bluuebunny/crossref_metadata_2025 huggingface dataset:
OMRT-1. Cannabidiol converts NFKB into a tumor-suppressor in glioblastoma with defined antioxidative properties
Authors: Volmar Marie , Cheng Jiying , Synowitz Michael , Schick Joel , Kälin Roland , Glass Rainer
Published: July 2021

Background

The transcription factor NFKB drives neoplastic progression of many cancers including primary brain tumors (glioblastoma; GBM). Precise therapeutic modulation of NFKB-activity can suppress central oncogenic signalling pathways in GBM, but clinically applicable compounds to achieve this goal have remained elusive.

Methods

In a pharmacogenomics study with a panel of transgenic glioma cells we observed that NFKB can be converted into a tumor-suppressor by the non-psychotropic cannabinoid Cannabidiol (CBD). Subsequently, we investigated the anti-tumor effects of CBD, which is used as an anticonvulsive drug (Epidiolex) in pediatric neurology, in a larger set of human primary GBM stem-like cells (hGSC). For this study we performed pharmacological assays, gene-expression profiling, biochemical and cell-biological experiments. We validated our findings using orthotopic in vivo models and bioinformatics-analysis of human GBM-datasets.

Results

We found that CBD promotes DNA-binding of the NFKB-subunit RELA and simultaneously prevents RELA-phosphorylation on serine-311, a key residue which permits genetic transactivation. Strikingly, sustained DNA-binding by RELA lacking phospho-serine 311 was found to mediate hGSC-cytotoxicity. Widespread sensitivity to CBD was observed in a cohort of hGSC defined by low levels of reactive oxygen-species (ROS), while high ROS-content in other tumors blocked CBD induced hGSC-death. Consequently, ROS-levels served as predictive biomarker for CBD-sensitive tumors.

Conclusions

This evidence demonstrates how a clinically approved drug can convert NFKB into a tumor-suppressor and suggests a promising repurposing option for GBM-therapy.
OTEH-4. Deeper insight into intratumoral heterogeneity by MRI and PET-guided stereotactic biopsies from glioblastoma patients
Authors: Anand Atul , Petersen Jeanette Krogh , Burton Mark , Larsen Martin Jakob , Andersen Lars van Brakel , Harwood Dylan Scott Lykke , Pedersen Christian Bonde , Poulsen Frantz Rom , Grupe Peter , Kruse Torben A , Thomassen Mads , Kristensen Bjarne Winther
Published: July 2021

Glioblastoma is one of the most aggressive cancers, but the molecular evolution is still not fully understood. We used PET imaging combined with deep sequencing of glioblastoma biopsies at both the RNA and DNA levels to get a deeper insight into molecular evolution. In the clinical setting, PET imaging provides information about metabolically active tumor areas, but the molecular interpretation is unclear. Our primary objective was to perform an intratumoral spatial comparison of biopsies from potentially aggressive and less aggressive areas in glioblastomas according to PET scans. Additionally, tissue from the tumor periphery was included. We used MRI, 11C-methionine(MET) PET, and 18F-FDG PET was used in combination to obtain a series of neurosurgical stereotactic biopsies from tumor areas with high MET and 18F-FDG uptake (hotspot), low MET and 18F-FDG uptake (coldspot), as well as tumor periphery of six glioblastoma patients that were processed for whole genome, exome, and transcriptome sequencing. Differential gene expression and gene ontology analysis showed that hotspots were enriched in gene sets associated with DNA replication, cell cycle, and ligand receptor interaction. Genome and exome analysis suggested hotspots and coldspots to have similar mutational profiles. However, a limited number of hotspot-specific mutations and fusion transcripts indicated that hotspot tumor cells developed from coldspot cells and point at the potential role of hotspot driver genes in glioblastoma. Our findings reveal that hotspots in glioblastomas represent a more advanced stage of molecular evolution than coldspots.
OTME-1. TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression
Authors: Kälin Roland , Cai Linzhi , Li Yuping , von Baumgarten Louisa , Schulz Christian , Hellmann Ines , Glass Rainer
Published: July 2021

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression.
OTME-8. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis
Authors: Gritsch Simon , Mathewson Nathan , Ashenberg Orr , Perez Elizabeth , Marx Sascha , Reardon David , Regev Aviv , Suva Mario , Wucherpfennig Kai
Published: July 2021

T-cells are critical effector cells of cancer immunotherapies, but little is known about T-cell gene expression programs in diffuse gliomas. We leveraged single-cell RNA-seq to chart the gene expression and clonal landscape of tumor-infiltrating T-cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. Our analysis revealed subsets of T-cells that expressed several NK-cell receptors, in particular the inhibitory CD161 receptor (KLRB1 gene). KLRB1 was overexpressed by clonally expanded CD8 T-cells, and larger populations of T-cells expressed CD161 than PD-1. The CLEC2D ligand of CD161 was expressed by malignant cells and myeloid cells, and inactivation of KLRB1 enhanced anti-tumor T-cell function. KLRB1 was also expressed by substantial T-cell populations in multiple other human cancers. CD161 and other NK-cell receptors expressed by T-cells represent opportunities for immunotherapy of diffuse gliomas and other human cancers.
OTME-15. Physical Confinement Induces Diverse Transcriptomic Changes and Chemoresistance in Migrating Glioblastoma Cells
Authors: Battiste James , Babu Anish , Sharp Rachel , Scott Sydney , Dunn Ian , Glenn Chad , Kim Young-tae , Jones Kenneth
Published: July 2021

