bluuebunny/crossref_metadata_2025 huggingface dataset:
ZIC2 is downregulated and represses tumor growth via the regulation of STAT3 in breast cancer
Authors: Liu Zhi‐Hua , Chen Mei‐Ling , Zhang Qi , Zhang Yu , An Xin , Luo Yi‐Ling , Liu Xue‐Min , Liu Shang‐Xin , Liu Qian , Yang Ting , Liu Yan‐Min , Liu Bin‐Liu , Zhou Ai‐Jun , Li Man‐Zhi , Liu Yu‐Jie , Liu Ze‐Xian , Zhong Qian
Published: February 2020

Although early detection and systemic therapies have improved the diagnosis and clinical cure rate of breast cancer, breast cancer remains the most frequently occurring malignant cancer in women due to a lack of sufficiently effective treatments. Thus, to develop potential targeted therapies and thus benefit more patients, it is helpful to understand how cancer cells work. ZIC family members have been shown to play important roles in neural development and carcinogenesis. In our study, we found that ZIC2 is downregulated in breast cancer tissues at both the mRNA and protein levels. Low expression of ZIC2 was correlated with poor outcome in breast cancer patients and serves as an independent prognostic marker. Furthermore, overexpression of ZIC2 repressed, whereas knockdown of ZIC2 promoted, cell proliferation and colony formation ability in vitro and tumor growth in vivo. Using ChIP‐seq and RNA‐seq analysis, we screened and identified STAT3 as a potential target for ZIC2. ZIC2 bound to the STAT3 promoter and repressed the promoter activities of STAT3. ZIC2 knockdown induced the expression of STAT3, increasing the level of phosphorylated STAT3. These results suggest that ZIC2 regulates the transcription of STAT3 by directly binding to the STAT3 promoter. Additionally, interfering STAT3 with siRNAs or inhibitors abrogated the oncogenic effects induced by decreased ZIC2. Taken together, our results indicate that ZIC2 serves as a useful prognostic marker in breast cancer and acts as a tumor suppressor by regulating STAT3, implying that STAT3 inhibitors might provide an alternative treatment option for breast cancer patients with ZIC2 downregulation.
Extracellular vesicles from human liver stem cells inhibit renal cancer stem cell‐derived tumor growth in vitro and in vivo
Authors: Brossa Alessia , Fonsato Valentina , Grange Cristina , Tritta Stefania , Tapparo Marta , Calvetti Ruggero , Cedrino Massimo , Fallo Sofia , Gontero Paolo , Camussi Giovanni , Bussolati Benedetta
Published: February 2020

Cancer stem cells (CSCs) are considered as responsible for initiation, maintenance and recurrence of solid tumors, thus representing the key for tumor eradication. The antitumor activity of extracellular vesicles (EVs) derived from different stem cell sources has been investigated with conflicting results. In our study, we evaluated, both in vitro and in vivo, the effect of EVs derived from human bone marrow mesenchymal stromal cells (MSCs) and from a population of human liver stem cells (HLSCs) of mesenchymal origin on renal CSCs. In vitro, both EV sources displayed pro‐apoptotic, anti‐proliferative and anti‐invasive effects on renal CSCs, but not on differentiated tumor cells. Pre‐treatment of renal CSCs with EVs, before subcutaneous injection in SCID mice, delayed tumor onset. We subsequently investigated the in vivo effect of MSC‐ and HLSC‐EVs systemic administration on progression of CSC‐generated renal tumors. Tumor bio‐distribution analysis identified intravenous treatment as best route of administration. HLSC‐EVs, but not MSC‐EVs, significantly impaired subcutaneous tumor growth by reducing tumor vascularization and inducing tumor cell apoptosis. Moreover, intravenous treatment with HLSC‐EVs improved metastasis‐free survival. In EV treated tumor explants, we observed both the transfer and the induction of miR‐145 and of miR‐200 family members. In transfected CSCs, the same miRNAs affected cell growth, invasion and survival. In conclusion, our results showed a specific antitumor effect of HLSC‐EVs on CSC‐derived renal tumors in vivo, possibly ascribed to the transfer and induction of specific antitumor miRNAs. Our study provides further evidence for a possible clinical application of stem cell‐EVs in tumor treatment.
Strain modulation of phase transformation of noble metal nanomaterials
Authors: Wu Tong , Sun Mingzi , Huang Bolong
Published: February 2020

Noble metals have been extensively studied owing to their high chemical stability and outstanding catalytic properties in various important reactions. However, their large‐scale application of noble metals is still challenged by their high expense and scarcity on the earth, as well as the yet insufficient activity to give a satisfying performance. For decades, enormous research efforts have been devoted to the nanoengineering of noble metal nanocrystals, such as the size‐, composition‐, shape‐, and/or morphology‐controlled syntheses, and impressive advances have been achieved. Meanwhile, the discovery that the crystal structure of noble metal nanocrystals also has a significant impact on their properties opened a new pathway that modulates the crystal phases of noble metals to achieve better properties. Among the feasible methods for crystal phase transformation, the presence of strain is not negligible. Strain generally has two roles: the driving force of the phase transformation and/or the origin of the distinct properties of the new crystal structure. Strain effect on noble metals has also been extensively studied due to its capability of fine‐tuning the surface catalytic activity. Therefore, combining the two hot research trends together, a possible research pathway is emerging. That is, utilizing the potential synergistic effect between novel crystal phases and the subsequent lattice strain to boost the performance of noble metal nanocrystal even further. Herein, a brief summary of the currently discovered noble metal phases and strain effect and the introduction of strain related phase modulation techniques along with the catalytic applications will be presented. Finally, a brief conclusion and future perspective is given.

