bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrointestinal cancers, ACE-2/TMPRSS2 expression and susceptibility to COVID-19
Authors: Shafiee Sepehr , Cegolon Luca , Khafaei Mostafa , Gholami Nasrin , Zhao Shi , Khalesi Nasrin , Moosavian Hamidreza , Fathi Saeid , Izadi Morteza , Ghadian Alireza , Javanbakht Mohammad , Javanbakht Amin , Akhavan-Sigari Reza 
Published: August 2021

AbstractRecent studies on the pathophysiology of COVID-19 are indicating that the Angiotensin convertase enzyme 2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) can act as a major component in the fusion of SARS-Cov-2 with target cells. It has also been observed that the expression of ACE-2 and TMPRSS2 can be altered in malignancies. Shedding light on this matter could be crucial since the COVID-19 pandemic interfered with many gastrointestinal cancer screening programs. Herein we discuss the possibility of severe forms of COVID-19 in patients with gastrointestinal cancers due to the gastrointestinal entry route of SARS-CoV-2 into the human body. The disruption of cancer screening programs caused by the current COVID-19 pandemic could therefore have massive negative health impact on patients affected by gastrointestinal malignancies.
Impact of sex differences on thrombin-induced hydrocephalus and white matter injury: the role of neutrophils
Authors: Peng Kang , Koduri Sravanthi , Xia Fan , Gao Feng , Hua Ya , Keep Richard F. , Xi Guohua 
Published: August 2021

Abstract
Background
Thrombin has been implicated in playing a role in hydrocephalus development following intraventricular hemorrhage (IVH). However, the mechanisms underlying the sex differences to the detrimental effects of thrombin post-IVH remain elusive.

Method
Three-month old male and female Sprague-Dawley rats underwent unilateral intracerebroventricular (ICV) injections of 3U or 5U thrombin, or saline, to examine differences in thrombin-induced hydrocephalus and white matter injury. Mortality, and lateral ventricle volume and white matter injury were measured on magnetic resonance imaging evaluation at 24 h post-injection. In addition, male rats were pretreated with 17-β estradiol (E2, 5 mg/kg) or vehicle at 24 and 2 h prior to ICV injection of 3U thrombin. All rats were euthanized at 24 h post-injection for histology and immunohistochemistry.

Results
ICV injection of 5U thrombin caused 100 and 0% mortality in female and male rats, respectively. 3U of thrombin resulted in significant ventricular dilation and white matter damage at 24 h in both male and female rats, but both were worse in females (p < 0.05). Furthermore, neutrophil infiltration into choroid plexus and periventricular white matter was enhanced in female rats and may play a critical role in the sex difference in brain injury. Pre-treating male rats with E2, increased thrombin (3U)-induced hydrocephalus, periventricular white matter injury and neutrophil infiltration into the choroid plexus and white matter.

Conclusions
ICV thrombin injection induced more severe ventricular dilation and white matter damage in female rats compared to males. Estrogen appears to contribute to this difference which may involve greater neutrophil infiltration in females. Understanding sex differences in thrombin-induced brain injury may shed light on future interventions for hemorrhagic stroke.
Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants
Authors: Murali Krithika , Dwarte Tanya M. , Nikfarjam Mehrdad , Tucker Katherine M. , Vaughan Rhys B. , Efthymiou Marios , Collins Allison , Spigelman Allan D. , Salmon Lucinda , Johns Amber L. , Williams David B. , Delatycki Martin B. , John Thomas , Stoita Alina 
Published: August 2021

Abstract
Background
The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment.

Methods
Individuals aged 40–80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative.
Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel.

Results
Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment.

