bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a novel KAT6A variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review
Authors: Bae Soyoung , Yang Aram , Kim Jinsup , Lee Hyun Ju , Park Hyun Kyung 
Published: December 2021

Abstract
Background
Arboleda-Tham syndrome (ARTHS), caused by a pathogenic variant of KAT6A, is an autosomal dominant inherited genetic disorder characterized by various degrees of developmental delay, dysmorphic facial appearance, cardiac anomalies, and gastrointestinal problems.

Case presentation
A baby presented multiple facial deformities including a high arched and cleft palate, with philtral ridge and vermilion indentation, a prominent nasal bridge, a thin upper lip, low-set ears, an epicanthal fold, and cardiac malformations. Whole exome sequencing (WES) revealed a heterozygous nonsense mutation in exon 8 of the KAT6A gene (c.1312C>T, p.[Arg438*]) at 2 months of age. After a diagnosis of ARTHS, an expressive language delay was observed during serial assessments of developmental milestones.

Conclusions
In this study, we describe a case with a novel KAT6A variant first identified in Korea. This case broadens the scope of clinical features of ARTHS and emphasizes that WES is necessary for early diagnosis in patients with dysmorphic facial appearances, developmental delay, and other congenital abnormalities.
The overexpression of GDNF in nucleus accumbens suppresses alcohol-seeking behavior in group-housed C57Bl/6J female mice
Authors: Koskela Maryna , Piepponen T. Petteri , Lindahl Maria , Harvey Brandon K. , Andressoo Jaan-Olle , Võikar Vootele , Airavaara Mikko 
Published: December 2021

Abstract
Background
Craving for alcohol, in other words powerful desire to drink after withdrawal, is an important contributor to the development and maintenance of alcoholism. Here, we studied the role of GDNF (glial cell line-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) on alcohol-seeking behavior in group-housed female mice.

Methods
We modeled alcohol-seeking behavior in C57Bl/6J female mice. The behavioral experiments in group-housed female mice were performed in an automated IntelliCage system. We conducted RT-qPCR analysis of Gdnf, Bdnf, Manf and Cdnf expression in different areas of the female mouse brain after alcohol drinking conditioning. We injected an adeno-associated virus (AAV) vector expressing human GDNF or BDNF in mouse nucleus accumbens (NAc) after ten days of alcohol drinking conditioning and assessed alcohol-seeking behavior. Behavioral data were analyzed by two-way repeated-measures ANOVA, and statistically significant effects were followed by Bonferroni’s post hoc test. The student’s t-test was used to analyze qPCR data.

Results
The RT-qPCR data showed that Gdnf mRNA level in NAc was more than four times higher (p < 0.0001) in the mice from the sweetened alcohol group compared to the water group. Our data showed a more than a two-fold decrease in Manf mRNA (p = 0.04) and Cdnf mRNA (p = 0.02) levels in the hippocampus and Manf mRNA in the VTA (p = 0.04) after alcohol consumption. Two-fold endogenous overexpression of Gdnf mRNA and lack of CDNF did not affect alcohol-seeking behavior. The AVV-GDNF overexpression in nucleus accumbens suppressed alcohol-seeking behavior while overexpression of BDNF did not.

Conclusions
The effect of increased endogenous Gdnf mRNA level in female mice upon alcohol drinking has remained unknown. Our data suggest that an increase in endogenous GDNF expression upon alcohol drinking occurs in response to the activation of another mesolimbic reward pathway participant.
Oscillatory mechanics at birth for identifying infants requiring surfactant: a prospective, observational trial
Authors: Lavizzari Anna , Veneroni Chiara , Beretta Francesco , Ottaviani Valeria , Fumagalli Claudia , Tossici Marta , Colnaghi Mariarosa , Mosca Fabio , Dellacà Raffaele L. 
Published: December 2021

Abstract
Background
Current criteria for surfactant administration assume that hypoxia is a direct marker of lung-volume de-recruitment. We first introduced an early, non-invasive assessment of lung mechanics by the Forced Oscillation Technique (FOT) and evaluated its role in predicting the need for surfactant therapy.

