bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiotherapeutic management of cervical lymph node metastases from an unknown primary site – experiences from a large cohort treated with modern radiation techniques
Authors: Sprave Tanja , Rühle Alexander , Hees Katharina , Kalckreuth Tobias , Verma Vivek , Stoian Raluca , Zamboglou Constantinos , Pfeiffer Jens , Laszig Roland , Knopf Andreas , Grosu Anca-Ligia , Nicolay Nils H. 
Published: April 2020

Abstract
Purpose
To analyze management and outcomes following (chemo)radiation therapy in patients with cervical lymph node metastases from an unknown primary site (CCUP) in a large single-center cohort.

Methods
Between 2008 and 2019, 58 patients with CCUP were treated with (chemo)radiation therapy at the University of Freiburg Medical Center and were included in this analysis. Overall survival (OS), locoregional progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The use of diagnostic procedures and their impact on oncological outcomes was analyzed by Cox regression, and treatment-related toxicities were quantified.

Results
Median follow-up was 29.9 months (range 4.6–121.9). Twenty-one patients (36.2%) received definitive RT, 35 (60.3%) underwent adjuvant RT, and 2 (3.4%) were treated for oligometastatic disease. Concurrent chemotherapy was prescribed in 40 patients (69.0%). 89.6% of patients completed the prescribed RT, and 65.0% completed the prescribed simultaneous chemotherapy. Locoregional recurrence was observed in 7 patients (12.1%) and distant metastases in 13 cases (22.4%). OS was 81,1, 64.9% and 56,6% after 1, 3 and 5 years, respectively.
Univariate analysis of age, gender, extracapsular spread, tumor grading, neck dissection, diagnostic utilization of 18F-fluorodeoxyglucose positron-emission tomography and concomitant chemotherapy showed no effect on OS (p > 0.05 for all), while smoking was significantly associated with decreased survival (p < 0.05). There was a trend towards impaired OS for patients with advanced nodal status (pN3) (p = 0.07). Three patients (5.2%) experienced grade 3 radiation dermatitis, and 12 (22.4%) developed grade 3 and 1 (1.7%) grade 4 mucositis.

Conclusions
RT of the panpharynx and cervical lymph nodes with concurrent chemotherapy in case of risk factors demonstrated good locoregional control, but the metachronous occurrence of distant metastases limited survival and must be further addressed.
MicroRNA-505 is involved in the regulation of osteogenic differentiation of MC3T3-E1 cells partially by targeting RUNX2
Authors: Li Weihua , Chen Zongchao , Cai Chuanqi , Li Gunjun , Wang Xiao , Shi Zhenyu 
Published: April 2020

Abstract
Objective
Evidence suggests that microRNAs (miRNAs) regulate the expression of genes involved in bone metabolism. This study aimed to investigate the role of miR-505 in the osteogenic differentiation of MC3T3-E1 cells.

Methods
We performed miRNA sequencing to identify differentially expressed miRNAs between MC3T3-E1 cells treated with osteogenic induction medium (OIM) and control cells. Bioinformatics analysis was performed by using the TargetScan and miRDB databases. The expression of miR-505 in MC3T3-E1 cells was detected during osteogenic differentiation. After transfection with miR-505 mimic or miR-505 inhibitor, MC3T3-E1 cells were induced to differentiate into osteoblasts, and the expression of osteogenic differentiation markers (Runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OCN), and osterix (OSX)) was detected.

Results
miR-505 was the most downregulated miRNA among the differentially expressed miRNAs. The RUNX2 gene was identified as a potential target of miR-505 using the target prediction program. miR-505 expression was downregulated during osteogenic differentiation of MC3T3-E1 cells. The expression of osteogenic marker genes was inhibited in MC3T3-E1 cells after transfection with miR-505. However, the expression of osteogenic marker genes was upregulated after transfection with miR-505 inhibitor.

