bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does the protocol-required uniform margin around the CTV adequately account for setup inaccuracies in whole breast irradiation?
Authors: Luo Jurui , Yin Zhihai , Zhang Zhen , Guo Xiaomao , Yu Xiaoli , Wang Juanqi 
Published: August 2021

Abstract
Purpose
To use cone-beam computed tomography (CBCT) imaging to determine the impacts of patient characteristics on the magnitude of geometric setup errors and obtain patient-specific planning target volume (PTV) margins from the correlated patient characteristics in whole breast irradiation (WBI).

Methods
Between January 2019 and December 2019, a total of 97 patients who underwent breast-conserving surgery, followed by intensity-modulated radiation therapy in WBI, were scanned with pre-treatment CBCT for the first three treatment fractions and weekly for the subsequent fractions. Setup errors in the left–right (LR), superior–inferior (SI) and anterior–posterior (AP) directions were recorded and analyzed with patient characteristics—including age, tumor location, body mass index (BMI), chest circumference (CC) and breast volume (BV)—to examine the predictors for setup errors and obtain specific PTV margins.

Results
A total of 679 CBCT images from 97 patients were acquired for analysis. The mean setup errors for the whole group were 2.32 ± 1.21 mm, 3.71 ± 2.21 mm and 2.75 ± 1.56 mm in the LR, SI and AP directions, respectively. Patients’ BMI, CC and BV were moderately associated with setup errors, especially in the SI directions (R = 0.40, 0.43 and 0.22, respectively). Setup errors in the SI directions for patients with BMI > 23.8 kg/m2, CC > 89 cm and BV > 657 cm3 were 4.56 ± 2.59 mm, 4.77 ± 2.42 mm and 4.30 ± 2.43 mm, respectively, which were significantly greater than those of patients with BMI ≤ 23.8 kg/m2, CC ≤ 89 cm and BV ≤ 657 cm3 (P < 0.05). Correspondingly, the calculated PTV margins in patients with BMI > 23.8 kg/m2, CC > 89 cm and BV > 657 cm3 were 4.25/7.95/4.93 mm, 4.37/7.66/5.24 mm and 4.22/7.54/5.29 mm in the LR/SI/AP directions, respectively, compared with 3.64/4.64/5.09 mm, 3.31/4.50/4.82 mm and 3.29/5.74/4.73 mm for BMI ≤ 23.8 kg/m2, CC ≤ 89 cm and BV ≤ 657 cm3, respectively.

Conclusions
The magnitude of geometric setup errors was moderately correlated with BMI, CC and BV. It was recommended to set patient-specific PTV margins according to patient characteristics in the absence of daily image-guided treatment setup.
HPV16 E6 enhances the radiosensitivity in HPV-positive human head and neck squamous cell carcinoma by regulating the miR-27a-3p/SMG1 axis
Authors: Long Dan , Xu Li , Deng Zeyi , Guo Dandan , Zhang Yangchun , Liu Zhaohui , Zhang Chunlin 
Published: August 2021

Abstract
Background
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common malignant cancer type worldwide. Radiosensitivity has been shown to be significantly increased in patients with human papillomavirus (HPV)-positive HNSCC compared with HPV-negative patients. However, the clinical significance of HPV and its regulatory mechanisms in HNSCC are largely unknown. The aim of our study was to explore the regulatory mechanism of miR-27a-3p in the radiosensitivity of HPV-positive HNSCC cells.

Methods
E6-overexpressing and E6-knockdown HNSCC cell lines were generated and the transfection efficiencies were evaluated by quantitative real-time PCR (RT-qPCR) and western blotting. The expression of miR-27a-3p and DiGeorge syndrome critical region 8 (DGCR8) was examined by RT-qPCR after transfection with E6 overexpressing plasmid or E6 siRNA. The effects of miR-27a-3p on the radiosensitivity of HNSCC cells were explored by a colony formation and TUNEL staining assays. Bioinformatic tools and luciferase reporter assays were used to identify that SMG1 is the direct target of miR-27a-3p. Furthermore, the effect of E6 overexpression on the regulation of the miR-27a-3p/SMG1 axis was investigated.

