bluuebunny/crossref_metadata_2025 huggingface dataset:
Metaproteomic Profile of the Colonic Luminal Microbiota From Patients With Colon Cancer
Authors: Tanca Alessandro , Abbondio Marcello , Fiorito Giovanni , Pira Giovanna , Sau Rosangela , Manca Alessandra , Muroni Maria Rosaria , Porcu Alberto , Scanu Antonio Mario , Cossu-Rocca Paolo , De Miglio Maria Rosaria , Uzzau Sergio
Published: April 2022

Recent studies have provided evidence of interactions among the gut microbiota (GM), local host immune cells, and intestinal tissues in colon carcinogenesis. However, little is known regarding the functions exerted by the GM in colon cancer (CC), particularly with respect to tumor clinical classification and lymphocyte infiltration. In addition, stool, usually employed as a proxy of the GM, cannot fully represent the original complexity of CC microenvironment. Here, we present a pilot study aimed at characterizing the metaproteome of CC-associated colonic luminal contents and identifying its possible associations with CC clinicopathological features. Colonic luminal contents were collected from 24 CC tissue specimens immediately after surgery. Samples were analyzed by shotgun metaproteomics. Almost 30,000 microbial peptides were quantified in the samples, enabling the achievement of the taxonomic and functional profile of the tumor-associated colonic luminal metaproteome. Upon sample aggregation based on tumor stage, grade, or tumor-infiltrating lymphocytes (TILs), peptide sets enabling discrimination of sample groups were identified through discriminant analysis (DA). As a result, Bifidobacterium and Bacteroides fragilis were significantly enriched in high-stage and high-grade CC, respectively. Among metabolic functions, formate–tetrahydrofolate ligase was significantly associated with high-stage CC. Finally, based on the results of this pilot study, we assessed the optimal sample size for differential metaproteomic studies analyzing colonic luminal contents. In conclusion, we provide a detailed picture of the microbial and host components of the colonic luminal proteome and propose promising associations between GM taxonomic/functional features and CC clinicopathological features. Future studies will be needed to verify the prognostic value of these data and to fully exploit the potential of metaproteomics in enhancing our knowledge concerning CC progression.
Sulfation Pathways During Neurodevelopment
Authors: Clarke Taylor , Fernandez Francesca E. , Dawson Paul A.
Published: April 2022

Sulfate is an important nutrient that modulates a diverse range of molecular and cellular functions in mammalian physiology. Over the past 2 decades, animal studies have linked numerous sulfate maintenance genes with neurological phenotypes, including seizures, impaired neurodevelopment, and behavioral abnormalities. Despite sulfation pathways being highly conserved between humans and animals, less than one third of all known sulfate maintenance genes are clinically reportable. In this review, we curated the temporal and spatial expression of 91 sulfate maintenance genes in human fetal brain from 4 to 17 weeks post conception using the online Human Developmental Biology Resource Expression. In addition, we performed a systematic search of PubMed and Embase, identifying those sulfate maintenance genes linked to atypical neurological phenotypes in humans and animals. Those findings, together with a search of the Online Mendelian Inheritance in Man database, identified a total of 18 candidate neurological dysfunction genes that are not yet considered in clinical settings. Collectively, this article provides an overview of sulfate biology genes to inform future investigations of perturbed sulfate homeostasis associated with neurological conditions.
Symmetry-Based Representations for Artificial and Biological General Intelligence
Authors: Higgins Irina , Racanière Sébastien , Rezende Danilo
Published: April 2022

Biological intelligence is remarkable in its ability to produce complex behavior in many diverse situations through data efficient, generalizable, and transferable skill acquisition. It is believed that learning “good” sensory representations is important for enabling this, however there is little agreement as to what a good representation should look like. In this review article we are going to argue that symmetry transformations are a fundamental principle that can guide our search for what makes a good representation. The idea that there exist transformations (symmetries) that affect some aspects of the system but not others, and their relationship to conserved quantities has become central in modern physics, resulting in a more unified theoretical framework and even ability to predict the existence of new particles. Recently, symmetries have started to gain prominence in machine learning too, resulting in more data efficient and generalizable algorithms that can mimic some of the complex behaviors produced by biological intelligence. Finally, first demonstrations of the importance of symmetry transformations for representation learning in the brain are starting to arise in neuroscience. Taken together, the overwhelming positive effect that symmetries bring to these disciplines suggest that they may be an important general framework that determines the structure of the universe, constrains the nature of natural tasks and consequently shapes both biological and artificial intelligence.
Non-Invasive Multimodal Neuromonitoring in Non-Critically Ill Hospitalized Adult Patients With COVID-19: A Systematic Review and Meta-Analysis
Authors: Battaglini Denise , Premraj Lavienraj , Huth Samuel , Fanning Jonathon , Whitman Glenn , Arora Rakesh C. , Bellapart Judith , Bastos Porto Diego , Taccone Fabio Silvio , Suen Jacky Y. , Li Bassi Gianluigi , Fraser John F. , Badenes Rafael , Cho Sung-Min , Robba Chiara ,   the COVID-19 Critical Care Consortium
Published: April 2022

Introduction

Neurological complications are frequent in patients with coronavirus disease-2019 (COVID-19). The use of non-invasive neuromonitoring in subjects without primary brain injury but with potential neurological derangement is gaining attention outside the intensive care unit (ICU). This systematic review and meta-analysis investigates the use of non-invasive multimodal neuromonitoring of the brain in non-critically ill patients with COVID-19 outside the ICU and quantifies the prevalence of abnormal neuromonitoring findings in this population.