Conclusion
Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.
Characterizing DNA methylation signatures and their potential functional roles in Merkel cell carcinoma
Authors: Gujar Hemant , Mehta Arjun , Li Hong-Tao , Tsai Yvonne C. , Qiu Xiangning , Weisenberger Daniel J. , Jasiulionis Miriam Galvonas , In Gino K. , Liang Gangning 
Published: August 2021

AbstractBackgroundMerkel cell carcinoma (MCC) is a rare but aggressive skin cancer with limited treatment possibilities. Merkel cell tumors display with neuroendocrine features and Merkel cell polyomavirus (MCPyV) infection in the majority (80%) of patients. Although loss of histone H3 lysine 27 trimethylation (H3K27me3) has been shown during MCC tumorigenesis, epigenetic dysregulation has largely been overlooked.MethodsWe conducted global DNA methylation profiling of clinically annotated MCC primary tumors, metastatic skin tumors, metastatic lymph node tumors, paired normal tissues, and two human MCC cell lines using the Illumina Infinium EPIC DNA methylation BeadArray platform.ResultsSignificant differential DNA methylation patterns across the genome are revealed between the four tissue types, as well as based on MCPyV status. Furthermore, 964 genes directly regulated by promoter or gene body DNA methylation were identified with high enrichment in neuro-related pathways. Finally, our findings suggest that loss of H3K27me3 occupancy in MCC is attributed toKDM6BandEZHIPoverexpression as a consequence of promoter DNA hypomethylation.ConclusionsWe have demonstrated specific DNA methylation patterns for primary MCC tumors, metastatic MCCs, and adjacent-normal tissues. We have also identified DNA methylation markers that not only show potential diagnostic or prognostic utility in MCC management, but also correlate with MCC tumorigenesis, MCPyV expression, neuroendocrine features, and H3K27me3 status. The identification of DNA methylation alterations in MCC supports the need for further studies to understand the clinical implications of epigenetic dysregulation and potential therapeutic targets in MCC.
Serum levels of 1,5-anhydroglucitol and 1,5-anhydrofructose-derived advanced glycation end products in patients undergoing hemodialysis
Authors: Tanaka Kenji , Sakasai-Sakai Akiko , Motomiya Yasuki , Yoneda Tatsuo , Takeuchi Masayoshi 
Published: August 2021

Abstract
Background
1,5-anhydroglucitol is a reduction product of 1,5-anhydrofructose. Circulating 1,5-anhydroglucitol is usually excreted by the kidneys and is reabsorbed via sodium-glucose co-transporter 4 in the renal tubules. In patients on hemodialysis, serum levels of 1,5-anhydroglucitol have been reported to be low; however, the underlying mechanism remains unclear.

Methods
We measured inter-dialysis changes in the levels of serum 1,5-anhydroglucitol and 1,5-anhydrofructose-derived advanced glycation end products (AGEs) in 78 patients on hemodialysis. Serum levels of 1,5-anhydrofructose-derived AGEs were also determined using a polyclonal antibody.

Results
The serum 1,5-anhydroglucitol level was decreased to as low as 2.0 μg/mL in the regular hemodialysis group; however, we could not verify changes in the serum 1,5-anhydroglucitol level during inter-dialysis days because of undetectable levels in 29 patients. The measured serum level of 1,5-anhydrofructose-derived AGEs was significantly increased in both patient groups. In addition, the 1,5-anhydrofructose-derived AGEs/1,5-anhydroglucitol ratio was higher in patients on hemodialysis than in controls.

Conclusions
Accelerated glycation of 1,5-anhydrofructose is one possible mechanism by which serum 1,5-anhydroglucitol levels are lowered in patients on HD, and we propose that the 1,5-anhydrofructose-derived AGEs/1,5-anhydroglucitol ratio should be measured in clinical settings in which patients have low serum levels of 1,5-AG.
Differences in the roles of types 1 and 2 diabetes in the susceptibility to the risk of fracture: a systematic review and meta-analysis
Authors: Dou Jiaqing , Wang Jing , Zhang Qiu 
Published: August 2021

