bluuebunny/crossref_metadata_2025 huggingface dataset:
Hippocampal neurons respond to brain activity with functional hypoxia
Authors: Butt Umer Javed , Steixner-Kumar Agnes A. , Depp Constanze , Sun Ting , Hassouna Imam , Wüstefeld Liane , Arinrad Sahab , Zillmann Matthias R. , Schopf Nadine , Fernandez Garcia-Agudo Laura , Mohrmann Leonie , Bode Ulli , Ronnenberg Anja , Hindermann Martin , Goebbels Sandra , Bonn Stefan , Katschinski Dörthe M. , Miskowiak Kamilla W. , Nave Klaus-Armin , Ehrenreich Hannelore
Published: February 2021

Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. Here we show in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression. A refined transgenic approach in mice, utilizing the oxygen-dependent degradation (ODD) domain of HIF-1α fused to CreERT2 recombinase, allows us to demonstrate hypoxic cells in the performing brain under normoxia and motor-cognitive challenge, and spatially map them by light-sheet microscopy, all in comparison to inspiratory hypoxia as strong positive control. We report that a complex motor-cognitive challenge causes hypoxia across essentially all brain areas, with hypoxic neurons particularly abundant in the hippocampus. These data suggest an intriguing model of neuroplasticity, in which a specific task-associated neuronal activity triggers mild hypoxia as a local neuron-specific as well as a brain-wide response, comprising indirectly activated neurons and non-neuronal cells.
Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis
Authors: Safadi Jenelle Marcelle , Quinton Alice M. G. , Lennox Belinda R. , Burnet Philip W. J. , Minichino Amedeo
Published: February 2021

Reduced gut-microbial diversity (“gut dysbiosis”) has been associated with an anhedonic/amotivational syndrome (“sickness behavior”) that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients showed increased levels of zonulin (four studies reporting data on bipolar disorder and depression, SMD = 0.97; 95% Cl = 0.10–1.85; P = 0.03, I2 = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42–1.12; P < 0.01; I2 = 0%), antibodies against endotoxin (seven studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.99; 95% CI = 0.27–1.70; P < 0.01, I2 = 97.14%), sCD14 (six studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.54; 95% Cl 0.16–0.81; P < 0.01, I2 = 90.68%), LBP (LBP, two studies reporting data on chronic fatigue and depression, SMD = 0.87; 95% Cl = 0.25–1.48; P < 0.01; I2 = 56.80%), alpha-1-antitripsin (six studies reporting data on bipolar disorder, depression, and schizophrenia, SMD = 1.23; 95% Cl = 0.57–1.88; P < 0.01, I2: 89.25%). Elevated levels of gut dysbiosis markers positively correlated with severity of sickness behavior in patients with severe mental illness and chronic fatigue. Our findings suggest that gut dysbiosis may underlie symptoms of sickness behavior across traditional diagnostic boundaries. Future investigations should validate these findings comparing the performances of the trans-diagnostic vs. categorical approach. This will facilitate treatment breakthrough in an area of unmet clinical need.
Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders
Authors: Akula Nirmala , Marenco Stefano , Johnson Kory , Feng Ningping , Zhu Kevin , Schulmann Anton , Corona Winston , Jiang Xueying , Cross Joanna , England Bryce , Nathan Aparna , Detera-Wadleigh Sevilla , Xu Qing , Auluck Pavan K. , An Kwangmi , Kramer Robin , Apud Jose , Harris Brent T. , Harker Rhodes C. , Lipska Barbara K. , McMahon Francis J.
Published: February 2021