Methods

A structured literature search was performed in MEDLINE/PubMed, Scopus, Cochrane, and EMBASE to investigate the use of non-invasive neuromonitoring tools, including transcranial doppler (TCD); optic nerve sheath diameter (ONSD); near-infrared spectroscopy (NIRS); pupillometry; and electroencephalography (EEG) inpatients with COVID-19 outside the ICU. The proportion of non-ICU patients with CVOID-19 and a particular neurological feature at neuromonitoring at the study time was defined as prevalence.

Results

A total of 6,593 records were identified through literature searching. Twenty-one studies were finally selected, comprising 368 non-ICU patients, of whom 97 were considered for the prevalence of meta-analysis. The pooled prevalence of electroencephalographic seizures, periodic and rhythmic patterns, slow background abnormalities, and abnormal background on EEG was.17 (95% CI 0.04–0.29), 0.42 (95% CI 0.01–0.82), 0.92 (95% CI 0.83–1.01), and.95 (95% CI 0.088–1.09), respectively. No studies investigating NIRS and ONSD outside the ICU were found. The pooled prevalence for abnormal neuromonitoring findings detected using the TCD and pupillometry were incomputable due to insufficient data.

Conclusions

Neuromonitoring tools are non-invasive, less expensive, safe, and bedside available tools with a great potential for both diagnosis and monitoring of patients with COVID-19 at risk of brain derangements. However, extensive literature searching reveals that they are rarely used outside critical care settings.

Systematic Review Registration:www.crd.york.ac.uk/prospero/display_record.php?RecordID=265617, identifier: CRD42021265617.
Simplified Post-stroke Functioning Assessment Based on ICF via Dichotomous Mokken Scale Analysis and Rasch Modeling
Authors: Feng Chun , Jiang Zhong-Li , Sun Ming-Xue , Lin Feng
Published: April 2022

Purpose

This study aims to accomplish two tasks for International Classification of Functioning, Disability and Health (ICF) application among persons with stroke: (1) to make an ICF tool for measuring personal abilities with simplified assessment operations; (2) to quantitatively evaluate ICF categories for being functioning rather than being disabled.

Methods

A total of 130 inpatients with stroke via convenience sampling were evaluated by the extended comprehensive ICF core set for stroke, modified Rankin scale, and modified Barthel index (MBI). This study investigated the responses to 118 stroke-related ICF items (59 items in b and d domains individually) using Mokken scale analysis followed with Rasch modeling.

Results

A Mokken scale with 47 items was extracted from the binary data (1 as no-impairment or mild-impairment and 0 as moderate to complete impairment). A Rasch model with 45 items was derived from the Mokken scale. The conversion chart was available involving the original ordinal scores to Rasch-transformed scores from 0 to 100 (interval scale). Total scores exhibited a high correlation with the personal abilities estimated by the Rasch model. The personal ability also demonstrated a significantly strong correlation with the score of the MBI. Thus, the 45 ICF items were suggested to rate potential functional ability as a single measurement.

Conclusion

Based on simple “functioning or disabled” judgment tasks, ICF assessment can be simplified to a questionnaire with answering “yes-or-no” questions for each category. Functioning level for each person and difficulty of being functioning for each category can be estimated by the Rasch model of this questionnaire.
Influential Factors, Treatment and Prognosis of Autoimmune Encephalitis Patients With Poor Response to Short-Term First-Line Treatment
Authors: Liu Fei , Zhang Bingbing , Huang Teng , Wang Baojie , Wang Chunjuan , Hao Maolin , Guo Shougang
Published: April 2022

Objective

This study was performed to assess the potential factors for poor short-term first-line treatment response, the appropriate further treatment options, and the prognosis in patients with autoimmune encephalitis (AE).

Methods

This retrospective study consisted of 135 patients with AE. According to their short-term first-line treatment response, patients were divided into the response group and the non-response group. The demographics, clinical characteristics, main accessory examinations, immunotherapy, and outcomes of patients were compared between the two groups. Univariate and multivariate logistic regression models were used to analyze whether non-responders have poor long-term outcomes. Further treatment and prognosis of non-responders were also analyzed.

Results

Of the 128 patients who were treated with first-line immunotherapy, 59 (46.1%) were non-responders. Patients in the non-response group had more symptoms and exhibited a higher proportion of mental behavior disorder, central hypoventilation, and autonomic nervous dysfunction. The modified Rankin scale (mRS) scores and neutrophil-to-lymphocyte ratio (NLR) levels were significantly higher and albumin, high-density lipoprotein cholesterol (HDL-C), apolipoprotein A (apoA) levels were significantly lower in the non-response group (p < 0.05, all). Multivariate logistic regression analysis showed that the number of clinical symptoms, mental behavior disorder, central hypoventilation, maximum mRS score, and albumin level was independently associated with non-response to short-term first-line treatment. Non-responders had poor long-term outcomes compared with the responders at all times of followed-up (p < 0.05, all). In multivariable analysis, initial first-line treatment response was independently associated with the long-term prognosis, both at 12-month [odds ratio (OR), 4.74, 95% CI, 1.44–15.59, and p=0.010] and 24-month follow-ups (OR, 8.81, 95% CI, 1.65–47.16; and p = 0.011). Among the non-responders, a higher improvement of mRS scores was observed in those who received second-line treatment than those who had no further treatment or repetition of first-line immunotherapy in the follow-up. However, the rate of a good outcome and median mRS scores were not significantly different among the three groups.