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LncRNA RP6‐65G23.1 accelerates proliferation and inhibits apoptosis via p‐ERK1/2/p‐AKT signaling pathway on keratinocytes
Authors: Duan Qiqi , Wang Guorong , Wang Min , Chen Caifeng , Zhang Mengdi , Liu Meng , Shao Yongping , Zheng Yan
Published: February 2020

Long non‐coding RNAs (LncRNAs) play essential roles in the development of various diseases including hepatic carcinoma, melanoma, and psoriasis. Meanwhile, lncRNA‐RP6‐65G23.1 was upregulated in psoriasis. However, it is still unclear whether lncRNA‐RP6‐65G23.1 expression is upregulated and contributes to keratinocytes proliferation and apoptosis, and which mechanisms are responsible for these processes. The aims of this study are to address these issues. RP6‐65G23.1 was significantly upregulated in M5‐stimulated keratinocytes and stimulated the proliferation and inhibited the apoptosis of HaCaT cells. Knockdown of RP6‐65G23.1 resulted in defects of growth and increased rates of apoptosis in HaCaT cells, while overexpression of RP6‐65G23.1 manifested the opposite effects. Consistently, the expression of antiapoptotic proteins Bcl‐xl and Bcl2 were decreased in RP6‐65G23.1‐knockdown cells but elevated in RP6‐65G23.1 overexpression cells. In addition, RP6‐65G23.1 depletion blunted the activity of extracellular regulated kinase 1/2 (ERK1/2) and AKT signaling pathways and induced G1/S‐growth arrest. By contrast, overexpression of RP6‐65G23.1 activates the ERK1/2 and AKT signaling pathways and inhibits the expression of p21 and p27 in an AKT‐dependent manner leading to promote the G1/S progression. Our results suggested that lncRNA‐RP6‐65G23.1 would contribute to the pathogenesis of psoriasis by regulating the proliferation and apoptosis of keratinocytes via the p‐ERK1/2 and p‐AKT pathways.
M3 receptor modulates extracellular matrix synthesis via ERK1/2 signaling pathway in human bladder smooth muscle cells
Authors: Chen Shulian , Liao Banghua , Jin Xi , Wei Tangqiang , He Qing , Lin Yifei , Ai Jianzhong , Gong Lina , Li Hong , Wang Kunjie
Published: February 2020

Extracellular matrix (ECM) accumulation plays a key role in the progression of bladder outlet obstruction (BOO). Muscarinic receptors have been widely reported to serve as pivotal regulators in lung tissue remodeling. However, the influence of them on human bladder smooth muscle cells (HBSMCs) and the underlying molecular mechanisms have not yet been evaluated. The purposes of the present study are to investigate the effect of muscarinic receptors on the synthesis of ECM in HBSMCs and the involvement of intracellular signal transducers. The results indicated that M1‐M5 muscarinic receptors were all encoded in HBSMCs. The expression rank order was M2 > M1 > M5 > M3 > M4. The gene and protein expression of collagen I (COL1), TIMP‐1, and TIMP‐2 was carbachol (CCH) concentration‐dependently enhanced. The synthesis of COL1 in the supernatant of cell culture medium was significantly elevated by exposure to CCH. The CCH‐induced protein expression of COL1, TIMP‐1, and TIMP‐2, however, was obviously reduced by the pretreatment of muscarinic receptor antagonists, atropine, and M3‐preferring antagonist (1,1‐dimethyl‐4‐diphenyl‐acetoxypiperidinium iodide [4‐DAMP]). Furthermore, ERK1/2 was activated by 100 µM CCH when compared with the control group and the pretreatment of ERK1/2 inhibitor significantly suppressed the synthesis of COL1 induced by 100 µM CCH. Besides, CCH‐induced phosphorylation of ERK1/2 was remarkably restrained by the pretreatment of 4‐DAMP. All in all, these findings demonstrated that M3 receptor can modulate extracellular matrix synthesis via the ERK1/2 signaling pathway, which may provide potential novel therapeutic targets for BOO.
Synthesis, spectroscopic characterization, and in vitro antimicrobial activity of fused pyrazolo[4′,3′:4,5]thieno[3,2‐d]pyrimidine
Authors: Saber Ahmed F. , Kamal El‐Dean Adel M. , Redwan Shaban M. , Zaki Remon M.
Published: February 2020

4‐Amino‐3‐methyl‐1‐phenyl‐1H‐thieno[2,3‐c]pyrazole‐5‐carboxamide (1), which had been previously synthesized according to literature, was used for synthesizing pyrazolothieno‐pyrimidine (2) in the presence of triethyl orthoformate and acetic acid. Chlorination of the latter compound upon reflux with phosphorus oxychloride afforded the chloropyrazolothienopyrimidine (3), which underwent heterocyclization reaction with sodium azide to produce the tetrazolo‐pyrazolothienopyrimidine (6). The chloropyrimidine (3) reacted with hydrazine hydrate to give the hydrazinopyrimidine derivative (4), which in turn underwent intramolecular condensation reactions with various 1,3‐dicarbonyl compounds, namely ethyl acetoacetate, ethyl benzoylacetate, ethyl cyanoacetate, acetylacetone, diethyl malonate, and ethyl (ethoxymethylene) cyanoacetate, yielding new pyrazolyl pyrazolothienopyrimidine ring systems. Also triazolopyrazolothieno‐pyrimidines and benzylidene Schiff's base compounds were obtained as a result of the reactions with carbon disulfide in pyridine and benzaldehyde, respectively. The chemical structures of the newly synthesized compounds were elucidated using elemental and spectroscopic analyses (FT‐IR, 1H‐NMR, 13C‐NMR, and mass spectroscopy). Some of the synthesized compounds possess high antibacterial and antifungal activities.
The role of miR‐34 in cancer drug resistance
Authors: Naghizadeh Sanaz , Mohammadi Ali , Duijf Pascal H. G. , Baradaran Behzad , Safarzadeh Elham , Cho William Chi‐Shing , Mansoori Behzad
Published: February 2020