Objectives
To evaluate whether lung reactance (Xrs) assessment by FOT within 2 h of birth identifies infants who would need surfactant within 24 h; to eventually determine Xrs performance and a cut-off value for early detection of infants requiring surfactant.

Methods
We conducted a prospective, observational, non-randomized study in our tertiary NICU in Milan. Eligible infants were born between 27+0 and 34+6 weeks’ gestation, presenting respiratory distress after birth. Exclusion criteria: endotracheal intubation at birth, major malformations participation in other interventional trials, parental consent denied. We assessed Xrs during nasal CPAP at 5 cmH2O at 10 Hz within 2 h of life, recording flow and pressure tracing through a Fabian Ventilator for off-line analysis. Clinicians were blinded to FOT results.

Results
We enrolled 61 infants, with a median [IQR] gestational age of 31.9 [30.3; 32.9] weeks and birth weight 1490 [1230; 1816] g; 2 infants were excluded from the analysis for set-up malfunctioning. 14/59 infants received surfactant within 24 h. Xrs predicted surfactant need with a cut-off − 33.4 cmH2O*s/L and AUC-ROC = 0.86 (0.76–0.96), with sensitivity 0.85 and specificity 0.83. An Xrs cut-off value of − 23.3 cmH2O*s/L identified infants needing surfactant or respiratory support > 28 days with AUC-ROC = 0.89 (0.81–0.97), sensitivity 0.86 and specificity 0.77. Interestingly, 12 infants with Xrs < − 23.3 cmH2O*s/L (i.e. de-recruited lungs) did not receive surfactant and subsequently required prolonged respiratory support.

Conclusion
Xrs assessed within 2 h of life predicts surfactant need and respiratory support duration in preterm infants. The possible role of Xrs in improving the individualization of respiratory management in preterm infants deserves further investigation.
E-cadherin on epithelial–mesenchymal transition in thyroid cancer
Authors: Zhu Xiaoyu , Wang Xiaoping , Gong Yifei , Deng Junlin 
Published: December 2021

AbstractThyroid carcinoma is a common malignant tumor of endocrine system and head and neck. Recurrence, metastasis and high malignant expression after routine treatment are serious clinical problems, so it is of great significance to explore its mechanism and find action targets. Epithelial–mesenchymal transition (EMT) is associated with tumor malignancy and invasion. One key change in tumour EMT is low expression of E-cadherin. Therefore, this article reviews the expression of E-cadherin in thyroid cancers (TC), discuss the potential mechanisms involved, and outline opportunities to exploit E-cadherin on regulating the occurrence of EMT as a critical factor in cancer therapeutics.
AGAP2-AS1 as a prognostic biomarker in low-risk clear cell renal cell carcinoma patients with progressing disease
Authors: Nakken Sigrid , Eikrem Øystein , Marti Hans-Peter , Beisland Christian , Bostad Leif , Scherer Andreas , Flatberg Arnar , Beisvag Vidar , Skandalou Eleni , Furriol Jessica , Strauss Philipp 
Published: December 2021

Abstract
Background
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in “low-risk” patients who were potentially eligible for adjuvant treatments or more intensive follow-up.

Methods
We assembled a cohort of ccRCC patients (n  = 443) and identified all “low-risk” patients who later developed progressing tumors (n  = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these “low-risk” patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas.

Results
Principal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p  < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p  = 2.44E−7).

