bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic evaluation with practical guidelines for single-cell and spatially resolved transcriptomics data simulation under multiple scenarios
Authors: Duo Hongrui , Li Yinghong , Lan Yang , Tao Jingxin , Yang Qingxia , Xiao Yingxue , Sun Jing , Li Lei , Nie Xiner , Zhang Xiaoxi , Liang Guizhao , Liu Mingwei , Hao Youjin , Li Bo
Published: June 2024

Background

Single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (SRT) have led to groundbreaking advancements in life sciences. To develop bioinformatics tools for scRNA-seq and SRT data and perform unbiased benchmarks, data simulation has been widely adopted by providing explicit ground truth and generating customized datasets. However, the performance of simulation methods under multiple scenarios has not been comprehensively assessed, making it challenging to choose suitable methods without practical guidelines.

Results

We systematically evaluated 49 simulation methods developed for scRNA-seq and/or SRT data in terms of accuracy, functionality, scalability, and usability using 152 reference datasets derived from 24 platforms. SRTsim, scDesign3, ZINB-WaVE, and scDesign2 have the best accuracy performance across various platforms. Unexpectedly, some methods tailored to scRNA-seq data have potential compatibility for simulating SRT data. Lun, SPARSim, and scDesign3-tree outperform other methods under corresponding simulation scenarios. Phenopath, Lun, Simple, and MFA yield high scalability scores but they cannot generate realistic simulated data. Users should consider the trade-offs between method accuracy and scalability (or functionality) when making decisions. Additionally, execution errors are mainly caused by failed parameter estimations and appearance of missing or infinite values in calculations. We provide practical guidelines for method selection, a standard pipeline Simpipe (https://github.com/duohongrui/simpipe; https://doi.org/10.5281/zenodo.11178409), and an online tool Simsite (https://www.ciblab.net/software/simshiny/) for data simulation.

Conclusions

No method performs best on all criteria, thus a good-yet-not-the-best method is recommended if it solves problems effectively and reasonably. Our comprehensive work provides crucial insights for developers on modeling gene expression data and fosters the simulation process for users.
Selectively superior production of docosahexaenoic acid in Schizochytrium sp. through engineering the fatty acid biosynthetic pathways
Authors: Liu Yana , Han Xiao , Chen Zongcheng , Yan Yihan , Chen Zhi
Published: June 2024

Background

Schizochytrium sp. is commercially used for production of docosahexaenoic acid (DHA). Schizochytrium sp. utilizes the polyketide synthase complex (PKS) and a single type I fatty acid synthase (FAS) to synthesize polyunsaturated fatty acids and saturated fatty acids, respectively. The acyl carrier protein (ACP) domains of FAS or PKS are used to load acyl groups during fatty acids biosynthesis. Phosphopantetheinyl transferase (PPTase) transfers the pantetheine moiety from Coenzyme A to the conserved serine residue of an inactive ACP domain to produce its active form.

Results

In this study, in order to improve production and content of DHA, we decreased the expression of fas, strengthened the expression of the PKS pathway, and enhanced the supply of active ACP in Schizochytrium sp. ATCC20888. Weakening the expression of fas or disruption of orfA both led to growth defect and reduction of lipid yields in the resulting strains WFAS and DPKSA, indicating that both FAS and PKS were indispensable for growth and lipid accumulation. Although WFAS had a higher DHA content in total fatty acids than the wild-type strain (WT), its growth defect and low DHA yield hinders its use for DHA production. Overexpression of the orfAB, orfC, orfC-DH (truncated orfC), or ppt promoted DHA and lipid production, respectively. The yields and contents of DHA were further increased by combined overexpression of these genes. Highest values of DHA yield (7.2 g/L) and DHA content (40.6%) were achieved in a recombinant OPKSABC-PPT, ⁓56.5% and 15.3% higher than the WT values, respectively.

Conclusions

This study demonstrates that genetic engineering of the fatty acid biosynthetic pathways provides a new strategy to enhance DHA production in Schizochytrium.
Humidity and temperature preference in two Neotropical species of sand flies
Authors: Vivero-Gomez Rafael , Duque-Granda Daniela , Rader Jonathan A. , Stuckert Adam , Santander-Gualdron Ricardo , Cadavid-Restrepo Gloria , Moreno-Herrera Claudia X. , Matute Daniel R.
Published: June 2024

Background

Arthropods vector a multitude of human disease-causing organisms, and their geographic ranges are shifting rapidly in response to changing climatic conditions. This is, in turn, altering the landscape of disease risk for human populations that are brought into novel contact with the vectors and the diseases they carry. Sand flies in the genera Lutzomyia and Pintomyia are vectors of serious disease-causing agents such as Leishmania (the etiological agent of leishmaniasis) and may be expanding their range in the face of climate change. Understanding the climatic conditions that vector species both tolerate physiologically and prefer behaviorally is critical to predicting the direction and magnitude of range expansions and the resulting impacts on human health. Temperature and humidity are key factors that determine the geographic extent of many arthropods, including vector species.

Methods

We characterized the habitat of two species of sand flies, Lutzomyia longipalpis and Pintomyia evansi. Additionally, we studied two behavioral factors of thermal fitness–thermal and humidity preference in two species of sand flies alongside a key aspect of physiological tolerance–desiccation resistance.

