bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics
Authors: Hassankalhori Mahdi , Bolcato Giovanni , Bissaro Maicol , Sturlese Mattia , Moro Stefano 
Published: September 2021

Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide—from a novel library of 8,988 sub-kilodalton macrocyclic peptides—in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle–protein molecular recognition studies.
Analysis of Heritability Across the Clinical Phenotypes of Frontotemporal Dementia and the Frequency of the C9ORF72 in a Colombian Population
Authors: López-Cáceres Andrea , Velasco-Rueda María , Garcia-Cifuentes Elkin , Zarante Ignacio , Matallana Diana 
Published: September 2021

Frontotemporal dementia (FTD) is a highly heritable condition. Up to 40% of FTD is familial and an estimated 15% to 40% is due to single-gene mutations. It has been estimated that the G4C2 hexanucleotide repeat expansions in the C9ORF72 gene can explain up to 37.5% of the familial cases of FTD, especially in populations of Caucasian origin. The purpose of this paper is to evaluate hereditary risk across the clinical phenotypes of FTD and the frequency of the G4C2 expansion in a Colombian cohort diagnosed with FTD.Methods: A total of 132 FTD patients were diagnosed according to established criteria in the behavioral variant FTD, logopenic variant PPA, non-fluent agrammatic PPA, and semantic variant PPA. Hereditary risk across the clinical phenotypes was established in four categories that indicate the pathogenic relationship of the mutation: high, medium, low, and apparently sporadic, based on those proposed by Wood and collaborators. All subjects were also examined for C9ORF72 hexanucleotide expansion (defined as &gt;30 repetitions).Results: There were no significant differences in the demographic characteristics of the patients between the clinical phenotypes of FTD. The higher rate phenotype was bvFTD (62.12%). In accordance with the risk classification, we found that 72 (54.4%) complied with the criteria for the sporadic cases; for the familial cases, 23 (17.4%) fulfilled the high-risk criteria, 23 (17.4%) fulfilled the low risk criteria, and 14 (10.6%) fulfilled the criteria to be classified as subject to medium risk. C9ORF72 expansion frequency was 0.76% (1/132).Conclusion: The FTD heritability presented in this research was very similar to the results reported in the literature. The C9ORF72 expansion frequency was low. Colombia is a triethnic country, with a high frequency of genetic Amerindian markers; this shows consistency with the present results of a low repetition frequency. This study provides an initial report of the frequency for the hexanucleotide repeat expansions in C9ORF72 in patients with FTD in a Colombian population and paves the way for further study of the possible genetic causes of FTD in Colombia.
Association of Preoperative Cerebrospinal Fluids Parameters With Early Shunt Obstruction in Patients With Post-hemorrhagic Hydrocephalus Treated by Lumboperitoneal Shunt
Authors: Sun Tong , Cui Wenyao , Chen Siyang , Yuan Yikai , Yang Jingguo , Zhou Yicheng , Li Xuepei , Yu Hang , You Chao , Guan Junwen 
Published: September 2021

Background: Early shunt obstruction (SO) remains the most common cause of lumboperitoneal shunt (LPS) failure. Although there is anecdotal evidence that the level of cerebrospinal fluid (CSF) parameters might affect shunt performance, its association with early LPS obstruction in adults with post-hemorrhagic hydrocephalus (PHH) is unclear.Methods: The retrospective study was performed by reviewing the adults with PHH treated by LPS from years 2014 to 2018. We included patients with CSF samples analyzed within 1 week prior to shunt insertion or at the time of shunt insertion. Baseline characteristics of each patient were collected. The primary outcomes were the incidence rate and associated factors of SO occurring within 3 months of shunt placement. The secondary outcomes included scores on the National Institute of Health Stroke Scale (NIHSS) and Evans Index at discharge.Results: A total of 76 eligible patients were analyzed, of whom 61 were obstruction-free and 15 were early SO. The overall rate of early SO was 15.6%. The RBCs count and nucleated cells count in preoperative CSF were actually higher in patients with early SO, compared to patients in the control group. Multivariate analysis identified RBC elevation (&gt;0 × 106/L; OR: 10.629, 95% CI: 1.238–91.224, p = 0.031) as a dependent risk factor for early SO. NIHSS dramatically decreased at discharge while the alteration of ventricular size was not observed.Conclusions: This study suggested that the presence of RBCs in preoperative CSF was associated with early SO in patients with PHH treated by LPS.
Physical Activity and Health-Related Quality of Life in Adults With a Neurologically-Related Mobility Disability During the COVID-19 Pandemic: An Exploratory Analysis
Authors: Nightingale Tom E. , Heneghan Nicola R. , Fenton Sally A. M. , Veldhuijzen van Zanten Jet J. C. S. , Jutzeler Catherine R. 
Published: September 2021