Glioblastoma multiforme (GBM) cells migrating in physically confined environments are affected by mechanical stress that potentially lead to transcriptomic changes. To simulate those stresses, microfluidic channels were made with micro-patterned polydimethylsiloxane (PDMS) replicating the physical microenvironment of white matter tracts by confining the cells in linear channels similar to the space between axons. We employed a combination of microarray transcriptomic profiling and single cell-sequencing analyses to investigate cells undergoing linear confined space migration (LCSM). GBM cells spontaneously migrate through confined spaces along 5x5 mm (height/width) microfluidic channels, 0.5 to 5 mm in length. Our previous studies demonstrated that cells migrating in LCSM are more resistant to treatment with temozolomide than the same cells growing in standard monolayer culture (SMC). Cells in confined migration evaluated by microarray-based transcriptomic profiling demonstrated that linear confined migration induces increased expression in pathways involving angiogenesis, cell adhesion, cell motility, DNA damage repair, extracellular matrix structure, HIF1α, and others. Single cell transcriptomic analysis could identify GBM cells in different migratory states (LCSM vs. SMC), and similar pathways were seen upregulated with additional changes in cholesterol biosynthesis pathways and cell cycle regulation pathways. Trajectory Inference aligned single cells according to changes in migration status and demonstrated transcript changes during LCSM were progressive but generally reversible on return to SMC. Pathway analyses showed alterations in the cholesterol biosynthesis pathway and cell cycle regulation in cell clusters of confined migrating cells. Molecular studies confirmed that cholesterol biosynthesis pathway regulatory genes (SQLE, MVD, and HMGCR) are upregulated during LCSM. Expression analysis demonstrated increased G1 phase delay in confined migrating cells (LCSM) confirmed by FUCCI expression analysis. We propose that migration in linear confined spaces like white matter structures produces significant transcriptome changes that produce chemoresistance as a new mechanism for treatment resistance of Glioblastoma.
OTME-18. Targeted CRISPR/Cas9 gene-editing regulates the brain tumor environment
Authors: Perez Joshua , Fierro Javier , Aguilar Rocio , Dou Huanyu
Published: July 2021

Glioblastoma multiform (GBM) is the most common malignant brain tumor. Recent immunotherapy has demonstrated potential to treat GBM. However, the immune suppressive tumor environment in the brain represents a significant barrier for the treatment of GBM. Overexpression of programmed death ligand-1 (PD-L1) in GBM tumor cells and macrophages plays a key role in GBM vitality, proliferation, and migration, while also suppressing the immune system. We developed a CRISPR/Cas9 gene-editing system to delete whole cell PD-L1. Human PD-L1 targeted sgRNA were cloned into CRISPR/Cas9 plasmids with or without an HDR templet. CRISPR/Cas9 were treated to human GBM U87 cells for 15, 30, 60, 120 and 240 minutes. The intracellular concentration of CRISPR/Cas9 exhibited a time-dependent increases. A GFP tagged CRISPR/Cas9 plasmid was developed to test the transfection efficacy. Higher levels of GFP+ U87 cells were observed at day 3. CRISPR/Cas9 showed a greater PD-L1 knockout at day 3. The PD-L1 reduction limited the proliferation of U87 cells. A scratch assay showed that PD-L1 deletion inhibited the migration of U87 cells. An in vitro GBM model was developed by co-cultivation of U87 cells and macrophages. CRISPR/Cas9 treated co-cultures changed the ratios of U87 cells and macrophages and polarized tumor associated macrophages (TAM) from M2 toward M1. CRISPR/Cas9 gene-editing effectively deleted PD-L1 in U87 cells. Successful deletion of PD-L1 prevented U87 cells growth and migration, and altered the TAMs plasticity and the tumor environment.
OTME-19. Regula Regulation of Gliomagenesis and Stemness Through Acid Sensor ASIC1a
Authors: King Pendelton , Wan Jingwei , guo Alyssa , Guo Shanchun , Jia Yugang , Liu Mingli
Published: July 2021

Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite intensive therapy including surgery, radiation, and chemotherapy, invariable tumor recurrence occurs, which suggests that glioblastoma stem cells (GSC) render these tumors persistent. Recently, GSC differentiation has emerged as an alternative method to treat GBM, and most of current studies aim to convert GSC to neurons by a combination of transcriptional factors. As the tumor microenvironment is typically acidic due to increased glycolysis in tumor cells, here, we explored the role of acid-sensing ion channel 1a (ASIC1a), an acid sensor, as a tumor suppressor in gliomagenesis and stemness. The bioinformatics data from TCGA shows that ASIC1 expression levels in GBM tumor tissues were lower than those in normal brain, and glioma patients with elevated ASIC1 expression have longer survival than those with lowered ASIC1 expression. Our immunohistochemistry data from tissue microarray shows that ASIC1a expression is negatively correlated with glioma grading. Functional studies reveal that the downregulation of ASIC1a promotes glioma cell proliferation and invasion, while upregulation of ASIC1a inhibits their proliferation and invasion. Furthermore, ASIC1a suppresses glioma cells’ growth and proliferation through G1/S arrest and apoptosis induction. Mechanistically, ASIC1a negatively modulates glioma stemness via inhibition of the Notch signaling pathway and GSC markers CD133 and ALDH1. Our findings indicate that ASIC1a is a tumor suppressor in gliomagenesis and stemness and may serve as a promising prognostic biomarker and target for GBM patients.
Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas
Authors: Keane Lily , Cheray Mathilde , Saidi Dalel , Kirby Caoimhe , Friess Lara , Gonzalez-Rodriguez Patricia , Gerdes Maren Elisabeth , Grabert Kathleen , McColl Barry W , Joseph Bertrand
Published: July 2021