Results

We found that Lu. longipalpis is found at cooler and drier conditions than Pi. evansi. Our results also show significant interspecific differences in both behavioral traits, with Pi. evansi preferring warmer, more humid conditions than Lu. longipalpis. Finally, we found that Lu. longipalpis shows greater tolerance to extreme low humidity, and that this is especially pronounced in males of the species.

Conclusions

Taken together, our results suggest that temperature and humidity conditions are key aspects of the climatic niche of Lutzomyia and Pintomyia sand flies and underscore the value of integrative studies of climatic tolerance and preference in vector biology.

Graphical Abstract
Intermittent hypoxia training enhances Aβ endocytosis by plaque associated microglia via VPS35-dependent TREM2 recycling in murine Alzheimer’s disease
Authors: Wang Xueting , Xie Yuqi , Fan Xiaoyang , Wu Xiaomei , Wang Dan , Zhu Li
Published: June 2024

Background

Beta-amyloid (Aβ) deposition in the brain parenchyma is a crucial initiating step in the amyloid cascade hypothesis of Alzheimer’s disease (AD) pathology. Furthermore, dysfunction of plaque-associated microglia, also known as disease-associated microglia (DAM) has been reported to accelerate Aβ deposition and cognitive impairment. Our previous research demonstrated that intermittent hypoxia training (IHT) improved AD pathology by upregulating autophagy in DAM, thereby enhancing oligomeric Aβ (oAβ) clearance. Considering that oAβ internalization is the initial stage of oAβ clearance, this study focused on the IHT mechanism involved in upregulating Aβ uptake by DAM.

Methods

IHT was administered to 8-month-old APP/PS1 mice or 6-month-old microglial vacuolar protein sorting 35 (VPS35) knockout mice in APP/PS1 background (MG VPS35 KO: APP/PS1) for 28 days. After the IHT, the spatial learning-memory capacity of the mice was assessed. Additionally, AD pathology was determined by estimating the nerve fiber and synapse density, Aβ plaque deposition, and Aβ load in the brain. A model of Aβ-exposed microglia was constructed and treated with IHT to explore the related mechanism. Finally, triggering receptor expressed on myeloid cells 2 (TREM2) intracellular recycling and Aβ internalization were measured using a fluorescence tracing technique.

Results

Our results showed that IHT ameliorated cognitive function and Aβ pathology. In particular, IHT enhanced Aβ endocytosis by augmenting the intracellular transport function of microglial TREM2, thereby contributing to Aβ clearance. Furthermore, IHT specifically upregulated VPS35 in DAM, the primary cause for the enhanced intracellular recycling of TREM2. IHT lost ameliorative effect on Aβ pathology in MG VPS35 KO: APP/PS1 mice brain. Lastly, the IHT mechanism of VPS35 upregulation in DAM was mediated by the transcriptional regulation of VPS35 by transcription factor EB (TFEB).

Conclusion

IHT enhances Aβ endocytosis in DAM by upregulating VPS35-dependent TREM2 recycling, thereby facilitating oAβ clearance and mitigation of Aβ pathology. Moreover, the transcriptional regulation of VPS35 by TFEB demonstrates a close link between endocytosis and autophagy in microglia. Our study further elucidates the IHT mechanism in improving AD pathology and provides evidence supporting the potential application of IHT as a complementary therapy for AD.

Graphical abstract
Design and analysis of CP-free OFDM PDMA transmission system
Authors: Liu Jiao , He Jianqiang
Published: June 2024

The paragraph introduces a proposed CP-free OFDM PDMA downlink transmission system. The main focus of the system is to address the capacity limitations caused by the overhead of cyclic prefix in traditional PDMA systems. The transmitter utilizes a pattern mapping unit before CP-free OFDM modulation to enhance system capacity and frequency efficiency. Decision feedback equalization (DFE) is employed in the receiver to eliminate intersymbol interference. The output signals from the DFE are then passed through a CP restoration unit to convert a linear-shifted signal into a cyclic-shifted signals. To assess the system's performance, simulations are conducted, investigating different key parameters such as overload rate, channel condition, and signal-to-noise ratio. The results indicate that, compared to CP OFDM PDMA systems, the proposed CP-free PDMA system significantly enhances system capacity under the same overload rate. Additionally, bit error rate is also evaluated during the simulations. Overall, the paragraph provides an overview of the proposed CP-free OFDM PDMA system, its components, and the simulation-based evaluation of its performance compared to traditional PDMA systems.
Assessing the mental health of slum dwellers: an ordinal logistic approach
Authors: Hijol Nasim Bin Jinnah , Salma Nahid , Sarker Indrani
Published: June 2024

Background

Stress, depression and anxiety are prevalent mental health concerns that are getting worse every day in the context of rapidly expanding megacities, where a rising number of people live in slums. The purpose of this study is to evaluate the state of mental health and related variables underlying mental health issues among the impoverished population.

Methodology

A total of 384 slum residents from the Khulna division responded to our questionnaire, which included the DASS-21 and other pertinent questions. Using ordinal logistic regression, the significant factors were extracted.