Conclusion
This study is the first to report miR-505 could bind to the RUNX2 gene and thus regulate partly the dysfunction of osteoblasts differentiation, which is expected to be targets for the treatment of osteoporosis.
Forebrain excitatory neuron-specific SENP2 knockout mouse displays hyperactivity, impaired learning and memory, and anxiolytic-like behavior
Authors: Huang Dehua , Liu Huiqing , Zhu Aoxue , Zhou Yi , Li Yong 
Published: April 2020

AbstractSentrin/SUMO-specific protease 2 (SENP2) is a member of SENPs family involved in maturation of SUMO precursors and deSUMOylation of specific target, and is highly expressed in the central nervous system (CNS). Although SENP2 has been shown to modulate embryonic development, fatty acid metabolism, atherosclerosis and epilepsy, the function of SENP2 in the CNS remains poorly understood. To address the role of SENP2 in the CNS and its potential involvement in neuropathology, we generated SENP2 conditional knockout mice by crossing floxed SENP2 mice with CaMKIIα-Cre transgenic mice. Behavioral tests revealed that SENP2 ablation induced hyper-locomotor activity, anxiolytic-like behaviors, spatial working memory impairment and fear-associated learning defect. In line with these observations, our RNA sequencing (RNA-seq) data identified a variety of differential expression genes that are particularly enriched in locomotion, learning and memory related biologic process. Taken together, our results indicated that SENP2 plays a critical role in emotional and cognitive regulation. This SENP2 conditional knockout mice model may help reveal novel mechanisms that underlie a variety of neuropsychiatric disorders associated with anxiety and cognition.
Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study
Authors: Lu Chang , Dong Xiao-Rong , Zhao Jun , Zhang Xu-Chao , Chen Hua-Jun , Zhou Qing , Tu Hai-Yan , Ai Xing-Hao , Chen Xiao-Feng , An Gai-Li , Bai Jun , Shan Jin-Lu , Wang Yi-Na , Yang Shuan-Ying , Liu Xiang , Zhuang Wu , Wu Hui-Ta , Zhu Bo , Xia Xue-Feng , Chen Rong-Rong , Gu De-Jian , Xu Hua-Min , Wu Yi-Long , Yang Jin-Ji 
Published: April 2020

AbstractBackgroundRearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). InRET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared.MethodsPatients diagnosed with NSCLCs withRETrearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs).ResultsAmong 129 patients withRET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitantTP53mutation appeared most frequently (20/53, 37.7%). Patients with concurrentTP53mutation (n= 15) had shorter overall survival than those without (n= 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8];P< 0.05). Patients with lower peripheral blood TCR diversity (n= 5) had superior overall survival compared with those with higher diversity (n= 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3];P= 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10).ConclusionsRET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrentTP53mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.
A painless erythematous swelling of the external ear as a manifestation of Lyme disease: a case report
Authors: Remiker Allison , Haslam David , Kalfa Theodosia A. 
Published: April 2020

AbstractBackgroundLyme disease is the most common tick-borne illness in the USA, Canada, and Europe. Clinical manifestations vary greatly, with localized skin findings functioning as early signs of the disease, followed by disseminated disease. The rarest dermatologic presentation of Lyme is a borrelial lymphocytoma, occurring distinctly in Europe and caused typically byBorrelia afzelii.Case presentationWe report a case of a Caucasian 5-year-old European-American boy with slowly progressing, painless edema and erythema of his right pinna. Travel history revealed significant exposure to ticks during a recent trip to Eastern Europe. Laboratory testing forBorrelia burgdorferidemonstrated mixed positivity. He was treated with a 21-day course of amoxicillin, with complete resolution of symptoms and no sign of secondary Lyme disease.ConclusionsBorrelial lymphocytoma is a rare manifestation of Lyme disease in North America, although not uncommon in Europe. Diagnosis is made by the presence of a painless erythematous swelling typically found on the ear lobe, nipples, or testes. Laboratory tests are available but with low sensitivity, therefore, a high index of suspicion is necessary for a clinical diagnosis to be made. Treatment for isolated borrelial lymphocytoma is doxycycline 4 mg/kg up to 100 mg twice daily, whereas for children less than 8 years of age amoxicillin 50 mg/kg divided three times daily, for 3–4 weeks, is preferred.
Calorie intake is associated with weight gain during transition phase of nutrition in female extremely low birth weight infants
Authors: Alur Pradeep , Kalikkot Thekkeveedu Renjithkumar , Meeks Madaleine , Hart Kyle C. , Desai Jagdish , Johnson Marla , Presley Sara Marie , Hussain Naveed 
Published: April 2020