Background

Diffuse intrinsic pontine gliomas (DIPG), within diffuse midline gliomas are aggressive pediatric brain tumors characterized by histone H3-K27M mutation. Small-molecule inhibitors for the EZH2-H3K27 histone methyltransferase have shown promise in preclinical animal models of DIPG, despite having little effect on DIPG cells in vitro. Therefore, we hypothesized that the effect of EZH2 inhibition could be mediated through targeting of this histone modifying enzyme in tumor-associated microglia.

Methods

Primary DIPG tissues, and cocultures between microglia and patient-derived DIPG or -pediatric high-grade glioma (pHGG) cell lines, were used to establish the H3-K27M status of each cell type. Antisense RNA strategies were used to target EZH2 gene expression in both microglia and glioma cells. Microglia anti-tumoral properties were assessed by gene expression profile, tumor cell invasion capacity, microglial phagocytic activity, and associated tumor cell death.

Results

In primary DIPG tissues, microglia do not carry the H3-K27M mutation, otherwise characteristic of the cancer cells. Activation of a microglial tumor-supportive phenotype by pHGG, independently of their H3-K27M status, is associated with a transient H3K27me3 downregulation. Repression of EZH2 in DIPG cells has no impact on tumor cell survival or their ability to activate microglia. However, repression of EZH2 in microglia induces an anti-tumor phenotype resulting in decreased cancer cell invasion capability, increased microglial phagocytosis, and tumor-related cell death.

Conclusions

These results indicate that microglia, beyond the tumor cells, contribute to the observed response of DIPG to EZH2 inhibition. Results highlight the potential importance of microglia as a new therapeutic avenue in DIPG.
Support policies that foster a healthy food environment and incentivize healthy food purchases to mitigate cancer inequities
Authors: Wolf Patricia G , Sanchez-Flack Jennifer C , Buscemi Joanna , Fitzgibbon Marian L , Gaskins H Rex , Ridlon Jason M , Kim Sage , Tussing-Humphreys Lisa
Published: July 2021

The COVID-19 pandemic has highlighted the inequitable access to resources, leading to a disproportionate burden of disease in vulnerable communities in the USA. However, these inequities in health outcomes are not limited to COVID-19. Approximately 18% of cancers are related to dietary behaviors and excess body weight. Underserved communities, such as minority racial/ethnic groups living in neighborhoods of low socioeconomic status, experience barriers to healthy eating including lack of access to high-quality healthy foods and higher availability of unhealthy foods and beverages in local retail food outlets. Strikingly, these same populations are more likely to die from cancers related to dietary intake and obesity like colorectal, liver, and pancreatic cancers. To reduce cancer inequities, policy makers can act by supporting programs that incentivize healthy food purchases and improve the local food environment in underserved communities.
Mentoring Experiences of Male Faculty in Nursing Programs
Authors: Ortiz Cristina P.
Published: July 2021

AIM

The aim of this study was to examine the mentoring experiences of male faculty in nursing programs.

BACKGROUND

Recruiting and retaining male nursing faculty is important to achieve a workforce that reflects the diversity of society. Mentoring is one way to help recruit and retain male nursing faculty.

METHOD

Ten male nursing faculty in academia comprised the sample for this qualitative, descriptive study.

RESULTS

Reflection on the mentoring male nursing faculty received for career and psychosocial development revealed the following themes: early supporters, figuring it out, making connections, paying it forward, and the role of gender. Facilitators and barriers to mentoring experiences are described.

CONCLUSION

Results of this study may be used to support investment in mentoring programs to recruit and retain male nursing faculty in academia and promote a diverse nursing workforce.
Preoperative Physical Function Association With Mental Health Improvement After Anterior Cervical Discectomy and Fusion
Authors: Parrish James M. , Jenkins Nathaniel W. , Lynch Conor P. , Cha Elliot D.K. , Brundage Thomas S. , Hrynewycz Nadia M. , Singh Kern
Published: July 2021

Study Design:

This was a retrospective study.

Objective:

This study investigates the influence of physical function and their influence on postoperative depressive symptom scores as measured by Patient Health Questionnaire-9 (PHQ-9) among anterior cervical decompression and fusion (ACDF) patients.

Background:

While ACDF is one of the most commonly performed ambulatory surgeries, research is limited on the predictive value of Patient-Reported Outcomes Measurement Information System (PROMIS) scores and their influence on depressive symptoms as measured by the PHQ-9.

Methods:

A prospectively maintained surgical registry was retrospectively reviewed from March 2016 to January 2019. Inclusion criteria were primary or revision ACDF procedures. Patients were grouped by preoperative PROMIS score (≥35.0, <35.0), with higher scores indicating greater physical function. The χ2 and Student t tests assessed categorical and continuous variables (eg, demographics, perioperative, and postoperative values). A t test evaluated postoperative improvement in PROMIS Physical Function (PF) scores between subgroups among PROMIS PF scores and PHQ-9 score improvement at 6, 12 weeks, 6 months, and 1 year. Linear regression assessed preoperative PROMIS scores influence on PHQ-9 score improvement.

