bluuebunny/crossref_metadata_2025_split huggingface dataset:
AAZTA5-squaramide ester: promising tool for 177Lu-labeling of monoclonal antibodies under mild conditions
Authors: Klasen Benedikt , Moon Euy Sung , Rösch Frank 
Published: April 2020

Abstract
Background

Combining the advantages of both cyclic and acyclic chelator systems, AAZTA (1,4-bis(carboxymethyl)‐6‐[bis(carboxymethyl)]amino‐6‐methylperhydro‐1,4‐diazepine) is well suited for complexation of various diagnostic and therapeutic radiometals such as gallium-68, scandium-44 and lutetium-177 under mild conditions. Due to its specificity for primary amines and pH dependent binding properties, squaric acid (SA) represents an excellent tool for selective coupling of the appropriate chelator to different target vectors. Therefore, the aim of this study was to evaluate radiolabeling properties of the novel bifunctional AAZTA5-SA being coupled to a model antibody (bevacizumab) in comparison to DOTA-SA using the therapeutic nuclide lutetium-177.
Results

As proof-of-concept, bevacizumab was first functionalized with either AAZTA5-SA or DOTA-SA. After purification via fractionated size exclusion chromatography (SEC), the corresponding immunoconjugates were subsequently radiolabeled with lutetium-177 at pH 7 and room temperature (RT) as well as 37 °C. After 90 min, labeling of AAZTA5-SA-mAb resulted in almost quantitative radiochemical yields (RCY) of > 98% and > 99%, respectively. After purification via SEC, the radioconjugate [177Lu]Lu-AAZTA5-SA-mAb could be obtained with a purity of > 99% and an apparent specific activity of 4.5 GBq/µmol. In contrast, 177Lu-labeling of DOTA-SA-mAb showed negligible radiochemical yields of < 2% both at room temperature and 37 °C. In vitro complex stability measurements of [177Lu]Lu-AAZTA5-SA-mAb in human serum at 37 °C indicated > 99% protein bound activity within 15 days. In phosphate buffered saline (PBS), a slightly decreased stability of > 93% intact conjugate was observed over the same period.
Conclusion

Coupling of AAZTA5-SA to the monoclonal antibody bevacizumab allowed for 177Lu-labeling with almost quantitative radiochemical yields both at room temperature and 37 °C. Within 15 days, the resulting radioconjugate indicated very high in vitro complex stability both in human serum and PBS. Therefore, AAZTA5-SA is a promising tool for 177Lu-labeling of sensitive biomolecules such as antibodies for theranostic applications.
Evaluation on Prognostic Ability of Serum Uric Acid for Very Old Acute Coronary Syndrome Patients with Diabetes Mellitus: A Prospective Cohort Study
Authors: Fu Zhenhong , Jiao Yang , Wang Jihang , Xi Qing , Yang Xia , Shen Mingzhi , Xue Hao , Guo Jun , Dong Wei , Chen Yundai 
Published: April 2020