Resistance to conventional chemotherapy remains a major cause of cancer relapse and cancer‐related deaths. Therefore, there is an urgent need to overcome resistance barriers. To improve cancer treatment approaches, it is critical to elucidate the basic mechanisms underlying drug resistance. Increasingly, the mechanisms involving micro‐RNAs (miRNAs) are studied because miRNAs are also considered practical therapeutic options due to high degrees of specificity, efficacy, and accuracy, as well as their ability to target multiple genes at the same time. Years of research have firmly established miR‐34 as a key tumor suppressor miRNA whose target genes are involved in drug resistance mechanisms. Indeed, numerous articles show that low levels of circulating miR‐34 or tumor‐specific miR‐34 expression are associated with poor response to chemotherapy. In addition, elevation of inherently low miR‐34 levels in resistant cancer cells effectively restores sensitivity to chemotherapeutic agents. Here, we review this literature, also highlighting some contradictory observations. In addition, we discuss the potential utility of miR‐34 expression as a predictive biomarker for chemotherapeutic drug response. Although caution needs to be exercised, miR‐34 is emerging as a biomarker that could improve cancer precision medicine.
Efficacy of the photon‐initiated photoacoustic streaming combined with different solutions on Enterococcus faecalis in the root canals
Authors: Wen Cheng , Kong Yuanyuan , Zhao Jian , Li Yang , Yu Miao , Zeng Sujuan , Shi Zhan , Jiang Qianzhou
Published: February 2020

This study aimed to evaluate the efficacy of different irrigation solutions used in photon‐initiated photoacoustic streaming (PIPS) or conventional needle irrigation (CNI) for eradication of Enterococcus faecalis from artificial root canals. Altogether, 240 artificial root canal samples were included. The models were split and incubated for 2 days to allow formation of E. faecalis biofilm. The models were randomly divided into two groups (n = 120): CNI and laser‐activated irrigation (LAI). Each group was divided into six subgroups according to different irrigation solutions: distilled water, 1% sodium hypochlorite (NaOCl), 2% NaOCl, 5.25% NaOCl, MTAD, and chlorhexidine, respectively. After irrigation, half of the samples (n = 10) were assessed immediately, and the other half of the samples (n = 10) were incubated for 6 hr. Bacterial suspensions were obtained from all samples before and after irrigation, and after incubation, and were quantified adenosine 5′‐triphosphate (ATP) assay kit. The biofilms were examined using fluorescent microscopy and analyzed by Image Pro Plus software. Significant reduction of ATP, average fluorescence density after irrigation, and growth after incubation was obtained in LAI group than in CNI group (p < .05). LAI can improve bacteriostasis effect of 2% NaOCl (p < .05). PIPS improved the antibacterial effect of the 2% NaOCl used in root canal therapy.
Effect of Shakuyaku‐kanzo‐to in patients with muscle cramps: A systematic literature review
Authors: Ota Koshi , Fukui Keisuke , Nakamura Eriko , Oka Masahiro , Ota Kanna , Sakaue Masahide , Sano Yohei , Takasu Akira
Published: February 2020

Background

Previous clinical studies have reported that Shakuyaku‐kanzo‐to (SKT) has a therapeutic effect on muscle cramps, but few studies have clarified how SKT acts to treat muscle cramps. The aim of this study was to perform an updated systematic review of clinical trials for SKT in patients with muscle cramps.

Methods

The literature was systematically reviewed to assess the effects of SKT in patients with muscle cramps. PubMed, Web of Science, Cochrane Library, Google Scholar, and Ichushi‐Web were searched using the terms “Shakuyaku‐kanzo‐to” (“shakuyakukanzoto”, etc), “clinical trials” and “muscle cramps”. Two quality assessments were conducted independently by three authors. Data were extracted using a standardized extraction tool, and a qualitative synthesis of evidence was performed.

Results

Three randomized controlled articles were identified and enrolled in this study. A systematic review, but not a meta‐analysis, was performed because of the high heterogeneity and limited number of studies. In patients with liver cirrhosis, the odds ratio (OR) for improvement with SKT compared to placebo was 1.27 (95% confidence interval [CI], 0.445‐2.086) and compared to Goshajinkigan was 0.81 (95%CI, −1.734‐0.114). The OR for improvement with SKT compared with eperisone hydrochloride in patients with lumbar spinal stenosis was 2.86 (95%CI, 0.980‐4.744).

Conclusions

Current evidence appears insufficient to allow a meta‐analysis of the effects of SKT, but SKT might show efficacy in treating muscle cramps in patients with cirrhosis or lumbar spinal stenosis.
Three‐colored asymmetric bipartite Ramsey number of connected matchings and cycles
Authors: Luo Zhidan , Peng Yuejian
Published: February 2020

Guaranteed by Szemerédi's Regularity Lemma, a technique originated by Łuczak is to reduce the problem of showing the existence of a monochromatic cycle to show the existence of a monochromatic matching in a component. So determining the Ramsey number of connected matchings is crucial in determining the Ramsey number of cycles. Let be integers and be the minimum integer such that for any red‐blue‐green coloring of , there is a red matching of size at least in a component, or a blue matching of size at least in a component, or a green matching of size at least in a component. Bucić, Letzter, and Sudakov determined the exact value of and led to the asymptotic value of 3‐colored bipartite Ramsey number of cycles (symmetric case). In this paper, we determine the exact value of completely. This answers a question of Bucić, Letzter, and Sudakov. The crucial part of the proof is the construction we give in Section 4. Applying the technique of Łuczak, we obtain the asymptotic value of 3‐colored bipartite Ramsey number of cycles for all asymmetric cases.
Systematic review on peri‐operative lactate measurements to predict outcomes in patients undergoing liver resection
Authors: Connolly Catherine , Stättner Stefan , Niederwieser Thomas , Primavesi Florian
Published: February 2020