Results:

The 121 subject cohort was 61.2% male with an average age of 49.6±9.8 years. Compared with the PROMIS ≥35.0 group, the PROMIS <35.0 group also had larger improvement of PROMIS scores at 6 weeks. No significant difference in postoperative PHQ-9 improvement was observed between subgroups. There was a negative association between preoperative PROMIS scores and improvement in PROMIS scores at 6, 12 weeks, 6 months, and 1 year. There was a positive association between preoperative PROMIS scores and magnitude of 1-year PHQ-9 change.

Conclusions:

Individuals with lower preoperative PROMIS PF scores had significantly higher PHQ-9 scores at 1 year. Patients with lower preoperative physical function, as evaluated by PROMIS PF scoring, had greater improvement of mental health at 1 year postoperatively. This suggests that many patients experience multidimensional health benefits after ACDF procedures.
A Locally Optimized Data-Driven Tool to Predict Sepsis-Associated Vasopressor Use in the ICU
Authors: Holder Andre L. , Shashikumar Supreeth P. , Wardi Gabriel , Buchman Timothy G. , Nemati Shamim
Published: July 2021

OBJECTIVES:

To train a model to predict vasopressor use in ICU patients with sepsis and optimize external performance across hospital systems using domain adaptation, a transfer learning approach.

DESIGN:

Observational cohort study.

SETTING:

Two academic medical centers from January 2014 to June 2017.

PATIENTS:

Data were analyzed from 14,512 patients (9,423 at the development site and 5,089 at the validation site) who were admitted to an ICU and met Center for Medicare and Medicaid Services definition of severe sepsis either before or during the ICU stay. Patients were excluded if they never developed sepsis, if the ICU length of stay was less than 8 hours or more than 20 days or if they developed shock up to the first 4 hours of ICU admission.

MEASUREMENTS AND MAIN RESULTS:

Forty retrospectively collected features from the electronic medical records of adult ICU patients at the development site (four hospitals) were used as inputs for a neural network Weibull-Cox survival model to derive a prediction tool for future need of vasopressors. Domain adaptation updated parameters to optimize model performance in the validation site (two hospitals), a different healthcare system over 2,000 miles away. The cohorts at both sites were randomly split into training and testing sets (80% and 20%, respectively). When applied to the test set in the development site, the model predicted vasopressor use 4–24 hours in advance with an area under the receiver operator characteristic curve, specificity, and positive predictive value ranging from 0.80 to 0.81, 56.2% to 61.8%, and 5.6% to 12.1%, respectively. Domain adaptation improved performance of the model to predict vasopressor use within 4 hours at the validation site (area under the receiver operator characteristic curve 0.81 [CI, 0.80–0.81] from 0.77 [CI, 0.76–0.77], p < 0.01; specificity 59.7% [CI, 58.9–62.5%] from 49.9% [CI, 49.5–50.7%], p < 0.01; positive predictive value 8.9% [CI, 8.5–9.4%] from 7.3 [7.1–7.4%], p < 0.01).

CONCLUSIONS:

Domain adaptation improved performance of a model predicting sepsis-associated vasopressor use during external validation.
Establish a normal fetal lung gestational age grading model and explore the potential value of deep learning algorithms in fetal lung maturity evaluation
Authors: Xia Tai-Hui , Tan Man , Li Jing-Hua , Wang Jing-Jing , Wu Qing-Qing , Kong De-Xing
Published: July 2021

Background:

Prenatal evaluation of fetal lung maturity (FLM) is a challenge, and an effective non-invasive method for prenatal assessment of FLM is needed. The study aimed to establish a normal fetal lung gestational age (GA) grading model based on deep learning (DL) algorithms, validate the effectiveness of the model, and explore the potential value of DL algorithms in assessing FLM.

Methods:

A total of 7013 ultrasound images obtained from 1023 normal pregnancies between 20 and 41 + 6 weeks were analyzed in this study. There were no pregnancy-related complications that affected fetal lung development, and all infants were born without neonatal respiratory diseases. The images were divided into three classes based on the gestational week: class I: 20 to 29 + 6 weeks, class II: 30 to 36 + 6 weeks, and class III: 37 to 41 + 6 weeks. There were 3323, 2142, and 1548 images in each class, respectively. First, we performed a pre-processing algorithm to remove irrelevant information from each image. Then, a convolutional neural network was designed to identify different categories of fetal lung ultrasound images. Finally, we used ten-fold cross-validation to validate the performance of our model. This new machine learning algorithm automatically extracted and classified lung ultrasound image information related to GA. This was used to establish a grading model. The performance of the grading model was assessed using accuracy, sensitivity, specificity, and receiver operating characteristic curves.

Results:

A normal fetal lung GA grading model was established and validated. The sensitivity of each class in the independent test set was 91.7%, 69.8%, and 86.4%, respectively. The specificity of each class in the independent test set was 76.8%, 90.0%, and 83.1%, respectively. The total accuracy was 83.8%. The area under the curve (AUC) of each class was 0.982, 0.907, and 0.960, respectively. The micro-average AUC was 0.957, and the macro-average AUC was 0.949.