Background: During the coronavirus-19 (COVID-19) pandemic various containment strategies were employed. Their impact on individuals with neurological conditions, considered vulnerable to COVID-19 complications, remains to be determined.Objective: To investigate associations between physical activity and health-related quality of life outcomes in individuals with a neurological condition during government mandated COVID-19 restrictions.Methods: An e-survey assessing fear of COVID-19, physical activity level and health-related quality of life outcomes (functional disability and pain, anxiety and depression, loneliness, fatigue, and vitality) was distributed to individuals with a neurologically-related mobility disability living in the United Kingdom. Open-ended questions were also included to contextualize barriers and facilitators to engage in physical activity during the COVID-19 pandemic. Gamma-weighted generalized linear models and tree-structured regression models were employed to determine the associations between physical activity and health-related quality of life.Results: Of 199 responses, 69% reported performing less physical activity compared to pre-pandemic. Tree-structured regression models revealed that lower leisure-time physical activity was significantly associated (p ≤ 0.009) with higher depression and fatigue, but lower vitality. The closure of leisure facilities and organized sport (27%) was the most commonly cited barrier to engage in physical activity, while 31% of participants mentioned concerns around their physical and mental health as a facilitator.Conclusion: Our analysis identified homogenous subgroups for depression, fatigue, and vitality based specifically on leisure-time physical activity cut points, irrespective of additional demographic or situational characteristics. Findings highlight the importance of and need to safely promote leisure-time physical activity during the COVID-19 pandemic in this at-risk population to help support health-related quality of life.
Aging With Cerebral Palsy: A Photovoice Study Into Citizenship
Authors: van Heijningen Vera G. , Cardol Mieke , van Heijningen-Tousain Heidi J. M. , Oosterveer Daniëlla M. , van Markus-Doornbosch Frederike , Sattoe Jane N. T. , van der Holst Menno , Hilberink Sander R. 
Published: September 2021

Background: Adults with cerebral palsy (CP) may experience an increasing impact of their disability on daily life and this may interfere with their citizenship. Citizenship is a layered construct. Next to formal and theoretical significations, and civil rights acts such as the UN Convention on the Rights for Persons with Disabilities (CRPD), the meaning of citizenship is formed by the person themselves. The present study aimed to gain insight into what citizenship means for adults with CP 40 years or older and what is needed to support and pursue their citizenship to improve person-centered rehabilitation which can facilitate this process.Methods: Adults with CP (&gt;40 years) without intellectual disability were recruited from medical records of a large rehabilitation center to participate in a qualitative study using the photovoice method. Participants were asked to take photos of objects or life situations that constituted citizenship for them; these photos were then the prompts for the semi-structured interviews that were held face-to-face at their homes. Background and clinical characteristics were gathered using a short face-to-face questionnaire. Data were analyzed through inductive thematic analysis.Results: Nineteen adults participated [mean age (SD) 57.8 (9.4) years (range 44–79), six men]. From the analysis four themes emerged: (a) Meanings of citizenship; (b) Citizenship: Facilitator and barriers; (c) Paradoxes of support and participation; and (d) Future. Furthermore, next to the ability to participate in society without restrictions, sense of belonging was reported to be an important aspect of “meanings of citizenship.” The physiotherapist was perceived as an important health professional to maintain physical activity and deal with the impact of aging with CP on daily activities. Complex healthcare and support services regulations and aging affected citizenship negatively.Conclusion: Middle-aged and older adults with CP view citizenship as the ability to participate and belong in society. To optimize their citizenship the challenges and individual needs must be seen and supported by person-centered rehabilitation and support services. Simplification of complex healthcare and services regulations can further improve citizenship.
The Higher Parietal Cortical Thickness in Abstinent Methamphetamine Patients Is Correlated With Functional Connectivity and Age of First Usage
Authors: Yang Ru , He Lei , Zhang Zhixue , Zhou Wenming , Liu Jun 
Published: September 2021