Lactate measurements have proven utility as a triage tool, therapeutic guide, and prognostic indicator, with broad use in Acute Care and transplantation. Its value in guiding therapy and predicting outcomes following liver resection is less well‐defined. This systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines assessed the relationship between peri‐operative lactate levels and morbidity and mortality after liver resection. Seven relevant studies comprising 2573 patients in total were identified. Six studies assessed intra‐operative or early postoperative lactate levels, one publication examined pre‐operative levels. All studies demonstrated a significant association between peri‐operative lactate levels and adverse outcomes. The influence of pre‐operative diabetes and cirrhosis on postoperative lactate levels was shown in one study each, no study assessed the association of lactate with post‐hepatectomy liver failure according to defined criteria. The heterogeneity of study measurements and end‐points precluded a meta‐analysis from being performed. Early postoperative lactate >3‐3.7 mmol/L is associated with mortality but validation of clear cut‐off levels for outcome prediction is pending. Literature suggests lactate is a useful predictive marker for outcomes post liver surgery, especially when measured in the early postoperative phase. Further research is required to standardize the use of lactate measurements in a meaningful therapeutic manner.
Redefining and revisiting cost estimates of routine ART care in Zambia: an analysis of ten clinics
Authors: Tucker Austin , Tembo Tannia , Tampi Radhika P , Mutale Jacob , Mukumba‐Mwenechanya Mpande , Sharma Anjali , Dowdy David W , Moore Carolyn B , Geng Elvin , Holmes Charles B , Sikazwe Izukanji , Sohn Hojoon
Published: February 2020

Introduction

Accurate costing is key for programme planning and policy implementation. Since 2011, there have been major changes in eligibility criteria and treatment regimens with price reductions in ART drugs, programmatic changes resulting in clinical task‐shifting and decentralization of ART delivery to peripheral health centres making existing evidence on ART care costs in Zambia out‐of‐date. As decision makers consider further changes in ART service delivery, it is important to understand the current drivers of costs for ART care. This study provides updates on costs of ART services for HIV‐positive patients in Zambia.

Methods

We evaluated costs, assessed from the health systems perspective and expressed in 2016 USD, based on an activity‐based costing framework using both top‐down and bottom‐up methods with an assessment of process and capacity. We collected primary site‐level costs and resource utilization data from government documents, patient chart reviews and time‐and‐motion studies conducted in 10 purposively selected ART clinics.

Results

The cost of providing ART varied considerably among the ten clinics. The average per‐patient annual cost of ART service was $116.69 (range: $59.38 to $145.62) using a bottom‐up method and $130.32 (range: $94.02 to $162.64) using a top‐down method. ART drug costs were the main cost driver (67% to 7% of all costs) and are highly sensitive to the types of patient included in the analysis (long‐term vs. all ART patients, including those recently initiated) and the data sources used (facility vs. patient level). Missing capacity costs made up 57% of the total difference between the top‐down and bottom‐up estimates. Variability in cost across the ten clinics was associated with operational characteristics.

Conclusions

Real‐world costs of current routine ART services in Zambia are considerably lower than previously reported estimates and sensitive to operational factors and methods used. We recommend collection and monitoring of resource use and capacity data to periodically update cost estimates.
Decreasing time to antiretroviral therapy initiation after HIV diagnosis in a clinic‐based observational cohort study in four African countries
Authors: Esber Allahna L , Coakley Peter , Ake Julie A , Bahemana Emmanuel , Adamu Yakubu , Kiweewa Francis , Maswai Jonah , Owuoth John , Robb Merlin L , Polyak Christina S , Crowell Trevor A ,   for the AFRICOS Study Group
Published: February 2020

Introduction

World Health Organization (WHO) guidelines have shifted over time to recommend earlier initiation of antiretroviral therapy (ART) and now encourage ART initiation on the day of HIV diagnosis, if possible. However, barriers to ART access may delay initiation in resource‐limited settings. We characterized temporal trends and other factors influencing the interval between HIV diagnosis and ART initiation among participants enrolled in a clinic‐based cohort across four African countries.

Methods

The African Cohort Study enrols adults engaged in care at 12 sites in Uganda, Kenya, Tanzania and Nigeria. Participants provide a medical history, complete a physical examination and undergo laboratory assessments every six months. Participants with recorded dates of HIV diagnosis were categorized by WHO guideline era (<2006, 2006 to 2009, 2010 to 2012, 2013 to 2015, ≥2016) at the time of diagnosis. Cox proportional hazard modelling was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for time to ART initiation.

Results and discussion

From January 2013 to September 2019, a total of 2888 adults living with HIV enrolled with known diagnosis dates. Median time to ART initiation decreased from 22.0 months (interquartile range (IQR) 4.0 to 77.3) among participants diagnosed prior to 2006 to 0.5 months (IQR 0.2 to 1.8) among those diagnosed in 2016 and later. Comparing those same periods, CD4 nadir increased from a median of 166 cells/mm3 (IQR: 81 to 286) to 298 cells/mm3 (IQR: 151 to 501). In the final adjusted model, participants diagnosed in each subsequent WHO guideline era had increased rates of ART initiation compared to those diagnosed before 2006. CD4 nadir ≥500 cells/mm3 was independently associated with a lower rate of ART initiation as compared to CD4 nadir <200 cells/mm3 (HR: 0.32; 95% CI: 0.28 to 0.37). Age >50 years at diagnosis was independently associated with shorter time to ART initiation as compared to 18 to 29 years (HR: 1.38; 95% CI: 1.19 to 1.61).