Conclusions:

The normal fetal lung GA grading model could accurately identify ultrasound images of the fetal lung at different GAs, which can be used to identify cases of abnormal lung development due to gestational diseases and evaluate lung maturity after antenatal corticosteroid therapy. The results indicate that DL algorithms can be used as a non-invasive method to predict FLM.
Comparison of a new IOL injector system against 3 standard IOL injector systems with different incision sizes: Miyake-Apple view experimental laboratory study
Authors: Zhang Lu , Schickhardt Sonja , Fang Hui , Auerbach Florian , Cagampang Perfecto , Merz Patrick R. , Auffarth Gerd U.
Published: July 2021

Purpose:

To compare 1 new intraocular lens (IOL) injector system against 3 standard injector systems in porcine eyes.

Setting:

David J Apple Center for Vision Research, Department of Ophthalmology, University Hospital Heidelberg, Heidelberg, Germany.

Design:

In vitro laboratory study.

Methods:

In 70 porcine eyes, +20.0 diopter IOLs were implanted with the following systems: multiSert, UltraSert, iTec, and RayOne, that is, S1.8 (incision size: 1.8 mm), S2.0 (2.0 mm), S2.2P (2.2 mm, push mode), S2.2S (2.2 mm, screw mode), U2.2 (2.2 mm), iT2.2 (2.2 mm), and R2.0 (2.0 mm). Corneal incision sizes were measured before and after implantation with an incision gauge set. Ease of use was evaluated using a Likert scale. IOL delivery time and performance were determined based on Miyake-Apple view videos.

Results:

Of the 70 eyes studied, the incision enlargements were 0.36 ± 0.08 mm (S1.8), 0.15 ± 0.07 mm (S2.0), 0.17 ± 0.12 mm (S2.2P), 0.28 ± 0.10 mm (S2.2S), 0.32 ± 0.09 mm (U2.2), 0.30 ± 0.08 mm (iT2.2), and 0.35 ± 0.11 mm (R2.0). Total scores of ease of use were 23.00 (S1.8), 25.00 (S2.0), 29.00 (S2.2P), 26.00 (S2.2S), 26.00 (U2.2), 25.00 (iT2.2), and 24.00 (R2.0). As for the mean delivery time, iT2.2 took the longest time (13.20 ± 3.29 seconds), whereas S2.2S took the shortest time (4.50 ± 0.71 seconds). Optic–haptic adhesion was observed in S1.8 (4, 40%), S2.2P (2, 20%), U2.2 (5, 50%), and iT2.2 (5, 50%).

Conclusions:

Injector S, with the appropriate incision size and implantation method, could achieve better results regarding incision enlargement, ease of use, delivery time, and performance than other injector systems. There was an indirect relationship between incision size and inadvertent events.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and thyroid disease. An update
Authors: Brix Thomas H. , Hegedüs Laszlo
Published: July 2021

Purpose of review

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with excess morbidity and mortality in patients with hypertension and diabetes but little is known about thyroid diseases. Thus, our goal was to review the literature with respect to: (i) Are patients with underlying hypo- or hyperthyroidism at increased risk of contracting SARS-CoV-2 infection? (ii) do underlying hypo- and hyperthyroidism impact the prognosis of SARS-CoV-2 infection? (iii) does SARS-CoV-2 infection cause de novo thyroid dysfunction?

Recent findings

Patients with hypo- or hyperthyroidism do not have an increased risk of contracting SARS-CoV-2, and a diagnosis of hypo- or hyperthyroidism is not associated with a worsened prognosis of SARS-CoV-2 infection. SARS-CoV-2 infection has been associated with subsequent thyrotoxicosis, euthyroid sick syndrome, subacute thyroiditis, and autoimmune thyroid disease.

These findings suggest that receiving treatment for thyroid dysfunction does not per se impact the patients’ risk of acquiring SARS-CoV-2 infection, or the management of those who already contracted it. Additional studies with larger numbers of patients and long-term follow-up are required in order to clarify whether patients with SARS-CoV-2 infection are more or less prone to develop thyroid dysfunction and/or thyroid autoimmunity than patients recovering from other virus infections.
Eyelid Lymphatics: An Anatomical Study by Microdissection
Authors: Wu Gaoyang , Yang Yayi , Sheng Lingling , Jiang Zhaohua , Cao Weigang , Li Shengli , Dai Tingting
Published: July 2021

Objective:

To obtain further understanding of the eyelid lymphatic anatomy.

Method:

Thirty-two halves of eyelids from 16 fresh fetus cadavers were studied by microdissection using a mixture of 3% Prussian blue and chloroform to visualize the lymphatic vessels.

Results:

Three layers of lymphatic plexuses were demonstrated in the eyelids: a superficial or preorbicularis muscle plexus; a pretarsal or postorbicular muscle plexus; and a deep or posttarsal plexus. Furthermore, communicating branches among these plexuses were also spotted.