Results

The Cronbach’s reliability coefficient for the DASS-21 scale lies between 0.79 and 0.89 which indicates the high reliability of the DASS-21 scales. According to the findings, roughly 72.7%, 84.1%, and 69% of participants slum dwellers experienced anxiety, depression, and anxiety problems respectively. The result of ordinal logistic regression shows, slum dwellers of female gender (B = 0.669*, 95% CI 0.141, 1.197), married (B = 1.506*, 95% CI 0.119, 2.893), having only one earning member in the family (B = 1.224*, 95% CI 0.526, 1.922), day laborers (B = 2.294*, 95% CI 1.115, 3.473), not being able to educate children due to financial problem (B = 0.558*, 95% CI 0.183, 0.932) were more likely to report high levels of anxiety, depression, and stress.

Conclusion

The study finds that a significant portion of people who live in slums struggle with mental health issues. It also points to the need for further support, intervention, and study on Khulna's slum inhabitants who are experiencing mental health issues. The authors anticipate that the results will spur policymakers and government representatives to enhance financing for slum dwellers and employ psychological intervention strategies, both of which will aid in achieving the Sustainable Development Goal.
Falsified and problematic methandienone products available online: active pharmaceutical ingredient identification by portable Raman spectrometers and quantification by ultra-high-performance liquid chromatography–Fourier transform mass spectrometry
Authors: Schreiber Robin , Hori Manami , Takahashi Chisato , Rahman Mohammad Sofiqur , Nakao Ayane , Zhu Shu , Zhu Feiyu , Yoshida Naoko , Maekawa Keiko , Kimura Kazuko
Published: June 2024

This study aimed on the one hand to clarify the quality, authenticity, safety, and other issues related to products of the anabolic-androgenic steroid methandienone advertised on the Internet and personally imported to Japan and on the other hand to evaluate the use of two portable Raman spectrometers in identifying the active pharmaceutical ingredient (API). The study found that all n = 15 samples purchased from 14 websites were problematic regarding their package, labeling, and/or content. Specifically, one sample (6.7%) was confirmed falsified, twelve samples (80%) were found either to be falsified or unlicensed as pharmaceutical product, and two samples (13.3%) were received without information on the manufacturers’ physical address or country of origin, with one sample (6.7%) having no labeling or other accompanying information at all. Both Raman spectrometers were able to identify the API in all samples as confirmed and quantified by ultra-high-performance liquid chromatography–Fourier transform mass spectrometry. Twelve samples contained on average less than 90% of the declared API content. By contacting national regulatory authorities in 44 countries, methandienone products were found to be approved in 1 country and not approved in 21 countries. To prevent health hazards and abuse, measures against the acquisition of anabolic-androgenic steroids from unknown sources are required. Portable Raman spectrometers may be suitable for the non-destructive and quick identification of methandienone in tablets.

Graphical Abstract
Advances and prospects in deuterium metabolic imaging (DMI): a systematic review of in vivo studies
Authors: Pan Feng , Liu Xinjie , Wan Jiayu , Guo Yusheng , Sun Peng , Zhang Xiaoxiao , Wang Jiazheng , Bao Qingjia , Yang Lian
Published: June 2024

Background

Deuterium metabolic imaging (DMI) has emerged as a promising non-invasive technique for studying metabolism in vivo. This review aims to summarize the current developments and discuss the futures in DMI technique in vivo.

Methods

A systematic literature review was conducted based on the PRISMA 2020 statement by two authors. Specific technical details and potential applications of DMI in vivo were summarized, including strategies of deuterated metabolites detection, deuterium-labeled tracers and corresponding metabolic pathways in vivo, potential clinical applications, routes of tracer administration, quantitative evaluations of metabolisms, and spatial resolution.

Results

Of the 2,248 articles initially retrieved, 34 were finally included, highlighting 2 strategies for detecting deuterated metabolites: direct and indirect DMI. Various deuterated tracers (e.g., [6,6′-2H2]glucose, [2,2,2′-2H3]acetate) were utilized in DMI to detect and quantify different metabolic pathways such as glycolysis, tricarboxylic acid cycle, and fatty acid oxidation. The quantifications (e.g., lactate level, lactate/glutamine and glutamate ratio) hold promise for diagnosing malignancies and assessing early anti-tumor treatment responses. Tracers can be administered orally, intravenously, or intraperitoneally, either through bolus administration or continuous infusion. For metabolic quantification, both serial time point methods (including kinetic analysis and calculation of area under the curves) and single time point quantifications are viable. However, insufficient spatial resolution remains a major challenge in DMI (e.g., 3.3-mL spatial resolution with 10-min acquisition at 3 T).

Conclusions

Enhancing spatial resolution can facilitate the clinical translation of DMI. Furthermore, optimizing tracer synthesis, administration protocols, and quantification methodologies will further enhance their clinical applicability.

Relevance statement

Deuterium metabolic imaging, a promising non-invasive technique, is systematically discussed in this review for its current progression, limitations, and future directions in studying in vivo energetic metabolism, displaying a relevant clinical potential.

Key points

• Deuterium metabolic imaging (DMI) shows promise for studying in vivo energetic metabolism.

• This review explores DMI’s current state, limits, and future research directions comprehensively.

• The clinical translation of DMI is mainly impeded by limitations in spatial resolution.

Graphical Abstract
Hypocitraturia as a biomarker of renal tubular acidosis in patients with Sjögren’s disease
Authors: Coradin Rafael , Lopes Maria Lúcia Lemos , Goldani João Carlos , Ventura Pedro Enrico , Keitel Elizete
Published: June 2024

Introduction

Sjögren’s disease (SD) is an immune-mediated chronic inflammatory disease that affects epithelial tissues, mainly salivary and lacrimal glands. It also presents extraglandular manifestations. The main renal manifestation is tubulointerstitial nephritis (TIN), which can manifest as renal tubular acidosis (RTA). Urinary citrate may be a biomarker of RTA in these patients. The objective of this study was to evaluate whether hypocitraturia is a predictive biomarker of RTA in a sample of patients with SD in a tertiary hospital in southern Brazil.