Despite strong evidence of heritability and growing discovery of genetic markers for major mental illness, little is known about how gene expression in the brain differs across psychiatric diagnoses, or how known genetic risk factors shape these differences. Here we investigate expressed genes and gene transcripts in postmortem subgenual anterior cingulate cortex (sgACC), a key component of limbic circuits linked to mental illness. RNA obtained postmortem from 200 donors diagnosed with bipolar disorder, schizophrenia, major depression, or no psychiatric disorder was deeply sequenced to quantify expression of over 85,000 gene transcripts, many of which were rare. Case–control comparisons detected modest expression differences that were correlated across disorders. Case–case comparisons revealed greater expression differences, with some transcripts showing opposing patterns of expression between diagnostic groups, relative to controls. The ~250 rare transcripts that were differentially-expressed in one or more disorder groups were enriched for genes involved in synapse formation, cell junctions, and heterotrimeric G-protein complexes. Common genetic variants were associated with transcript expression (eQTL) or relative abundance of alternatively spliced transcripts (sQTL). Common genetic variants previously associated with disease risk were especially enriched for sQTLs, which together accounted for disproportionate fractions of diagnosis-specific heritability. Genetic risk factors that shape the brain transcriptome may contribute to diagnostic differences between broad classes of mental illness.
An examination of the relationships between attention/deficit hyperactivity disorder symptoms and functional connectivity over time
Authors: Norman Luke J. , Sudre Gustavo , Bouyssi-Kobar Marine , Sharp Wendy , Shaw Philip
Published: February 2021

Previous cross-sectional work has demonstrated resting-state connectivity abnormalities in children and adolescents with attention/deficit hyperactivity disorder (ADHD) relative to typically developing controls. However, it is unclear to what extent these neural abnormalities confer risk for later symptoms of the disorder, or represent the downstream effects of symptoms on functional connectivity. Here, we studied 167 children and adolescents (mean age at baseline = 10.74 years (SD = 2.54); mean age at follow-up = 13.3 years (SD = 2.48); 56 females) with varying levels of ADHD symptoms, all of whom underwent resting-state functional magnetic resonance imaging and ADHD symptom assessments on two occasions during development. Resting-state functional connectivity was quantified using eigenvector centrality mapping. Using voxelwise cross-lag modeling, we found that less connectivity at baseline within right inferior frontal gyrus was associated with more follow-up symptoms of inattention (significant at an uncorrected cluster-forming threshold of p ≤ 0.001 and a cluster-level familywise error corrected threshold of p < 0.05). Findings suggest that previously reported cross-sectional abnormalities in functional connectivity within inferior frontal gyrus in patients with ADHD may represent a longitudinal risk factor for the disorder, in line with efforts to target this region with novel therapeutic methods.
Effects of topiramate on neural responses to alcohol cues in treatment-seeking individuals with alcohol use disorder: preliminary findings from a randomized, placebo-controlled trial
Authors: Wetherill Reagan R. , Spilka Nathaniel , Jagannathan Kanchana , Morris Paige , Romer Danielle , Pond Timothy , Lynch Kevin G. , Franklin Teresa R. , Kranzler Henry R.
Published: February 2021

Topiramate, a GABA/glutamate modulator, is efficacious in reducing alcohol consumption, though the mechanisms underlying this effect are not well characterized. This study analyzed functional magnetic resonance imaging (fMRI) data from 22 heavy drinkers enrolled in a 12-week placebo-controlled, randomized clinical trial of topiramate to examine the effects of topiramate on alcohol cue-elicited brain responses, craving, and heavy drinking in individuals with DSM-5 alcohol use disorder. Patients were randomized to receive either topiramate (maximal daily dosage of 200 mg/day) or placebo and were administered an fMRI alcohol cue-reactivity task at baseline (before starting medication) and after 6 weeks of double-blind treatment. Analyses compared the topiramate (n = 12) and placebo (n = 8) groups on (1) the change in brain responses during alcohol cue exposure (vs non-alcohol cues) within five a priori regions of interest related to reward—the bilateral and medial orbitofrontal cortex (OFC) and bilateral ventral striatum (VS) and (2) change in craving and heavy drinking days (HDDs) from baseline and scan 2. Topiramate, relative to placebo, reduced alcohol cue-elicited activation of the left VS, bilateral OFC, and medial OFC, alcohol cue-elicited craving, and HDDs between baseline and 6 weeks of treatment. The reduction in alcohol cue-elicited activation in the medial OFC correlated with reductions in craving, and reduced activation in the right VS, right OFC, and medial OFC correlated with the reduction in HDD. This preliminary study provides evidence that topiramate’s attenuation of alcohol cue-elicited brain activation and craving are key elements of the drug’s neurobiological mechanism of action in reducing heavy drinking.
Identification of pannexin 1-regulated genes, interactome, and pathways in rhabdomyosarcoma and its tumor inhibitory interaction with AHNAK
Authors: Xiang Xiao , Langlois Stéphanie , St-Pierre Marie-Eve , Blinder Anna , Charron Philippe , Graber Tyson E. , Fowler Stephanie L. , Baird Stephen D. , Bennett Steffany A. L. , Alain Tommy , Cowan Kyle N.
Published: February 2021