AbstractWe sought to determine whether there are sex-based differences in the requirements for calories or protein for optimal growth during the transition phase (TP) when an extremely low birth weight (ELBW) infant, defined as a preterm infant with a birth weight of < 1000 g, is progressing from parenteral to enteral feeds. A retrospective review of ELBW infants born from 2014 to 2016 was performed at a tertiary NICU. Infants with necrotizing enterocolitis, short bowel syndrome, or chromosomal anomalies were excluded. TP was defined as the period when the infant’s enteral feeds were increased from 30 up to 120 ml/kg/day while weaning parenteral nutrition (PN). Effects of sex and protein-calorie intake on the change in growth parameters from the beginning to the end of TP were analyzed. Pre-TP growth percentiles and calorie and protein intake were similar in both sexes. There was a significant (r= 0.22,p= 0.026) correlation of total calorie intake with a change in weight percentiles (wt.pc) for the whole group, but on sex-specific analysis, this correlation was more robust and significant only in girls (r= 0.28,p= 0.015). Protein intake did not correlate with the changes in wt.pc in either sex. Despite a similar intake of calories and protein during the TP, we found a significant decrease in wt.pc only in girls. More extensive studies are needed to understand the sex-based differences in caloric needs and metabolic rate in ELBW infants.
[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action
Authors: Clemente Gonçalo S. , Rickmeier Jens , Antunes Inês F. , Zarganes-Tzitzikas Tryfon , Dömling Alexander , Ritter Tobias , Elsinga Philip H. 
Published: April 2020

Abstract
Background
Statins are lipid-lowering agents that inhibit cholesterol synthesis and are clinically used in the primary and secondary prevention of cardiovascular diseases. However, a considerable group of patients does not respond to statin treatment, and the reason for this is still not completely understood. [18F]Atorvastatin, the 18F-labeled version of one of the most widely prescribed statins, may be a useful tool for statin-related research.

Results
[18F]Atorvastatin was synthesized via an optimized ruthenium-mediated late-stage 18F-deoxyfluorination. The defluoro-hydroxy precursor was produced via Paal-Knorr pyrrole synthesis and was followed by coordination of the phenol to a ruthenium complex, affording the labeling precursor in approximately 10% overall yield. Optimization and automation of the labeling procedure reliably yielded an injectable solution of [18F]atorvastatin in 19% ± 6% (d.c.) with a molar activity of 65 ± 32 GBq·μmol−1. Incubation of [18F]atorvastatin in human serum did not lead to decomposition. Furthermore, we have shown the ability of [18F]atorvastatin to cross the hepatic cell membrane to the cytosolic and microsomal fractions where HMG-CoA reductase is known to be highly expressed. Blocking assays using rat liver sections confirmed the specific binding to HMG-CoA reductase. Autoradiography on rat aorta stimulated to develop atherosclerotic plaques revealed that [18F]atorvastatin significantly accumulates in this tissue when compared to the healthy model.