Conclusions:

The study results demonstrated the topographic distribution of the eyelid lymphatic vessels and confirmed the existence of communicating branches. This discovery will be conducive to understanding the route and mechanism by which inflammation of the eyelid spreads and cancer disseminates. It also provides anatomical insights to apply during eyelid surgery with regard to the prevention of possible eyelid lymphatic injury.
Multiple Arterial Vascular Anomalies in the Periorbital, Paranasal, and Intracranial Spaces Treated With Systemic Bevacizumab
Authors: Karlin Justin N. , Ahankoob Niaz , Rootman Daniel B.
Published: July 2021

Arteriovenous malformations of the orbit are rare congenital hamartomas defined by a direct connection between the arterial and venous systems without an intervening capillary bed. Treatment can be challenging, as these lesions are anatomically complex, often involve multiple locations, and have a tendency to recur. A multidisciplinary approach is typically required, involving endovascular and surgical teams. The authors present a case of a 33-year-old man with a complex, recurrent orbital arteriovenous malformations in the context of wider head and neck vascular anomaly syndrome involving the paranasal sinuses, deep facial tissues, and intracranial spaces. The complex and evolving clinical manifestations of this disease are presented with emphasis on the interdependence of the anomalies and biologic management strategies.
Temporal Trends in Utilization and Outcomes of DCD Livers in the United States
Authors: Ruck Jessica M. , Jackson Kyle R. , Motter Jennifer D. , Massie Allan B. , Philosophe Benjamin , Cameron Andrew M. , Ottmann Shane E. , Wesson Russell , Gurakar Ahmet O. , Segev Dorry L. , Garonzik-Wang Jacqueline
Published: July 2021

Background.

Historically, donation after circulatory death (DCD) livers were frequently discarded because of higher mortality and graft loss after liver transplantation (LT). However, the demand for LT continues to outstrip the supply of “acceptable” organs. Additionally, changes in the donor pool, organ allocation, and clinical management of donors and recipients, and improved clinical protocols might have altered post-DCD-LT outcomes.

Methods.

We studied 5975 recovered DCD livers using US Scientific Registry of Transplant Recipients data from 2005 to 2017, with a comparison group of 78 235 adult donation after brain death (DBD) livers recovered during the same time period. We quantified temporal trends in discard using adjusted multilevel logistic regression and temporal trends in post-LT mortality and graft loss for DCD LT recipients using adjusted Cox regression.

Results.

DCD livers were more likely to be discarded than DBD livers across the entire study period, and the relative likelihood of discard increased over time (adjusted odds ratio [aOR] of discard DCD versus DBD 3.854.455.14 2005–2007, 5.225.876.59 2015–2017) despite improving outcomes after DCD LT. Mortality risk for DCD LTs decreased in each time period (compared with 2005–2007, aHR 2008–2011 0.720.840.97, aHR 2012–2014 0.480.580.70, aHR 2015–2017 0.340.430.55), as did risk of graft loss (compared with 2005–2007, aHR 2008–2011 0.690.810.94, aHR 2012–2014 0.450.550.67, aHR 2015–2017 0.360.450.56).

Conclusions.

Despite dramatic improvements in outcomes of DCD LT recipients, DCD livers remain substantially more likely to be discarded than DBD livers, and this discrepancy has actually increased over time. DCD livers are underutilized and have the potential to expand the donor pool.
Musiré: multimodal simulation and reconstruction framework for the radiological imaging sciences
Authors: Peter Jörg
Published: July 2021

A software-based workflow is proposed for managing the execution of simulation and image reconstruction for SPECT, PET, CBCT, MRI, BLI and FMI packages in single and multimodal biomedical imaging applications. The workflow is composed of aBashscript, the purpose of which is to provide an interface to the user, and to organize data flow between dedicated programs for simulation and reconstruction. The currently incorporated simulation programs compriseGATEfor Monte Carlo simulation of SPECT, PET and CBCT,SpinScenariofor simulating MRI, andLiprosfor Monte Carlo simulation of BLI and FMI. Currently incorporated image reconstruction programs includeCASToRfor SPECT and PET as well asRTKfor CBCT. MetaImage (mhd) standard is used for voxelized phantom and image data format. Meshlab project (mlp) containers incorporating polygon meshes and point clouds defined by the Stanford triangle format (ply) are employed to represent anatomical structures for optical simulation, and to represent tumour cell inserts. A number of auxiliary programs have been developed for data transformation and adaptive parameter assignment. The software workflow uses fully automatic distribution to, and consolidation from, any number of Linux workstations and CPU cores. Example data are presented for clinical SPECT, PET and MRI systems using theMidahead phantom and for preclinical X-ray, PET and BLI systems employing theDigimousephantom. The presented method unifies and simplifies multimodal simulation setup and image reconstruction management and might be of value for synergistic image research.

This article is part of the theme issue ‘Synergistic tomographic image reconstruction: part 2’.
Core Imaging Library - Part II: multichannel reconstruction for dynamic and spectral tomography
Authors: Papoutsellis Evangelos , Ametova Evelina , Delplancke Claire , Fardell Gemma , Jørgensen Jakob S. , Pasca Edoardo , Turner Martin , Warr Ryan , Lionheart William R. B. , Withers Philip J.
Published: July 2021

The newly developed core imaging library (CIL) is a flexible plug and play library for tomographic imaging with a specific focus on iterative reconstruction. CIL provides building blocks for tailored regularized reconstruction algorithms and explicitly supports multichannel tomographic data. In the first part of this two-part publication, we introduced the fundamentals of CIL. This paper focuses on applications of CIL for multichannel data, e.g. dynamic and spectral. We formalize different optimization problems for colour processing, dynamic and hyperspectral tomography and demonstrate CIL’s capabilities for designing state-of-the-art reconstruction methods through case studies and code snapshots.