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, is an aggressive cancer with a poor prognosis. Despite current management, the 5-year survival rate for patients with metastatic RMS is ∼30%; underscoring the need to develop better treatment strategies. We have recently reported that pannexin 1 (PANX1) levels are downregulated in RMS and that restoring its expression inhibits RMS progression. Here, we have surveyed and characterized the molecular changes induced by PANX1 re-expression in RMS. We cataloged transcriptomic changes in this context by RNA sequencing. At the protein level, we unveiled PANX1 interactors using BioID, complemented by co-immunoprecipitation coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry performed in PANX1-enriched fractions. Using these data, we generated searchable public databases for the PANX1 interactome and changes to the RMS transcriptome occurring when PANX1 expression is restored. STRING network analyses revealed a PANX1 interactome involving plasma membrane and cytoskeleton-associated proteins including the previously undescribed interactor AHNAK. Indeed, AHNAK knockdown abrogated the PANX1-mediated reduction in RMS cell viability and migration. Using these unbiased approaches, we bring insight to the mechanisms by which PANX1 inhibits RMS progression, identifying the cell migration protein AHNAK as a key modifier of PANX1-mediated changes in RMS malignant properties.
MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma
Authors: Ke Xin-Yu , Chen Ye , Tham Valarie Yu-Yan , Lin Ruby Yu-Tong , Dakle Pushkar , Nacro Kassoum , Puhaindran Mark Edward , Houghton Peter , Pang Angela , Lee Victor Kwanmin , Ding Ling-Wen , Gery Sigal , Hill Jeffrey , Chen Leilei , Xu Liang , Koeffler H. Phillip
Published: February 2021

Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.
Classification of node-positive melanomas into prognostic subgroups using keratin, immune, and melanogenesis expression patterns
Authors: Netanely Dvir , Leibou Stav , Parikh Roma , Stern Neta , Vaknine Hananya , Brenner Ronen , Amar Sarah , Factor Rivi Haiat , Perluk Tomer , Frand Jacob , Nizri Eran , Hershkovitz Dov , Zemser-Werner Valentina , Levy Carmit , Shamir Ron
Published: February 2021

Cutaneous melanoma tumors are heterogeneous and show diverse responses to treatment. Identification of robust molecular biomarkers for classifying melanoma tumors into clinically distinct and homogenous subtypes is crucial for improving the diagnosis and treatment of the disease. In this study, we present a classification of melanoma tumors into four subtypes with different survival profiles based on three distinct gene expression signatures: keratin, immune, and melanogenesis. The melanogenesis expression pattern includes several genes that are characteristic of the melanosome organelle and correlates with worse survival, suggesting the involvement of melanosomes in melanoma aggression. We experimentally validated the secretion of melanosomes into surrounding tissues by melanoma tumors, which potentially affects the lethality of metastasis. We propose a simple molecular decision tree classifier for predicting a tumor’s subtype based on representative genes from the three identified signatures. Key predictor genes were experimentally validated on melanoma samples taken from patients with varying survival outcomes. Our three-pattern approach for classifying melanoma tumors can contribute to advancing the understanding of melanoma variability and promote accurate diagnosis, prognostication, and treatment.
RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing
Authors: Yan Qiuxia , Zeng Peng , Zhou Xiuqin , Zhao Xiaoying , Chen Runqiang , Qiao Jing , Feng Ling , Zhu Zhenjie , Zhang Guozhi , Chen Cairong
Published: February 2021

The prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.
The microRNA-195 - BDNF pathway and cognitive deficits in schizophrenia patients with minimal antipsychotic medication exposure
Authors: Pan Shujuan , Feng Wei , Li Yanli , Huang Junchao , Chen Song , Cui Yimin , Tian Baopeng , Tan Shuping , Wang Zhiren , Yao Shangwu , Chiappelli Joshua , Kochunov Peter , Chen Shuo , Yang Fude , Li Chiang-Shan R. , Tian Li , Tan Yunlong , Elliot Hong L.
Published: February 2021

Cognitive impairment is a core characteristic of schizophrenia, but its underlying neural mechanisms remain poorly understood. Reduced brain-derived neurotrophic factor (BDNF), a protein critical for neural plasticity and synaptic signaling, is one of the few molecules consistently associated with cognitive deficits in schizophrenia although the etiological pathway leading to BDNF reduction in schizophrenia is unclear. We examined microRNA-195 (miR-195), a known modulator of BDNF protein expression, as a potential mechanistic component. One-hundred and eighteen first-episode patients with schizophrenia either antipsychotic medication-naïve or within two weeks of antipsychotic medication exposure and forty-seven age- and sex-matched healthy controls were enrolled. MiR-195 and BDNF mRNA and BDNF protein levels in peripheral blood were tested. Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). MiR-195 was significantly higher (p = 0.01) whereas BDNF mRNA (p < 0.001) and protein (p = 0.016) levels were significantly lower in patients compared with controls. Higher miR-195 expression was significantly correlated to lower BDNF protein levels in patients (partial r = −0.28, p = 0.003) and lower BDNF protein levels were significantly associated with poorer overall cognitive performance by MCCB and also in speed of processing, working memory, and attention/vigilance domains composite score (p = 0.002–0.004). The subgroup of patients with high miR-195 and low BDNF protein showed the lowest level of cognitive functions, and miR-195 showed significant mediation effects on cognitive functions through BDNF protein. Elevated miR-195 may play a role in regulating BDNF protein expression thereby influencing cognitive impairments in schizophrenia, suggesting that development of cognition enhancing treatment for schizophrenia may consider a micro-RNA based strategy.
Prognosis of young patients with monoclonal gammopathy of undetermined significance (MGUS)
Authors: Pang Li , Rajkumar S. Vincent , Kapoor Prashant , Buadi Francis , Dispenzieri Angela , Gertz Morie , Lacy Martha , Kyle Robert , Kumar Shaji
Published: February 2021