AimThis study aimed to explore the changes of cortical thickness in abstinent methamphetamine (MA) patients compared with healthy controls.Materials and MethodsThree-tesla structural and functional magnetic resonance imaging (MRI) was obtained from 38 abstinent methamphetamine-dependent (AMD) patients and 32 demographically equivalent healthy controls. The cortical thickness was assessed using FreeSurfer software. General linear model was used to get brain regions with significant different cortical thickness between groups (p &lt; 0.05, Monte Carlo simulation corrected). The mean cortical thickness value and functional connectivity with all other brain regions was extracted from those significant regions. Moreover, correlation coefficients were calculated in the AMD group to assess the relations between the mean cortical thickness, functional connectivity and age when they first took MA and the duration of both MA use and abstinence.ResultsThe AMD group showed significant cortical thickness increase in one cluster located in the parietal cortex, including right posterior central gyrus, supramarginal gyrus, and superior parietal lobule. In addition, cortical thickness values of those regions were all significant and negatively correlated with the age when patients first used MA. The cortical thickness of right posterior gyrus were positively correlated with its functional connectivities with left middle frontal gyrus and both left and right medial orbitofrontal gyrus.ConclusionThe higher cortical thickness in the parietal cortex of the AMD group is in agreement with findings in related studies of increased glucose metabolism and gray matter volume. Importantly, the negative correlation between parietal cortical thickness and age of first MA suggested that adolescent brains are more vulnerable to MA’s neurotoxic effect.
A Nutraceutical Formula Is Effective in Raising the Circulating Vitamin and Mineral Levels in Healthy Subjects: A Randomized Trial
Authors: Nenseth Hatice Zeynep , Sahu Aparna , Saatcioglu Fahri , Osguthorpe Steven 
Published: September 2021

Low levels of nutrient intake are common in industrialized countries. This has negative implications on health and is associated with chronic diseases. Supplementation of vitamins, minerals, and key nutrients to optimal levels may, therefore, be beneficial for individual health and for the health economy. Although the use of supplements has become very common, due to a lack of monitoring, there is very limited data on the efficacy of supplementation with different formulas. In this study, we present the results of a randomized controlled study on the efficacy of a novel formulated nutraceutical, N247, in 250 healthy volunteers aged 26–75 years and a placebo control group (n = 35). The broad-spectrum formulation of N247 includes essential vitamins, minerals, and trace elements that are adequately balanced in regard to synergies and related metabolic functions. Moreover, tolerance, safety, and nutrient availability is an important aspect of daily, long-term use of N247. After 3 months of regular N247 use, levels of vitamins and minerals in serum were significantly increased in the N247 group compared with the control group and a placebo group, with excellent compliance rates. Coupled with additional natural ingredients that aim to increase the potency of the nutrients, N247 may represent a novel and beneficial supplement for individuals with nutritional deficiencies.Clinical Trial Registration:https://clinicaltrials.gov/, identifier: NCT04054505.
Management of Large Cell Neuroendocrine Carcinoma
Authors: Corbett Virginia , Arnold Susanne , Anthony Lowell , Chauhan Aman 
Published: September 2021