Conclusion
AGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as “low risk” at the time of surgery.
Putative pleiotropic effects of the knockdown resistance (L1014F) allele on the life-history traits of Anopheles gambiae
Authors: Medjigbodo Adandé A. , Djogbénou Luc S. , Djihinto Oswald Y. , Akoton Romaric B. , Abbey Emmanuella , Kakossou Rosaria M. , Sonounameto Eric G. , Salavi Esther B. J. , Djossou Laurette , Badolo Athanase 
Published: December 2021

Abstract
Background
Existing mechanisms of insecticide resistance are known to help the survival of mosquitoes following contact with chemical compounds, even though they could negatively affect the life-history traits of resistant malaria vectors. In West Africa, the knockdown resistance mechanism kdrR (L1014F) is the most common. However, little knowledge is available on its effects on mosquito life-history traits. The fitness effects associated with this knockdown resistance allele in Anopheles gambiae sensu stricto (s.s.) were investigated in an insecticide-free laboratory environment.

Methods
The life-history traits of Kisumu (susceptible) and KisKdr (kdr resistant) strains of An. gambiae s.s. were compared. Larval survivorship and pupation rate were assessed as well as fecundity and fertility of adult females. Female mosquitoes of both strains were directly blood fed through artificial membrane assays and then the blood-feeding success, blood volume and adult survivorship post-blood meal were assessed.

Results
The An. gambiae mosquitoes carrying the kdrR allele (KisKdr) laid a reduced number of eggs. The mean number of larvae in the susceptible strain Kisumu was three-fold overall higher than that seen in the KisKdr strain with a significant difference in hatching rates (81.89% in Kisumu vs 72.89% in KisKdr). The KisKdr larvae had a significant higher survivorship than that of Kisumu. The blood-feeding success was significantly higher in the resistant mosquitoes (84%) compared to the susceptible ones (34.75%). However, the mean blood volume was 1.36 µL/mg, 1.45 µL/mg and 1.68 µL/mg in Kisumu, homozygote and heterozygote KisKdr mosquitoes, respectively. After blood-feeding, the heterozygote KisKdr mosquitoes displayed highest survivorship when compared to that of Kisumu.

Conclusions
The presence of the knockdown resistance allele appears to impact the life-history traits, such as fecundity, fertility, larval survivorship, and blood-feeding behaviour in An. gambiae. These data could help to guide the implementation of more reliable strategies for the control of malaria vectors.
Impact of COVID-19 on routine malaria indicators in rural Uganda: an interrupted time series analysis
Authors: Namuganga Jane F. , Briggs Jessica , Roh Michelle E. , Okiring Jaffer , Kisambira Yasin , Sserwanga Asadu , Kapisi James A. , Arinaitwe Emmanuel , Ebong Chris , Ssewanyana Isaac , Maiteki-Ssebuguzi Catherine , Kamya Moses R. , Staedke Sarah G. , Dorsey Grant , Nankabirwa Joaniter I. 
Published: December 2021

Abstract
Background
In March 2020, the government of Uganda implemented a strict lockdown policy in response to the COVID-19 pandemic. Interrupted time series analysis (ITSA) was performed to assess whether major changes in outpatient attendance, malaria burden, and case management occurred after the onset of the COVID-19 epidemic in rural Uganda.

Methods
Individual level data from all outpatient visits collected from April 2017 to March 2021 at 17 facilities were analysed. Outcomes included total outpatient visits, malaria cases, non-malarial visits, proportion of patients with suspected malaria, proportion of patients tested using rapid diagnostic tests (RDTs), and proportion of malaria cases prescribed artemether-lumefantrine (AL). Poisson regression with generalized estimating equations and fractional regression was used to model count and proportion outcomes, respectively. Pre-COVID trends (April 2017-March 2020) were used to predict the’expected’ trend in the absence of COVID-19 introduction. Effects of COVID-19 were estimated over two six-month COVID-19 time periods (April 2020-September 2020 and October 2020–March 2021) by dividing observed values by expected values, and expressed as ratios.