Conclusions

Consistent with changing guidelines, the interval between diagnosis and ART initiation has decreased over time. Still, many adults living with HIV initiated treatment with low CD4, highlighting the need to diagnose HIV earlier while improving access to immediate ART after diagnosis.
Dietary lipids in glycogen storage disease type III: A systematic literature study, case studies, and future recommendations
Authors: Rossi Alessandro , Hoogeveen Irene J. , Bastek Vanessa B. , de Boer Foekje , Montanari Chiara , Meyer Uta , Maiorana Arianna , Bordugo Andrea , Dianin Alice , Campana Carmen , Rigoldi Miriam , Kishnani Priya S. , Pendyal Surekha , Strisciuglio Pietro , Gasperini Serena , Parenti Giancarlo , Parini Rossella , Paci Sabrina , Melis Daniela , Derks Terry G. J.
Published: February 2020

A potential role of dietary lipids in the management of hepatic glycogen storage diseases (GSDs) has been proposed, but no consensus on management guidelines exists. The aim of this study was to describe current experiences with dietary lipid manipulations in hepatic GSD patients. An international study was set up to identify published and unpublished cases describing hepatic GSD patients with a dietary lipid manipulation. A literature search was performed according to the Cochrane Collaboration methodology through PubMed and EMBASE (up to December 2018). All delegates who attended the dietetics session at the IGSD2017, Groningen were invited to share unpublished cases. Due to multiple biases, only data on GSDIII were presented. A total of 28 cases with GSDIII and a dietary lipid manipulation were identified. Main indications were cardiomyopathy and/or myopathy. A high fat diet was the most common dietary lipid manipulation. A decline in creatine kinase concentrations (n = 19, P < .001) and a decrease in cardiac hypertrophy in paediatric GSDIIIa patients (n = 7, P < .01) were observed after the introduction with a high fat diet. This study presents an international cohort of GSDIII patients with different dietary lipid manipulations. High fat diet may be beneficial in paediatric GSDIIIa patients with cardiac hypertrophy, but careful long‐term monitoring for potential complications is warranted, such as growth restriction, liver inflammation, and hepatocellular carcinoma development.
An emerging role for endothelial barrier support therapy for congenital disorders of glycosylation
Authors: Brucker William J. , Croteau Stacy E. , Prensner John R. , Cullion Kate , Heeney Matthew M. , Lo Jeffrey , McAlvin James B. , Peeler Katherine , Shah Nidhi , Yee Christina S. K. , Berry Gerard T. , Bodamer Olaf
Published: February 2020

Congenital disorders of glycosylation (CDGs) are clinically heterogeneous disorders defined by a decreased ability to modify biomolecules with oligosaccharides. Critical disruptions in protein recognition, interaction, binding, and anchoring lead to broad physiological effects. Patients present with endocrinopathy, immunodeficiency, hepatopathy, coagulopathy, and neurodevelopmental impairment. Patients may experience mortality/morbidity associated with shock physiology that is frequently culture negative and poorly responsive to standard care. Oedema, pleural and pericardial effusions, ascites, proteinuria, and protein‐losing enteropathy are observed with an exaggerated inflammatory response. The negative serum protein steady state results from several mechanisms including reduced hepatic synthesis and secretion, increased consumption, and extravasation. Disruption of the glycocalyx, a layer of glycosylated proteins that lines the endothelium preventing thrombosis and extravasation, is a suspected cause of endothelial dysfunction in CDG patients. We performed a retrospective review of CDG patients admitted to our institution with acute illness over the past 2 years. Longitudinal clinical and laboratory data collected during the sick and well states were assessed for biomarkers of inflammation and efficacy of interventions. Six patients representing 4 CDG subtypes and 14 hospitalisations were identified. Acute D‐dimer elevation, proteinuria, decreased serum total protein levels, coagulation proteins, and albumin were observed with acute illness. Infusion of fresh frozen plasma, and in some cases protein C concentrate, was associated with clinical and biomarker improvement. This was notable with intra‐patient comparison of treated vs untreated courses. Use of endothelial barrier support therapy may reduce endothelial permeability by restoring both regulatory serum protein homeostasis and supporting the glycocalyx and is likely a critical component of care for this population.
TCR repertoire analysis reveals phosphoantigen-induced polyclonal proliferation of Vγ9Vδ2 T cells in neonates and adults
Authors: Fichtner Alina S , Bubke Anja , Rampoldi Francesca , Wilharm Anneke , Tan Likai , Steinbrück Lars , Schultze-Florey Christian , von Kaisenberg Constantin , Prinz Immo , Herrmann Thomas , Ravens Sarina
Published: February 2020