BackgroundLarge cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive cancer with a dismal prognosis. The majority of cases occur in the lung and the gastrointestinal tract; however, it can occur throughout the body. Recently advances in the understanding of the molecular underpinnings of this disease have paved the way for additional novel promising therapies. This review will discuss the current best evidence for management of LCNEC and new directions in the classification and treatment of this rare disease.MethodsWe performed a PubMed search for “Large cell neuroendocrine carcinoma” and “High grade neuroendocrine carcinoma.” All titles were screened for relevance to the management of LCNEC. Papers were included based on relevance to the management of LCNEC.ResultsPapers were included reviewing both pulmonary and extra pulmonary LCNEC. We summarized the data driven best practices for the management of both early and advanced stage LCNEC. We describe emerging therapies with promising potential.DiscussionLCNEC are rare and aggressive neoplasms. In advanced disease, the historical regimen of platinum based therapy in combination with etoposide or irinotecan remains among the commonly used first line therapies, however for extra thoracic LCNEC regimens like FOLFOX, FOLFOIRI and CAPTEM can also be used. Further effective and safe treatment options are desperately needed. Recently, new advances including a new understanding of the genetic subcategories of LCNEC and immunotherapy agents may guide further treatments.
Polymorphism of MUC1 Gene in Vietnamese Gastric Cancer Patients: A Multicenter Case–Control Study
Authors: Nguyen Ngoc-Lan Thi , Dang Ngoc-Dzung Thi , Dang Quang-Huy , Tran Van-Chuc , Vo Hoang-Long , Yamaguchi Masamitsu , Ta Thanh-Van 
Published: September 2021

BackgroundA few studies revealed that the polymorphisms of Mucin 1 gene have a role and significance as a susceptible factor contributing to gastric cancer. To better understand the roles of two MUC1 genotype polymorphisms of rs4072037 and rs2070803 in the development of gastric cancer in Vietnamese population, a multicenter, large-sample, case–control study was conducted to investigate the potential association of these single-nucleotide polymorphisms (SNPs) of MUC1 gene with gastric cancer risk and to evaluate the combination factors in relation with these SNPs.MethodsThis case–control study included 302 gastric cancer patients and 304 controls at four national medical hospitals between 2016 and 2018. All participants were interviewed for sociodemographic characteristics, smoking and drinking status, and personal and family history of gastric diseases. Genotyping was done using polymerase chain reaction–restriction fragment length polymorphism analysis. The association of SNPs with gastric cancer was explored using logistic regression models.ResultsAA genotype for rs4072037 was significantly associated with increased gastric cancer. Those with AA genotype had higher gastric cancer risk than had patients with AG (OR: 2.09, 95% CI: 1.48–2.96) and a combination of AG+GG (OR: 1.85, 95% CI: 1.33–2.56). In rs2070803, GG genotype increased gastric cancer risk when compared with AG (OR: 1.97, 95% CI: 1.39–2.80) and AG+AA (OR: 1.71, 95% CI: 1.23–2.39). AG genotypes in both SNPs decreased gastric cancer risk when compared with homogenous genotype, more specifically AA (OR: 0.51, 95% CI: 0.35–0.72) and GG (OR: 0.58, 95% CI: 0.35–0.97). These genotypes in combination with above-60-year-old age, male gender, alcoholism, and personal history of gastric disease were also significantly elevated risk factors for gastric cancer.Conclusionsrs4072037 and rs2070803 of Mucin 1 genes are two genotypic risk factors for gastric cancer. Those in combination with gender, family history, smoking, and drinking habits significantly increase the risk of gastric cancer.
Comparison of Multiple Clinical Testing Modalities for Assessment of NPM1-Mutant AML
Authors: Lopez Amanda , Patel Sanjay , Geyer Julia T. , Racchumi Joelle , Chadburn Amy , Simonson Paul , Ouseph Madhu M. , Inghirami Giorgio , Mencia-Trinchant Nuria , Guzman Monica L. , Gomez-Arteaga Alexandra , Lee Sangmin , Desai Pinkal , Ritchie Ellen K. , Roboz Gail J. , Tam Wayne , Kluk Michael J. 
Published: September 2021