Results
A total of 1,442,737 outpatient visits were recorded. Malaria was suspected in 55.3% of visits and 98.8% of these had a malaria diagnostic test performed. ITSA showed no differences between observed and expected total outpatient visits, malaria cases, non-malarial visits, or proportion of visits with suspected malaria after COVID-19 onset. However, in the second six months of the COVID-19 time period, there was a smaller mean proportion of patients tested with RDTs compared to expected (relative prevalence ratio (RPR) = 0.87, CI (0.78–0.97)) and a smaller mean proportion of malaria cases prescribed AL (RPR = 0.94, CI (0.90–0.99)).

Conclusions
In the first year after the COVID-19 pandemic arrived in Uganda, there were no major effects on malaria disease burden and indicators of case management at these 17 rural health facilities, except for a modest decrease in the proportion of RDTs used for malaria diagnosis and the mean proportion of malaria cases prescribed AL in the second half of the COVID-19 pandemic year. Continued surveillance will be essential to monitor for changes in trends in malaria indicators so that Uganda can quickly and flexibly respond to challenges imposed by COVID-19.
Pathways to loneliness: a mediation analysis investigating the social gradient of loneliness in persons with disabilities in Switzerland
Authors: Tough Hannah , Gross-Hemmi Mirja , Eriks-Hoogland Inge , Fekete Christine 
Published: December 2021

Abstract
Background
The experience of loneliness can have drastic consequences for health and quality of life. Given that loneliness is highly prevalent in persons with physical disabilities and that loneliness more profoundly affects persons of low socioeconomic status, more evidence is required in order to understand the mechanisms determining loneliness in this population. The objective of this study is therefore to investigate the potential pathways through which socioeconomic status influences loneliness in persons with spinal cord injury.

Methods
Mediation analysis utilising structural equation models and bias corrected and accelerated confidence intervals were used in order to test the mediation effects of health status, functioning, participation, social support and self-efficacy on the association between socioeconomic status and loneliness in persons with spinal cord injury. A latent construct was created for socioeconomic status with the indicators education, household income, financial hardship, subjective social status and engagement in paid work.

Results
This study found evidence to support the mediating role of psychosocial resources and of secondary health conditions in the association between socioeconomic status and loneliness. The study demonstrated robust associations between socioeconomic status and all potential mediators, whereby higher socioeconomic status was associated with better health, participation and psychosocial resources, however, not all potential mediators were associated with loneliness. The serial mediation model explained the interplay between socioeconomic status, mediators on different levels, and loneliness. For example, emotional support and self-efficacy were both positively associated with fewer restrictions to participation (0.08 (CI: 0.05, 0.12); 0.29 (CI: 0.24, 0.36) respectively), and fewer restrictions to participation were found to be a result of improved functional independence and fewer secondary health conditions (0.23 (CI: 0.15, 0.39); − 0.29 (CI: − 0.36, − 0.20) respectively).

Conclusions
Our findings highlight the vulnerability of persons with low socioeconomic status to loneliness in persons with spinal cord injury and identified potential mediating factors, such as health, functioning, participation and psychosocial resources, in the association between socioeconomic status and loneliness. This population-based evidence suggests potential targets of interventions on the pathway to loneliness, through which socioeconomic status influences loneliness. The complexity of the model shows the need for comprehensive interprofessional rehabilitation to identify and support people with lower socioeconomic status and concomitant risk factors for loneliness.
Epigenetic modulation of antitumor immunity for improved cancer immunotherapy
Authors: Dai Enyong , Zhu Zhi , Wahed Shudipto , Qu Zhaoxia , Storkus Walter J. , Guo Zong Sheng 
Published: December 2021

AbstractEpigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.
3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway
Authors: Wang Ning , Li Xiajing , Zhong Zhiyong , Qiu Yaqi , Liu Shoupei , Wu Haibin , Tang Xianglian , Chen Chuxin , Fu Yingjie , Chen Qicong , Guo Tingting , Li Jinsong , Zhang Shuai , Zern Mark A. , Ma Keqiang , Wang Bailin , Ou Yimeng , Gu Weili , Cao Jie , Chen Honglin , Duan Yuyou 
Published: December 2021