Conclusion

Disease severity, clinical features, anti-N-methyl-D-aspartate receptor subtypes, antibody titers, NLR, albumin, HDL-C, and apoA levels were all associated with non-response to short-term first-line treatment. The short-term first-line treatment response is a valuable predictor of long-term outcomes in patients with AE. Second-line immunotherapy may be a more aggressive treatment option for patients who failed short-term first-line immunotherapy.
Use of Benzodiazepines and Z-Drugs in Multiple Sclerosis
Authors: Marrie Ruth Ann , Fisk John D. , Walld Randy , Bolton James M. , Sareen Jitender , Patten Scott B. , Singer Alexander , Lix Lisa M. , Hitchon Carol A. , El-Gabalawy Renée , Katz Alan , Marriott James J. , Bernstein Charles N. ,   the CIHR Team in Defining the Burden Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease
Published: April 2022

Objective

Use of benzodiazepines and Z-drugs (non-benzodiazepine sedative hypnotics) is controversial due to adverse health outcomes in the general population. However, little is known about their use in people with multiple sclerosis (MS). We estimated the incidence and prevalence of benzodiazepine and Z-drug use (jointly BZD) in the MS population as compared to an age-, sex- and geographically-matched population without MS, and examined the association of mood/anxiety disorders with the use of BZD over a twenty-year period.

Methods

Using administrative data from Manitoba, Canada, we identified 2,985 persons with incident MS and 14,891 persons without MS matched 5:1 on sex, birth year and region. We applied validated case definitions to identify persons with any mood/anxiety disorder. Dispensations of BZD were identified. To assess the association between MS, mood/anxiety disorders and BZD use we constructed generalized linear models adjusting for age, sex, index year, socioeconomic status, urban/rural residence, physical comorbidities, and health care use. We also examined patterns of BZD use.

Results

In 2016, the crude incidence of benzodiazepine use in the MS cohort was 2.10% (95%CI: 1.43–2.98%), 1.49-fold higher than in the non-MS cohort (1.41%; 95%CI: 1.18–1.67%). The crude incidence of Z-drug use in the MS cohort was 1.77% (95%CI: 1.20–2.51%), 1.78-fold higher than in the non-MS cohort (0.99%; 95%CI: 0.81–1.21%). After adjusting for covariates, among individuals without an active mood/anxiety disorder, the MS cohort had a 39% increased incidence rate of benzodiazepine use and a 72% increased incidence rate of Z-drug use as compared to the non-MS cohort. Among individuals with an active mood/anxiety disorder, the incidence of BZD use did not differ between the MS and non-MS cohorts. A higher proportion of people with MS used BZD for ≥6 months than people without MS.

Conclusion

Use of BZD is more common in people with MS than in general population controls, and use of these agents is in persons with MS is often chronic.
Towards User-Centred Prosthetics Research Beyond the Laboratory
Authors: Jones Hannah , Webb Lynda , Dyson Matthew , Nazarpour Kianoush
Published: April 2022

The purpose of this study was to explore a range of perspectives on how academic research and clinical assessment of upper-limb prosthetics could happen in environments outside of laboratories and clinics, such as within peoples’ homes. Two co-creation workshops were held, which included people who use upper limb prosthetic devices (hereafter called users), clinicians, academics, a policy stakeholder, and a representative from the upper-limb prosthetics industry (hereafter called professionals). The discussions during the workshops indicate that research and clinical assessment conducted remotely from a laboratory or clinic could inform future solutions that address user needs. Users were open to the idea of sharing sensor and contextual data from within their homes to external laboratories during research studies. However, this was dependent upon several considerations, such as choice and control over data collection. Regarding clinical assessment, users had reservations of how data may be used to inform future prosthetic prescriptions whilst, clinicians were concerned with resource implications and capacity to process user data. The paper presents findings of the discussions shared by participants during both workshops. The paper concludes with a conjecture that collecting sensor and contextual data from users within their home environment will contribute towards literature within the field, and potentially inform future care policies for upper limb prosthetics. The involvement of users during such studies will be critical and can be enabled via a co-creation approach. In the short term, this may be achieved through academic research studies, which may in the long term inform a framework for clinical in-home trials and clinical remote assessment.
A Model of Discovery: The Role of Imaging Established and Emerging Non-mammalian Models in Neuroscience
Authors: Haynes Elizabeth M. , Ulland Tyler K. , Eliceiri Kevin W.
Published: April 2022

