bluuebunny/crossref_metadata_2025_split huggingface dataset:
B-332 Evaluation of the Analytical Performance of Seven Therapeutic Drug Monitoring Assays on the Atellica® CI 1900 Analyzer
Authors: Bogard A , Coward T , Kolewe K , Paudel P , Tyler C , Arrode-Bruses G , Rhea-McManus J , Snyder J 
Published: September 2023

Abstract

Background
The Atellica® CI 1900 Analyzer is an automated, mid-throughput integrated chemistry and immunoassay analyzer employing both Atellica CH and Atellica IM assays. This study was designed to evaluate the analytical performance of the Atellica CH Vancomycin (Vanc), Carbamazepine (Carb), Gentamicin (Gent), Phenytoin (Phny), Tobramycin (Tob), Valproic Acid (VPA), and Theophylline (Theo) assays* on the Atellica CI 1900 Analyzer.

Methods
The Atellica CI 1900 Vanc, Carb, Gent, Phny, Tob, VPA, and Theo assays use the same reagents and calibrators as the Atellica chemistry assays. Precision and method comparison (MC) were used as performance indicators for the Atellica CI 1900 Analyzer. Precision studies were performed according to CLSI EP05-A3 using native and contrived human serum samples. One aliquot of each sample pool was tested in duplicate in two runs per day ≥2 h apart on each analyzer for ≥20 days. MC studies were performed according to CLSI EP09-A3. Individual native and contrived human serum samples were analyzed using the Atellica chemistry assays on both the Atellica CH and Atellica CI 1900 Analyzers. Precision and MC were evaluated with three reagent lots on one system.

Results
Representative precision and MC results observed from one reagent lot across indicated sample ranges are listed in the table below for each assay. Over the seven assays tested, repeatability and within-lab % CVs were &lt;6.5% and &lt;11.0%, respectively. Slopes determined by the Deming linear regression model were approximately equal to 1.

Conclusion
Evaluation of the Atellica CH Vanc, Carb, Gent, Phny, Tob, VPA, and Theo assays using the Atellica CI 1900 Analyzer demonstrated good precision and equivalent performance compared to the same assays on the Atellica CH 930 Analyzer.*The products/features mentioned here are not commercially available in all countries. Their future availability cannot be guaranteed.
B-361 Novel Blood-based Assay for Early Cancer Detection Demonstrates High Precision and Reproducibility on Low Tumor Content
Authors: Charlton J , Gilley C , Brown E , Gowen K , Williams M , DuRoss C , Sun J , Gregg J 
Published: September 2023

Abstract

Background
Early detection of cancer has significant potential to impact human health and society by decreasing cancer-related morbidity and mortality. While previous approaches to identify cancer-informative biomarkers are predominantly statistical, Harbinger Health has utilized foundational discoveries from developmental biology to design a targeted methylation assay for early cancer detection from cell-free DNA (cfDNA) extracted from plasma. Utilizing this biologically informed approach, we developed a fixed multi-layered logistic regression-based machine learning algorithm, trained with an in-house generated dataset of 1046 samples (621 cancer, 425 non-cancer) that predicts a binary classification (yes/no) for cfDNA samples processed through our assay. We have previously reported high sensitivity for multi-cancer detection, including for early-stage disease.

Methods
Here, we perform a comprehensive independent analytical validation of our assay and algorithm, encompassing 69 subjects: 19 with newly diagnosed treatment-naïve cancer (8 different cancer types) and 50 individuals with no history, diagnosis, or cancer symptoms. In total, we utilized 122 replicate samples to assess reproducibility and precision, 8 non-template controls (water) to determine limit of blank (LOB), and cohorts of matched biopsy and cfDNA to determine tumor content limit of detection (LOD).

Results
Precision was assessed within five different sub-studies, by comparing concordance of predicted binary cancer classification between replicate samples, giving results of 0.90 (0.95 CI: 0.764–0.959) for inter-run precision, 1.00 (0.95 CI: 0.796–1.000) for intra-run precision, 1.00 (0.95 CI: 0.871–1.000) for inter-operator precision, 0.96 (0.95 CI: 0.930–0.998) for inter-instrument precision and 0.83 (0.95 CI: 0.641–0.933) for inter-day precision. To determine LOB, we carried 8 non-template controls (water) through the entire assay and detected on average ∼0.02% unique aligned reads of a true sample on the same sequencing run. Finally, to assess tumor content LOD, we developed methodology that uses methylation signal to estimate the amount of tumor-derived DNA in each cfDNA sample and validated our estimates using whole exome sequencing, an orthogonal gold-standard approach. We then assessed the relationship between tumor content and classifier sensitivity using our training data of 625 cancer cfDNA samples and determined that our tumor content LOD whereby 95% true cancer samples were correctly predicted to be 0.037%.

