bluuebunny/crossref_metadata_2025 huggingface dataset:
The genomes of Vischeria oleaginous microalgae shed light on the molecular basis of hyper-accumulation of lipids
Authors: Gao Baoyan , Xu Meng , Shan Dai , Zhang Chi , Yang Yulan , Dong Zhensheng , Zhang Hu , Han Boping , Huang Luodong , Zhang Chengwu
Published: June 2023

Background

With the urgent need to reduce carbon emissions, and the dwindling reserves of easily exploitable fossil fuel, microalgae-based biofuels that can be used for transport systems and CO2 abatement have attracted great attention worldwide in recent years. One useful characteristic of microalgae is their ability to accumulate high levels of lipid content, in particular under conditions of nitrogen deprivation, with numerous species identified so far. However, a trade-off between levels of lipid accumulation and biomass productivity hinders the commercial applicability of lipids from microalgae. Here, we sequenced the genomes of Vischeria sp. CAUP H4302 and Vischeria stellata SAG 33.83, which can accumulate high content of lipids rich in nutraceutical fatty acids and with excellent biomass yield in nitrogen-limiting culture.

Results

A whole-genome duplication (WGD) event was revealed in V. sp. CAUP H4302, which is a rare event in unicellular microalgae. Comparative genomic analyses showed that a battery of genes encoding pivotal enzymes involved in fatty acids and triacylglycerol biosynthesis, storage polysaccharide hydrolysis, and nitrogen and amino acid-related metabolisms are expanded in the genus Vischeria or only in V. sp. CAUP H4302. The most highlighted is the expansion of cyanate lyase genes in the genus Vischeria, which may enhance their detoxification ability against the toxic cyanate by decomposing cyanate to NH3 and CO2, especially under nitrogen-limiting conditions, resulting in better growth performance and sustained accumulation of biomass under the aforementioned stress conditions.

Conclusions

This study presents a WGD event in microalgae, providing new insights into the genetic and regulatory mechanism underpinning hyper-accumulation of lipids and offering potentially valuable targets for future improvements in oleaginous microalgae by metabolic engineering.
Disease-specific health spending by age, sex, and type of care in Norway: a national health registry study
Authors: Kinge Jonas Minet , Dieleman Joseph L. , Karlstad Øystein , Knudsen Ann Kristin , Klitkou Søren Toksvig , Hay Simon I. , Vos Theo , Murray Christopher J. L. , Vollset Stein Emil
Published: June 2023

Background

Norway is a high-income nation with universal tax-financed health care and among the highest per person health spending in the world. This study estimates Norwegian health expenditures by health condition, age, and sex, and compares it with disability-adjusted life-years (DALYs).

Methods

Government budgets, reimbursement databases, patient registries, and prescription databases were combined to estimate spending for 144 health conditions, 38 age and sex groups, and eight types of care (GPs; physiotherapists & chiropractors; specialized outpatient; day patient; inpatient; prescription drugs; home-based care; and nursing homes) totaling 174,157,766 encounters. Diagnoses were in accordance with the Global Burden of Disease study (GBD). The spending estimates were adjusted, by redistributing excess spending associated with each comorbidity. Disease-specific DALYs were gathered from GBD 2019.

Results

The top five aggregate causes of Norwegian health spending in 2019 were mental and substance use disorders (20.7%), neurological disorders (15.4%), cardiovascular diseases (10.1%), diabetes, kidney, and urinary diseases (9.0%), and neoplasms (7.2%). Spending increased sharply with age. Among 144 health conditions, dementias had the highest health spending, with 10.2% of total spending, and 78% of this spending was incurred at nursing homes. The second largest was falls estimated at 4.6% of total spending. Spending in those aged 15–49 was dominated by mental and substance use disorders, with 46.0% of total spending. Accounting for longevity, spending per female was greater than spending per male, particularly for musculoskeletal disorders, dementias, and falls. Spending correlated well with DALYs (Correlation r = 0.77, 95% CI 0.67–0.87), and the correlation of spending with non-fatal disease burden (r = 0.83, 0.76–0.90) was more pronounced than with mortality (r = 0.58, 0.43–0.72).

Conclusions

Health spending was high for long-term disabilities in older age groups. Research and development into more effective interventions for the disabling high-cost diseases is urgently needed.
Trends in cognitive function before and after stroke in China
Authors: Hua Jianian , Dong Jianye , Chen Guo-Chong , Shen Yueping
Published: June 2023

Background

While cognitive impairment after stroke is common, cognitive trends before stroke are poorly understood, especially among the Chinese population who have a relatively high stroke burden. We aimed to model the trajectories of cognitive function before and after new-onset stroke among Chinese.