Conclusions
The improved ruthenium-mediated 18F-deoxyfluorination procedure overcomes previous hurdles such as the addition of salt additives, the drying steps, or the use of different solvent mixtures at different phases of the process, which increases its practical use, and may allow faster translation to clinical settings. Based on tissue uptake evaluations, [18F]atorvastatin showed the potential to be used as a tool for the understanding of the mechanism of action of statins. Further knowledge of the in vivo biodistribution of [18F]atorvastatin may help to better understand the origin of off-target effects and potentially allow to distinguish between statin-resistant and non-resistant patients.
PRRT of neuroendocrine tumors: individualized dosimetry or fixed dose scheme?
Authors: Haug Alexander R. 
Published: April 2020

AbstractGreat efforts have been made in dosimetry for individualizing PRRT. However, many centers do not use dosimetry and its results hardly influence treatment. A reason for that is that reliable thresholds for organs-at-risk, kidneys and bone marrow, and treatment response are lacking. The nuclear medicine community must provide solid data from large trials delivering reliable thresholds, which then help to tailor PRRT according to organ doses (in order to reduce toxicity or increase treatment activity) or tumor doses (in order to increase activity to meet the response-threshold). Otherwise, development of radionuclide therapies will be done like big pharmaceutical companies do it currently: classical dose escalation studies and agreement on acceptable toxicity probabilities. Therapeutic radiopharmaceuticals will then be handled like other drugs, which on the other hand will increase availability of radionuclide therapies.
Newcastle disease virus RNA-induced IL-1β expression via the NLRP3/caspase-1 inflammasome
Authors: Gao Pei , Chen Libin , Fan Lei , Ren Jinlian , Du Haoyun , Sun Minhua , Li Yaling , Xie Peng , Lin Qiuyan , Liao Ming , Xu Chenggang , Ning Zhangyong , Ding Chan , Xiang Bin , Ren Tao 
Published: April 2020

AbstractNewcastle disease virus (NDV) infection causes severe inflammation and is a highly contagious disease in poultry. Virulent NDV strains (GM) induce large quantities of interleukin-1β (IL-1β), which is the central mediator of the inflammatory reaction. Excessive expression of IL-1β exacerbates inflammatory damage. Therefore, exploring the mechanisms underlying NDV-induced IL-1β expression can aid in further understanding the pathogenesis of Newcastle disease. Here, we showed that anti-IL-1β neutralizing antibody treatment decreased body temperature and mortality following infection with virulent NDV. We further explored the primary molecules involved in NDV-induced IL-1β expression from the perspective of both the host and virus. This study showed that overexpression of NLRP3 resulted in increased IL-1β expression, whereas inhibition of NLRP3 or caspase-1 caused a significant reduction in IL-1β expression, indicating that the NLRP3/caspase-1 axis is involved in NDV-induced IL-1β expression. Moreover, ultraviolet-inactivated GM (chicken/Guangdong/GM/2014) NDV failed to induce the expression of IL-1β. We then collected virus from GM-infected cell culture supernatant using ultracentrifugation, extracted the viral RNA, and stimulated the cells further with GM RNA. The results revealed that RNA alone was capable of inducing IL-1β expression. Moreover, NLRP3/caspase-1 was involved in GM RNA-induced IL-1β expression. Thus, our study elucidated the critical role of IL-1β in the pathogenesis of Newcastle disease while also demonstrating that inhibition of IL-1β via anti-IL-1β neutralizing antibodies decreased the damage associated with NDV infection; furthermore, GM RNA induced IL-1β expression via NLRP3/caspase-1.
On some new fixed point results in fuzzy b-metric spaces
Authors: Rakić Dušan , Mukheimer Aiman , Došenović Tatjana , Mitrović Zoran D. , Radenović Stojan 
Published: April 2020

AbstractThis paper consists of several fixed point theorems in the fuzzy b-metric spaces. As an important result, we give a sufficient condition for a sequence to be Cauchy in the fuzzy b-metric space. Thus we simplify the proofs of many fixed point theorems in the fuzzy b-metric spaces with the well-known contraction conditions.
Interaction of lead and cadmium on growth and leaf morphophysiological characteristics of European hackberry (Celtis australis) seedlings
Authors: Hatamian Mansoure , Rezaei Nejad Abdolhossein , Kafi Mohsen , Souri Mohammad Kazem , Shahbazi Karim 
Published: April 2020

Abstract
Background
In the present study, different concentrations of lead (factor A; 0, 15, and 30 mg L −1) and cadmium (factor B; 0 and 5 mg L −1) were applied via irrigation water during 6 months to evaluate their effects on growth of European hackberry (Celtis australis L.) plants. The experiment was arranged in factorial with completely randomized design and four replications under greenhouse conditions.