Methods

All patients with SD who met the inclusion criteria and who participated in the rheumatology outpatient clinic of the Irmandade Santa Casa de Misericórdia de Porto Alegre were included. Demographic, SD, serological and urinary data were obtained. RTA was considered in those patients who persistently presented urinary pH above 5.5 and serum pH below 7.35. Patients who persistently had urinary pH above 5.5 underwent a urinary acidification test with furosemide and fludrocortisone. These patients received 1 mg of fludrocortisone and 40 mg of furosemide and had their urine samples tested 2, 4 and 6 h after taking the medications. The test was stopped at any urine sample with pH 5.5 or less. The variables were expressed as mean and standard deviation or interquartile range. The association between hypocitraturia and RTA was assessed using the chi-square.

Results

Forty-two patients were included, 95.2% female with a median age of 61.73 years. The prevalence of complete distal RTA was 4.88%. Twenty-eight patients underwent urine acidification testing. Five patients had hypocitraturia, and two of them had complete distal RTA. The association between hypocitraturia and RTA was statistically significant (p < 0.012), with a sensitivity of 100%, specificity of 91.2% and accuracy of 91.7%. The negative predictive value was 100%. The global renal assessment of the population demonstrated two patients with RTA, one patient with decreased renal function and six patients with proteinuria greater than 0.5 g/24 h.

Conclusion

The prevalence of RTA in the studied population was 4.88%. Hypocitraturia had high sensitivity and accuracy for the diagnosis of RTA.
Patients’ expectations surrounding revision total hip arthroplasty: a literature review
Authors: Mohammad Omar , Shaarani Shahril , Mohammad Adnan , Konan Sujith
Published: June 2024

Background

Revision total hip arthroplasties (RTHA) are associated with a higher complication rate than primary total hip arthroplasties (THA), and therefore it is important for patients to have realistic expectations regarding outcomes. The aim of this literature review was to gather and summarize the available evidence on patients’ expectations following RTHA.

Methods

A literature search was conducted in PubMed, PsycINFO, Cochrane, Google Scholar, Web of Science and Embase from inception to November 2023. Articles assessing patient expectations for RTHA were included. Methodological quality was assessed by two independent reviewers using the National Heart, Lung and Blood Institute (NIH) study quality assessment tool for observational cohort and cross-sectional studies. A qualitative analysis was performed involving the summarization of study characteristics and outcomes.

Results

The search strategy generated 7,450 references, of which 5 articles met the inclusion criteria. Methodological quality scores ranged from 7–10. Patients had high expectations concerning future walking ability, pain and implant longevity relative to actual postoperative outcomes. A significant positive correlation was found between fulfilled expectations of pain and walking ability and patient satisfaction (r = 0.46–0.47). Only two studies assessed the fulfillment of patient expectations. Great variability was seen in the measurement of expectations.

Conclusion

Patients undergoing RTHA appeared to have high expectations for pain and functionality compared to postoperative outcomes. However, there was a paucity of high-quality data in this area, limiting the accuracy of the conclusion. Further research is needed, that emphasizes developing a sound theoretical framework for expectations, allowing for the consistent implementation of valid measurement tools for patient expectations.
A multicentre survey of knowledge and implementation of radiation protection techniques in cardiac cath-lab medical personnel
Authors: Mansour Amr , Gamal Noha M. , Tohamy Ali , Abdeltawab Adham
Published: June 2024

Background

Awareness of radiation hazards and methods to reduce radiation dose is a sine qua non for all staff working in the cath-lab for their own safety and their patient’s safety.

Results

There were large variations in the implementation of radiation protection techniques with overall inadequate radiation risk knowledge. Some members of the cath-lab team are at higher risk of radiation-induced side effects, including the fellows, nurses, technicians, and anaesthesiologists because they spent longer time in the cath-lab and/or their position in relation to the source of radiation. About 10% of the participants have reported different health problems potentially induced by radiation exposure.

Conclusions

There is lack of radiation risks knowledge with inadequate radiation protection practice among cath-lab team. Some members such as fellows, nurse, technicians, and cardiac anaesthesiologist are at higher risks. They represent the forgotten members of the Cath-Lab team.
Novel approaches to uncertainty estimation in seismic subsurface characterization
Authors: Walker Matt , Crosby Alistair , Lomas Angus , Kazlauskas Eric , Biswas Reetam , Paramo Pedro , Wolf Kevin , Vyas Madhav
Published: June 2024