AbstractBackgroundDiabetes mellitus (DM) causes excess risk of fracture at varied sites. Whereas, the difference between the roles of types 1 DM (T1DM) and 2 DM (T2DM) diabetes in the risk of fractures remains limited and inconclusive. We, therefore, conducted a meta-analysis to assess the differences for the associations of T1DM and T2DM with the risk of fractures.MethodsWe systematically searched PubMed, Embase, and the Cochrane library for eligible studies until May 2021. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the pooled effect estimates for the associations of T1DM and T2DM with the risk of fractures using the random-effects model. An indirect comparison results for the ratio of OR (ROR) with 95% CI were also applied to assess the difference between T1DM and T2DM with the risk of fractures.ResultsTwenty-two cohort studies involving a total of 6,484,851 individuals were selected for meta-analysis. We noted that T1DM was associated with an increased risk of all fractures (OR: 1.72; 95% CI 1.36–2.19;P < 0.001), and fractures at the hip (OR: 4.01; 95% CI 2.90–5.54;P < 0.001), upper arm (OR: 2.20; 95% CI 1.61–3.00;P < 0.001), ankle (OR: 1.97; 95% CI 1.24–3.14;P = 0.004), and vertebrae (OR: 2.18; 95% CI 1.85–2.57;P < 0.001). Moreover, T2DM induced excess risk to all fractures (OR: 1.19; 95% CI 1.09–1.31;P < 0.001), including fractures at the hip (OR: 1.25; 95% CI 1.15–1.35;P < 0.001), upper arm (OR: 1.42; 95% CI 1.20–1.67;P < 0.001), and ankle (OR: 1.15; 95% CI 1.01–1.31;P = 0.029). Furthermore, we noted that T1DM versus T2DM was associated with greater risk to all fractures (ROR: 1.45; 95% CI 1.12–1.87;P = 0.005), including fractures at the hip (ROR: 3.21; 95% CI 2.30–4.48;P < 0.001), upper arm (ROR: 1.55; 95% CI 1.09–2.20;P = 0.015), and ankle (ROR: 1.71; 95% CI 1.06–2.78;P = 0.029).ConclusionsThis study found that T1DM caused an excess risk to all fractures, including fractures at the hip, upper arm, and ankle than T2DM. Further studies should therefore be conducted to directly compare the differences between T1DM and T2DM with the risk of fractures at various sites.
Visualizing cellularity and angiogenesis in newly-diagnosed glioblastoma with diffusion and perfusion MRI and FET-PET imaging
Authors: Liesche-Starnecker Friederike , Prokop Georg , Yakushev Igor , Preibisch Christine , Delbridge Claire , Meyer Hanno S. , Aftahy Kaywan , Barz Melanie , Meyer Bernhard , Zimmer Claus , Schlegel Jürgen , Wiestler Benedikt , Gempt Jens 
Published: August 2021

Abstract
Purpose
Combining imaging modalities has become an essential tool for assessment of tumor biology in glioblastoma (GBM) patients. Aim of this study is to understand how tumor cellularity and neovascularization are reflected in O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography ([18F] FET PET) and magnetic resonance imaging (MRI) parameters, including cerebral blood volume (CBV), fractional anisotropy (FA) and mean diffusivity (MD).

Methods
In this prospective cohort, 162 targeted biopsies of 43 patients with therapy-naïve, isocitrate dehydrogenase (IDH) wildtype GBM were obtained after defining areas of interest based on imaging parameters [18F] FET PET, CBV, FA and MD. Histopathological analysis of cellularity and neovascularization was conducted and results correlated to imaging data.

Results
ANOVA analysis showed a significant increase of CBV in areas with high neovascularization. For diffusion metrics, and in particular FA, a trend for inverse association with neovascularization was found. [18F] FET PET showed a significant positive correlation to cellularity, while CBV also showed a trend towards correlation with cellularity, not reaching significant levels. In contrast, MD and FA were negatively associated with cellularity.

Conclusion
Our study confirms that amino acid PET and MR imaging parameters are indicative of histological tumor properties in glioblastoma and highlights the ability of multimodal imaging to assess tumor biology non-invasively.
Forebrain Shh overexpression improves cognitive function and locomotor hyperactivity in an aneuploid mouse model of Down syndrome and its euploid littermates
Authors: Gao Feng J. , Klinedinst Donna , Fernandez Fabian-Xosé , Cheng Bei , Savonenko Alena , Devenney Benjamin , Li Yicong , Wu Dan , Pomper Martin G. , Reeves Roger H. 
Published: August 2021