Results
Application of 5 mg L −1 Cd or the lead levels (15 and 30 mg L −1) significantly reduced new shoot growth, plant leaf area, SPAD value, leaf water conductance and leaf photosynthesis, whereas significant increase in number of chlorotic and necrotic leaves, leaf transpiration rate, leaf proline and soluble sugars was observed. Higher reduction in new shoot growth and leaf water conductance and higher increase in leaf soluble sugars and proline was observed over the interaction of 5 mg L −1 Cd and 30 mg L −1 Pb. The highest soluble sugars and proline were in Pb30Cd5 (a3b2) treatment. Leaf Pb or Cd concentration was increased following their treatment. Application of cadmium significantly reduced leaf Pb, and similarly leaf Cd was significantly reduced by application of lead at both levels compared to untreated plants.

Conclusion
The results showed that the hackberry growth was influenced by positive and negative interactions of Pb and Cd applied in irrigation water. The extent of growth reduction indicates that hackberry represents a relatively tolerant ornamental tree to high Pb and Cd levels.
Clinical outcomes of empirical high-dose meropenem in critically ill patients with sepsis and septic shock: a randomized controlled trial
Authors: Lertwattanachai Tospon , Montakantikul Preecha , Tangsujaritvijit Viratch , Sanguanwit Pitsucha , Sueajai Jetjamnong , Auparakkitanon Saranya , Dilokpattanamongkol Pitchaya 
Published: April 2020

Abstract
Background
Appropriate antimicrobial dosing is challenging because of changes in pharmacokinetics (PK) parameters and an increase in multidrug-resistant (MDR) organisms in critically ill patients. This study aimed to evaluate the effects of an empirical therapy of high-dose versus standard-dose meropenem in sepsis and septic shock patients.

Methods
We performed a prospective randomized open-label study to compare the changes of modified sequential organ failure assessment (mSOFA) score and other clinical outcomes of the high-dose meropenem (2-g infusion over 3 h every 8 h) versus the standard-dose meropenem (1-g infusion over 3 h every 8 h) in sepsis and septic shock patients. Patients’ characteristics, clinical and microbiological outcomes, 14 and 28-day mortality, vasopressor- and ventilator-free days, intensive care unit (ICU) and hospital-free days, percent of the time of antibiotic concentrations above the minimum inhibitory concentration (%T>MIC), and safety were assessed.

Results
Seventy-eight patients were enrolled. Median delta mSOFA was comparable between two groups (– 1 in the high-dose group vs. – 1 in the standard-dose group; P value = 0.75). There was no difference between the two groups regarding clinical and microbiological cure, 14- and 28-day mortality, vasopressor- and ventilator-free days, and ICU- and hospital-free days. In patients admitted from the emergency department (ED) with a mSOFA score ≥ 7, the high-dose group demonstrated significantly better microbiological cure compared with the standard-dose group (75% (9/12 patients) vs. 20% (2/10 patients); P value = 0.03). Likewise, the high-dose group presented higher microbiological cure rate in patients admitted from ED who had either APACHE II score > 20 (83.3% (10/12) vs. 28.6% (2/7); P value = 0.045) or on mechanical ventilator (87.5% (7/8) vs. 23.1% (3/13); P value = 0.008) than the standard-dose group. Adverse events were comparable between the two groups.

Conclusions
Empirical therapy with the high-dose meropenem presented comparable clinical outcomes to the standard-dose meropenem in sepsis and septic shock patients. Besides, subgroup analysis manifested superior microbiological cure rate in sepsis or septic shock patients admitted from ED.

Trial registration
ClinicalTrials.gov, NCT03344627, registered on November 17, 2017