Uncertainty estimation in subsurface characterization workflows is an important input to decision-making in earth science-related problems. We present three methods to characterize seismic-related uncertainty, each of which includes a real data case study. Two of these methods are designed to characterize depth uncertainty in positioning of migrated reflectors. Such estimates may be used in derisking well depth prognoses, analysis of well misties, and for estimating ranges on resource volume. The first method derives rapid and robust estimates of depth uncertainty around an existing velocity model using traditional velocity analysis to constrain the solution space while limiting a-priori constraints, consistent with a frequentist approach to uncertainty characterization. The second method characterizes depth uncertainty more rigorously in respect to the physics and prior information available by performing full-waveform inversion in a Bayesian framework. This method produces similar uncertainty estimates to the first in the case of simple velocity models but is more accurate where the overburden is complex; however, it requires significantly greater computational expense, thus limiting current practical applications. The third method is an amplitude variation with angle (AVA) inversion for reservoir properties designed to output uncertainty products for interpreters, utilizing the Bayesian framework and Zoeppritz equations to define the forward physics. Application to an offshore Egypt field demonstrates that it can generate reliable estimates of reservoir properties (e.g., lithofluid type or shale volume) including uncertainty, useful in various parts of subsurface characterization. These results also show that the method could provide improved point estimates of reservoir properties compared to conventional deterministic AVA inversion approaches. There is usually a trade-off between increasing the accuracy of subsurface characterization versus creating faster, less expensive, and more readily understood workflows for practitioners. We discuss how the relative importance of these competing factors should be considered within the context of how the outputs will be used.
Memorial
Authors:   Friends and family of Sven Treitel, Yilmaz Öz
Published: June 2024

Sven Treitel
Understanding clozapine-related blood dyscrasias. Developments, genetics, ethnicity and disparity: it's a CIN
Authors: Silva Edward , Legge Sophie , Casetta Cecilia , Whiskey Eromona , Oloyede Ebenezer , Gee Siobhan
Published: June 2024

Clozapine remains the gold standard intervention for treatment-resistant schizophrenia; however, it remains underused, especially for some minority groups. A significant impediment is concern about propensity to neutropenia. The aim of this article is to provide an update on current knowledge relating to: the pattern and incidence of severe blood dyscrasias; the effectiveness of current monitoring regimes in reducing harm; the mechanisms of and the distinctions between clozapine-induced neutropenia and agranulocytosis; benign ethnic neutropenia; and changes to the monitoring thresholds in the USA and other international variations. These all have implications for the practical use of clozapine; specifically, how barriers to initiating, maintaining and restarting clozapine can be understood and in many cases overcome, especially for patients from minority groups, potentially with simpler approaches than the use of lithium or G-CSF.
Involvement of propranolol in suicides: cross-sectional study using coroner-reported data
Authors: Gorton Hayley C. , Archer Charlotte , Algahtani Thikra , Mughal Faraz , Copeland Caroline S.
Published: June 2024

Background

Propranolol is a beta-blocker medication indicated mostly for heart rhythm conditions and for physical symptoms of anxiety. Prescriptions for propranolol in the UK have increased since 2008. Recently, there have been concerns about the involvement of propranolol in intentional poisonings, but such deaths are not routinely reported. Therefore, use of coroner-reported and toxicology data enables unique investigation into the scale of involvement of propranolol in suicide.

Aims

To describe the extent to which propranolol is involved in suicides, including patterns over time and characteristics of people whose suicide involved propranolol compared with other suicides.

Method

Data were derived from the National Programme on Substance Use Mortality (NPSUM). All suicides and deaths of undetermined intent between 2010 and 2021 in England, Wales and Northern Ireland were extracted, and a subset was identified where propranolol was involved in death.

Results

There were 4473 suicides of which 297 (6.6%) involved propranolol, with the proportion involving propranolol nearly quadrupling during the study period (3.4% v. 12.3%). Compared with all other suicides, a greater proportion of propranolol suicides were in women (56.6% v. 37.1%) and in people with diagnoses of depression (39.1% v. 27.1%) and anxiety (22.2% v. 8.6%). When suicide involved propranolol, an antidepressant was detected at post-mortem in 81.8% of deaths, most commonly a selective serotonin reuptake inhibitor (SSRIs) (51.5%), and most often citalopram (24.6%).

Conclusions

A small number, but increasing proportion, of suicides reported to the NPSUM involve propranolol. Vigilance to the combined toxicity profile of medicines used alongside propranolol may be pertinent.
Efficacy and safety of entrectinib in children with extracranial solid or primary central nervous system (CNS) tumors harboring NTRK or ROS1 fusions.
Authors: Desai Ami V. , Robinson Giles W. , Wu Yeming , Wang Huanmin , Basu Ellen M. , Bagchi Aditi , Casanova Michela , van Tilburg Cornelis Martinus , Campbell-Hewson Quentin , Armstrong Amy E. , André Nicolas , Devlin Clare E. , Wulff Jade , Cardenas Alison , Meneses-Lorente Georgina , Hutchinson Katherine E. , Lian Qinshu , Ryklansky Carolina , Fox Elizabeth , Gajjar Amar J.
Published: June 2024