Methods

A total of 13,311 Chinese participants aged ≥ 45 years and without a history of stroke were assessed at baseline between June 2011 and March 2012 and in at least one cognitive test between 2013 (wave 2) and 2018 (wave 4). Cognitive function was assessed using a global cognition score, which included episodic memory, visuospatial abilities, and a 10-item Telephone Interview of Cognitive Status (TICS-10) test to reflect calculation, attention, and orientation abilities.

Results

During the 7-year follow-up, 610 (4.6%) participants experienced a first stroke. Both stroke and non-stroke groups showed declined cognitive function during follow-up. After adjustment for covariates, there was no significant difference in pre-stroke cognitive trajectories between stroke patients and stroke-free participants. The stroke group showed an acute decline in episodic memory (− 0.123 SD), visuospatial abilities (− 0.169 SD), and global cognition (− 0.135 SD) after stroke onset. In the years following stroke, the decline rate of the TICS-10 test was higher than the rate before stroke (− 0.045 SD/year).

Conclusions

Chinese stroke patients had not experienced steeper declines in cognition before stroke compared with stroke-free individuals. Incident stroke was associated with acute declines in global cognition, episodic memory, visuospatial abilities, and accelerated declines in calculation, attention, and orientation abilities.
Data-independent acquisition-based mass spectrometry(DIA-MS) for quantitative analysis of patients with chronic hepatitis B
Authors: Wang Bo , Zhang Qian , Wu Lili , Deng Cunliang , Luo Meiyan , Xie Yu , Wu Gang , Chen Wen , Sheng Yunjian , Zhu Peng , Qin Gang
Published: June 2023

Chronic hepatitis B is a significant public health problem and complex pathologic process, and unraveling the underlying mechanisms and pathophysiology is of great significance. Data independent acquisition mass spectrometry (DIA-MS) is a label-free quantitative proteomics method that has been successfully applied to the study of a wide range of diseases. The aim of this study was to apply DIA-MS for proteomic analysis of patients with chronic hepatitis B. We performed comprehensive proteomics analysis of protein expression in serum samples from HBV patients and healthy controls by using DIA-MS. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein network analysis were performed on differentially expressed proteins and were further combined with literature analysis. We successfully identified a total of 3786 serum proteins with a high quantitative performance from serum samples in this study. We identified 310 differentially expressed proteins (DEPs) (fold change > 1.5 and P value < 0.05 as the criteria for a significant difference) between HBV and healthy samples. A total of 242 upregulated proteins and 68 downregulated proteins were among the DEPs. Some protein expression levels were significantly elevated or decreased in patients with chronic hepatitis B, indicating a relation to chronic liver disease, which should be further investigated.
Prognosis of incidental pulmonary embolism vs. symptomatic pulmonary embolism in cancer patients: a single-center retrospective cohort study in China
Authors: Wang Yanfei , Liu Zhongfen , Li Qiuyu , Xia Lina , Wang Yunyi , Jiang Danfeng , Chen Xiaoyan , Zheng Yanqun , Liu Wei , Wang Dan , Xue Dong
Published: June 2023

Background

The incidence of incidental pulmonary embolism (IPE) has greatly increased, but its clinical characteristics and outcomes are still controversial. This study aimed to compare the clinical characteristics and outcomes between cancer patients with IPE and patients with symptomatic pulmonary embolism (SPE).

Patients/Methods

Clinical data of 180 consecutive patients with cancer complicated with pulmonary embolism admitted to Beijing Cancer Hospital from July 2011 to December 2019 were retrospectively collected and analysed. General characteristics, diagnosis time of pulmonary embolism (PE), location of PE, concurrent deep venous thrombosis, anticoagulant treatment, impact of PE on anti-tumor treatment, recurrent venous thromboembolism, rate of bleeding after anticoagulation therapy, survival and risk factors of IPE were compared with SPE.

Results

Of 180 patients, 88 (49%) had IPEs and 92 (51%) had SPEs. Patients with IPE and SPE did not differ in age, sex, tumor type, or tumor stage. Median diagnosis times of IPE and SPE after cancer were 108 (45, 432) days and 90 (7, 383) days, respectively. Compared to SPE, IPE tended to be central (44% versus 26%; P < 0.001), isolated (31.8% versus 0.0%; P < 0.001), and unilateral (67.1% versus 12.8%; P < 0.00). The rate of bleeding after anticoagulation therapy did not differ between IPE and SPE. Patients with IPE had a better prognosis than patients with SPE in terms of 30-, and 90-day mortality, as well as overall survival after diagnosis of PE (median: 314.5 vs. 192.0 days, log-rank P = 0.004) and cancer (median: 630.0 vs. 450.5 days, log-rank P = 0.018). SPE (compared to IPE) was an independent risk factor for poor survival after diagnosis of PE in multivariate analysis (hazard ratio [HR] = 1.564, 95% confidence interval [CI]: 1.008–2.425, p = 0.046).