Monoclonal gammopathy of undetermined significance (MGUS) is rare in young patients (age <40 years at diagnosis), with a prevalence of <0.3%, representing ~2% of all patients with MGUS. We hypothesized that MGUS detected in young patients may be associated with a higher risk of progression. We examined 249 patients with MGUS < 40 years old. Among these, 135 patients had immune-related conditions, including infections, autoimmune and inflammatory disorders at the time of diagnosis of MGUS. The risk of progression to multiple myeloma or a related disorder at 5 years and 10 years was 6.0% and 13.8%, respectively. The size of M protein was a significant risk factor for progression (HR 4.2, 95% CI 2.2–7.9). There was a trend that the risk of progression was higher in patients without immune-related conditions (HR 2.36, 95% CI 0.85–6.52, p = 0.088). The M protein resolved in 36 (14%) patients, with a greater likelihood of resolution in patients with immune-related conditions (RR 1.9, 95% CI 1.02–3.6). Young patients with MGUS have a similar risk of progression as older patients, 1.4% per year. Over 50% are diagnosed in the setting of immune-related disorders. Patients with immune-related disorders may have a lower risk of progression.
Mass spectrometry for the evaluation of monoclonal proteins in multiple myeloma and related disorders: an International Myeloma Working Group Mass Spectrometry Committee Report
Authors: Murray David L. , Puig Noemi , Kristinsson Sigurdur , Usmani Saad Z. , Dispenzieri Angela , Bianchi Giada , Kumar Shaji , Chng Wee Joo , Hajek Roman , Paiva Bruno , Waage Anders , Rajkumar S. Vincent , Durie Brian
Published: February 2021

Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs.
Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19
Authors: Barbui Tiziano , De Stefano Valerio , Alvarez-Larran Alberto , Iurlo Alessandra , Masciulli Arianna , Carobbio Alessandra , Ghirardi Arianna , Ferrari Alberto , Cancelli Valeria , Elli Elena Maria , Andrade-Campos Marcio Miguel , Kabat Mercedes Gasior , Kiladjian Jean-Jaques , Palandri Francesca , Benevolo Giulia , Garcia-Gutierrez Valentin , Fox Maria Laura , Foncillas Maria Angeles , Morcillo Carmen Montoya , Rumi Elisa , Osorio Santiago , Papadopoulos Petros , Bonifacio Massimiliano , Cervantes Keina Susana Quiroz , Serrano Miguel Sagues , Carreno-Tarragona Gonzalo , Sobas Marta Anna , Lunghi Francesca , Patriarca Andrea , Elorza Begoña Navas , Angona Anna , Mazo Elena Magro , Koschmieder Steffen , Carli Giuseppe , Cuevas Beatriz , Hernandez-Boluda Juan Carlos , Abadia Emma Lopez , Cirici Blanca Xicoy , Guglielmelli Paola , Garrote Marta , Cattaneo Daniele , Daffini Rosa , Cavalca Fabrizio , Bellosillo Beatriz , Benajiba Lina , Curto-Garcia Natalia , Bellini Marta , Betti Silvia , Harrison Claire , Rambaldi Alessandro , Vannucchi Alessandro Maria
Published: February 2021

In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (−23.3%, p < 0.0001) than in PV (−16.4%, p = 0.1730) and was associated with higher mortality rate (p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.
Transforming the landscape of early cancer detection using blood tests—Commentary on current methodologies and future prospects
Authors: Liu Minetta C.
Published: February 2021

Early cancer detection should lead to an overall stage shift, less-intensive treatments and better patient outcomes. Current recommended screening programmes are limited to a handful of individual cancers. A multi-cancer early detection test that simultaneously detects and localises multiple cancers could reduce the morbidity and mortality associated with cancer.
The tele-transition of toxicity management in routine oncology care during the severe acute respiratory syndrome (SARS-CoV-2) pandemic
Authors: Rasschaert Marika , Vanclooster Pieterjan , Mertens Tim , Roelant Ella , Lesage Katrien , Prenen Hans , Verlinden Anke , van Brussel Ilse , Ravelingien Jo , Janssens Annelies , Van Dam Peter , Peeters Marc
Published: February 2021

Background

Telehealth modalities were introduced during the SARS-CoV-2 pandemic to assure continuation of cancer care and maintain social distance.

Methods

This is a retrospective cohort analysis of our telehealth expansion programme. We adapted two existing patient-reported outcome (PRO) telemonitoring tools that register and (self-)manage toxicities to therapy, while screening for SARS-CoV-2-related symptoms. Outpatients from a tertiary cancer centre were enrolled. The adapted PRO interface allowed for uniform registration of SARS-CoV-2-related symptoms and effective triage of patients at home where we also implemented systematic throat washings, when available.