Abstract
Background This study sought to evaluate the prognostic power of serum uric acid (UA) in predicting adverse events of very old acute coronary syndrome (ACS) patients with diabetes mellitus (DM).Methods This analysis involved 718 ACS patients > 80 years old who were collected general clinical data and baseline blood biochemical indicators prospectively from January 2006 to December 2012, and these patients were classified into two groups based on DM, then followed up after discharge. Kaplan–Meier method was performed for major adverse cardiac events (MACE) rates and all-cause mortality. Multivariate Cox regression was performed to analyze the relationship between UA level and long-term clinical prognosis. Receiver operating characteristic (ROC) curve was analyzed to predict the cutoff value of UA of the very old ACS patients with DM.Results There were 242 and 476 patients in groups DM and non-DM(NDM) and the follow-up time after discharge was 40–120 months (median: 63 months; interquartile range: 51–74 months). The differences in all-cause mortality, cardiac mortality and MACE rates in DM and NDM patients between the control group were statistically significant (P = 0.001). All-cause mortality, cardiac mortality and MACE incidence in DM patients with moderate and high UA level were significantly higher than those in control group (P = 0.001). There were statistically significant differences in long-term survival rates among the ACS groups (P = 0.001), and long-term survival rates decreased significantly with the increase of UA level. UA (OR = 2.106, 95%CI = 1.244–3.568, P = 0.006) was found to be an independent risk factor for all-cause mortality and MACE in very old ACS patients with DM. The cutoff value of UA was 353.6 µmol/L (sensitivity: 67.4%; specificity: 65.7%). The elevation of serum UA level play an important role in predicting the development of all-cause mortality in elderly ACS patients with DM.Conclusion Serum UA level is a strong independent predictor of long-term all-cause death and MACE in very old ACS patients with DM.
Neoadjuvant PD-1 Inhibitor combines with Chemotherapy in Resectable Squamous Cell Non-Small Cell Lung Cancer
Authors: Feng Yuan , Sun Wei , Zhang Jie , Wang Yang , Chen Jinfeng , Liu Xinying , Wang Liang , Li Shaolei , LV Chao , Lu Fangliang , Zhang Jianzhi , Hong Yang , Xiao Shanshan , Wang Tao , Jiao Raymond , Wang Ziping , Qi Liping , Li Nan , Yang Yue , Lin Dongmei , Fang Jian 
Published: April 2020

Abstract
Background

Single agent of PD-1 or PD-L1 inhibitor has been explored recently for resectable patients before surgery. However, the effectiveness and safety of neoadjuvant PD-1 blockade combine with platinum-based doublet chemotherapy has not been fully investigated.
Methods

21 patients with squamous cell lung cancer accepted neoadjuvant therapy followed by surgery in Beijing Cancer Hospital were involved. 8 patients accepted two cycles of neoadjuvant platinum-based doublet chemotherapy combine with anti-PD-1 therapy, while 13 patients accepted two cycles of neoadjuvant platinum doublet chemotherapy. Besides baseline tumor staging, chest CT was repeated two to three weeks before surgery. Adverse events were monitored. Peripheral lymphocytes counting was tested during whole treatment. The residual viable tumor cells were counted after surgery to decide a major pathological response (MPR) rate. Selected specimen was sent for immunohistochemical, multiplex immunofluorescence analyses, and T-cell receptor DNA sequencing.
Results

Comparing with neoadjuvant chemotherapy alone, combination with PD-1 blockade and chemotherapy increased the pathological complete response rate (37·5% Vs. 7·69%) and MPR rate (50% Vs. 38·46%). The pathological evaluation is not consistent with that of radiological evaluation. Although peripheral lymphocyte counting was influenced by neoadjuvant therapy, no unknown adverse effects were reported for all the patients. The tumor infiltrating lymphocytes were observed more in patients accepted PD-1 blockade, and seem infiltrated more in relative “non-responders”. No special pathological features associated with PD-1 blockade were found. Multiplexed immunofluorescence analyses revealed potential immune suppression status in the peritumoral spaces around the residual tumor cells. T-cell receptor DNA sequencing found although some amino acids were shared in primary tumor and lymph nodes in single patients, they are hardly shared among different patients.
Conclusions

Neoadjuvant chemotherapy combine with PD-1 blockade is safe and feasible for patients with potentially resectable squamous cell lung cancer, to improve the clinical and pathological outcome. Even with PD-1 blockade, the immune suppressive status around the residual tumor cells still exists. The squamous cell lung cancers, and corresponding immune responses are extremely highly individualized. The treatment needs to be designed accordingly. The combination strategy of traditional neoadjuvant chemotherapy with current anti-PD-1 inhibitor are still need further investigation.
Targeted sequencing on neurodegenerative genes identified novel causal and risk variants of familial Alzheimer's disease
Authors: Zhang Weiwei , Jiao Bin , Xiao Tingting , Liu Xixi , Xiao Xuewen , Liao Xinxin , Guo Lina , Yan Xinxiang , Tang Beisha , Shen Lu 
Published: April 2020

Abstract
Background

Mutations of APP, PSEN1 and PSEN2 only account for a small portion of familial Alzheimer’s disease (AD), leaving the genetic factors for the rest AD families unexplained. Neurodegenerative diseases have some neuropathological, clinical and genetic crossover. The effect of neurodegenerative genes to familial AD remains unknown. We hypothesized that rare variants of neurodegenerative diseases genes may lead to family aggregation of AD. The aim of the study was to investigate the effect of neurodegenerative genes to familial AD.
Methods