Conclusions

IPE accounts for nearly one half of PE cases among Chinese cancer patients. With active anticoagulation treatment, IPE is expected to achieve better survival rates than SPE.
Maternal microbiota and gestational diabetes: impact on infant health
Authors: Singh Parul , Elhaj Duaa Ahmed Idris , Ibrahim Ibrahim , Abdullahi Hala , Al Khodor Souhaila
Published: June 2023

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that has been associated with an increased risk of obesity and diabetes in the offspring. Pregnancy is accompanied by tightly regulated changes in the endocrine, metabolic, immune, and microbial systems, and deviations from these changes can alter the mother’s metabolism resulting in adverse pregnancy outcomes and a negative impact on the health of her infant. Maternal microbiomes are significant drivers of mother and child health outcomes, and many microbial metabolites are likely to influence the host health. This review discusses the current understanding of how the microbiota and microbial metabolites may contribute to the development of GDM and how GDM-associated changes in the maternal microbiome can affect infant’s health. We also describe microbiota-based interventions that aim to improve metabolic health and outline future directions for precision medicine research in this emerging field.
Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation
Authors: Meulendijks Eva R. , Al-Shama Rushd F. M. , Kawasaki Makiri , Fabrizi Benedetta , Neefs Jolien , Wesselink Robin , Ernault Auriane C. , Piersma Sander , Pham Thang V. , Jimenez Connie R. , Knol Jaco C. , van Boven Wim J. P. , Driessen Antoine H. G. , de Vries Tim A. C. , van der Leeden Britt , Niessen Hans W. M. , de Boer Onno J. , Krul Sébastien P. J. , de Groot Joris R.
Published: June 2023

Background

Epicardial adipose tissue (EAT) secretome induces fibrosis. Fibrosis, primarily extracellular matrix (ECM) produced by fibroblasts, creates a substrate for atrial fibrillation (AF). Whether the EAT secretome from patients with AF activates human atrial fibroblasts and through which components, remains unexplored.

Research aims

(a) To investigate if the EAT secretome from patients with versus without AF increases ECM production in atrial fibroblasts. (b) To identify profibrotic proteins and processes in the EAT secretome and EAT from patients with, who will develop (future onset), and without AF.

Methods

Atrial EAT was obtainded during thoracoscopic ablation (AF, n = 20), or open-heart surgery (future onset and non-AF, n = 35). ECM gene expression of human atrial fibroblasts exposed to the EAT secretome and the proteomes of EAT secretome and EAT were assessed in patients with and without AF. Myeloperoxidase and neutrophil extracellular traps (NETs) were assessed immunohistochemically in patients with paroxysmal, persistent, future onset, and those who remain free of AF (non-AF).

Results

The expression of COL1A1 and FN1 in fibroblasts exposed to secretome from patients with AF was 3.7 and 4.7 times higher than in patients without AF (p < 0.05). Myeloperoxidase was the most increased protein in the EAT secretome and EAT from patients with versus without AF (FC 18.07 and 21.57, p < 0.005), as was the gene-set neutrophil degranulation. Immunohistochemically, myeloperoxidase was highest in persistent (FC 13.3, p < 0.0001) and increased in future onset AF (FC 2.4, p = 0.02) versus non-AF. Myeloperoxidase aggregated subepicardially and around fibrofatty infiltrates. NETs were increased in patients with persistent versus non-AF (p = 0.03).

Conclusion

In AF, the EAT secretome induces ECM gene expression in atrial fibroblasts and contains abundant myeloperoxidase. EAT myeloperoxidase was increased prior to AF onset, and both myeloperoxidase and NETs were highest in persistent AF, highlighting the role of EAT neutrophils in the pathophysiology of AF.
Mitochondrial folate pathway regulates myofibroblast differentiation and silica-induced pulmonary fibrosis
Authors: Qu Yaqian , Zhai Ruonan , Wang Dandan , Wang Zheng , Hou Guangjie , Wu Chenchen , Tang Meian , Xiao Xiongbin , Jiao Jie , Ba Yue , Zhou Fang , Qiu Jian , Yao Wu
Published: June 2023

Background

Silica-induced pulmonary fibrosis (silicosis) is a diffuse interstitial fibrotic disease characterized by the massive deposition of extracellular matrix in lung tissue. Fibroblast to myofibroblast differentiation is crucial for the disease progression. Inhibiting myofibroblast differentiation may be an effective way for pulmonary fibrosis treatment.