Rodents have been the dominant animal models in neurobiology and neurological disease research over the past 60 years. The prevalent use of rats and mice in neuroscience research has been driven by several key attributes including their organ physiology being more similar to humans, the availability of a broad variety of behavioral tests and genetic tools, and widely accessible reagents. However, despite the many advances in understanding neurobiology that have been achieved using rodent models, there remain key limitations in the questions that can be addressed in these and other mammalian models. In particular, in vivo imaging in mammals at the cell-resolution level remains technically difficult and demands large investments in time and cost. The simpler nervous systems of many non-mammalian models allow for precise mapping of circuits and even the whole brain with impressive subcellular resolution. The types of non-mammalian neuroscience models available spans vertebrates and non-vertebrates, so that an appropriate model for most cell biological questions in neurodegenerative disease likely exists. A push to diversify the models used in neuroscience research could help address current gaps in knowledge, complement existing rodent-based bodies of work, and bring new insight into our understanding of human disease. Moreover, there are inherent aspects of many non-mammalian models such as lifespan and tissue transparency that can make them specifically advantageous for neuroscience studies. Crispr/Cas9 gene editing and decreased cost of genome sequencing combined with advances in optical microscopy enhances the utility of new animal models to address specific questions. This review seeks to synthesize current knowledge of established and emerging non-mammalian model organisms with advances in cellular-resolution in vivo imaging techniques to suggest new approaches to understand neurodegeneration and neurobiological processes. We will summarize current tools and in vivo imaging approaches at the single cell scale that could help lead to increased consideration of non-mammalian models in neuroscience research.
Cyclotrons Operated for Nuclear Medicine and Radiopharmacy in the German Speaking D-A-CH Countries: An Update on Current Status and Trends
Authors: Zippel Claus , Ermert Johannes , Patt Marianne , Gildehaus Franz Josef , Ross Tobias L. , Reischl Gerald , Kuwert Torsten , Solbach Christoph , Neumaier Bernd , Kiss Oliver , Mitterhauser Markus , Wadsak Wolfgang , Schibli Roger , Kopka Klaus
Published: April 2022

Background

Cyclotrons form a central infrastructure and are a resource of medical radionuclides for the development of new radiotracers as well as the production and supply of clinically established radiopharmaceuticals for patient care in nuclear medicine.

Aim

To provide an updated overview of the number and characteristics of cyclotrons that are currently in use within radiopharmaceutical sciences and for the development of radiopharmaceuticals to be used for patient care in Nuclear Medicine in Germany (D), Austria (A) and Switzerland (CH).

Methods

Publicly available information on the cyclotron infrastructure was (i) consolidated and updated, (ii) supplemented by selective desktop research and, last but not least, (iii) validated by members of the committee of the academic “Working Group Radiochemistry and Radiopharmacy” (AGRR), consisting of radiochemists and radiopharmacists of the D-A-CH countries and belonging to the German Society of Nuclear Medicine (DGN), as well as the Radiopharmaceuticals Committee of the DGN.

Results

In total, 42 cyclotrons were identified that are currently being operated for medical radionuclide production for imaging and therapy in Nuclear Medicine clinics, 32 of them in Germany, 4 in Austria and 6 in Switzerland. Two thirds of the cyclotrons reported (67%) are operated by universities, university hospitals or research institutions close to a university hospital, less by/in cooperation with industrial partners (29%) or a non-academic clinic/ PET-center (5%). Most of the cyclotrons (88%) are running with up to 18 MeV proton beams, which is sufficient for the production of the currently most common cyclotron-based radionuclides for PET imaging.

Discussion

The data presented provide an academically-updated overview of the medical cyclotrons operated for the production of radiopharmaceuticals and their use in Nuclear Medicine in the D-A-CH countries. In this context, we discuss current developments and trends with a view to the cyclotron infrastructure in these countries, with a specific focus on organizational aspects.
Maternal High-Fat Diet Impairs Placental Fatty Acid β-Oxidation and Metabolic Homeostasis in the Offspring
Authors: Zhang Ling , Wang Ziwei , Wu Honghua , Gao Ying , Zheng Jia , Zhang Junqing
Published: April 2022

Maternal overnutrition can affect fetal growth and development, thus increasing susceptibility to obesity and diabetes in later life of the offspring. Placenta is the central organ connecting the developing fetus with the maternal environment. It is indicated placental fatty acid metabolism plays an essential role in affecting the outcome of the pregnancy and fetus. However, the role of placental fatty acid β-oxidation (FAO) in maternal overnutrition affecting glucose metabolism in the offspring remains unclear. In this study, C57BL/6J female mice were fed with normal chow or high-fat diet before and during pregnancy and lactation. The placenta and fetal liver were collected at gestation day 18.5, and the offspring's liver was collected at weaning. FAO-related genes and AMP-activated protein kinase (AMPK) signaling pathway were examined both in the placenta and in the human JEG-3 trophoblast cells. FAO-related genes were further examined in the liver of the fetuses and in the offspring at weaning. We found that dams fed with high-fat diet showed higher fasting blood glucose, impaired glucose tolerance at gestation day 14.5 and higher serum total cholesterol (T-CHO) at gestation day 18.5. The placental weight and lipid deposition were significantly increased in maternal high-fat diet group. At weaning, the offspring mice of high-fat diet group exhibited higher body weight, impaired glucose tolerance, insulin resistance and increased serum T-CHO, compared with control group. We further found that maternal high-fat diet downregulated mRNA and protein expressions of carnitine palmitoyltransferase 2 (CPT2), a key enzyme in FAO, by suppressing the AMPK/Sirt1/PGC1α signaling pathway in the placenta. In JEG-3 cells, protein expressions of CPT2 and CPT1b were both downregulated by suppressing the AMPK/Sirt1/PGC1α signaling pathway under glucolipotoxic condition, but were later restored by the AMPK agonist 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). However, there was no difference in CPT2 and CPT1 gene expression in the liver of fetuses and offspring at weaning age. In conclusion, maternal high-fat diet can impair gene expression involved in FAO in the placenta by downregulating the AMPK signaling pathway, and can cause glucose and lipid dysfunction of offspring at weaning, indicating that placental FAO may play a crucial role in regulating maternal overnutrition and metabolic health in the offspring.
The Profiles of Tet-Mediated DNA Hydroxymethylation in Human Gliomas
Authors: Brągiel-Pieczonka Aneta , Lipka Gabriela , Stapińska-Syniec Angelika , Czyżewski Michał , Żybura-Broda Katarzyna , Sobstyl Michał , Rylski Marcin , Grabiec Marta
Published: April 2022

