samples were analyzed. Two hundred eighty‐two (74.4%) patients were men, and 143 (37.7%) were White. Patients had a median intensive care unit length of stay (LOS) of 5.8 days and hospital LOS of 12 days. Using single variate analyses, eight different cytokines were differentially associated with alcohol. Cytokines IL‐12 and IL‐6 were important nodes in both models and IL‐10 was a prominent node in the nonalcohol model. This study found select immune function differed between traumatically injured patients with measurable serum alcohol levels as compared with those without. Traumatically injured patients with positive blood alcohol content appear less able to inhibit inflammatory stress. Alcohol appears to suppress pro‐inflammatory IL‐12 and IL‐6, whereas patients without alcohol have greater levels of anti‐inflammatory IL‐10 expressed at injury and may better regulate anti‐inflammatory pathways. Future studies should determine the relationship with these markers with clinically oriented outcomes.
Development of sacral/buttock retiform purpura as an ominous presenting sign of COVID‐19 and clinical and histopathologic evolution during severe disease course
Authors: McBride Jeffrey D. , Narang Jatin , Simonds Robert , Agrawal Shruti , Rodriguez E. Rene , Tan Carmela D. , Baldwin William M. , Dvorina Nina , Krywanczyk Alison R. , Fernandez Anthony P.
Published: May 2021

Retiform purpura has been described as a relatively frequent cutaneous finding in patients with coronavirus disease 2019 (COVID‐19). The etiology is hypothesized to be related to thrombotic vasculopathy based on lesional biopsy specimen findings, but the pathogenesis of the vasculopathy is not completely understood. Here, we present a case of a retiform purpuric patch on the sacrum/buttocks in a hospitalized patient prior to subsequent diagnosis of COVID‐19 and an eventual fatal disease course. Two lesional biopsy specimens at different time points in the disease course revealed thrombotic vasculopathy, despite therapeutic anticoagulation. Detailed histopathologic evaluation using immunohistochemical markers suggest the etiology of the vasculopathy involves both persistent complement activation and platelet aggregation, which possibly promote ongoing thrombus formation. This case highlights that sacral/buttock retiform purpuric patches may be a presenting sign of infection with SARS‐CoV‐2 virus and may represent an ominous sign supporting a future severe disease course. In addition, biopsy specimen findings at separate time points demonstrate that cutaneous vasculopathy may persist despite adequate systemic anticoagulation, possibly due to the combination of persistent complement and platelet activation. Finally, occlusive thrombi in sacral/buttock retiform purpuric patches may contribute to future ulceration and significant cutaneous morbidity in patients who survive COVID‐19.
Becoming a Learning Organization
Authors: Korn Randi , Chandler Katie , Marzec Colleen
Published: May 2021

When staff at the National Museum of Natural History (NMNH) opened their newest visitor‐experience space, Q?rius (pronounced curious), in 2013, they intended to create an innovative science‐learning space that would provide visitors with hands‐on access to the museum’s world‐renowned natural history collections, skill‐building experiences, and personal encounters with science experts. Over the years since Q?rius opened, education staff noticed changes in how their colleagues from different departments were working together and suspected that in some contexts the organization was operating differently. In 2018, RK&A studied institutional‐level changes at NMNH as a result of Q?rius, and, more broadly, helped staff and leadership understand the ways in which NMNH is a “learning organization” and where there is room for development. In this article we explore the concept of a learning organization, present key takeaways of the NMNH study and how they have been applied in practice, and for those who wish for their organization to grow into a learning organization, provide essential concepts to help them think through how they might pursue such work in their museum.
Redefining Curatorial Leadership and Activating Community Expertise to Build Equitable and Inclusive Art Museums
Authors: Pegno Marianna , Brindza Christine
Published: May 2021

Leadership in art museums is a changing construct: historically, these institutions were established as hierarchical, top‐down structures that prioritized sole expertise to dictate success. Today, museums are searching for ways to become more responsive, collaborative, and multivocal institutions that value community voices and expertise. A growing variety of museum professionals ask how to better reflect and integrate local communities within their museums. We share reflections, insights, and lessons learned from a multi‐year case study at the Tucson Museum of Art and Historic Block (TMA), which focuses on redefining curatorial leadership as community‐based and collaborative to expand approaches to exhibition development and interpretation. The authors of this article highlight how network governance/collaborative leadership can be applied to curatorial practice to develop exhibitions rooted in collaborative stewardship, multivocality, and community‐based approaches. Here, leadership is defined as a way in which a museum influences its communities and vice versa. In addition, we discuss strategies for building multi‐directional and collaborative initiatives to shape a more equitable and inclusive museum.
Museum Leadership for Engaging, Equitable Education: The Transformative Potential of Digitized Collections for Authentic Learning Experiences
Authors: Butcher Kirsten R. , Power Mitchell J. , Larson Madlyn , Orr Matthew P. , Velásquez‐Franco Susana , Hudson Michelle A. , Bailey Vanessa J.
Published: May 2021