Conclusion
Our assay shows high performance and high technical reproducibility. Our previously reported high sensitivity for stage 1 and stage 2 cancers, as well as extremely low tumor content LOD reported here supports our ability to perform early-stage multi-cancer detection, where the levels of circulating tumor DNA are low.
B-373 The Development of a Logic-Gate Probe to Investigate Hypoxia in Cancer Stem Cells
Authors: Swartchick C B , Chan J 
Published: September 2023

Abstract

Background
Cancer stem cells (CSCs) represent only a small fraction of the tumor population, yet they present a profound challenge to cancer treatment. CSCs contribute to tumor complexity via their unique ability to self-renew, develop into multiple lineages, and maintain an unchecked proliferation potential. To identify CSCs, the cytoprotective enzyme aldehyde dehydrogenase 1A1 (ALDH1A1) is a well-annotated biomarker of cancer stemness which is associated with a poor prognosis in patients with gastric and lung cancers when overexpressed. Within CSCs, ALDH1A1 functions to regulate oxidative stress by transforming biological aldehydes into their corresponding non-toxic carboxylic acid counterparts and further is linked to the retinaldehyde signaling pathway. Beyond this enzyme, oxygen availability within the tumor microenvironment (TME) can also influence stemness properties. Specifically, hypoxia, is required to maintain the CSC phenotype by prolonging the undifferentiated state.

Methods
To study the mechanistic underpinnings of complex relationship in vivo new technologies are needed as current approaches are insufficient. Indeed, probes have been developed to study ALDH1A1 and hypoxia in parallel, however, imaging approaches lack the requisite resolution to ensure they are reporting on the same CSC population. To this end, we have designed a powerful logic-gate probe that links the reporters of ALDH1A1 activity and oxygenation in a unique manner such that different readouts will result (color of light) depending on the TME environment.

Results
Our lab has previously developed a near-infrared hypoxia-sensing fluorescent probe that is fundamental to our current logic-gate design. This component has been validated in 4T1 murine breast cancer cells, to yield a 1.6-fold increase in ratiometric fluorescence response when incubated under hypoxic conditions as compared to its normoxic controls. Additionally, the ALDH1A1 sensing component has been validated via purified enzyme to yield an increase in bioluminescent signal enabling its use for future in vivo studies.

Conclusion
This technology has important clinical implications to understand the mechanistic underpinnings between oxygenation and cancer stemness. Further research is being conducted to further test the hypothesis that metformin (anticancer drug) kills cancer by altering oxygen metabolism which in turn depletes the CSC population. Furthermore, this probe has far-reaching implications in monitoring novel therapeutic cancer treatment.
Multi-omics analysis reveals the potential pathogenesis and therapeutic targets of diabetic kidney disease
Authors: Wei Lan , Gao Jingjing , Wang Liangzhi , Tao Qianru , Tu Chao 
Published: September 2023

Abstract
Clinicians have long been interested in understanding the molecular basis of diabetic kidney disease (DKD)and its potential treatment targets. Its pathophysiology involves protein phosphorylation, one of the most recognizable post-transcriptional modifications, that can take part in many cellular functions and control different metabolic processes. In order to recognize the molecular and protein changes of DKD kidney, this study applied Tandem liquid chromatography-mass spectrometry (LC-MS/MS) and Next-Generation Sequencing, along with Tandem Mass Tags (TMT) labeling techniques to evaluate the mRNA, protein and modified phosphorylation sites between DKD mice and model ones. Based on Gene Ontology (GO) and KEGG pathway analyses of transcriptome and proteome, The molecular changes of DKD include accumulation of extracellular matrix, abnormally activated inflammatory microenvironment, oxidative stress and lipid metabolism disorders, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress has been emphasized as an important factor in DKD and progression to ESKD, which is directly related to podocyte injury, albuminuria and renal tubulointerstitial fibrosis. A histological study of phosphorylation further revealed that kinases were crucial. Three groups of studies have found that RAS signaling pathway, RAP1 signaling pathway, AMPK signaling pathway, PPAR signaling pathway and HIF-1 signaling pathway were crucial for the pathogenesis of DKD. Through this approach, it was discovered that targeting specific molecules, proteins, kinases and critical pathways could be a promising approach for treating DKD.
Innovation and competitiveness in the copper-mining GVC: developing local suppliers in Peru
Authors: Bamber Penny , Fernandez-Stark Karina , Molina Oswaldo 
Published: September 2023