Gliomas are the most common primary malignant intracranial brain tumors. Their proliferative and invasive behavior is controlled by various epigenetic mechanisms. 5-hydroxymethylcytosine (5-hmC) is one of the epigenetic DNA modifications that employs ten-eleven translocation (TET) enzymes to its oxidation. Previous studies demonstrated altered expression of 5-hmC across gliomagenesis. However, its contribution to the initiation and progression of human gliomas still remains unknown. To characterize the expression profiles of 5-hmC and TET in human glioma samples we used the EpiJET 5-hmC and 5-mC Analysis Kit, quantitative real-time PCR, and Western blot analysis. A continuous decline of 5-hmC levels was observed in solid tissue across glioma grades. However, in glioblastoma (GBM), we documented uncommon heterogeneity in 5-hmC expression. Further analysis showed that the levels of TET proteins, but not their transcripts, may influence the 5-hmC abundance in GBM. Early tumor-related biomarkers may also be provided by the study of aberrant DNA hydroxymethylation in the blood of glioma patients. Therefore, we explored the patterns of TET transcripts in plasma samples and we found that their profiles were variously regulated, with significant value for TET2. The results of our study confirmed that DNA hydroxymethylation is an important mechanism involved in the pathogenesis of gliomas, with particular reference to glioblastoma. Heterogeneity of 5-hmC and TET proteins expression across GBM may provide novel insight into define subtype-specific patterns of hydroxymethylome, and thus help to interpret the heterogeneous outcomes of patients with the same disease.
Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer
Authors: Hao Chunfang , Wang Chen , Lu Ning , Zhao Weipeng , Li Shufen , Zhang Li , Meng Wenjing , Wang Shuling , Tong Zhongsheng , Zeng Yanwu , Lu Leilei
Published: April 2022

Background

Clinical characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are important biomarkers in the treatment of breast cancer, but how genomic mutations affect their status is rarely studied. This study aimed at finding genomic mutations associated with these clinical characteristics.

Methods

There were 160 patients with breast cancer enrolled in this study. Samples from those patients were used for next-generation sequencing, targeting a panel of 624 pan-cancer genes. Short nucleotide mutations, copy number variations, and gene fusions were identified for each sample. Fisher’s exact test compared each pair of genes. A similarity score was constructed with the resulting P-values. Genes were clustered with the similarity scores. The identified gene clusters were compared to the status of clinical characteristics including ER, PR, HER2, and a family history of cancer (FH) in terms of the mutations in patients.

Results

Gene-by-gene analysis found that CCND1 mutations were positively correlated with ER status while ERBB2 and CDK12 mutations were positively correlated with HER2 status. Mutation-based clustering identified four gene clusters. Gene cluster 1 (ADGRA2, ZNF703, FGFR1, KAT6A, and POLB) was significantly associated with PR status; gene cluster 2 (COL1A1, AXIN2, ZNF217, GNAS, and BRIP1) and gene cluster 3 (FGF3, FGF4, FGF19, and CCND1) were significantly associated with ER status; gene cluster 2 was also negatively associated with a family history of cancer; and gene cluster 4 was significantly negatively associated with age. Patients were classified into four corresponding groups. Patient groups 1, 2, 3, and 4 had 24.1%, 36.5%, 38.7%, and 41.3% of patients with an FDA-recognized biomarker predictive of response to an FDA-approved drug, respectively.

Conclusion

This study identified genomic mutations positively associated with ER and PR status. These findings not only revealed candidate genes in ER and PR status maintenance but also provided potential treatment targets for patients with endocrine therapy resistance.
Improved Survival Prediction by Combining Radiological Imaging and S-100B Levels Into a Multivariate Model in Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibition
Authors: Burgermeister Simon , Gabryś Hubert S. , Basler Lucas , Hogan Sabrina A. , Pavic Matea , Bogowicz Marta , Martínez Gómez Julia M. , Vuong Diem , Tanadini-Lang Stephanie , Foerster Robert , Huellner Martin W. , Dummer Reinhard , Levesque Mitchell P. , Guckenberger Matthias
Published: April 2022

Purpose

We explored imaging and blood bio-markers for survival prediction in a cohort of patients with metastatic melanoma treated with immune checkpoint inhibition.

Materials and Methods

94 consecutive metastatic melanoma patients treated with immune checkpoint inhibition were included into this study. PET/CT imaging was available at baseline (Tp0), 3 months (Tp1) and 6 months (Tp2) after start of immunotherapy. Radiological response at Tp2 was evaluated using iRECIST. Total tumor burden (TB) at each time-point was measured and relative change of TB compared to baseline was calculated. LDH, CRP and S-100B were also analyzed. Cox proportional hazards model and logistic regression were used for survival analysis.

Results

iRECIST at Tp2 was significantly associated with overall survival (OS) with C-index=0.68. TB at baseline was not associated with OS, whereas TB at Tp1 and Tp2 provided similar predictive power with C-index of 0.67 and 0.71, respectively. Appearance of new metastatic lesions during follow-up was an independent prognostic factor (C-index=0.73). Elevated LDH and S-100B ratios at Tp2 were significantly associated with worse OS: C-index=0.73 for LDH and 0.73 for S-100B. Correlation of LDH with TB was weak (r=0.34). A multivariate model including TB change, S-100B, and appearance of new lesions showed the best predictive performance with C-index=0.83.