Targeted sequencing of 277 neurodegenerative disease genes was performed on probands from 75 AD families of Chinese origin. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control.
Results

A novel mutation, P410S of PLD3, and a known causative mutation, I2012T of LRRK2 were identified in two early-onset AD families respectively. The p.P143S, rs192694824 in ABCA7 and rs374551420 in CR1 were significantly associated with familial AD (p = 0.005437, 0.001383, 0.000549), the rs200820365 in TREM2 was significantly associated with AD (p = 0.000396) when compared with the East Asian controls in ExAC database. The p. G223del of FUS was frequent in AD cases and significantly associated with familial AD (p = 0.008).
Conclusions

Our results revealed that rare variants of AD risk genes, FTD/ALS and PD causative genes may lead to family aggregation of AD. We proposed that targeted sequencing on neurodegenerative genes was necessary for genetically unclear AD families.
Prognostic value of an autophagy-related gene expression signature for endometrial cancer patients
Authors: Wang Hui , Ma Xiaoling , Liu Jinhui , Wan Yicong , Jiang Yi , Xia Yankai , Cheng Wenjun 
Published: April 2020

Abstract
Background: Autophagy is associated with cancer development. Autophagy-related genes play significant roles in endometrial cancer (EC), a major gynecological malignancy worldwide, but little was known about their value as prognostic markers. Here we evaluated the value of a prognostic signature based on autophagy-related genes for EC.Methods: First, various autophagy-related genes were obtained via the Human Autophagy Database and their expression profiles were downloaded from The Cancer Genome Atlas. Second, key prognostic autophagy-related genes were identified via univariat, LASSO, and multivariate Cox regression analyses. Finally, a risk score to predict the prognosis of EC was calculated and validated by using the test and the entire data sets. Besides, gene set enrichment and somatic mutation analyses were also used for these prognostic autophagy-related genes. Results: A total of 40 differentially expressed autophagy-related genes in EC were screened and five of them were prognosis-related (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1). A prognostic signature was constructed based on these five genes using the train set, which stratified EC patients into high-risk and low-risk groups (P<0.05). In terms of overall survival, the analyses of the test set and the entire set yielded consistent results (test set: p < 0.05; entire set: p < 0.05). Time-dependent ROC analysis suggested that the risk score predicted EC prognosis accurately and independently (0.674 at 1 year, 0.712 at 3 years and 0.659 at 5 years). A nomogram with clinical utility was built. Patients in the high-risk group displayed distinct mutation signatures compared with those in the low-risk group. Gene set enrichment analysis revealed high risk score was associated with tumor initiation and progression associated pathways.Conclusions: Based on five autophagy-related genes (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1), our model can independently predict the OS of EC patients by combining molecular signature and clinical characteristics.
Functional glutamate transporters are expressed in the carotid chemoreceptor
Authors: Li Chaohong , Huang Lu , Jia Xianglei , Zhao Baosheng , Chen Lingyun , Liu Yuzhen 
Published: April 2020