Abstract
Background
Exosomes secreted from stem cells exerted salutary effects on the fibrotic liver. Herein, the roles of exosomes derived from human embryonic stem cell (hESC) in anti-fibrosis were extensively investigated. Compared with two-dimensional (2D) culture, the clinical and biological relevance of three-dimensional (3D) cell spheroids were greater because of their higher regeneration potential since they behave more like cells in vivo. In our study, exosomes derived from 3D human embryonic stem cells (hESC) spheroids and the monolayer (2D) hESCs were collected and compared the therapeutic potential for fibrotic liver in vitro and in vivo.

Results
In vitro, PKH26 labeled-hESC-Exosomes were shown to be internalized and integrated into TGFβ-activated-LX2 cells, and reduced the expression of profibrogenic markers, thereby regulating cellular phenotypes. TPEF imaging indicated that PKH26-labeled-3D-hESC-Exsomes possessed an enhanced capacity to accumulate in the livers and exhibited more dramatic therapeutic potential in the injured livers of fibrosis mouse model. 3D-hESC-Exosomes decreased profibrogenic markers and liver injury markers, and improved the level of liver functioning proteins, eventually restoring liver function of fibrosis mice. miRNA array revealed a significant enrichment of miR-6766-3p in 3D-hESC-Exosomes, moreover, bioinformatics and dual luciferase reporter assay identified and confirmed the TGFβRII gene as the target of miR-6766-3p. Furthermore, the delivery of miR-6766-3p into activated-LX2 cells decreased cell proliferation, chemotaxis and profibrotic effects, and further investigation demonstrated that the expression of target gene TGFβRII and its downstream SMADs proteins, especially phosphorylated protein p-SMAD2/3 was also notably down-regulated by miR-6766-3p. These findings unveiled that miR-6766-3p in 3D-hESC-Exosomes inactivated SMADs signaling by inhibiting TGFβRII expression, consequently attenuating stellate cell activation and suppressing liver fibrosis.

Conclusions
Our results showed that miR-6766-3p in the 3D-hESC-Exosomes inactivates smads signaling by restraining TGFβRII expression, attenuated LX2 cell activation and suppressed liver fibrosis, suggesting that 3D-hESC-Exosome enriched-miR-6766-3p is a novel anti-fibrotic therapeutics for treating chronic liver disease. These results also proposed a significant strategy that 3D-Exo could be used as natural nanoparticles to rescue liver injury via delivering antifibrotic miR-6766-3p.

Graphical Abstract
Recent advances of nanotechnology-based tumor vessel-targeting strategies
Authors: Zhu Dongjie , Li Yang , Zhang Zhengjia , Xue Zeyu , Hua Zhenglai , Luo Xinyi , Zhao Ting , Lu Cheng , Liu Yuanyan 
Published: December 2021

AbstractTumor vessels can provide oxygen and nutrition for solid tumor tissue, create abnormal tumor microenvironment (TME), and play a vital role in the development, immune escape, metastasis and drug resistance of tumor. Tumor vessel-targeting therapy has become an important and promising direction in anti-tumor therapy, with the development of five anti-tumor therapeutic strategies, including vascular disruption, anti-angiogenesis, vascular blockade, vascular normalization and breaking immunosuppressive TME. However, the insufficient drug accumulation and severe side effects of vessel-targeting drugs limit their development in clinical application. Nanotechnology offers an excellent platform with flexible modified surface that can precisely deliver diverse cargoes, optimize efficacy, reduce side effects, and realize the combined therapy. Various nanomedicines (NMs) have been developed to target abnormal tumor vessels and specific TME to achieve more efficient vessel-targeting therapy. The article reviews tumor vascular abnormalities and the resulting abnormal microenvironment, the application of NMs in the tumor vessel-targeting strategies, and how NMs can improve these strategies and achieve multi-strategies combination to maximize anti-tumor effects.
Graphical Abstract