The Vγ9Vδ2 T cell subset is the major γδ T cell subset in human peripheral blood and has the unique ability to contribute to immune surveillance by detecting pyrophosphorylated metabolites of isoprenoid synthesis, termed phosphoantigens (pAgs). Vγ9Vδ2 T cells are first detected at midgestation and show postnatal expansion. Interestingly, neonatal Vγ9Vδ2 T cells display a higher TCR repertoire diversity with more public clonotypes and lower pAg responsiveness than in adults. Notably, it is not known whether postnatal changes occur by TCR-dependent reactivity to pAg exposure. Here, we applied next-generation sequencing of γδ TCR repertoires to understand potential differences in the pAg-mediated response of neonatal and adult Vγ9Vδ2 T cells at the level of the expressed γδ TCR. We observed a polyclonal pAg-induced response of neonatal and adult Vγ9Vδ2 T cells, albeit neonatal γδ T cells showed less in vitro pAg responsiveness. Neonatal Vγ9Vδ2 T cells displayed a less pronounced bias for Jδ1 usage and a more frequent use of Jδ2 or Jδ3 that remained stable after pAg exposure. In addition, public and private Vδ2 TRD clones took part in the polyclonal pAg-induced response in neonates and adults. In conclusion, adult and neonatal Vγ9Vδ2 T cells both undergo polyclonal pAg-induced proliferation, whereas especially adult Vγ9Vδ2 T cells display a high stability at the level of the expressed TCR repertoire.
Ultrasound Microvascular Imaging Based on Super‐Resolution Radial Fluctuations
Authors: Zhang Jiabin , Li Nan , Dong Feihong , Liang Shuyuan , Wang Di , An Jian , Long Yunfei , Wang Yuexiang , Luo Yukun , Zhang Jue
Published: February 2020

Objectives

Super‐resolution ultrasound (SRUS) has become a tool for in vivo microvascular imaging. Most of the SRUS methods are based on microbubble localization: namely, ultrasound localization microscopy (ULM). The aim of this study was to develop a nonlocalization SRUS method and verify its feasibility in microvascular imaging.

Methods

We introduce a new super‐resolution strategy based on the postprocessing of contrast‐enhanced ultrasound. The proposed method, which is termed ultrasound diffraction attenuation microscopy (UDAM), uses super‐resolution radial fluctuations instead of microbubble localization to overcome acoustic diffraction limits. Biceps of Japanese long‐ear white rabbits were adopted to validate its feasibility on muscle vascular imaging, using a clinical accessible ultrasound system at a frame rate of 30 Hz under a single bolus injection of SonoVue (Bracco SpA, Milan, Italy). The super‐resolution image was compared with the maximum‐intensity projection and ULM.

Results

The animal study illustrates that the proposed UDAM can obtain super‐resolution microvascular images of rabbits’ muscles under a single bolus injection of SonoVue with a 150‐second contrast‐enhanced ultrasound video. Both ULM and UDAM can achieve a very similar vascular structure with the maximum‐intensity projection but much higher spatial resolution. The measurement of 1‐dimensional signals shows that UDAM can distinguish the subwavelength structures and substantial reduce the full width at half‐maximum of microvessels.

Conclusions

We conclude UDAM provides a noninvasive tool for in vivo super‐resolution microvascular imaging.
Surgery versus Imaging in Non‐Localizing Primary Hyperparathyroidism: A Cost‐Effectiveness Model
Authors: Frank Ethan , Watson WayAnne , Fujimoto Shannon , De Andrade Filho Pedro , Inman Jared , Simental Alfred
Published: February 2020

Objective

To determine whether advanced imaging is cost‐effective compared to primary bilateral neck exploration in the management of non‐localizing primary hyperparathyroidism.

Study Design

Cost‐effectiveness analysis.

Methods

Cost‐effectiveness analysis based on decision tree model and available Medicare financial data using data from 347 consecutive patients having parathyroidectomy for primary hyperparathyroidism with either 1) positive, concordant ultrasound and sestamibi or 2) negative sestamibi and negative ultrasound.

Results

Bilateral neck exploration (BNE) costs $9578 and has a success rate of 97.3%. Single photon emission computed tomography (SPECT) + minimally invasive parathyroidectomy (MIP) was modeled to have a total cost of $8197 with a success rate of 98.6%. SPECT/computed tomography (CT) + MIP was modeled to have a total cost of $8271 and a 98.9% success rate. Four‐dimensional (4D)–CT + MIP was modeled to cost $8146 with a success rate of 99%. Incremental cost‐effectiveness ratios (IECR) (as compared to BNE) were −536.1, −605.5, and −701.6 ($/percent cure rate) for SPECT, SPECT/CT, and 4D‐CT respectively. One‐way sensitivity analyses demonstrate the change in IECR and cut‐off points (IECR = 0) for four major variables.

Conclusions

In patients with non‐localizing primary hyperparathyroidism, advanced imaging is associated with cost‐savings compared to routine bilateral neck exploration. Increased cost‐savings were predicted with increased imaging accuracy and decreased imaging costs. Increasing time for BNE or decreasing time for MIP were associated with increased cost savings.

Level of Evidence

III Laryngoscope, 2020
Peri‐Interview Communication in the Otolaryngology Residency Match: The Applicant Perspective
Authors: Masciello Maria , Malekzadeh Sonya
Published: February 2020

Objectives/Hypothesis

To evaluate peri‐interview communication in the otolaryngology Match from the applicant's perspective.

Study Design

Cross‐sectional survey study.

Methods

A survey link was emailed to 401 otolaryngology residency applicants from the 2019 Match cycle. Survey items queried peri‐interview communication practices and applicants' attitudes toward communication in the postinterview period. Data were collected anonymously. Qualitative analysis was performed for descriptive statistics. Responses from female and male participants were compared using Fisher exact tests.

Results

The survey yielded a 44% (56% male, 44% female) response rate and a 100% completion rate. Of applicants, 18% were told they were ranked to match, and 19% were asked how highly they planned to rank a given program. Interview questions regarding marital status and plans for children were asked to 38% and 12%, respectively. The majority (75%) believe peri‐interview communication should be allowed. Most (65%) participants felt obligated to inform top program(s) of their high rank; however, only 45% of applicants found this to be stressful. Peri‐interview communication may have altered the rank list for 10% of applicants. Of applicants, 96% created their final rank list based on where they most wanted to match rather than where they would most likely match.

