bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blocking glutamate mGlu5 receptors with the negative allosteric modulator CTEP improves disease course in SOD1G93A mouse model of amyotrophic lateral sclerosis
Authors: Milanese Marco , Bonifacino Tiziana , Torazza Carola , Provenzano Francesca , Kumar Mandeep , Ravera Silvia , Zerbo Arianna Roberta , Frumento Giulia , Balbi Matilde , Nguyen T. P. Nhung , Bertola Nadia , Ferrando Sara , Viale Maurizio , Profumo Aldo , Bonanno Giambattista 
Published: May 2021

Background and PurposeThe pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully clarified, although excessive glutamate (Glu) transmission and the downstream cytotoxic cascades are major mechanisms for motor neuron death. Two metabotropic glutamate receptors (mGlu1 and mGlu5) are overexpressed in ALS and regulate cellular disease processes. Expression and function of mGlu5 receptors are altered at early symptomatic stages in the SOD1G93A mouse model of ALS and knockdown of mGlu5 receptors in SOD1G93A mice improved disease progression.Experimental ApproachWe treated male and female SOD1G93A mice with 2‐chloro‐4‐((2,5‐dimethyl‐1‐(4‐(trifluoromethoxy)phenyl)‐1H‐imidazol‐4‐yl)ethynyl)pyridine (CTEP), an orally available mGlu5 receptor negative allosteric modulator (NAM), using doses of 2 mg·kg−1 per 48 h or 4 mg·kg−1 per 24 h from Day 90, an early symptomatic disease stage. Disease progression was studied by behavioural and histological approaches.Key ResultsCTEP dose‐dependently ameliorated clinical features in SOD1G93A mice. The lower dose increased survival and improved motor skills in female mice, with barely positive effects in male mice. Higher doses significantly ameliorated disease symptoms and survival in both males and females, females being more responsive. CTEP also reduced motor neuron death, astrocyte and microglia activation, and abnormal glutamate release in the spinal cord, with equal effects in male and female mice. No differences were also observed in CTEP access to the brain.Conclusion and ImplicationsOur results suggest that mGlu5 receptors are promising targets for the treatment of ALS and highlight mGlu5 receptor NAMs as effective pharmacological tools with translational potential.
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 Purposel‐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 ApproachVascular 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 ResultsCSE‐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 ImplicationsThe 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

AbstractSeveral 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

AbstractThe 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

AbstractWnt, 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

AbstractBladder 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

AbstractReactive 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

AbstractAdjuvant 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

AbstractTraditional 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

AbstractThe 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

AbstractBackgroundLower 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.AimsTo study the association between 1st trimester thyroid function and 3rd trimester glucose status.DesignIn 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.ResultsWomen 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.ConclusionWomen 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

AbstractYouth 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.