Methods

The experiments were conducted in TGF-β treated human lung fibroblasts to induce myofibroblast differentiation in vitro and silica treated mice to induce pulmonary fibrosis in vivo.

Results

By quantitative mass spectrometry, we revealed that proteins involved in mitochondrial folate metabolism were specifically upregulated during myofibroblast differentiation following TGF-β stimulation. The expression level of proteins in mitochondrial folate pathway, MTHFD2 and SLC25A32, negatively regulated myofibroblast differentiation. Moreover, plasma folate concentration was significantly reduced in patients and mice with silicosis. Folate supplementation elevated the expression of MTHFD2 and SLC25A32, alleviated oxidative stress and effectively suppressed myofibroblast differentiation and silica-induced pulmonary fibrosis in mice.

Conclusion

Our study suggests that mitochondrial folate pathway regulates myofibroblast differentiation and could serve as a potential target for ameliorating silica-induced pulmonary fibrosis.
Traditional supports and contemporary disrupters of high fertility desires in sub-Saharan Africa: a scoping review
Authors: Church Anna C. , Ibitoye Mobolaji , Chettri Shibani , Casterline John B.
Published: June 2023

Rationale

The desired number of children is markedly higher in Sub-Saharan Africa (SSA) than in other major regions. Efforts to understand how and why these desires are generated and maintained have yielded a broad research literature. Yet there is no full picture of the range of contextual, cultural, and economic factors that support and disrupt high fertility desires.

Objective

This scoping review synthesizes thirty years of research on the determinants of fertility desires in SSA to better understand what factors underlie men and women’s stated fertility desires and how they weigh the costs and benefits of having (more) children.

Method

We identified and screened 9863 studies published from 1990 to 2021 from 18 social science, demographic, and health databases. We appraised determinants of fertility desires from 258 studies that met inclusion criteria according to their roles as traditional supports or contemporary disrupters of high fertility desires.

Results

We identified 31 determinants of high fertility desires, which we organized into six overarching themes: economy and costs; marriage; the influence of others; education and status; health and mortality; and demographic predictors. For each theme, we summarize ways in which the determinants both support and disrupt high fertility desires. We find that high fertility remains desirable in many regions of sub-Saharan Africa but contemporary disrupters, such as the economic situations and increases to family planning and education, cause individuals to decrease their desired fertility with such decreases often viewed as a temporary adjustment to temporary conditions. Most included studies were quantitative, cross-sectional, and based on survey data.

Conclusion

This review demonstrates how traditionally supportive and contemporary disruptive forces simultaneously influence fertility desires in sub-Saharan Africa. Future studies analyzing fertility desires in sub-Saharan Africa should be informed by the lived experiences of men and women in this region, with qualitative and longitudinal studies prioritized.
Psychological capital and alienation among patients with COVID-19 infection: the mediating role of social support
Authors: Wu Chao , He Chun-yan , Yan Jia-ran , Zhang Hong-li , Li Lu , Tian Ci , Chen Nana , Wang Qing-yi , Zhang Yu-hai , Lang Hong-juan
Published: June 2023

Background

COVID-19 infection continues all over the world, causing serious physical and psychological impacts to patients. Patients with COVID-19 infection suffer from various negative emotional experiences such as anxiety, depression, mania, and alienation, which seriously affect their normal life and is detrimental to the prognosis. Our study is aimed to investigate the effect of psychological capital on alienation among patients with COVID-19 and the mediating role of social support in this relationship.

Methods

The data were collected in China by the convenient sampling. A sample of 259 COVID-19 patients completed the psychological capital, social support and social alienation scale and the structural equation model was adopted to verify the research hypotheses.

Results

Psychological capital was significantly and negatively related to the COVID-19 patients’ social alienation (p < .01). And social support partially mediated the correlation between psychological capital and patients’ social alienation (p < .01).

Conclusion

Psychological capital is critical to predicting COVID-19 patients’ social alienation. Social support plays an intermediary role and explains how psychological capital alleviates the sense of social alienation among patients with COVID-19 infection.
Linear epitopes on the capsid protein of norovirus commonly elicit high antibody response among past-infected individuals
Authors: Deng Yilin , He Taojun , Li Bin , Yuan Hanmei , Zhang Fang , Wu Hui , Ning Jie , Zhang Yanping , Zhai Aixia , Wu Chao
Published: June 2023

Background

Human norovirus (HuNoV) is the leading cause of acute nonbacterial gastroenteritis globally, and its infection is usually self-limited, so most people become past Norovirus (NoV)-infected individuals. It is known that some antibody responses may play a critical role in preventing viral infection and alleviating disease; however, the characteristics and functions of particular antibody responses in persons with previous infections are not fully understood. Capsid proteins, including VP1 and VP2, are crucial antigenic components of NoV and may regulate antibody immune responses, while epitope-specific antibody responses to capsid proteins have not been comprehensively characterized.