AbstractDown syndrome (DS) is the leading genetic cause of intellectual disability and causes early-onset dementia and cerebellar hypoplasia. The prevalence of attention deficit hyperactivity disorder is elevated in children with DS. The aneuploid DS mouse model “Ts65Dn” shows prominent brain phenotypes, including learning and memory deficits, cerebellar hypoplasia, and locomotor hyperactivity. Previous studies indicate that impaired Sonic hedgehog (Shh) signaling contributes to neurological phenotypes associated with DS and neurodegenerative diseases. However, because of a lack of working inducible Shh knock-in mice, brain region-specific Shh overexpression and its effects on cognitive function have not been studied in vivo. Here, with Gli1-LacZ reporter mice, we demonstrated that Ts65Dn had reduced levels of Gli1, a sensitive readout of Shh signaling, in both hippocampus and cerebellum at postnatal day 6. Through site-specific transgenesis, we generated an inducible human Shh knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), simultaneously expressing dually-lipidated Shh-Np and Zsgreen1 marker in the presence of transactivator (tTA). Double transgenic mice “Camk2a-tTA;TRE-hShh” and “Pcp2-tTA;TRE-hShh” induced Shh overexpression and activated Shh signaling in a forebrain and cerebellum, respectively, specific manner from the perinatal period. Camk2a-tTA;TRE-hShh normalized locomotor hyperactivity and improved learning and memory in 3-month-old Ts65Dn, mitigated early-onset severe cognitive impairment in 7-month-old Ts65Dn, and enhanced spatial cognition in euploid mice. Camk2a-tTA;TRE-hShh cohort maintained until 600days old showed that chronic overexpression of Shh in forebrain from the perinatal period had no effect on longevity of euploid or Ts65Dn. Pcp2-tTA;TRE-hShh did not affect cognition but mitigated the phenotype of cerebellar hypoplasia in Ts65Dn. Our study provides the first in vivo evidence that Shh overexpression from the perinatal period protects DS brain integrity and enhances learning and memory in normal mice, indicating the broad therapeutic potential of Shh ligand for other neurological conditions. Moreover, the first inducible hShh site-specific knock-in mouse could be widely used for spatiotemporal Shh signaling regulation.
Impact of the conjugation of antibodies to the surfaces of polymer nanoparticles on the immune cell targeting abilities
Authors: Lee Na Kyeong , Wang Chi-Pin James , Lim Jaesung , Park Wooram , Kwon Ho-Keun , Kim Se-Na , Kim Tae-Hyung , Park Chun Gwon 
Published: August 2021

AbstractAntibodies have been widely used to provide targeting ability and to enhance bioactivity owing to their high specificity, availability, and diversity. Recent advances in biotechnology and nanotechnology permit site-specific engineering of antibodies and their conjugation to the surfaces of nanoparticles (NPs) in various orientations through chemical conjugations and physical adhesions. This study proposes the conjugation of poly(lactic-co-glycolic acid) (PLGA) NPs with antibodies by using two distinct methods, followed by a comparison between the cell-targeting efficiencies of both techniques. Full-length antibodies were conjugated to the PLGA-poly(ethylene glycol)-carboxylic acid (PLGA-PEG-COOH) NPs through the conventional carbodiimide coupling reaction, and f(ab′)2 antibody fragments were conjugated to the PLGA-poly(ethylene glycol)-maleimide(PLGA-PEG-Mal) NPs through interactions between the f(ab′)2 fragment thiol groups and the maleimide located on the nanoparticle surface. The results demonstrate that the PLGA nanoparticles conjugated with the f(ab′)2 antibody fragments had a higher targeting efficiency in vitro and in vivo than that of the PLGA nanoparticles conjugated with the full-length antibodies. The results of this study can be built upon to design a delivery technique for drugs through biocompatible nanoparticles.
LncRNA FBXL19-AS1 promotes proliferation and metastasis of cervical cancer through upregulating COL1A1 as a sponge of miR-193a-5p
Authors: Huang Xiaoyong , Shi Haiyan , Shi Xinghai , Jiang Xuemei 
Published: August 2021