10000

Background: Entrectinib previously yielded durable responses in children with NTRK or ROS1 fusion-positive extracranial solid or primary CNS tumors in STARTRK-NG (NCT02650401). We present updated data from STARTRK-NG, TAPISTRY (NCT04589845) and STARTRK-2 (NCT02568267): pediatric patients from these trials were combined to enable an integrated efficacy and safety analysis on a larger cohort than previously. Methods: Eligible patients were TRK or ROS1 inhibitor naïve and aged < 18 years, had locally advanced or metastatic extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion, and had measurable or evaluable-only disease. Once enrolled, patients received ≥1 daily dose of oral entrectinib until disease progression, unacceptable toxicity, or consent withdrawal. Tumor responses were confirmed by blinded independent central review (BICR) per RECIST v1.1 or RANO criteria. Patients were included if they had been followed for ≥6 months. The primary endpoint was confirmed objective response rate (ORR) per BICR. Key secondary endpoints included ORR in patients with baseline measurable disease per BICR, duration of confirmed response (DoR), time to confirmed response (TTR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. Results: At clinical cutoff (16 July 2023), out of 91 safety-evaluable patients (regardless of fusion), 44 patients in the NTRK cohort and 20 patients in the ROS1 cohort were efficacy evaluable. Median duration of survival follow-up was 24.2 months ( NTRK: range 1–66) and 27.6 months ( ROS1: range 1–73). The ORR was 72.7% (95% CI 57.2–85.0) in the NTRK cohort and 65.0% (95% CI 40.8–84.6) in the ROS1 cohort. In patients with baseline measurable disease, the ORR was 81.1% ( NTRK: n=30/37; 95% CI 64.8–92.0) and 62.5% ( ROS1: n=10/16; 95% CI 35.4–84.8). Efficacy outcomes are shown in the Table. The most common adverse events were pyrexia (50.5%), vomiting (40.7%) and anemia (40.7%). Conclusions: Entrectinib continued to yield rapid and durable responses in pediatric patients with extracranial solid or primary CNS tumors harboring an NTRK or ROS1 fusion. The safety profile of entrectinib was in line with previous reports. Clinical trial information: NCT02650401 / NCT04589845 / NCT02568267 . [Table: see text]
Precision genome profiling for pediatric leukemia with a software-controlled enrichment method using nanopore sequencer.
Authors: Kato Shota , Sato-Otsubo Aiko , Nakamura Wataru , Sugawa Masahiro , Hidaka Moe , Sekiguchi Masahiro , Watanabe Kentaro , Shiraishi Yuichi , Kato Motohiro
Published: June 2024

10027

Background: The real-time nature of nanopore sequencing allows for simultaneous basecalling of DNA sequences during sequencing. This unique capability enables adaptive sampling (AS), a software-controlled targeted sequencing method. AS is notable for its ability to rapidly and flexibly enrich multiple genes with long fragment reads and detect various modalities of genetic aberrations in a single run. However, the feasibility and significance of AS for cancer have not been previously reported. Methods: We performed AS on a GridION sequencer using samples from 28 pediatric leukemia patients (10 acute myeloid leukemia, 13 B-cell acute lymphoblastic leukemia, and 5 T-cell acute lymphoblastic leukemia). Target regions were comprised of 466 genes associated with hematologic malignancies and included 30-kilo base pairs of flanking regions. After 3 days of sequencing, single-nucleotide variants (SNVs), structural variations (SVs), and copy number variations (CNVs) were determined. In 21 samples, variant calling accuracy was evaluated using short-read-based whole genome sequencing (WGS). Results: In the on-target regions, mean depth was 21.0× and N50 was 11,191 bps at the median. Of the 13 samples with genetic alterations previously detected through clinical testing for diagnostic classifications, all were reconfirmed by AS. Detecting DUX4 rearrangement needed an additional analysis pipeline because of its structural complexity. Among the 15 remaining samples whose genetic alterations had not been determined by clinical diagnostic testing, AS identified putative driver aberrations in 14 samples. All of these genomic abnormalities were structural variations (SVs) or copy number variations (CNVs), most of which were not encompassed within the genes or regions targeted in clinical diagnostic testing. Detected SVs were described with accurate genomic breakpoints, enabling the efficient detection of gene rearrangements and deletions of the entire region of an exon or a gene. Regarding CNVs, both chromosomal-level CNVs, such as high-hyperdiploid, and focal CNVs, such as CDKN2A deletion, were detectable using genome-wide low-coverage reads in the off-target regions. In the other case with acute myeloid leukemia in which genetic abnormalities were not detected either by clinical testing or AS, WGS identified an NPM1 frameshift deletion located outside of known hotspots. Among variants identified by WGS, AS detected 60.9% of the SNVs, 17.6% of the small indels, and 89.2% of the SVs, with a tendency of poor detection efficiency for variants with low variant allele frequency. Conclusions: AS provides a rapid and precise description of the genomic profile of pediatric leukemia, particularly advantageous for identifying SVs and CNVs, which are difficult to detect by capture-based short-read sequencing.
Racial disparities in pediatric patients with acute myeloid leukemia.
Authors: Becker Ashley , Mishra Anjali , Mathews Maya , Silberstein Peter T. , Swedek Michelle
Published: June 2024