Conclusion

Our analysis shows only a weak correlation between LDH and TB. Additionally, baseline TB was not a prognostic factor in our cohort. A multivariate model combining early blood and imaging biomarkers achieved the best predictive power with regard to survival, outperforming iRECIST.
Osimertinib-Centered Therapy Against Uncommon Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer- A Mini Review
Authors: Song Chengyang , Yang Xueying
Published: April 2022

Osimertinib is a third-generation, irreversible mutant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). Osimertinib is currently the first line drug recommended by National Comprehensive Cancer Network (NCCN) guidelines against lung cancer harboring the EGFR TKI-sensitive mutation and acquired EGFR T790M resistance mutation. Osimertinib demonstrated some efficacy in clinical trials and case reports in patients bearing certain uncommon EGFR mutations, but it is not active in patients with other mutations such as C797S. This mini-review presents the mechanisms underlying the variations in patient responses, discusses the use of osimertinib against non-small-cell lung carcinomas with uncommon EGFR mutations, and addresses the future prospects of osimertinib-centered therapy.
Paediatric Erdheim-Chester Disease in the Lateral Ventricle: A Case Report and Review of the Literature
Authors: Ma Yimei , Guo Xia , Wan Zhi , Liu Hanmin , Gao Ju
Published: April 2022

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis caused by the expression of CD68-positive and CD1a-negative foam tissue cells, which is polar in pediatric patients. The study reports a case of an 8-year-old Chinese boy who presented with polydipsia and polyuria for 4 years, followed by central nervous system symptoms. Magnetic resonance imaging (MRI) showed a large lesion in the lateral ventricle. The histiocytes stained positively for CD68, CD163 and negatively for CD1a, glial fibrillary acidic protein (GFAP) and langerin, and were partially positive for S100 by immunohistochemical assay. More importantly, BRAFV600E staining was positive in tissue, and the BRAFV600E mutations was also detected by real-time quantitative PCR (RT-qPCR) in the intracranial lesion tissue. According to our review of the literature, this is a rare case of ECD in the ventricle, with a younger age.
Computational Model of Heterogeneity in Melanoma: Designing Therapies and Predicting Outcomes
Authors: Hodgkinson Arran , Trucu Dumitru , Lacroix Matthieu , Le Cam Laurent , Radulescu Ovidiu
Published: April 2022

Cutaneous melanoma is a highly invasive tumor and, despite the development of recent therapies, most patients with advanced metastatic melanoma have a poor clinical outcome. The most frequent mutations in melanoma affect the BRAF oncogene, a protein kinase of the MAPK signaling pathway. Therapies targeting both BRAF and MEK are effective for only 50% of patients and, almost systematically, generate drug resistance. Genetic and non-genetic mechanisms associated with the strong heterogeneity and plasticity of melanoma cells have been suggested to favor drug resistance but are still poorly understood. Recently, we have introduced a novel mathematical formalism allowing the representation of the relation between tumor heterogeneity and drug resistance and proposed several models for the development of resistance of melanoma treated with BRAF/MEK inhibitors. In this paper, we further investigate this relationship by using a new computational model that copes with multiple cell states identified by single cell mRNA sequencing data in melanoma treated with BRAF/MEK inhibitors. We use this model to predict the outcome of different therapeutic strategies. The reference therapy, referred to as “continuous” consists in applying one or several drugs without disruption. In “combination therapy”, several drugs are used sequentially. In “adaptive therapy” drug application is interrupted when the tumor size is below a lower threshold and resumed when the size goes over an upper threshold. We show that, counter-intuitively, the optimal protocol in combination therapy of BRAF/MEK inhibitors with a hypothetical drug targeting cell states that develop later during the tumor response to kinase inhibitors, is to treat first with this hypothetical drug. Also, even though there is little difference in the timing of emergence of the resistance between continuous and adaptive therapies, the spatial distribution of the different melanoma subpopulations is more zonated in the case of adaptive therapy.
Epstein–Barr Virus, But Not Human Papillomavirus, Is Associated With Preinvasive and Invasive Ocular Surface Squamous Neoplasias in Zambian Patients
Authors: Julius Peter , Siyumbwa Stepfanie N. , Moonga Phyllis , Maate Fred , Kaile Trevor , Haynatski Gleb , Minhas Veenu , Snow Jazmine , Peterson Kerstin , Gihozo Patience , Streeter Sam , Kaur Salan , Evans Annika , Gonzalez Daniela , Samwel Kandali , Kang Guobin , West John T. , Wood Charles , Angeletti Peter C.
Published: April 2022

Background

The etiopathogenesis of ocular surface squamous neoplasia (OSSN) is not fully understood. We assessed the frequency of oncogenic viruses in OSSN by immunohistochemistry (IHC) and polymerase chain reaction (PCR) for human papillomavirus (HPV), Epstein–Barr virus (EBV), Merkel cell polyomavirus (MCPyV), Kaposi sarcoma virus, and adenovirus. Cases from Zambia were prospectively enrolled using a cross-sectional study design between November 2017 and March 2020.