Conclusions

National Resident Matching Program peri‐interview communication violations occur in the otolaryngology Match at similar rates when compared to other specialties. Although peri‐interview communication can cause significant stress, the majority of otolaryngology residency applicants believe peri‐interview communication should be allowed and do not believe it alters applicants' rank lists.

Level of Evidence

NA Laryngoscope, 131:28–32, 2021
Permafrost response to land use and land cover change in the last millennium across the Northern Hemisphere
Authors: Peng Xiaoqing , Zhang Tingjun , Frauenfeld Oliver W. , Du Ran
Published: February 2020

Land use and land cover change (LULCC) can alter surface climate through biogeophysical feedbacks including the modification of energy, moisture, and momentum exchanges between the land and atmosphere. Permafrost, a component of the cryosphere, plays an important role in the climate system. However, the role of permafrost in LULCC in cold regions is still not clearly understood. Here, we employ a LULCC sensitivity experiment carried out by the community Earth system model last millennium ensemble project to investigate the effect of LULCC in permafrost regions across the Northern Hemisphere during 850–2005. LULCC is associated with statistically significant large‐scale cooling in permafrost regions. The overall area‐averaged annual surface air temperature decreased 0.37°C during 850–2005, and soil temperature decreased 0.39°C. Active layer thickness declined at a rate of −0.54 cm/100 year ± 0.023 cm, with a net decline of 6.24 ± 0.26 cm during 850–2005 in association with LULCC. Soil moisture also showed a decrease, most pronounced in summer and autumn. Seasonally, the greatest surface air temperature decreases occurred in autumn at a rate of −0.042°C/100 year, and 0.2 m winter soil temperature decreased 0.036°C/100 year, both with time lags. Comparisons of cooling associated with LULCC demonstrate that permafrost regions are more sensitive to LULCC than the rest of the Northern Hemisphere.
A Ninhydrin‐Type Urea Sorbent for the Development of a Wearable Artificial Kidney
Authors: Jong Jacobus A. W. , Guo Yong , Hazenbrink Diënty , Douka Stefania , Verdijk Dennis , van der Zwan Johan , Houben Klaartje , Baldus Marc , Scheiner Karina C. , Dalebout Remco , Verhaar Marianne C. , Smakman Robert , Hennink Wim E. , Gerritsen Karin G.F. , van Nostrum Cornelus F.
Published: February 2020

The aim of this study is to develop polymeric chemisorbents with a high density of ninhydrin groups, able to covalently bind urea under physiological conditions and thus potentially suitable for use in a wearable artificial kidney. Macroporous beads are prepared by suspension polymerization of 5‐vinyl‐1‐indanone (vinylindanone) using a 90:10 (v/v) mixture of toluene and nitrobenzene as a porogen. The indanone groups are subsequently oxidized in a one‐step procedure into ninhydrin groups. Their urea absorption kinetics are evaluated under both static and dynamic conditions at 37 °C in simulated dialysate (urea in phosphate buffered saline). Under static conditions and at a 1:1 molar ratio of ninhydrin: urea the sorbent beads remove ≈0.6–0.7 mmol g−1 and under dynamic conditions and at a 2:1 molar excess of ninhydrin ≈0.6 mmol urea g−1 sorbent in 8 h at 37 °C, which is a step toward a wearable artificial kidney.
Fully Green Poly(vinyl alcohol)/Tea Polyphenol Composites and Super Anti‐Ultraviolet and ‐Bacterial Properties
Authors: Zhang Li‐Hua , Shen Qing
Published: February 2020

Several fully green composites are prepared by taking the tea polyphenols (TP) with various percentages to blend with poly(vinyl alcohol) (PVA). The as‐prepared PVA/TP composite with only 5% TP shows superb anti‐UV properties even after water washing, the presented UV protection factor (UPF) value is still greater than that of the standard values reported by Australia and New Zealand (AS/NZS 4399‐1996). Moreover, the UPF value of those PVA/TP composites is found capable of furthermore enhancement by increasing the TP percent. This PVA/TP composite also shows good antibacterial and biodegradability while it is kept with certain mechanical properties to fit required application cases.
Rational Design of Soluble Polyaramid for High‐Efficiency Energy Storage Dielectric Materials at Elevated Temperatures
Authors: Xu Da , Xu Wenhan , Seery Thomas , Zhang Haibo , Zhou Chenyi , Pang Jinhui , Zhang Yunhe , Jiang Zhenhua
Published: February 2020

High‐temperature polymer dielectrics are in great demand for harsh‐environment applications. Maintaining high‐energy storage density and low loss at elevated temperatures remains a major challenge for polymer dielectrics. In this work, a new type of polymer dielectric material is designed, which exhibits comparable dielectric properties in the start‐of‐the‐art dielectric nanocomposites and a superior potential for scale up. A soluble, glassy state polymer with a polarizing group is designed by introducing a weakly polar group into the polyaramid (PA) backbone to dilute the hydrogen bonding of the PA parent species. This increases the mobility of the molecular dipole within the polymer in the glassy state, thereby increasing its dielectric constant while maintaining the high‐temperature performance. The result of this design is a polymer with a glass transition temperature of 251 °C, a dielectric constant of up to 4.5, and a dielectric loss of 1%, while maintaining 2.1 J cm−3 energy density and 86.8% efficiency at 200 °C. This polymer, with its excellent, intrinsic, electrical‐energy‐storage properties can also be adapted for a roll‐to‐roll capacitor film production. Breaking intermolecular hydrogen bonds to enhance the electrical‐energy‐storage properties of polymers is an excellent path for designing polymer dielectrics with high‐temperature capabilities.
Ratio of the zygote cytoplasm to the paternal genome affects the reprogramming and developmental efficiency of androgenetic embryos
Authors: Liao Chen , Shen Xinghui , Zhang Yuwei , Lei Lei
Published: February 2020