Abstract
Although Peru is one of the main producers of copper worldwide, the domestic industry has not yet fully taken advantage of the potential that the exploitation of this commodity offers. This paper explores the opportunities and challenges that Peruvian suppliers face in their insertion into the mining global value chain. Our analysis is based on a mixed-methods approach, combining both quantitative and qualitative primary and secondary sources, including semi-structured interviews with key actors in the Peruvian mining sector. Our findings suggest that the weak presence of Peruvian suppliers in a sector dominated by few foreign firms is due to global industry dynamics as well as the underdeveloped capabilities of local firms operating in a fragile local institutional setting. However, their opportunities for their insertion are primarily in areas where new solutions are required, which places a demand on the supplier’s innovative capacity.
Burden of ischemic stroke in mainland China and Taiwan province from 1990 to 2019: with forecast for the next 11 years
Authors: Yu Jia , Liu Fude , Cheng Yawen , Wang Jianyi , Ma Wenlong , Chen Chen , Sun Peng , Shang Suhang 
Published: September 2023

Abstract
Ischemic stroke is featured with high incidence, mortality, and disability. The aim of this study is to use Global Burden of Disease database to describe and compare the burden of ischemic stroke in mainland China and Taiwan province and to further predict the expected changes in the next 11 years using statistical modeling methods. Information on ischemic stroke incidence and mortality in China (mainland and Taiwan province) during 1990–2019 was obtained from the Global Burden of Disease database to analyze the effects of region, gender, and age on the incidence and mortality of ischemic stroke in China. The autoregressive integrated moving average model was used to predict the age-standardized incidence rate and age-standardized mortality rate of ischemic stroke in males and females in mainland China and Taiwan province in the next 11 years. The period from 1990 to 2019 witnessed an overall upward trend in the number of incidence and deaths in mainland China and Taiwan province. In 2019, there were nearly 2.87 million ischemic incidence cases with stroke in mainland China, with more female patients than male in the age group of over 60 years. Among the nearly 1.03 million deaths, the death toll of men under the age of 85 years was higher than that of women, while in Taiwan province, the number of incidence was 28 771, with more female patients of all ages than male. Among the 6788 deaths, the death toll of men under the age of 80 years was higher than that of women. In 2019, the age group with the highest number of patients in the two regions was 65–69 years, while the highest number of deaths was found in people aged 85 years and above. As our autoregressive integrated moving average model predicted, the age-standardized incidence rate value of ischemic stroke is expected to be 163.23/100 000 persons in mainland China by 2030, which would continue to increase, while the age-standardized mortality rate value of ischemic stroke is expected to be 16.41/100 000 persons in Taiwan province by 2030, which showed a decreasing trend. Disease burden of ischemic stroke is still increasing in mainland China and Taiwan province, and health resources should be deployed to implement effective prevention and control strategies, taking into account region, gender, and age.
‘Low-value’ clinical care in general practice: a cross-sectional analysis of low-value care in early-career GPs’ practice
Authors: Ralston Anna , Fielding Alison , Holliday Elizabeth , Ball Jean , Tapley Amanda , van Driel Mieke , Davey Andrew , Turner Rachel , Moad Dominica , FitzGerald Kristen , Spike Neil , Mitchell Ben , Tran Michael , Fisher Katie , Magin Parker 
Published: September 2023