Methods

We prepared purified VP1 and VP2 proteins by ion exchange chromatography and measured serum antigen-specific IgG levels in 398 individuals by ELISA. Overlapping 18-mer peptides covering the full length of VP1 and VP2 were synthesized, and then we identified linear antigenic epitopes from 20 subjects with strong IgG positivity. Subsequently, specific antibody responses to these epitopes were validated in 185 past infected individuals, and the conservation of epitopes was analyzed. Finally, we obtained epitope-specific antiserum by immunizing mice and expressed virus-like particles (VLPs) in an insect expression system for a blockade antibody assay to evaluate the receptor-blocking ability of epitope-specific antibodies.

Results

The IgG responses of VP1 were significantly stronger than those of VP2, both of which had high positive rates of over 80%. The overall positive rate of VP1-IgG and/or VP2-IgG was approximately 94%, which may be past NoV-infected individuals. Four linear antigenic B-cell epitopes of capsid proteins were identified, namely, VP1199–216, VP1469–492, VP297–120, and VP2241–264, all of which were conserved. The IgG response rates of the above epitopes in past NoV-infected individuals were 38.92%, 22.16%, 8.11% and 28.11%, respectively. In addition, VP1199–216- and VP1469–492-specific antibodies can partially block the binding of VLPs to the receptor histo-blood group antigen (HBGA).

Conclusion

This is the first study to describe specific antibody responses of VP2 and to identify its B-cell epitopes. Our findings offer data for a more thorough understanding of norovirus capsid protein-specific IgG responses and could provide useful information for designing and developing vaccines.
Factors associated with delayed initiation and non-exclusive breastfeeding among children in India: evidence from national family health survey 2019-21
Authors: Sharma Madhurima , Anand Abhishek , Goswami Indrajit , Pradhan Manas Ranjan
Published: June 2023

Background

In India, more than half of the newborns experience delayed breastfeeding, and non-exclusive breastfeeding is practiced in 63% of babies below the age of six months. The goal of this study is to investigate the extent to which external environment, demographic and socioeconomic, pregnancy and birthing characteristics, as well as utilization of maternal care services, are associated with delayed initiation and non-exclusive breastfeeding among children in India.

Methods

Data was gathered from the fifth round of the National Family Health Survey (NFHS), which was conducted in 2019-21. This study used information on 85,037 singleton infants aged 0–23 months and 22,750 singleton infants aged 0–5 months. Delayed initiation of breastfeeding and non-exclusive breastfeeding was used as outcome variables in this study. Unadjusted and adjusted multivariable binary logistic regression was performed to analyse the association of delayed breastfeeding and non-exclusive breastfeeding with selected background characteristics.

Results

Factors significantly associated with increased risks of delayed initiation of breastfeeding included infants from in the central region (OR 2.19; 95% CI 2.09, 2.29), mothers in the 20 to 29 years age group at the time of childbirth (OR 1.02; 95% CI 0.98, 1.05), caesarean deliveries (OR 1.97; 95% CI 1.90, 2.05). The likelihoods for non-exclusive breastfeeding significantly increased among children belonging to the richest household status (OR 1.30; 95% CI 1.17, 1.45), mothers who had less than nine months of pregnancy period (OR 1.15; 95% CI 1.06, 1.25), and mothers who gave birth in non-health facility (OR 1.17; 95% CI 1.05, 1.31).

Conclusions

The connections between several different categories of factors and non-exclusive breastfeeding and delayed breastfeeding initiation show the need for comprehensive public health programmes using a multi-sectoral approach to promote breastfeeding behaviours in India.
Real-world analysis of healthcare resource utilization by patients with X-linked myotubular myopathy (XLMTM) in the United States
Authors: Graham Robert J. , Darras Basil T. , Haselkorn Tmirah , Fisher Dan , Genetti Casie A. , Miller Weston , Beggs Alan H.
Published: June 2023

Background

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, often requiring invasive ventilator support, gastrostomy tube feeding, and wheelchair use. Understanding healthcare resource utilization in patients with XLMTM is important for development of targeted therapies but data are limited.