AbstractBackgroundCervical cancer (CC) is one of the most common and malignant tumors in women. In this study, we aim to explore the role and mechanism of F-box and leucine rich repeat protein 19 antisense RNA 1 (FBXL19-AS1), a novel long-chain non coding RNA (lncRNA) with marked roles in a variety of tumors, in regulating the proliferation and metastasis of CC.MethodsThe expression of FBXL19-AS1, miR-193a-5p and COL1A1 were detected by RT-PCR and western blot. Gain- and loss-of functional assays of FBXL19-AS1 and miR-193a-5p were performed in CC cell lines in vitro or in vivo. The proliferation, migration, invasion, apoptosis and epithelial-mesenchymal transition (EMT) of CC cells were determined.ResultsFBXL19-AS1 and COL1A1 were significantly up-regulated in CC tissues, while miR-193a-5p was significantly down-regulated. Overexpression of FBXL19-AS1 significantly promoted the proliferation, migration, invasion, EMT and growth of CC cells and inhibited apoptosis, while knockdown of FBXL19-AS1 had the opposite effects. On the other hand, miR-193a-5p inhibited the proliferation and metastasis of CC cells. Mechanistically, FBXL19-AS1 functioned as a competitive endogenous RNA (ceRNA) and inhibited the expression of miR-193a-5p, which targeted at the 3’-UTR site of COL1A1 and negatively regulated COL1A1 expression.ConclusionsFBXL19-AS1 promotes the proliferation and metastasis of CC cells by sponging miR-193a-5p and up-regulating COL1A1.
Glycemic fluctuation exacerbates inflammation and bone loss and alters microbiota profile around implants in diabetic mice with experimental peri-implantitis
Authors: Li Hao , Wang Yufeng , Zhang Dong , Chen Tsute , Hu Arthur , Han Xiaozhe 
Published: August 2021

Abstract
Background
The impact of glycemic fluctuation under diabetic condition on peri-implantitis in diabetic patients remains unclear. We hypothesized that glycemic fluctuation has greater adverse effect on experimental peri-implantitis, compared with sustained high blood glucose in diabetes.

Results
Maxillary left first and second molars of diabetic db/db mice were extracted and were replaced with one dental implant in the healed edentulous space. Glycemic control or fluctuation were managed by constant or interrupted oral administration of rosiglitazone to these mice. Meanwhile, experimental peri-implantitis was induced by ligation around implants. After 14 weeks, inflammatory responses, and peri-implant bone loss, together with oral microbiota profile were analyzed. Diabetic mice with glycemic fluctuation showed greater peri-implant bone loss, inflammatory cell infiltration, and osteoclastogenesis, compared with mice with sustained hyperglycemia. Compared to sustained hyperglycemia, glycemic fluctuation led to further increase in IL-1β, TNFα, RANKL, TLR2/4, IRAK1, and TRAF6 mRNA expression in peri-implant gingival tissues. Both rosiglitazone-induced glycemic control and glycemic fluctuation caused microbiota profile change in diabetic mice compared to that in uncontrolled hyperglycemic mice.

Conclusions
This study suggests that glycemic fluctuation may aggravate peri-implantitis inflammation and bone loss, which may be associated with a shift in peri-implant microbial profile towards dysbiotic changes and the activation of TLR2/4-IRAK1-TRAF6 signaling.
Investigating seasonality, policy intervention and forecasting in the Indian gold futures market: a comparison based on modeling non-constant variance using two different methods
Authors: Nargunam Rupel , Wei William W. S. , Anuradha N. 
Published: August 2021

AbstractThis study focuses on the Indian gold futures market where primary participants hold sentimental value for the underlying asset and are globally ranked number two in terms of the largest private holdings in the physical form. The trade of gold futures relates to seasons, festivity, and government policy. So, the paper will discuss seasonality and intervention in the analysis. Due to non-constant variance, we will also use the standard variance stabilization transformation method and the ARIMA/GARCH modelling method to compare the forecast performance on the gold futures prices. The results from the analysis show that while the standard variance transformation method may provide better point forecast values, the ARIMA/GARCH modelling method provides much shorter forecast intervals. The empirical results of this study which rationalise the effect of seasonality in the Indian bullion derivative market have not been reported in literature.