BackgroundNPM1 mutation status can influence prognosis and management in AML. Accordingly, clinical testing (i.e., RT-PCR, NGS and IHC) for mutant NPM1 is increasing in order to detect residual disease in AML, alongside flow cytometry (FC). However, the relationship of the results from RT-PCR to traditional NGS, IHC and FC is not widely known among many practitioners. Herein, we aim to: i) describe the performance of RT-PCR compared to traditional NGS and IHC for the detection of mutant NPM1 in clinical practice, and also compare it to FC, and ii) provide our observations regarding the advantages and disadvantages of each approach in order to inform future clinical testing algorithms.MethodsPeripheral blood and bone marrow samples collected for clinical testing at variable time points during patient management were tested by quantitative, real-time, RT-PCR and results were compared to findings from a Myeloid NGS panel, mutant NPM1 IHC and FC.ResultsRT-PCR showed superior sensitivity compared to NGS, IHC and FC with the main challenge of NGS, IHC and FC being the ability to identify a low disease burden (&lt;0.5% NCN by RT-PCR). Nevertheless, the positive predictive value of NGS, IHC and FC were each ≥ 80% indicating that positive results by those assays are typically associated with RT-PCR positivity. IHC, unlike bulk methods (RT-PCR, NGS and FC), is able provide information regarding cellular/architectural context of disease in biopsies. FC did not identify any NPM1-mutated residual disease not already detected by RT-PCR, NGS or IHC.ConclusionOverall, our findings demonstrate that RT-PCR shows superior sensitivity compared to a traditional Myeloid NGS, suggesting the need for “deep-sequencing” NGS panels for NGS-based monitoring of residual disease in NPM1-mutant AML. IHC provides complementary cytomorphologic information to RT-PCR. Lastly, FC may not be necessary in the setting of post-therapy follow up for NPM1-mutated AML. Together, these findings can help inform future clinical testing algorithms.
Extending the Applicability of In Ovo and Ex Ovo Chicken Chorioallantoic Membrane Assays to Study Cytostatic Activity in Neuroblastoma Cells
Authors: Merlos Rodrigo Miguel Angel , Casar Berta , Michalkova Hana , Jimenez Jimenez Ana Maria , Heger Zbynek , Adam Vojtech 
Published: September 2021

PurposeThe chick chorioallantoic membrane (CAM) assay can provide an alternative versatile, cost-effective, and ethically less controversial in vivo model for reliable screening of drugs. In the presented work, we demonstrate that CAM assay (in ovo and ex ovo) can be simply employed to delineate the effects of cisplatin (CDDP) and ellipticine (Elli) on neuroblastoma (Nbl) cells in terms of their growth and metastatic potential.MethodsThe Nbl UKF-NB-4 cell line was established from recurrent bone marrow metastases of high-risk Nbl (stage IV, MYCN amplification, 7q21 gain). Ex ovo and in ovo CAM assays were optimized to evaluate the antimetastatic activity of CDDP and Elli. Immunohistochemistry, qRT-PCR, and DNA isolation were performed.ResultsEx ovo CAM assay was employed to study whether CDDP and Elli exhibit any inhibitory effects on growth of Nbl xenograft in ex ovo CAM assay. Under the optimal conditions, Elli and CDDP exhibited significant inhibition of the size of the primary tumor. To study the efficiency of CDDP and Elli to inhibit primary Nbl tumor growth, intravasation, and extravasation in the organs, we adapted the in ovo CAM assay protocol. In in ovo CAM assay, both studied compounds (CDDP and Elli) exhibited significant (p &lt; 0.001) inhibitory activity against extravasation to all investigated organs including distal CAM.ConclusionsTaken together, CAM assay could be a helpful and highly efficient in vivo approach for high-throughput screening of libraries of compounds with expected anticancer activities.