Museums are local‐to‐global organizations operating in a digitized, distributed, and diverse 21st century world. Museums leaders face significant challenges in achieving broader relevance, meaningful engagement, and equitable outreach. This article examines the transformative potential of digitized collections to increase public engagement and enhance authentic educational efforts of museums, with specific emphasis on visual media as a key resource to achieve these outcomes. Using digitized collections to broaden learning opportunities and support a wide range of users will require museum leaders to engage in strategic digitization efforts—supplementing research images, making conscious decisions about meeting educational needs when setting digitization policies, and investing in meaningful outreach with digitized collections. Educational opportunities are contextualized with brief case studies of authentic investigations for middle school learners using digitized objects from a natural history museum. Three lessons learned during development and evaluation are described and implications for museum leaders are discussed.
Treatment satisfaction in chronic urticaria during guideline‐based therapy
Authors: Rönsch Henriette , Berndt Katja , Bauer Andrea
Published: May 2021

Background and objectives

Patients with chronic urticaria are often unsatisfied with their treatment. We aimed to assess patient satisfaction, chronic urticaria control, treatment goals, self‐treatment competence, knowledge, and factors influencing treatment satisfaction.

Patients and methods

Eighty‐seven adult patients with chronic urticaria who were previously insufficiently treated with oral antihistamines received guideline‐based care for six months and completed questionnaires.

Results

This study included patients with chronic spontaneous (80 %) and/or inducible urticaria (CIndU, 32 %). Significant median improvements were observed with the urticaria control test (UCT, from 7 to 11), the urticaria activity score for patients with chronic spontaneous urticaria (from 19 to 10), and treatment satisfaction (from 5.2 to 8.4). Six significant, independent factors of treatment satisfaction after six months of treatment were identified (negative: male sex, CIndU, sleep disturbances; positive: UCT, baseline treatment satisfaction, perceived competence of the study physician). Adequate urticaria control (UCT ≥ 12) was achieved in 19 % of patients with CIndU and 61 % of patients without CIndU.

Conclusions

In patients with chronic urticaria who were previously insufficiently treated with antihistamines, six months of guideline‐based therapy significantly improved disease control and treatment satisfaction. Adequate control requires several consultations for many patients and is considerably more difficult to achieve for CIndU.
Endoscopic retrieval of a sheared guidewire remnant from walled‐off necrosis
Authors: Hirakawa Noriyuki , Tonozuka Ryosuke , Itoi Takao
Published: May 2021

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Transgender and cisgender children's essentialist beliefs about sex and gender identity
Authors: Gülgöz Selin , Alonso Daniel J. , Olson Kristina R. , Gelman Susan A.
Published: May 2021

Children essentialize gender from a young age, viewing it as inborn, biologically based, unchanging, and predictive of preferences and behaviors. Children's gender essentialism appears to be so pervasive that it is found within conservative and liberal communities, and among transgender and cisgender children. However, it remains unclear what aspect of gender the children participating in past studies essentialized. Such studies used labels such as “girl” or “boy” without clarifying how children (or researchers) interpreted them. Are they indicators of the target's biological categorization at birth (sex), the target's sense of their own gender (gender identity), or some third possible interpretation? This distinction becomes particularly relevant when transgender children are concerned, as their sex assigned at birth and gender identity are not aligned. In the present two studies, we discovered that 6‐ to 11‐year‐old transgender children, their cisgender siblings, and unrelated cisgender children, all essentialized both sex and gender identity. Moreover, transgender and cisgender children did not differ in their essentialism of sex (i.e., whether body parts would remain stable over time). Importantly, however, transgender children were less likely than unrelated cisgender children to essentialize when hearing an ambiguous gender/sex label (“girl” or “boy”). Finally, the two studies showed mixed findings on whether the participant groups differed in reasoning about the stability of a gender‐nonconforming target's gender identity. These findings illustrate that a child's identity can relate to their conceptual development, as well as the importance of diversifying samples to enhance our understanding of social cognitive development.