Abstract
Nonevidence-based and ‘low-value’ clinical care and medical services are ‘questionable’ clinical activities that are more likely to cause harm than good or whose benefit is disproportionately low compared with their cost. This study sought to establish general practitioner (GP), patient, practice, and in-consultation associations of an index of key nonevidence-based or low-value ‘questionable’ clinical practices.
The study was nested in the Registrar Clinical Encounters in Training study—an ongoing (from 2010) cohort study in which Australian GP registrars (specialist GP trainees) record details of their in-consultation clinical and educational practice 6-monthly. The outcome factor in analyses, performed on Registrar Clinical Encounters in Training data from 2010 to 2020, was the score on the QUestionable In-Training Clinical Activities Index (QUIT-CAI), which incorporates recommendations of the Australian Choosing Wisely campaign. A cross-sectional analysis used negative binomial regression (with the model including an offset for the number of times the registrar was at risk of performing a questionable activity) to establish associations of QUIT-CAI scores.
A total of 3206 individual registrars (response rate 89.9%) recorded 406 812 problems/diagnoses where they were at risk of performing a questionable activity. Of these problems/diagnoses, 15 560 (3.8%) involved questionable activities being performed.
In multivariable analyses, higher QUIT-CAI scores (more questionable activities) were significantly associated with earlier registrar training terms: incidence rate ratios (IRRs) of 0.91 [95% confidence interval (CI) 0.87, 0.95] and 0.85 (95% CI 0.80, 0.90) for Term 2 and Term 3, respectively, compared to Term 1. Other significant associations of higher scores included the patient being new to the registrar (IRR 1.27; 95% CI 1.12, 1.45), the patient being of non-English-speaking background (IRR 1.24; 95% CI 1.04, 1.47), the practice being in a higher socioeconomic area decile (IRR 1.01; 95% CI 1.00, 1.02), small practice size (IRR 1.05; 95% CI 1.00, 1.10), shorter consultation duration (IRR 0.99 per minute; 95% CI 0.99, 1.00), and fewer problems addressed in the consultation (IRR 0.84; 95% CI 0.79, 0.89) for each additional problem].
Senior registrars’ clinical practice entailed less ‘questionable’ clinical actions than junior registrars’ practice. The association of lower QUIT-CAI scores with a measure of greater continuity of care (the patient not being new to the registrar) suggests that continuity should be supported and facilitated during GP training (and in established GPs’ practice).
Analysis of the stepwise acquisition of blaCTX-M-2 and subsequent acquisition of either blaIMP-1 or blaIMP-6 in highly conserved IncN-pST5 plasmids
Authors: Ikegaya Kazuko , Aoki Kotaro , Komori Kohji , Ishii Yoshikazu , Tateda Kazuhiro 
Published: September 2023

Abstract

Objectives
ESBL and carbapenemase genes in Enterobacterales spread via plasmids. Nosocomial outbreaks caused by Enterobacterales producing both CTX-M-2 and either IMP-1 or IMP-6-type carbapenemases have been reported. These organisms carry the incompatibility type N plasmid belonging to plasmid ST 5 (IncN-pST5). We investigated the construction process of the ESBL and carbapenemase genes co-carrying IncN-pST5.

Methods
We retrospectively performed draft WGS analysis for blaIMP- or blaCTX-M-positive Enterobacterales in our strain collection (n = 281).

Results
We selected four types of Escherichia coli plasmids for our study: type A, which carries both blaCTX-M-2 and blaIMP-1 (n = 6); type B, which carries both blaCTX-M-2 and blaIMP-6 (n = 2); type C, which carries blaCTX-M-2 (n = 10); and type D, which carries no β-lactamase genes (n = 1). It should be noted that type D plasmid was only detected in E. coli TUM2805, which carries the blaCTX-M-14 on the IncB/O/B/Z plasmid. Long-read sequencing using MinION revealed that all types of IncN-pST5 were highly conserved and carried a class 1 integron. Integron numbers were type A for In798, type B for In1690, type C for In127 and type D for In207. Because the gene cassettes downstream of blaIMP were different between In798 and In1690, the change from blaIMP-1 to blaIMP-6 by point mutation was unlikely. Representative plasmids from types A, B and C were conjugatively transferred with quite a high frequency between 1.3 × 10−1 and 2.5 × 10−2.

Conclusions
This study suggested that IncN-pST5 acquired blaCTX-M-2 by ISEcp1 in a stepwise manner, followed by either blaIMP-1 or blaIMP-6 into a class 1 integron.
Current Evidence for Combined Targeted Therapy for the Treatment of Inflammatory Bowel Disease
Authors: Wetwittayakhlang Panu , Lakatos Peter L 
Published: September 2023