Results
In our study, we found overexpression of HPV E6 upregulated the expression of DGCR8 and miR-27a-3p in HNSCC cells. We next confirmed that DGCR8 positively regulated the expression of miR-27a-3p in HNSCC cells. The luciferase reporter gene results verified that miR-27a-3p targeted the 3’UTR of SMG1 mRNA. MiR-27a-3p mimics transfection resulted in a decrease in SMG1 expression and miR-27a-3p inhibitor transfection increased SMG1 expression. Apoptotic activity of HNSCC cells was significantly increased in miR-27a-3p mimics HNSCC cells compared with control HNSCC cells. After treatment with 4 Gy irradiation, UM-SCC47 cells transfected with miR-27a-3p inhibitor or SMG1 overexpressing plasmid formed more colonies than the corresponding control cells. Furthermore, the rescue experiments demonstrated that HPV16 E6 improved the radiosensitivity of HNSCC cells by targeting miR-27a-3p/SMG1.

Conclusion
Our study demonstrated that HPV16 E6 activated the DGCR8/miR-27a-3p/SMG1 axis to enhance the radiosensitivity. Our findings might provide a novel therapeutic target to improve the response of HNSCC to radiotherapy.
Chromatin interaction neural network (ChINN): a machine learning-based method for predicting chromatin interactions from DNA sequences
Authors: Cao Fan , Zhang Yu , Cai Yichao , Animesh Sambhavi , Zhang Ying , Akincilar Semih Can , Loh Yan Ping , Li Xinya , Chng Wee Joo , Tergaonkar Vinay , Kwoh Chee Keong , Fullwood Melissa J. 
Published: August 2021

AbstractChromatin interactions play important roles in regulating gene expression. However, the availability of genome-wide chromatin interaction data is limited. We develop a computational method, chromatin interaction neural network (ChINN), to predict chromatin interactions between open chromatin regions using only DNA sequences. ChINN predicts CTCF- and RNA polymerase II-associated and Hi-C chromatin interactions. ChINN shows good across-sample performances and captures various sequence features for chromatin interaction prediction. We apply ChINN to 6 chronic lymphocytic leukemia (CLL) patient samples and a published cohort of 84 CLL open chromatin samples. Our results demonstrate extensive heterogeneity in chromatin interactions among CLL patient samples.
CardioTox net: a robust predictor for hERG channel blockade based on deep learning meta-feature ensembles
Authors: Karim Abdul , Lee Matthew , Balle Thomas , Sattar Abdul 
Published: August 2021

AbstractMotivationEther-a-go-go-related gene (hERG) channel blockade by small molecules is a big concern during drug development in the pharmaceutical industry. Blockade of hERG channels may cause prolonged QT intervals that potentially could lead to cardiotoxicity. Various in-silico techniques including deep learning models are widely used to screen out small molecules with potential hERG related toxicity. Most of the published deep learning methods utilize a single type of features which might restrict their performance. Methods based on more than one type of features such as DeepHIT struggle with the aggregation of extracted information. DeepHIT shows better performance when evaluated against one or two accuracy metrics such as negative predictive value (NPV) and sensitivity (SEN) but struggle when evaluated against others such as Matthew correlation coefficient (MCC), accuracy (ACC), positive predictive value (PPV) and specificity (SPE). Therefore, there is a need for a method that can efficiently aggregate information gathered from models based on different chemical representations and boost hERG toxicity prediction over a range of performance metrics.ResultsIn this paper, we propose a deep learning framework based on step-wise training to predict hERG channel blocking activity of small molecules. Our approach utilizes five individual deep learning base models with their respective base features and a separate neural network to combine the outputs of the five base models. By using three external independent test sets with potency activity of IC50at a threshold of 10$$\upmu$$μm, our method achieves better performance for a combination of classification metrics. We also investigate the effective aggregation of chemical information extracted for robust hERG activity prediction. In summary, CardioTox net can serve as a robust tool for screening small molecules for hERG channel blockade in drug discovery pipelines and performs better than previously reported methods on a range of classification metrics.
Multiple functions of autophagy in vascular calcification
Authors: Zhou Xin , Xu Sui-Ning , Yuan Shu-Tong , Lei Xinjuan , Sun Xiaoying , Xing Lu , Li Hui-Jin , He Chun-Xia , Qin Wei , Zhao Dong , Li Peng-Quan , Moharomd Edward , Xu Xuehong , Cao Hui-Ling 
Published: August 2021

Abstract
Background
Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns.