Methods

We analyzed individual medical codes as governed by Healthcare Common Procedure Coding System, Current Procedural Terminology, and International Classification of Diseases, 10th Revision (ICD-10) for a defined cohort of XLMTM patients within a US medical claims database. Using third-party tokenization software, we defined a cohort of XLMTM patient tokens from a de-identified dataset in a research registry of diagnostically confirmed XLMTM patients and de-identified data from a genetic testing company. After approval of an ICD-10 diagnosis code for XLMTM (G71.220) in October 2020, we identified additional patients.

Results

A total of 192 males with a diagnosis of XLMTM were included: 80 patient tokens and 112 patients with the new ICD-10 code. From 2016 to 2020, the annual number of patients with claims increased from 120 to 154 and the average number of claims per patient per year increased from 93 to 134. Of 146 patients coded with hospitalization claims, 80 patients (55%) were first hospitalized between 0 and 4 years of age. Across all patients, 31% were hospitalized 1–2 times, 32% 3–9 times, and 14% ≥ 10 times. Patients received care from multiple specialty practices: pulmonology (53%), pediatrics (47%), neurology (34%), and critical care medicine (31%). The most common conditions and procedures related to XLMTM were respiratory events (82%), ventilation management (82%), feeding difficulties (81%), feeding support (72%), gastrostomy (69%), and tracheostomy (64%). Nearly all patients with respiratory events had chronic respiratory claims (96%). The most frequent diagnostic codes were those investigating hepatobiliary abnormalities.

Conclusions

This innovative medical claims analysis shows substantial healthcare resource use in XLMTM patients that increased over the last 5 years. Most patients required respiratory and feeding support and experienced multiple hospitalizations throughout childhood and beyond for those that survived. This pattern delineation will inform outcome assessments with the emergence of novel therapies and supportive care measures.
Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer
Authors: de Heer E. C. , Zois C. E. , Bridges E. , van der Vegt B. , Sheldon H. , Veldman W. A. , Zwager M. C. , van der Sluis T. , Haider S. , Morita T. , Baba O. , Schröder C. P. , de Jong S. , Harris A. L. , Jalving M.
Published: June 2023

Background

Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models.

Methods

mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs.

Results

High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53–121) and other Ki67-high tumors (median H-score 85, IQR 57–124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis.

Conclusions

Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.
Adrenal insufficiency management in the pediatric emergency setting and risk factors for adrenal crisis development
Authors: Abrigo Enrica , Munarin Jessica , Bondone Claudia , Tuli Gerdi , Castagno Emanuele , de Sanctis Luisa , Matarazzo Patrizia
Published: June 2023

Background

In patients with adrenal insufficiency (AI), adrenal crisis (AC) represents a clinical emergency. Early recognition and prompt management of AC or AC-risk conditions in the Emergency Department (ED) can reduce critical episodes and AC-related outcomes. The aim of the study is to report the clinical and biochemical characteristics of AC presentation to improve their timely recognition and proper management in a ED setting.

Methods

Single-centre, retrospective, observational study on pediatric patients followed at the Department of Pediatric Endocrinology of Regina Margherita Children’s Hospital of Turin for primary AI (PAI) and central AI (CAI).

Results

Among the 89 children followed for AI (44 PAI, 45 CAI), 35 patients (21 PAI, 14 CAI) referred to the PED, for a total of 77 accesses (44 in patients with PAI and 33 with CAI). The main causes of admission to the PED were gastroenteritis (59.7%), fever, hyporexia or asthenia (45.5%), neurological signs and respiratory disorders (33.8%). The mean sodium value at PED admission was 137.2 ± 1.23 mmol/l and 133.3 ± 1.46 mmol/l in PAI and CAI, respectively (p = 0.05). Steroids administration in PED was faster in patients with CAI than in those with PAI (2.75 ± 0.61 and 3.09 ± 1.47 h from PED access, p = 0.83). Significant factors related to the development of AC were signs of dehydration at admission (p = 0.027) and lack of intake or increase of usual steroid therapy at home (p = 0.059). Endocrinological consulting was requested in 69.2% of patients with AC and 48.4% of subjects without AC (p = 0.032).

Conclusion

children with AI may refer to the PED with an acute life-threatening condition that needs prompt recognition and management. These preliminary data indicate how critical the education of children and families with AI is to improve the management at home, and how fundamental the collaboration of the pediatric endocrinologist with all PED personnel is in raising awareness of early symptoms and signs of AC to anticipate the proper treatment and prevent or reduce the correlated serious events.
ANKRD29, as a new prognostic and immunological biomarker of non–small cell lung cancer, inhibits cell growth and migration by regulating MAPK signaling pathway
Authors: Zhao Hanqing , Wang Yanbo , He Yaomei , Zhang Peng , Zeng Cheng , Du Tongxuan , Shen Qiushuo , Zhao Song
Published: June 2023

Background

The predominant cancer-related deaths worldwide are caused by lung cancer, particularly non-small cell lung cancer (NSCLC), despite the fact that numerous therapeutic initiatives have been devised to improve the outcomes. Ankyrin repeat domain (ANKRD) is one of the widespread protein structural motifs in eukaryotes but the functions of ANKRD proteins in NSCLC progression remains unclear.