Abstract
Background: The carotid body (CB) plays a critical role in cyclic intermittent hypoxia (CIH)-induced chemosensitivity; however, the underlying mechanism remains uncertain. We have demonstrated the presence of multiple inotropic glutamate receptors (iGluRs) in CB, and that CIH exposure alters the level of some iGluRs in CB, indicating glutamatergic signaling functioning in the carotid chemoreflex response to hypoxia. The glutamatergic neurotransmission is not only dependent on glutamate and glutamate receptors, but is also dependent on glutamate transporters, including vesicular glutamate transporters (VGluTs) and excitatory amino acid transporters (EAATs). Here, we have further assessed the expression and distribution of VGluTs and EAATs in human and rat CB and the effect of CIH exposure on the expression level of glutamate transporters.Methods: The mRNA and protein expression of VGluTs and EAATs in the CB were detected by RT-PCR and Western blot. The distribution of VGluT3, EAAT2 and EAAT3 were observed by immunohistochemistry staining and immunofluorescence staining. Male Sprague-Dawley (SD) rats were exposed to CIH (FIO2 10%-21%, 3 min/3 min for 8 hours per day) for 2 weeks. The Student’s t test was performed.Results: Here, we report on the presence of mRNAs for VGluT1-3 and EAAT1-3 in human CB, which is consistent with our previous results in rat CB. The proteins of VGluT1 and 3, EAAT2 and 3, but not VGluT2 and EAAT1, were detected with diverse levels in human and rat CB. Immunostaining showed that VGluT3, the major type of VGluTs in CB, was co-localized with tyrosine hydroxylase in type I cells. EAAT2 and EAAT3 were distributed not only in type I cells, but also in glial fibrillary acidic protein positive type II cells. Moreover, we found that exposure of SD rats to CIH enhanced the protein level of EAAT3 as well as TH, but attenuated the level of VGluT3 and EAAT2 in CB. Conclusions: Our study suggests that glutamate transporters are expressed in the CB, and that glutamate transporters may contribute to glutamatergic signaling-dependent carotid chemoreflex to CIH.
Sentinel lymph node identification in early stage ovarian cancer: is it still possible after prior tumor resection?
Authors: Laven Pim , Kruitwagen Roy , Zusterzeel Petra , Slangen Brigitte , Gorp Toon van , Pol Jochem van der , Lambrechts Sandrina 
Published: April 2020

Abstract
Objective: Sentinel lymph node (SLN) detection in ovarian cancer is feasible when tracers are injected before the pathological ovary is resected. This study aims to investigate whether the SLN identification is also feasible in patients whose ovarian tumor has already been resected with injection of the tracer into the ovarian ligaments stumps, i.e. in the event that a frozen section confirms malignancy. Methods: Patients who underwent laparotomy with frozen section confirming an ovarian malignancy, and those who underwent a second staging laparotomy after prior resection of a malignant ovarian mass, were included. Blue dye and a radioactive isotope were injected in the stumps of the ligamentum ovarium proprium and the ligamentum infundibulo-pelvicum. After an interval of at least 15-minutes, the sentinel node(s) were identified using either the gamma-probe and / or blue dye.Results: A total of 11 patients were included in the study, the sentinel node (SLN) procedure was completed in all 11 patients. At least one SLN was identified in 3 patients, resulting in a rather low detection rate of 27,3%. Conclusion: In this study we showed that SLN procedure after (previous) resection of the tumor seems inferior to detect sentinel nodes when compared to injection of the tracer in the ovarian ligaments before tumor resection.Trial registration on clinical trials: NCT02540551 https://clinicaltrials.gov/ct2/show/NCT02540551
Determination Of State Economic Activities - Developing Countries In East Asia &amp; Pacific Using Classical Approaches
Authors: Fuddin Muhammad Khoirul 
Published: April 2020

Abstract
Countries in East Asia and the Pacific region are potential countries with fairly strong economic growth rates amid slowing global economic growth. One contributing factor to economic growth in East Asia and the Pacific can be seen using a classical approach where economic growth is seen from capital, natural resources, incoming foreign investment and the use of technology. This research wants to see how big these factors are in influencing the economic activities of developing countries in East Asia and the Pacific. The methodology used in this study is to use a Vector Error Correction Model by focusing on the impulse response function and variance decomposition to see the response of several variables due to changes in other variables and to see how much the proportion of one variable affects other variables in the short term or long term. In the short term, incoming foreign investment and technology affect productive land while in the long run productive land is influenced by incoming foreign investment and human resources. In the short term, GDP is not affected by any variable, whereas in the long term GDP is affected by human resources, incoming foreign investment, and technology. In the long run, human resources are affected by incoming foreign investment. Foreign investment that enters in the short term is influenced by productive land and human resources, whereas in the long run, only human resources can directly influence foreign investment. Technology in the short term is influenced by productive land and incoming foreign investment while in the long run technology is influenced by incoming foreign investment and human resources. The economic growth reflected in GDP and productive land contained in East Asia and the Pacific was largely influenced by technology in the final period. Incoming foreign investment and technology are largely influenced by productive land. Whereas the human resources found in East Asia and the Pacific are mostly influenced by GDP.
An exploration of perceptions and preferences for healthy eating in Dutch consumers: A qualitative pilot study
Authors: Coumans Juul M.J. , Bolman Catherine A.W. , Lechner Lilian , Oenema Anke 
Published: April 2020