Methods
In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification.

Results
Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, β-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/β-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA‑PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34–beclin-1-related bone mineralization via vascular calcification.

Conclusion
The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.
Solutions of nonlinear difference equations in the domain of $(\zeta _{n})$-Cesàro matrix in $\ell _{t(\cdot)}$ of nonabsolute type, and its pre-quasi ideal
Authors: Bakery Awad A. , Mohammed Mustafa M. 
Published: August 2021

AbstractWe have constructed the sequence space$(\Xi (\zeta ,t) )_{\upsilon }$(Ξ(ζ,t))υ, where$\zeta =(\zeta _{l})$ζ=(ζl)is a strictly increasing sequence of positive reals tending to infinity and$t=(t_{l})$t=(tl)is a sequence of positive reals with$1\leq t_{l}<\infty $1≤tl<∞, by the domain of$(\zeta _{l})$(ζl)-Cesàro matrix in the Nakano sequence space$\ell _{(t_{l})}$ℓ(tl)equipped with the function$\upsilon (f)=\sum^{\infty }_{l=0} ( \frac{ \vert \sum^{l}_{z=0}f_{z}\Delta \zeta _{z} \vert }{\zeta _{l}} )^{t_{l}}$υ(f)=∑l=0∞(|∑z=0lfzΔζz|ζl)tlfor all$f=(f_{z})\in \Xi (\zeta ,t)$f=(fz)∈Ξ(ζ,t). Some geometric and topological properties of this sequence space, the multiplication mappings defined on it, and the eigenvalues distribution of operator ideal withs-numbers belonging to this sequence space have been investigated. The existence of a fixed point of a Kannan pre-quasi norm contraction mapping on this sequence space and on its pre-quasi operator ideal formed by$(\Xi (\zeta ,t) )_{\upsilon }$(Ξ(ζ,t))υands-numbers is presented. Finally, we explain our results by some illustrative examples and applications to the existence of solutions of nonlinear difference equations.
Long-term antimicrobial effectiveness of a silver-impregnated foil on high-touch hospital surfaces in patient rooms
Authors: Widmer Andreas F. , Kuster Sonja , Dangel Marc , Jäger Sammy , Frei Reno 
Published: August 2021

Abstract
Background
The hospital environment has got more attention as evidence as source for bacterial transmission and subsequent hospital-acquired infection increased. Regular cleaning and disinfection have been proposed to lower the risk of infection, in particular for gram-positive bacteria. Auto-disinfecting surfaces would allow to decrease survival of pathogens, while limiting resource to achieve a safe environment in patient rooms.

Methods
A controlled trial to evaluate the antimicrobial effectiveness of a polyvinyl chloride foil containing an integrated silver-based agent (containing silver ions 2%) on high-touch surfaces in patient rooms.

Results
The overall log reduction of the mean values was 1.8 log10 CFU, the median 0.5 log10 CFU comparing bioburden of control vs antimicrobial foil (p < 0.01). Important pathogens were significantly less likely recovered from the foil, in particular enterococci. These effects were present even after 6 months of in-use.

Conclusions
A foil containing an integrated silver-based agent applied to high-touch surfaces effectively results in lower recovery of important pathogens from such surfaces over a 6-month study period.
Determination of phytocomponents and validation of squalene in ethanolic extract of Clerodendrum serratum Linn roots—using gas chromatography-mass spectroscopy and GC-FID technique
Authors: Reddy Kalyani , Gurupadayya B M  , Choezom Lodoe , Vikram P R Hemanth 
Published: August 2021

Abstract
Background
Clerodendrum serratum Linn commonly known as Bharangi in India has wide applications in the Ayurveda and Siddha system of medicine which has been attributed to the treatment of various diseases like asthma, cough, fever, rheumatism, and cephalalgia ophthalmia. Squalene has nutritional, medicinal, and pharmaceutical health benefits, hence possess antioxidant and cytoprotective effects.