Methods

We performed integrative bioinformatical analysis to determine the dysregulated expression of ANKRDs in multiple tumors and the association between ANKRD29 expression and the NSCLC tumor environment. Quantitative real-time PCR (qRT-PCR), western blot, immunohistochemistry (IHC), and tissue microarray (TMA) assays were used to investigate the expression of ANKRD29 in NSCLC cell lines. The role of ANKRD29 in NSCLC cell proliferation and migration in vitro was deteceted by 5-bromodeoxyuridine (BrdU) incorporation, colony formation, flow cytometry, would-healing, trans-well, and western blot experiment. RNA-seq technology was applied to deciper the molecular mechanism regulated by ANKRD29 in NSCLC.

Results

We constructed a valuable risk-score system for predicting the overall survival outcomes of NSCLC patients based on the expression of five hub ANKRD genes. And we found that the hub gene ANKRD29 was remarkedly decreased in NSCLC tissues and cell lines due to the promoter hypermethylation, and revealed that high ANKRD29 expression obviously correlated with patients’ better clinical outcome. Overexpression of ANKRD29 significantly inhibited cell proliferation and migration, promoted the cancerous cells’ sensitivity to carboplatin and enhanced the killing ability of T cells in NSCLC cells. Interestingly, ANKRD29 can be served as a biomarker to predict the response to immunotherapy in NSCLC. Mechanically, RNA-seq results showed that ANKRD29 could regulate MAPK signaling pathway. Moreover, we screened two potential agonists for ANKRD29.

Conclusions

ANKRD29 functions as a new tumor suppressor in NSCLC tumorigenesis and could be developed as a biomarker for prognostic prediction, immunotherapy response, and drug susceptibility evaluation of NSCLC in the future.
A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis
Authors: Dierig A , Hoelscher M , Schultz S , Hoffmann L , Jarchow-MacDonald A , Svensson EM , Te Brake L , Aarnoutse R , Boeree M , McHugh TD , Wildner LM , Gong X , Phillips PPJ , Minja LT , Ntinginya N , Mpagama S , Liyoyo A , Wallis RS , Sebe M , Mhimbira FA , Mbeya B , Rassool M , Geiter L , Cho YL , Heinrich N
Published: June 2023

Background

Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure–response and exposure–toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.

Methods

Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response.

Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.

Discussion

DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.

Trial registration

DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).
More efficient and inclusive time-to-event trials with covariate adjustment: a simulation study
Authors: Momal Raphaëlle , Li Honghao , Trichelair Paul , Blum Michael G. B. , Balazard Félix
Published: June 2023

Adjustment for prognostic covariates increases the statistical power of randomized trials. The factors influencing the increase of power are well-known for trials with continuous outcomes. Here, we study which factors influence power and sample size requirements in time-to-event trials. We consider both parametric simulations and simulations derived from the Cancer Genome Atlas (TCGA) cohort of hepatocellular carcinoma (HCC) patients to assess how sample size requirements are reduced with covariate adjustment. Simulations demonstrate that the benefit of covariate adjustment increases with the prognostic performance of the adjustment covariate (C-index) and with the cumulative incidence of the event in the trial. For a covariate that has an intermediate prognostic performance (C-index=0.65), the reduction of sample size varies from 3.1% when cumulative incidence is of 10% to 29.1% when the cumulative incidence is of 90%. Broadening eligibility criteria usually reduces statistical power while our simulations show that it can be maintained with adequate covariate adjustment. In a simulation of adjuvant trials in HCC, we find that the number of patients screened for eligibility can be divided by 2.4 when broadening eligibility criteria. Last, we find that the Cox-Snell $${R}_{\mathsf{C}\mathsf{S}}^{2}$$

R

C
S

2

is a conservative estimation of the reduction in sample size requirements provided by covariate adjustment. Overall, more systematic adjustment for prognostic covariates leads to more efficient and inclusive clinical trials especially when cumulative incidence is large as in metastatic and advanced cancers. Code and results are available at https://github.com/owkin/CovadjustSim.
End-ischemic hypothermic oxygenated perfusion for extended criteria donors in liver transplantation: a multicenter, randomized controlled trial—HOPExt
Authors: Pradat Pierre , Pantel Solene , Maynard Marianne , Lalande Laure , Thevenon Sylvie , Adam Rene , Allard Marc-Antoine , Robin Fabien , Rayar Michel , Boleslawski Emmanuel , Scatton Olivier , Chirica Mircea , Faitot François , Bachellier Philippe , Soubrane Olivier , Mohkam Kayvan , Mabrut Jean-Yves , Lesurtel Mickaël
Published: June 2023

Background

Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia–reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury.