10031

Background: Leukemia is a cancer of the blood and bone marrow characterized by the rapid and uncontrolled production of abnormal white blood cells. Acute myeloid leukemia (AML) makes up 15–20% of all childhood acute leukemias (1). The purpose of this study is to use the National Cancer Database (NCDB) to provide an updated investigation of racial disparities in survival in pediatric patients with AML. Investigating the different factors associated with poor outcomes provides valuable information when allocating resources and understanding where policies will be useful to improve patient outcomes. Methods: Pediatric (0-19 years old) AML patients were identified in this retrospective cohort study via the 2004-2020 NCDB. Chi square analysis, Fischer's exact test, and t-tests were used to analyze demographic variables. Kaplan Meier survival analysis was used to compare mean survival across race categories which was repeated with demographic variables of interest using a multivariate Cox regression. Results: A total of 4765 patients were identified in this study. Most patients were male (53.5%), White (73.0%), held private insurance (52.3%), and resided in metropolitan areas (82.0%). The mean age at diagnosis was 8.1 years old. There was no significant difference in age at diagnosis and time to treatment start across racial categories. Black patients had lower mean survival compared to White patients (131 vs 148 months, p<0.001). When controlling for age, sex, metropolitan status, comorbidity status, income, education, and insurance status as covariates, Black race independently portended a poorer prognosis compared to White race (hazard ratio: 1.174, 95% confidence interval: 1.003-1.376, p=0.046). Black patients were more likely to be uninsured (4.1%) compared to White patients (2.8%) (p<0.001). Black patients were more likely to reside in zip codes with lower incomes (36.0% vs 17.6%, p<0.001) and lower education attainment (38.7% vs 27.8%, p<0.001) compared to White patients. Black patients were more likely to have comorbidities with a Charlson-Deyo score of >1 than White patients (11.2% vs 6.2%, p<0.001). Black patients were also more likely to be from metropolitan areas than White patients (90.5% compared to 83.9%, p<0.001). Conclusions: This study indicates that Black AML patients experience lower survival rates and are subject to more predictors of poor outcomes. Black patients were more likely to be uninsured, have comorbidities, live in zip codes with lower incomes and lower education attainment. 1. Morais, R. V. de et al (2021). J De Pediatria, 97(2), 204–210. https://doi.org/10.1016/j.jped.2020.02.003.
Demographic factors of prognosis in pediatric neuroblastoma.
Authors: Mathews Maya , Silberstein Peter T. , Swedek Michelle
Published: June 2024

10041

Background: Neuroblastoma is a rare type of pediatric tumor derived from neural crest progenitor cells. It can arise anywhere along the sympathetic chain but is most commonly found in the retroperitoneum from the adrenal glands. At diagnosis, approximately 50% of patients have hematogenous spread of metastases and so timely, aggressive treatment may be life-saving. The National Cancer Database (NCDB) is an oncology database that collects data from over 1500 cancer centers in the United States. This study will utilize the NCDB to analyze how demographic factors may impact prognosis in patients with pediatric neuroblastoma. Methods: We conducted a retrospective analysis using the National Cancer Database (NCDB) and identified patients diagnosed with pediatric neuroblastoma under the age of 18 between 2004-2020 with ICD code 9500/3 (n = 2323). Multivariate Cox regression analysis was used to calculate hazard ratios (HR) analyzing race, Spanish/Hispanic origin, facility type, education, income, insurance status, age at diagnosis, distance traveled to the facility, and urban characteristics of the facility on prognosis. Results: The median age at diagnosis was one year-old. Patients aged greater than one year-old composed 48% of the sample and had a less favorable prognosis compared to patients younger than one-year old (HR 1.99, 95% CI 1.69-2.35, p < 0.001). The median distance to the facility was 21.4 miles. 50% of the sample patients lived greater than 21.4 miles of their chosen facility and had a poorer prognosis compared to patients who lived closer (HR 1.25, 95% CI 1.06-1.47, p = 0.008). Conversely, patients with private insurance composed 59% of the sample and had a more favorable prognosis (HR 0.54, 95% CI 0.30-0.99, p = 0.046) compared to patients with no insurance. Conclusions: To our knowledge, this study provides the most updated analysis on how demographic factors impact prognosis in patients with pediatric neuroblastoma. We highlight potential barriers to care including age, distance to facility, and insurance. We hope this study may serve as a foundation for further investigation into the systemic barriers that affect patients with pediatric neuroblastoma.
Pediatric cancer registry in Turkey 2002-2023: 22 years of achievement (TPOG & TPHD).
Authors: Kutluk M. Tezer , Yeşilipek Akif
Published: June 2024

10051

Background: The survival rates for childhood cancer have seen significant improvements in high-income countries over the past few decades. However, in low- and middle-income countries, it remains a substantial challenge. Access to care remains a significant barrier to improving survival rates in low- and middle-income countries (LMICs). The pediatric cancer registry is a crucial component of pediatric cancer control efforts. In this context, we present the findings from 22 years of the pediatric cancer registry in Turkey. Methods: The present pediatric cancer registry was established by Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association in 2002. The childhood cancer cases registered between 2002-2023 was included in this analysis. International Childhood Cancer Classification System was used for the classification. Essential demographic findings, ICD-O-3 morphology and topography codes were recorded for each case. Results: During the 22 years from 2002 to 2023, 50887 cases were registered. For all cases, median age was 6.5 year (0-19; M/F 28641/22233, 6 hermaphrodite, 7 unknown). Age distribution was 0-4 yrs, 41.1%; 5-9 yrs, 24.7%; 10-14 yrs, 23.1%; 15-19 yrs, 11.0%) The distribution of the tumor types were [number of cases, percentage of total, median age yrs, M/F]: Leukemia (14633, 28.8%, 5.6, 8510/6123); Lymphoma & other RES tumors (8958, 17.6%, 9.2, 5956/3000, 2 unknown); CNS [brain & spinal] (7299, 14.3%, 7.0, 4066/3232, 1 unkown); Sympathetic system (3783, 7.4%, 2.4, 1951/1831, 1 hermaphrodite); Retinoblastoma (1444, 2.8%, 1.5, 752/692); Renal (2310, 4.5%, 3.1, 1140/1168, 1 hermaphrodite & 1 unknown); Liver (732, 1.4%, 2.1, 428/304); Malignant bone (3122, 6.1%, 12.5, 1747/1375); Soft tissue sarcomas (3675, 7.2%, 7.3, 2047/1628); Germ cell (2933, 5.8%, 8.9, 1077/1849, 4 hermaphrodite, 3 unknown); Carcinoma & other malignant epithelial (1628, 3.2%, 13.1, 783/845); Other/non-specific malignant (370, 0.7%, 7.8, 184/186). Five-year survival rate was found as 71.1%. Conclusions: The survival rates for children and adolescents have improved to 70%, a figure comparable to that of other middle-income countries and reflective of the quality of pediatric cancer care in Turkey. This represents a successful pediatric cancer registry from a middle-income country, covering a period of over 20 years. It has become a valuable resource for stakeholders at both the national and international levels.
Feasibility of tumor-informed circulating tumor DNA (ctDNA) for molecular residual disease (MRD) assessment in pediatric patients with solid tumors.
Authors: Mitchell Michael
Published: June 2024