Method
The study presents the GC-MS analysis of phytoconstituents present in the Clerodendrum serratum roots and further estimation of one of the constituents, i.e., squalene which is ought to be present in the roots as per mass spectral data obtained. Squalene was determined from the ethanolic extract of C. serratum roots using GC-FID without derivatization.

Results
Four major constituents, i.e., squalene, methyl palmitate, hexadecenoic acid, and stigmasterol were detected by GC-MS. Squalene from the extract was eluted at 17.5min which was confirmed with the standard squalene peak eluted at the same retention time. The linearity range chosen was 5–30ug/mL, and the method was found to be pretty linear (R=0.995), accurate with satisfactory repeatability. Hence, the phytochemical compounds were detected by GC-MS and the squalene was determined and validated according to the ICH guidelines.

Conclusion
Thus, the green gas chromatographic method can be used for quantification and qualification of active constituents in the roots of ethanolic extract of C. serratum. In addition, the presence of metabolite squalene by the GC-FID method was developed for the extract which is simple, fast, and environmentally friendly.
Multiple sclerosis is not associated with an increased risk for severe COVID-19: a nationwide retrospective cross-sectional study from Germany
Authors: Richter Daniel , Faissner Simon , Bartig Dirk , Tönges Lars , Hellwig Kerstin , Ayzenberg Ilya , Krogias Christos , Gold Ralf 
Published: August 2021

Abstract
Background
Since the coronavirus disease 2019 (COVID-19) has risen, several risk factors have been identified, predicting a worse outcome. It has been speculated that patients with Multiple sclerosis (MS) have an increased risk for a severe course of COVID-19 due to a suspected higher vulnerability. Therefore, we aimed to analyze the impact of comorbid MS on the outcome of patients with COVID-19 in Germany.

Methods
We conducted a retrospective cross-sectional study using the administrative database of all hospitalized patients diagnosed with PCR-confirmed COVID-19 (n = 157,524) in Germany during 2020. The cohort was stratified according to the presence (n = 551) or absence (n = 156,973) of comorbid MS, including discrimination of MS subtypes. Primary outcome measures were admission to the intensive care unit (ICU), use of invasive or non-invasive ventilation, and in-hospital mortality. Differences were investigated using rates and odds ratios as estimates. Pooled overall estimates, sex-stratified estimates, age-group stratified estimates, and MS subtype stratified estimates were calculated for all outcomes under the random-effects model.

Results
Among 157,524 patients hospitalized with COVID-19, 551 had a concurrent MS diagnosis (0.3%). Overall, univariate analysis showed lower rates of ICU admission (17.1% versus 22.7%, p < 0.001), lower use of ventilation (9.8% versus 14.5%, p < 0.001) and lower in-hospital mortality (11.1% versus 19.3%, p < 0.001) among COVID-19 patients with comorbid MS. This finding was stable across the subgroup analysis of sex and MS subtype but was attenuated by age-stratification, confirming equal odds of in-hospital mortality between COVID-19 patients with and without MS (log OR: 0.09 [95% CI: − 0.40, 0.59]).

Conclusions
Although there might be differences in risk within the MS patients’ population, this large-scale nationwide analysis found no evidence for a worse outcome of COVID-19 in patients with comorbid MS compared to non-MS individuals.
Frontonasal encephalocele with subependymal heterotopias and cerebellar dysplasia: a rare case report with review of literature
Authors: Singh Kunwar Pal , Kaur Sukhdeep , Sidhu Bikramjit Singh 
Published: August 2021

Abstract
Background
Encephaloceles are herniation of brain parenchyma through the defect in the dura and the skull bones. This case report reveals a rare association of frontonasal encephalocele, subependymal nodular heterotopias and cerebellar dysplasia with review of literature.

Case presentation
Frontonasal encephalocele is a rare entity. We report an 18-months-old male child who presented to the department of pediatrics with chief complaint of congenital swelling in the region of forehead. Swelling was increasing in size as told by the parents of the child. The child was born full term with normal vaginal delivery. There was no history of any obstetrical complications. The swelling was soft, transilluminant and pulsatile in nature. He was referred to the department of radio diagnosis for imaging evaluation. His CT and MRI images revealed defect in the anterior cranial fossa with herniation of meninges and brain parenchyma through it. There was also evidence of subependymal nodular heterotopias in this patient along with hypoplasia of left cerebellar hemisphere and left middle cerebellar peduncle with left cerebellar dysplasia.