Abstract
Background Unhealthy dietary patterns are highly prevalent in Western countries, and they have been associated with depression, hypertension, heart diseases, cancer, diabetes type 2 and obesity. Many dietary interventions have been developed to promote dietary behaviour, yet most do not achieve the intended dietary change. This study aims to provide a better understanding of what (Dutch) consumers perceive as a healthy diet (and how this relates to the current (Dutch) nutrition guidelines) and their preferences for how to eat (more) healthily. This is an essential consideration for the development of tailored interventions aimed to help people adopt changes in their dietary behaviour.Methods Seventy-eight participants filled in an online questionnaire containing both open-and closed-ended questions. The qualitative data was analysed using content analysis resulting in a classification scheme that two students used to identify to which category each part of a participant’s answer belonged.Results For both the perception of a healthy diet and how to eat healthily four major categories and a residual category were identified but some with different subcategories: dietary patterns, food processing, food products, content/nutrients, and other. The results showed that how people perceived a healthy diet was mostly represented at the level of food product (vegetables and fruit) and the content/nutrient level (carbohydrates); whereas how they would like to eat healthily was mostly represented at the level of food processing (preparation), food product (vegetables) and dietary patterns (amount).Conclusions Our findings are mostly in line with how the Dutch dietary guidelines are communicated (“product level”). However, laypersons primarily mention separate aspects instead of naming the guidelines as a whole. Health policymakers can use this insight in future communications regarding guidelines to the general public. A challenge for future (eHealth) diet interventions is how to implement and tailor dietary information that optimally connects with the perceptions of the target population.
Ischemia considerations for the development of an organ and tissue donor derived bone marrow bank
Authors: Woods Erik John , Sherry Aubrey M. , Woods John R. , Hardin James W. , LaFontaine Michael , Brandacher Gerald , Johnstone Brian H. 
Published: April 2020

Abstract
Background
Deceased organ donors represent an untapped source of therapeutic bone marrow (BM) that can be recovered in 3–5 times the volume of that obtained from living donors, tested for quality, cryopreserved, and banked indefinitely for future on-demand use. However, a challenge for a future BM banking system built to a genetically diverse scale, will be to manage the prolonged ischemia times that inevitably occur, when bones procured at geographically-dispersed locations are shipped to distant facilities for processing. The goals of this study were: (a) to quantify, under realistic and scaled procurement and shipping conditions, the relationship between ischemia time and the quality of hematopoietic stem and progenitor cells (HSPCs) derived from deceased-donor BM; (b) to identify ischemia-time boundaries beyond which HSPC quality is adversely affected; and (c) to investigate whole-body cooling as a strategy for preserving cell viability and function.
Methods
Seventy-five bones from 62 deceased donors were analyzed for CD34 + viability following their exposure to various periods of warm-ischemia time (WIT), cold-ischemia time (CIT), and body-cooling time (BCT). Regression models were developed to quantify the independent associations of WIT, CIT, and BCT, with the viability and function of recovered HSPCs.
Results
Results demonstrate that under “real-world” scenarios: (a) combinations of warm- and cold-ischemia times favorable to the recovery of high-quality HSPCs are achievable (e.g., CD34 + cell viabilities in the range of 80–90% were commonly observed); (b) cooling the body prior to bone recovery is detrimental to cell viability (e.g., CD34 + viability < 73% with, vs. >89% without body cooling); and (c) vertebral bodies (VBs) are a superior source of HSPCs compared to ilia (IL) (e.g., %CD34 + viability > 80% when VBs were the source, vs. <74% when IL were the source).
Conclusions
Our quantitative models can be used to formulate ischemia-time tolerance limits and HSPC quality-acceptance criteria, and to inform an emerging BM banking system seeking to institute data-driven industry standards.