10058

Background: Circulating Tumor DNA (ctDNA) is a noninvasive biomarker which has been validated as a prognostic tool in multiple adult cancers. There is evolving evidence that ctDNA may be prognostic in pediatric solid tumors, but experience with commercially available assays in pediatric patients is scarce. Signatera is a ctDNA assay which utilizes whole exome sequencing of tumor and whole blood to identify 16 tumor-specific, clonal, somatic variants. These variants are then monitored in plasma as a molecular residual disease (MRD) assessment. Methods: From November 2021 through August 2023, 30 patients were enrolled on a single center study evaluating the feasibility and utility of Signatera MRD monitoring in pediatric patients with solid tumors. Patients 6 months to 25 years of age with any malignant extracranial solid tumor including lymphoma were eligible. Peripheral blood has been collected every 3 weeks to 3 months while on therapy and every 3 to 6 months while off therapy for up to 2 years. A minimum of 22mL of blood was required for the first draw, and 16mL for subsequent draws. Timing of blood draws was aligned with standard of care blood draws when possible. Results of ctDNA MRD were compared with imaging obtained for disease response and surveillance as standard of care. Results: The cohort consisted of 6 cases of neuroblastoma, 6 osteosarcomas, 4 Wilms tumors, 4 carcinomas, 3 soft tissue sarcomas, 2 Ewing sarcomas, 2 germ cell tumors, 2 lymphomas, and one hepatoblastoma. Of 30 patients enrolled, a tumor-informed ctDNA assay was successfully created for 27 (90%). Of 25 patients who had radiographic evidence of disease at any time of monitoring, 23 (92%) had simultaneous detectable ctDNA. Seven patients have had disease recurrence, of whom all seven had detectable ctDNA at or preceding time of recurrence. Conclusions: Signatera tumor-informed ctDNA assay is a feasible noninvasive tool which may be utilized in parallel with standard of care imaging to monitor for disease recurrence in pediatric patients with extracranial solid tumors. Additional analysis of a larger patient cohort is needed to identify tumor types and clinical scenarios for which its application is most useful.
Experiences of underrepresented adolescent and young adult (AYA) cancer survivors engaging in research-related activities.
Authors: Ghazal Lauren Victoria , Zhang Anao
Published: June 2024

10073

Background: Adolescent and young adult (AYA) cancer survivors are an age-defined cohort (15-39 years at diagnosis) confronting unique biopsychosocial needs throughout their cancer experience. Underrepresented (sexual and gender minority [SGM] and/or Black, Indigenous, and People of Color [BIPOC]) AYAs face additional challenges associated with discrimination, mistrust of providers, and culturally incongruent services. As a result, many underrepresented AYAs experience suboptimal oncological care and disparate outcomes when compared to cis-gendered heterosexual and/or white peers. This study explored the experiences of underrepresented AYA cancer survivors engaging in research-related activities. Methods: This study is part of a larger Patient Centered Outcomes Research Institute (PCORI)-funded project that is evaluating multilevel facilitators and barriers to oncological care and research for underrepresented AYA cancer survivors. With support from five academic cancer centers and five community-based organizations supporting AYAs across the US, we have assembled an intersectional community advisory panel (CAP) of 10 AYAs who identify as BIPOC and/or SGM. Together with the CAP, a semistructured interview guide was developed, and from January to February 2024, we conducted video interviews. Data were analyzed using thematic analysis of verbatim transcribed interview scripts. The CAP assisted the investigative team in the analyses and interpretation of data. Results: Of the 20 participants interviewed, roughly 70% identified as BIPOC, 40% as SGM, and 10% as both BIPOC and SGM. Participants included underrepresented AYA cancer survivors who, prior to this specific study, had or had not participated in cancer-related research. Three major themes affecting underrepresented AYAs and engagement in research-related activities were discovered, and included: 1) Layering of identities, culture, and stigma; 2) The role of trusted conduits in facilitating engagement; and 3) Beyond compensation: reasons of pursuance. Conclusions: The resultant themes illuminate multilevel facilitators and barriers to research engagement among underrepresented AYA cancer survivors. Findings will assist in guiding researchers, oncology care providers and program administrators both in academic and community settings in the design of inclusive and equitable cancer care delivery programs for underrepresented AYA cancer survivors.