Uniparental embryos have uniparental genomes and are very useful models for studying the specific gene expression of parents or for exploring the biological significance of genomic imprinting in mammals. However, the early developmental efficiency of androgenetic embryos is significantly lower than that of parthenogenetic embryos. In addition, oocytes are able to reprogram sperm nuclei after fertilization to guarantee embryonic development by maternally derived reprogramming factors, which accumulate during oogenesis. However, the importance of maternal material in the efficiency of reprogramming the pronucleus of androgenetic embryos is not known. In this study, androgenetic embryos were constructed artificially by pronucleus transfer (PT) or double sperm injection (DS). Compared with DS embryos, PT embryos that were derived from two zygotes contained more maternal material, like 10–11 translocation methylcytosine deoxygenase 3 (Tet3) and histone variant 3.3 (H3.3). Our experiments confirmed the better developmental potential of PT embryos, which had higher blastocyst rates, a stronger expression of pluripotent genes, a lower expression of apoptotic genes, and superior blastocyst quality. Our findings indicate that the aggregation of more maternal materials in the paternal pronucleus facilitate the reprogramming of the paternal genome, improving embryonic development in PT androgenesis.
Two‐level Fourier analysis of multigrid for higher‐order finite‐element discretizations of the Laplacian
Authors: He Yunhui , MacLachlan Scott
Published: February 2020

In this paper, we employ local Fourier analysis (LFA) to analyze the convergence properties of multigrid methods for higher‐order finite‐element approximations to the Laplacian problem. We find that the classical LFA smoothing factor, where the coarse‐grid correction is assumed to be an ideal operator that annihilates the low‐frequency error components and leaves the high‐frequency components unchanged, fails to accurately predict the observed multigrid performance and, consequently, cannot be a reliable analysis tool to give good performance estimates of the two‐grid convergence factor. While two‐grid LFA still offers a reliable prediction, it leads to more complex symbols that are cumbersome to use to optimize parameters of the relaxation scheme, as is often needed for complex problems. For the purposes of this analytical optimization as well as to have simple predictive analysis, we propose a modification that is “between” two‐grid LFA and smoothing analysis, which yields reasonable predictions to help choose correct damping parameters for relaxation. This exploration may help us better understand multigrid performance for higher‐order finite element discretizations, including for Q2‐Q1 (Taylor‐Hood) elements for the Stokes equations. Finally, we present two‐grid and multigrid experiments, where the corrected parameter choice is shown to yield significant improvements in the resulting two‐grid and multigrid convergence factors.
Eltrombopag for thrombocytopenia following allogeneic hematopoietic stem cell transplantation in children
Authors: Masetti Riccardo , Vendemini Francesca , Quarello Paola , Girardi Katia , Prete Arcangelo , Fagioli Franca , Pession Andrea , Locatelli Franco
Published: February 2020

Persistent thrombocytopenia is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT). While the use of thrombopoietin receptor agonists was retrospectively investigated in adults, data in pediatric posttransplant thrombocytopenia are lacking. We evaluated the safety and efficacy of eltrombopag in nine children with platelet transfusion‐dependent persistent thrombocytopenia after HSCT. Eltrombopag was started at a median of 147 days after allo‐SCT and continued for a median period of 64 days, the starting dose being 50 mg per day. The therapy was well tolerated. After a median time of treatment of 36 days, eight patients (88%) reached sustained platelets count >50 000/μL.
Minimally invasive surgery for unilateral Wilms tumors: Multicenter retrospective analysis of 50 transperitoneal laparoscopic total nephrectomies
Authors: Bouty Aurore , Blanc Thomas , Leclair Marc David , Lavrand Frederic , Faure Alice , Binet Aurelien , Rod Julien , O'Brien Mike , Sarnacki Sabine , Nightingale Michael , Heloury Yves , Varlet Francois , Scalabre Aurelien
Published: February 2020

Purpose

To evaluate feasibility and outcomes of minimally invasive surgery (MIS) in Wilms tumor (WT).

Methods

International multicenter review of MIS total nephrectomies for WT between 2006 and 2018. Medical records of confirmed WT were retrospectively assessed for demographic, imaging, treatment, pathology, and oncological outcome data.

Results

Fifty patients, with a median age of 38 months (6‐181), were included in 10 centers. All patients received neoadjuvant chemotherapy, as per SIOP protocol. Median tumor volume post‐chemotherapy was 673 mL (18‐3331), 16 tumors crossed the lateral border of the spine, and three crossed the midline. Six patients with tumors that crossed the lateral border of the spine (tumor volumes 1560 mL [299‐2480]) were converted to an open approach. There was no intraoperative tumor rupture. Overall, MIS was completed in 19% of the 195 nephrectomies for WT presenting during the study period. Tumor was stage I in 29, II in 16, and III in 5, and histology was reported as low in three, intermediate in 42, and high risk in five. Three patients had positive tumor margins. After a median follow‐up of 34 months (2‐138), there were two local recurrences (both stage I, intermediate risk, 7 and 9 months after surgery) and one metastatic relapse (stage III, high risk, four months after surgery). The three‐year event‐free survival was 94%.

Conclusion

MIS is feasible in 20% of WT, with oncological outcomes comparable with open surgery, no intraoperative rupture, and a low rate of local relapse. Ongoing surveillance is, however, needed to evaluate this technique as it becomes widespread.