Methods

Demographic and clinical data [age, sex, HIV status, antiretroviral therapy (ART) history, CD4 count, plasma viral load] and tumor biopsies were collected from 243 consenting patients. Tumor samples were bisected, and half was used for DNA isolation, while the other half was formalin fixed and paraffin embedded (FFPE) for histopathology analysis. The expressions of latent EBV nuclear antigen 1 (EBNA1), CDKN2A/p16INK4A (p16), and MCPyV large T-antigen (LT) were tested by IHC. Multiplex PCR was used to detect 16 HPV genotypes and four other DNA tumor viruses [Kaposi’s sarcoma-associated herpesvirus (KSHV), EBV, MCPyV, and adenovirus]. Relationships between HIV status, viral DNA and protein expression, and tumor grades were determined by statistical analysis.

Results

OSSN tumors from patients were 29.6% preinvasive and 70.4% invasive. Patients presented with unilateral tumors that were 70.4% late stage (T3/T4). OSSN patients were HIV positive (72.8%). IHC on 243 FFPE biopsies resulted in the detection of EBNA1 (EBV), p16 high-risk HPV (HR-HPV), and MCPyV LT expression in 89.0%, 4.9%, and 0.0%, respectively. EBNA1 was expressed in all grades of preinvasive [cornea–conjunctiva intraepithelial neoplasia (CIN)1, 100%; CIN2, 85.7%; CIN3, 95.8%; and carcinoma in situ (CIS), 83.8%] and in invasive (89.2%) OSSN. PCR on 178 samples detected EBV, HR-HPV, and MCPyV in 80.3%, 9.0%, and 13.5% of tumors, respectively. EBV was detected in all grades of preinvasive and invasive OSSN. EBV detection was associated with high HIV viral loads (p = 0.022). HR-HPV was detected in 0.0% CIN1, 0.0% CIN2, 5.6% CIN3, 13.0% CIS, and 7.0% invasive OSSN.

Conclusions

Our findings of EBV DNA and EBNA1 protein in all the grades of preinvasive and especially invasive OSSN are consistent with a potential causal role for EBV in OSSN. A role of HPV in OSSN was not clearly established in this study.
Prognostic Implication of Energy Metabolism-Related Gene Signatures in Lung Adenocarcinoma
Authors: Mu Teng , Li Haoran , Li Xiangnan
Published: April 2022

Background

Lung adenocarcinoma (LUAD) is the major non-small-cell lung cancer pathological subtype with poor prognosis worldwide. Herein, we aimed to build an energy metabolism-associated prognostic gene signature to predict patient survival.

Methods

The gene expression profiles of patients with LUAD were downloaded from the TCGA and GEO databases, and energy metabolism (EM)-related genes were downloaded from the GeneCards database. Univariate Cox and LASSO analyses were performed to identify the prognostic EM-associated gene signatures. Kaplan–Meier and receiver operating characteristic (ROC) curves were plotted to validate the predictive effect of the prognostic signatures. A CIBERSORT analysis was used to evaluate the correlation between the risk model and immune cells. A nomogram was used to predict the survival probability of LUAD based on a risk model.

Results

We constructed a prognostic signature comprising 13 EM-related genes (AGER, AHSG, ALDH2, CIDEC, CYP17A1, FBP1, GNB3, GZMB, IGFBP1, SORD, SOX2, TRH and TYMS). The Kaplan–Meier curves validated the good predictive ability of the prognostic signature in TCGA AND two GEO datasets (p<0.0001, p=0.00021, and p=0.0034, respectively). The area under the curve (AUC) of the ROC curves also validated the predictive accuracy of the risk model. We built a nomogram to predict the survival probability of LUAD, and the calibration curves showed good predictive ability. Finally, a functional analysis also unveiled the different immune statuses between the two different risk groups.

Conclusion

Our study constructed and verified a novel EM-related prognostic gene signature that could improve the individualized prediction of survival probability in LUAD.
Hemato-Oncological Diseases as Risk Factor for Recurrence or Metastasis of Pleomorphic Dermal Sarcoma
Authors: Helbig Doris
Published: April 2022

Background

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are increasingly common sarcomas of the skin with a genetic UV signature. Immunosuppression is a known risk factor for developing other UV-induced skin cancers such as cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and Merkel cell carcinoma with increased mortality. In case reports or small case series of AFX/PDS patients, immunosuppression has been hypothesized as a risk factor for the development of distant metastases. The aim of the present study was to analyze immunosuppression as a risk factor for AFX/PDS in a large patient cohort.

Methods

A cohort of 164 patients with AFX/PDS (47 AFX and 117 PDS) was collected between 2003 and 2021 and analyzed for clinicopathological data with a special focus on immunosuppression.

Results

Of all patients, 29.9% had any kind of immunosuppression; 6.4% of the AFX and 12.0% of the PDS patients had underlying hemato-oncological diseases. Patients with immunosuppression due to an underlying hemato-oncological disease had a significantly increased risk of progressing to (p = 0.010) and developing distant organ metastases (p = 0.000).

Conclusions

Immunosuppression seems to be a risk factor for developing AFX/PDS with worse clinical outcomes. Therefore, immunosuppression, especially underlying hemato-oncological diseases, should be considered in the treatment and follow-up care of patients with AFX/PDS.
Case Report: MR-Guided Adaptive Radiotherapy, Some Room to Maneuver
Authors: Li Winnie , Winter Jeff , Padayachee Jerusha , Dang Jennifer , Kong Vickie , Chung Peter
Published: April 2022

Background

A magnetic resonance linear accelerator (MR-Linac) provides superior soft tissue contrast to evaluate inter- and intra-fraction motion and facilitate online adaptive radiation therapy (ART). We present here an unusual case of locally advanced castrate-resistant prostate cancer treated with high-dose palliative ultra-hypofractionated radiation therapy on the MR-Linac with significant inter-fraction tumor regression.