Abstract
Biologicals and small molecules have revolutionized the medical management of inflammatory bowel diseases (IBD), yet they are only effective in a proportion of patients, and their impact on changing the natural history of the disease is still debatable. Recently, the concept of combining targeted biologics and small-molecule therapies has been introduced to the treatment of IBD. Dual-targeted therapy (sequential and combined), which is the combination of two targeted therapies, might be a reasonable choice for patients to break through the therapeutic ceiling. A recent randomized clinical trial (VEGA) provided the first controlled evidence that the short-term combination of two biological agents may lead to superior disease control than either of the agents alone in patients with ulcerative colitis (UC) without jeopardizing safety. Multiple studies are underway in both Crohn’s disease and UC. Additionally, real-world evidence is accumulating in IBD patients receiving combination therapies with concomitant IBD and extraintestinal manifestations or in patients with medically refractory IBD. Of note, the majority of these patients were exposed to multiple biological agents earlier and lost response to at least one of the agents in the combination. This review summarizes current knowledge regarding this attractive novel therapeutic option in IBD. Clearly, more controlled data are needed to evaluate optimal timing, efficacy, and mitigation of safety concerns.
Axonal regrowth under release of myelin-associated glycoprotein: chemotaxis by pioneer Schwann cells and Cajal’s gigantic clubs
Authors: Torigoe Kojun 
Published: September 2023

Abstract
Myelin-associated glycoprotein (MAG), released from pre-degenerated distal nerves following axotomy, blocks the regrowth of sprouts and naked axons. Ensheathed axons, however, continue to elongate and reach MAG-releasing distal nerves. To determine the regenerative mechanism of ensheathed axons without navigators of axonal growth cones by the film model method, we inserted a MAG-releasing distal nerve segment treated with liquid nitrogen (N2DS) between the two films, facing the proximal end of the common peroneal nerves in mice transected 4 days earlier for axons to become ensheathed. On the third postoperative day (Day 3), axon fascicles, subjected to silver staining, extended toward N2DS but with few branches, forming terminal swellings called Cajal’s gigantic clubs (CGCs) that are filled with axonal growth cones. Filter paper wetted with either 250 pg/ml MAG or N2DS showed the same configurations when inserted between the two films. This effect was lost following anti-MAG treatment; fascicles strayed near the parent nerve with numerous branches, formed a net of axons and tapered toward thin tips at their ends, just like controls without N2DS. Schwann cell bundles on Day 3 detected with anti-S100, formed sheaths of CGCs at their ends and connected to pioneer Schwann cells (pSCs). To analyze the physiology of Schwann cells, independent of axons, the parent nerve transected 4 days prior was crushed. On Day 2, with pSCs ahead, Schwann cell bundles extended toward N2DS. On Day 4, main bundles regressed, leaving pSCs motionless. Thus, MAG is a candidate chemoattractant for both pSCs and CGCs.
Double-modified oncolytic adenovirus armed with a recombinant interferon-like gene enhanced abscopal effects against malignant glioma
Authors: Jiang Shan , Chai Hui-Hui , Fang Xian-Long , Xu Hou-Shi , Li Tian-Wen , Tang Qi-Sheng , Gu Jin-Fa , Zhang Kang-Jian , Liu Xin-Yuan , Shi Zhi-Feng , Cao Xue-Ping , Wu Zan-Yi , Zhou Liang-Fu 
Published: September 2023

Abstract

Background
The development of new therapies for malignant gliomas has been stagnant for decades. Through the promising outcomes in clinical trials of oncolytic virotherapy, there is now a glimmer of hope in addressing this situation. To further enhance the antitumor immune response of oncolytic viruses, we have equipped a modified oncolytic adenovirus (oAds) with a recombinant interferon-like gene (YSCH-01) and conducted a comprehensive evaluation of the safety and efficacy of this modification compared to existing treatments.

Methods
To assess the safety of YSCH-01, we administered the oAds intracranially to Syrian hamsters, which are susceptible to adenovirus. The efficacy of YSCH-01 in targeting glioma was evaluated through in vitro and in vivo experiments utilizing various human glioma cell lines. Furthermore, we employed a patient-derived xenograft model of recurrent glioblastoma to test the effectiveness of YSCH-01 against temozolomide.

Results
By modifying the E1A and adding survivin promoter, the oAds have demonstrated remarkable safety and an impressive ability to selectively target tumor cells. In animal models, YSCH-01 exhibited potent therapeutic efficacy, particularly in terms of its distant effects. Additionally, YSCH-01 remains effective in inhibiting the recurrent GBM patient-derived xenograft model.

Conclusions
Our initial findings confirm that a double-modified oncolytic adenovirus armed with a recombinant interferon-like gene is both safe and effective in the treatment of malignant glioma. Furthermore, when utilized in combination with a targeted therapy gene strategy, these oAds exhibit a more profound effect in tumor therapy and an enhanced ability to inhibit tumor growth at remote sites.