Conclusions
This case report describes the coexistence of frontonasal encephaloceles, subependymal nodular heterotopias and cerebellar dysplasia, which is a very rare association.
Chlorpyrifos and other pesticide exposure and suspected developmental delay in children aged under 5 years: a case-control study in Phitsanulok, Thailand
Authors: Juntarawijit Yuwayong , Chaichanawirote Uraiwan , Rakmeesri Paphada , Chairattanasakda Punaphop , Pumyim Varintorn , Juntarawijit Chudchawal 
Published: August 2021

Background: Developmental delay among children under 5 years of age is a serious global public health problem and much research has been carried out to find potential causes. Pesticides - especially organophosphates - are suspected to be one of the main causes of the problem. This study aimed to investigate the association between pesticide use by the mother during pregnancy and preschool children development using a case-control study.Methods: Data on prenatal and postnatal pesticide exposure of 442 children with suspected developmental delay, and 413 controls with normal development were included for analysis. The children were matched for gender, age, and residency. Data on pesticide exposure were collected via interview with the mother, and data on pregnancy outcomes abstracted from hospital records. Results: Chlorpyrifos exposure significantly increased the risk of developmental delay with an odds ratio (OR) of 3.71 (95% CI 1.03-13.36) for ever use of the pesticide, and an OR of 5.92 (95% CI 1.01-34.68) for postnatal exposure (p <0.05). Some other pesticides also had a positive association with developmental delay but none were statistically significant (p <0.05). Those pesticides were insecticide, fungicide, herbicide, and molluscicide. Individual pesticides with a positive association were glyphosate, paraquat, butachlor, methyl parathion (pholidon), savin, methomyl, endosulfan, carbosulfan, methamidophos, monochrotofos, mancozeb, and bordeaumixture.Conclusions: This case-control study found that chlorpyrifos and some other pesticide exposure during pregnancy was positively associated with developmental delay in children aged under 5 years. Further research should be conducted to better understand this potential effect of pesticides on child neurodevelopment, and the public - especially those who plan to have families - should be informed.
Non-commercial pharmaceutical R&D: what do neglected diseases suggest about costs and efficiency?
Authors: Vieira Marcela , Kimmitt Ryan , Moon Suerie 
Published: August 2021

Background: The past two decades have witnessed significant growth in non-commercial research and development (R&D) initiatives, particularly for neglected diseases, but there is limited understanding of the ways in which they compare with commercial R&D. This study analyses costs, timelines, and attrition rates of non-commercial R&D across multiple initiatives and how they compare to commercial R&D. Methods: This is a mixed-method, observational, descriptive, and analytic study. We contacted 48 non-commercial R&D initiatives and received either quantitative and/or qualitative data from 13 organizations. We used the Portfolio to Impact (P2I) model’s estimates of average costs, timelines, and attrition rates for commercial R&D, while noting that P2I cost estimates are far lower than some previous findings in the literature. Results: The quantitative data suggested that the costs and timelines per candidate per phase (from preclinical through Phase 3) of non-commercial R&D for new chemical entities are largely in line with commercial averages. The quantitative data was insufficient to compare attrition rates. The qualitative data identified more reasons why non-commercial R&D costs would be lower than commercial R&D, timelines would be longer, and attrition rates would be equivalent or higher, though the data does not allow for estimating the magnitude of these effects. Conclusions: The quantitative data suggest that costs and timelines per candidate per phase were largely in line with (lower-end estimates of) commercial averages. We were unable to draw conclusions on overall efficiency, however, due to insufficient data on attrition rates. Given that non-commercial R&D is a nascent area of research with limited data available, this study contributes to the literature by generating hypotheses for further testing against a larger sample of quantitative data. It also offers a range of explanatory factors for further exploration regarding how non-commercial and commercial R&D may differ in costs and efficiency.