Case Presentation

The patient was a 65-year-old man diagnosed with metastatic prostate cancer to bone and pelvic lymph nodes 7 years prior. At diagnosis, he presented with a PSA of 23 ng/ml and was commenced on a luteinizing hormone-releasing hormone agonist, achieving a PSA nadir of 4.68 ng/ml at 12 months. The patient subsequently had progressive lower urinary tract symptoms, his PSA increased to 47 ng/ml, and there was a markedly enlarged pelvic mass involving the prostate with gross extra-capsular disease and invasion into the posterior bladder wall. The patient was referred for palliative radiation to the pelvic mass due to urinary symptoms, pain, and lower limb paraesthesia. Treatment was planned to be delivered on the MR-Linac with a schedule of 36 Gy over 6 weekly factions allowing for maximal target dose delivery while minimizing surrounding organs at risk (OARs) radiation exposure. Unexpectedly, the target volume had a marked 49% (453 cc to 233 cc) reduction that was accounted for in the online adaptive process. A new reference plan was generated after 3 fractions to add sacral plexus as an OAR, previously not visible due to mass encroachment. The patient reported ongoing reduction in urinary symptoms, pelvic pain, and lower limb paresthesia by the end of treatment.

Conclusion

Using daily MR-guided ART, improved visualization of the changing target and OARs ensured safe dose escalation. The unexpected positive response of the target and improved patient outcomes demonstrated the added value of the MR-Linac for online adaptive radiotherapy in this setting.
Relieving Chronic Musculoskeletal Pain in Older Adults Using Transcranial Direct Current Stimulation: Effects on Pain Intensity, Quality, and Pain-Related Outcomes
Authors: Harvey Marie-Philippe , Martel Marylie , Houde Francis , Daguet Inès , Riesco Eléonor , Léonard Guillaume
Published: April 2022

Introduction

Chronic pain is a significant health problem and is particularly prevalent amongst the elderly. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has been proposed to reduce chronic pain. The aim of this study was to evaluate and compare the efficacy of active and sham tDCS in reducing pain in older individuals living with chronic musculoskeletal pain.

Materials and Methods

Twenty-four older individuals (mean age: 68 ± 7 years) suffering from chronic musculoskeletal pain were randomized to receive either anodal tDCS over the contralateral motor cortex (2 mA, 20 min; n = 12) or sham tDCS (20 min; n = 12) for five consecutive days. Pain logbooks were used to measure pain intensity. Questionnaires (McGill Pain Questionnaire, Brief Pain Inventory, Beck Depression Inventory [BDI], Beck Anxiety Inventory, Pain Catastrophizing Scale [PCS], and Margolis Pain Drawing and Scoring System [MPDSS]) were also used to assess pain in its globality.

Results

Analysis of pain logbooks revealed that active tDCS led to a reduction in daily average pain intensity (all p ≤ 0.04), while sham tDCS did not produce any change (p = 0.15). Between-group comparisons for change in pain intensity reduction between active and sham tDCS showed a trend during treatment (p = 0.08) which was significant at the follow-up period (p = 0.02). Active tDCS also improved scores of all questionnaires (all p ≤ 0.02), while sham tDCS only reduced MPDSS scores (p = 0.04). Between-group comparisons for the pain-related outcomes showed significant differences for BDI et PCS after the last tDCS session.

Conclusions

These results suggest that anodal tDCS applied over the primary motor cortex is an effective modality to decrease pain in older individuals. tDCS can also improve other key outcomes, such as physical and emotional functioning, and catastrophic thinking.
Pain Symptoms in Optic Neuritis
Authors: Yang Xiayin , Li Xuefen , Lai Mengying , Wang Jincui , Tan Shaoying , Chan Henry Ho-lung
Published: April 2022

Signs and symptoms of optic neuritis (ON), an autoimmune disorder of the central nervous system (CNS), differ between patients. Pain, which is commonly reported by ON patients, may be the major reason for some patients to visit the clinic. This article reviews the presence of pain related to ON with respect to underlying disorders, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein associated disease (MOGAD). The aim of this review is to provide an overview of pain symptoms in accordance with the context of various pathophysiological explanations, assist in differential diagnosis of ON patients, especially at the onset of disease, and make recommendations to aid physicians make decisions for follow up diagnostic examinations.
Fatal SARS in X-Linked Lymphoproliferative Disease Type 1: A Case Report
Authors: Chung Ming Hin , Chua Gilbert T. , Leung Daniel , Chan Koon Wing , Nicholls John , Lau Yu Lung
Published: April 2022

X-linked lymphoproliferative disease (XLP1) is an inborn error of immunity (IEI) with severe immune dysregulation caused by a mutation in the SH2D1A gene resulting in the absence or dysfunction of signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). The severe acute respiratory syndrome (SARS) caused by SARS-coronavirus (CoV), a highly pathogenic CoV, has been shown to only cause mild diseases in Asian children. We report on a 5-year-old Nepalese boy with agammaglobulinemia and probable SARS who died of diffuse alveolar damage 22 days after admission amid the SARS outbreak. The index patient and his younger brother were genetically confirmed to have XLP1. In the current coronavirus disease 2019 (COVID-19) pandemic, most children also had mild disease only. Children with severe COVID-19 would warrant investigations for underlying IEI, particularly along the pathways leading to immune dysregulation.