Methods

HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage.

Discussion

We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing.

Trial registration

ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.
MicroRNA-29a-3p prevents Schistosoma japonicum-induced liver fibrosis by targeting Roundabout homolog 1 in hepatic stellate cells
Authors: Kong Hongyan , Song Qiqin , Hu Wenjiang , Guo Shusen , Xiang Dandan , Huang Shuaiwen , Xu Xin , He Jinan , Pan Lanyue , Tao Ran , Yu Haijing , Huang Jiaquan
Published: June 2023

Background

Schistosomiasis is a serious but neglected parasitic disease in humans that may lead to liver fibrosis and death. Activated hepatic stellate cells (HSCs) are the principal effectors that promote the accumulation of extracellular matrix (ECM) proteins during hepatic fibrosis. Aberrant microRNA-29 expression is involved in the development of fibrotic diseases. However, less is known about the role of miR-29 in Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis.

Methods

The levels of microRNA-29a-3p (miR-29a-3p) and Roundabout homolog 1 (Robo1) were examined in liver tissues during S. japonicum infection. The possible involvement of the miR-29a-3p-Robo1 signaling pathway was determined. We used MIR29A conditional knock-in mice and mice injected with an miR-29a-3p agomir to investigate the role of miR-29a-3p in schistosomiasis-induced hepatic fibrosis. The functional contributions of miR-29a-3p-Robo1 signaling in liver fibrosis and HSC activation were investigated using primary mouse HSCs and the human HSC cell line LX-2.

Results

MiR-29a-3p was downregulated in humans and mice with schistosome-induced fibrosis, and Robo1 was upregulated in liver tissues. The miR-29a-3p targeted Robo1 and negatively regulated its expression. Additionally, the expression level of miR-29a-3p in schistosomiasis patients was highly correlated with the portal vein and spleen thickness diameter, which represent the severity of fibrosis. Furthermore, we demonstrated that efficient and sustained elevation of miR-29a-3p reversed schistosome-induced hepatic fibrosis. Notably, we showed that miR-29a-3p targeted Robo1 in HSCs to prevent the activation of HSCs during infection.

Conclusions

Our results provide experimental and clinical evidence that the miR-29a-3p-Robo1 signaling pathway in HSCs plays an important role in the development of hepatic fibrosis. Therefore, our study highlights the potential of miR-29a-3p as a therapeutic intervention for schistosomiasis and other fibrotic diseases.

Graphical Abstract
Imaging features of the postoperative spine: a guide to basic understanding of spine surgical procedures
Authors: Girão Marília Maria Vasconcelos , Miyahara Lucas Kenzo , Dwan Viviane Sayuri Yamachira , Baptista Eduardo , Taneja Atul Kumar , Gotfryd Alberto , do Amaral e Castro Adham
Published: June 2023

Spinal surgical procedures are becoming more common over the years, and imaging studies can be requested in the postoperative setting, such as a baseline study when implants are used, or when there is a new postoperative issue reported by the patient or even as routine surveillance. Therefore, it helps the surgeon in the appropriate management of cases. In this context, there is increasing importance of the radiologist in the adequate interpretation of postoperative images, as well as in the choice of the most appropriate modality for each case, especially among radiographs, computed tomography, magnetic resonance imaging and nuclear medicine. It is essential to be familiar with the main types of surgical techniques and imaging characteristics of each one, including the type and correct positioning of hardware involved, to differentiate normal and abnormal postoperative appearances. The purpose of this pictorial essay is to illustrate and discuss the more frequently used spine surgical interventions and their imaging characteristics, with an emphasis on classical decompression and fusion/stabilization procedures.

Graphical Abstract

Key points

Plain radiographs remain the main modality for baseline, dynamic evaluation, and follow-ups.

CT is the method of choice for assessing bone fusion, hardware integrity and loosening.

MRI should be used to evaluate bone marrow and soft tissue complications.

Radiologists should be familiar with most performed spinal procedures in order to differentiate normal and abnormal.

Critical relevance statement

This article discusses the main surgical procedures involved in the spine, which can be didactically divided into decompression, stabilization-fusion, and miscellaneous, as well as the role of diagnostic imaging methods and their main findings in this context.