This article is part of the theme issue ‘Synergistic tomographic image reconstruction: part 2’.
Synergistic tomographic image reconstruction: part 2
Authors: Tsoumpas Charalampos , Sauer Jørgensen Jakob , Kolbitsch Christoph , Thielemans Kris
Published: July 2021

This special issue is the second part of a themed issue that focuses on synergistic tomographic image reconstruction and includes a range of contributions in multiple disciplines and application areas. The primary subject of study lies within inverse problems which are tackled with various methods including statistical and computational approaches. This volume covers algorithms and methods for a wide range of imaging techniques such as spectral X-ray computed tomography (CT), positron emission tomography combined with CT or magnetic resonance imaging, bioluminescence imaging and fluorescence-mediated imaging as well as diffuse optical tomography combined with ultrasound. Some of the articles demonstrate their utility on real-world challenges, either medical applications (e.g. motion compensation for imaging patients) or applications in material sciences (e.g. material decomposition and characterization). One of the desired outcomes of the special issues is to bring together different scientific communities which do not usually interact as they do not share the same platforms such as journals and conferences.

This article is part of the theme issue ‘Synergistic tomographic image reconstruction: part 2’.
Impact of cilia-related genes on mitochondrial dynamics during Drosophila spermatogenesis
Authors: Bauerly Elisabeth , Akiyama Takuya , Yi Kexi , Gibson Matthew C.
Published: July 2021

Spermatogenesis is a dynamic process of cellular differentiation that generates the mature spermatozoa required for reproduction. Errors that arise during this process can lead to sterility due to low sperm counts and malformed or immotile sperm. While is estimated that 1 out of 7 couples encounter infertility, the underlying cause of male infertility can only be identified in 50% of cases. Here, we describe and examine the genetic requirements for missing minor mitochondria (mmm), sterile affecting ciliogenesis (sac), and testes of unusual size (tous), three previously uncharacterized genes that are predicted to be components of the flagellar axoneme. Using Drosophila, we demonstrate that these genes are essential for male fertility and that loss of mmm, sac, or tous results in complete immotility of the sperm flagellum. Cytological examination uncovered additional roles for sac and tous during cytokinesis and transmission electron microscopy of developing spermatids in mmm, sac, and tous mutant animals revealed defects associated with mitochondria and the accessory microtubules required for the proper elongation of the mitochondria and flagella during ciliogenesis. This study highlights the complex interactions of cilia-related proteins within the cell body and advances our understanding of male infertility by uncovering novel mitochondrial defects during spermatogenesis.
Dopaminergic axon tracts within a hyaluronic acid hydrogel encasement for implantation to restore the nigrostriatal pathway
Authors: Gordián-Vélez Wisberty J. , Browne Kevin D. , Galarraga Jonathan H. , Duda John E. , España Rodrigo A. , Chen H. Isaac , Burdick Jason A. , Cullen D. Kacy
Published: July 2021

Parkinson’s disease (PD) affects 10 million patients worldwide, making it the second most prevalent neurodegenerative disease. Motor symptoms emerge from the loss of dopamine in the striatum after the death of dopaminergic neurons and the long-projecting axons of the nigrostriatal pathway. Current treatments, such as dopamine replacement, deep brain stimulation or cell therapies, disregard the loss of this pathway at the core of symptoms. We sought to address this by improving our tissue-engineered nigrostriatal pathway (TE-NSP) technology, which consists of a tubular hydrogel with a collagen/laminin core that encases an aggregate of dopaminergic neurons and their axons in a way that resembles the nigrostriatal pathway. These constructs can be implanted to replace the lost neurons and axons with fidelity to the pathway, and thus provide dopamine according to feedback from the host circuitry. While TE-NSPs have been traditionally fabricated with agarose, here we utilized a hyaluronic acid (HA) hydrogel to expand the functionality of the encasement and our control over its properties. Using rat ventral midbrain neurons, we found that TE-NSPs exhibited longer and faster neurite growth with HA relative to agarose, with no differences observed in electrically-evoked dopamine release. When transplanted, HA hydrogels reduced host neuron loss and inflammation around the implant compared to agarose, and the cells and axons within TE-NSPs survived and maintained their cytoarchitecture for at least 2 weeks.

Highlights

We fabricated engineered dopaminergic axons encased in a tubular hydrogel.

We made hydrogels from methacrylated hyaluronic acid and compared them to agarose.

Axons in HA hydrogels had longer and faster axon growth and displayed evoked dopamine release.

HA hydrogels reduced the host inflammatory response and supported neuron and axon survival in vivo.

This platform may be used to reconstruct the nigrostriatal pathway to treat Parkinson’s disease.
Deleting in vivo β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumors
Authors: Loesch Robin , Caruso Stefano , Paradis Valérie , Godard Cecile , Gougelet Angélique , Picard Simon , Perret Christine , Taketo Makoto Mark , Zucman-Rossi Jessica , Colnot Sabine
Published: July 2021

Background and aims

One-third of hepatocellular carcinomas (HCCs) have mutations that activate the β-catenin pathway with mostly CTNNB1 mutations. Mouse models using Adenomatous polyposis coli (Apc) loss-of-functions (LOF) are widely used to mimic β-catenin-dependent tumorigenesis. Considering the low prevalence of APC mutations in human HCCs we aimed to generate hepatic tumors through CTNNB1 exon 3 deletion (βcatΔex3) and to compare them to hepatic tumors with Apc LOF engineered through a frameshift in exon 15 (Apcfs-ex15).

Methods

We used hepatic-specific and inducible Cre-lox mouse models as well as a hepatic-specific in vivo CRISPR/Cas9 approach using AAV vectors, to generate Apcfs-ex15 and βcatΔex3 hepatic tumors harboring activation of the β-catenin pathway. Tumors generated by the Cre-lox models were analyzed phenotypically using immunohistochemistry and were selected for transcriptomic analysis using RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (normal tissues (8), HCCs (48) and hepatoblastomas (9)) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry.

Results

Mice with βcatΔex3 alteration in hepatocytes developed liver tumors. Generated tumors were indistinguishable from those arising in Apcfs-ex15 mice. Both Apcfs-ex15 and βcatΔex3 mouse models induced two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that mouse differentiated tumors are close to human well differentiated CTNNB1-mutated tumors, while undifferentiated ones are closer to human mesenchymal hepatoblastomas, and are activated for YAP signaling.

Conclusion

Apcfs-ex15 and βcatΔex3 mouse models similarly induce tumors transcriptionally close to either well differentiated β-Catenin activated human HCCs or mesenchymal hepatoblastomas.
Based on the identification of tumor antigens and immune subtypes in renal clear cell carcinoma for mRNA vaccine development
Authors: Zhang Shichao , Xiong Yu , Kang Shijing , Mao Chengju , Wang Yue , Zeng Zhu , Peng Jian , Ouyang Yan
Published: July 2021

Background

Cancer vaccine based on mRNA is considered as a promising strategy and has become a new hot spot in cancer immunotherapy. However, its application to KIRC is not clear. A growing body of research has shown that immunotyping can reflect the comprehensive immune status and immune microenvironment of tumor, which is closely related to treatment response and vaccination potential. The aim of this study was to identify the potential antigens of KIRC for the development of anti-KIRC mRNA vaccines, and to further differentiate the immune subtypes of KIRC to construct an immune landscape for the selection of appropriate patients for vaccination.

Methods

Gene expression profiles and corresponding clinical information of 265 KIRC patients and RNA-seq data of 539 KIRC patients were retrieved from were collected from GEO and TCGA. cBioPortal was used to visualize and compare genetic alterations, while GEPIA2 was used to calculate the prognostic index of selected antigens. The relationship between the infiltration of antigen presenting cells and the expression of the identified antigen was visualized with TIMER, and consensus clustering analysis was used to determine the immune subtypes. Finally, the immune landscape of KIRC is visualized through the dimensionality reduction analysis based on graph learning.

Results

Two tumor antigens associated with prognostic and antigen-presenting infiltrating cells were identified in KIRC, including LRP2, and DOCK8. KIRC patients were classified into six immune subtypes based on different molecular, cellular, and clinical characteristics. Patients with IS5 and IS6 tumors had an immune “hot” and immunosuppressive phenotype, which was associated with better survival compared to other subtypes, whereas patients with IS1-4 tumors had an immune “cold” phenotype, which was associated with a higher tumor mutation burden. In addition, the expression of immune checkpoints and immunogenic cell death modulators differed significantly in different immunosubtypes of tumors. Finally, the immune landscape of KIRC shows a high degree of heterogeneity across patients.

Conclusions

LRP2 and FEM2 are potential KIRC antigens for mRNA vaccine development, and patients with immune subtypes IS1-4 are suitable for vaccination.
Detection ofRamularia collo-cygnifrom barley (Hordeum vulgare) in Australia using triplex quantitative and digital PCR
Authors: Knight N. L. , Moslemi A. , Begum F. , Dodhia K. N. , Covarelli L. , Hills A. L. , Lopez-Ruiz F. J.
Published: July 2021

Ramularia leaf spot (RLS), caused byRamularia collo-cygni, is an emerging threat to barley (Hordeum vulgare) production. RLS has been reported in Australia; however only minimal information is available regarding its detection and distribution. Due to initial asymptomatic growthin planta, slow growthin vitroand symptomatic similarities to net blotch and physiological leaf spots, detection of this pathogen can be challenging. Quantitative PCR-based methods forR. collo-cygni-specific identification and detection have been described, however these assays (based upon the internal transcribed spacer [ITS] region) have been demonstrated to lack specificity. False-positive detections may have serious implications, thus we aimed to design a robustR. collo-cygni-specific PCR method. Using the phylogenetically informative RNA polymerase II second largest subunit (rpb2) and translation elongation factor 1-α (tef1-α) genes, along with thetef1-αgene ofH. vulgare, a triplex assay was developed for both quantitative and digital PCR. The triplex assay was used to assess DNA of barley leaves from New South Wales, South Australia, Tasmania, Victoria and Western Australia, along with DNA of seeds from Western Australia. Detection ofR. collo-cygniDNA was confirmed for leaf samples from New South Wales, South Australia, Tasmania, Victoria and Western Australia, indicating a distribution ranging across the southern barley growing regions of Australia. NoR. collo-cygniDNA was detected in seed from Western Australia. TheR. collo-cygni-specific assay will be a valuable tool to assist with monitoring the distribution ofR. collo-cygniin Australia and other regions.