Results

Three hundred and sixty patients registered to the telemonitoring systems from March 13 to May 15, 2020. Four prespecified SARS-CoV-2 alarms resulted in three patients with positive PCR testing. Other Covid-19 symptoms (fever 5× and cough 2×) led to pretreatment triage resulting in 1 seroconversion after initial negative testing. One of the 477 throat washings proved positive.

Conclusions

The rapid adoption of an amended PRO (self-)registrations and toxicity management system was feasible and coordinated screening for Covid-19. Continued clinical cancer care was maintained, with significant decreased waiting time. The systemic screening with throat washings offered no real improvement.
Determination of breast cancer prognosis after neoadjuvant chemotherapy: comparison of Residual Cancer Burden (RCB) and Neo-Bioscore
Authors: Laas Enora , Labrosse Julie , Hamy Anne-Sophie , Benchimol Gabriel , de Croze Diane , Feron Jean-Guillaume , Coussy Florence , Balezeau Thomas , Guerin Julien , Lae Marick , Pierga Jean-Yves , Reyal Fabien
Published: February 2021

Background

To compare RCB (Residual Cancer Burden) and Neo-Bioscore in terms of prognostic performance and see if adding pathological variables improve these scores.

Methods

We analysed 750 female patients with invasive breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) at Institut Curie between 2002 and 2012. Scores were compared in global population and by BC subtype using Akaike information criterion (AIC), C-Index (concordance index), calibration curves and after adding lymphovascular invasion (LVI) and pre-/post-NAC TILs levels.

Results

RCB and Neo-Bioscore were significantly associated to disease-free and overall survival in global population and for triple-negative BC. RCB had the lowest AICs in every BC subtype, corresponding to a better prognostic performance. In global population, C-Index values were poor for RCB (0.66; CI [0.61–0.71]) and fair for Neo-Bioscore (0.70; CI [0.65–0.75]). Scores were well calibrated in global population, but RCB yielded better prognostic performances in each BC subtype. Concordance between the two scores was poor. Adding LVI and TILs improved the performance of both scores.

Conclusions

Although RCB and Neo-Bioscore had similar prognostic performances, RCB showed better performance in BC subtypes, especially in luminal and TNBC. By generating fewer prognostic categories, RCB enables an easier use in everyday clinical practice.
Early cancer diagnosis: reaching targets across whole populations amidst setbacks
Authors: McCormack Valerie , Aggarwal Ajay
Published: February 2021

Early diagnosis of cancer, followed by timely and appropriate therapy, are the cornerstones of the secondary prevention of cancer, thus the NHS has set a 2028 target to achieve 75% early stage (TNM I/II) at cancer diagnosis. In this context, Barclay et al. evaluated overall, sex, age and deprivation-group-specific progress towards this target based on 202,000 cancer patients diagnosis in 2015. Herein, we discuss their findings which form a valuable pre-COVID-19 pandemic status. We discuss the impact of the pandemic and the efforts being made in innovative early detection and diagnosis research.
Socio-demographic variation in stage at diagnosis of breast, bladder, colon, endometrial, lung, melanoma, prostate, rectal, renal and ovarian cancer in England and its population impact
Authors: Barclay M. E. , Abel G. A. , Greenberg David. C. , Rous B. , Lyratzopoulos G.
Published: February 2021

Background

Stage at diagnosis strongly predicts cancer survival and understanding related inequalities could guide interventions.

Methods

We analysed incident cases diagnosed with 10 solid tumours included in the UK government target of 75% of patients diagnosed in TNM stage I/II by 2028. We examined socio-demographic differences in diagnosis at stage III/IV vs. I/II. Multiple imputation was used for missing stage at diagnosis (9% of tumours).

Results

Of the 202,001 cases, 57% were diagnosed in stage I/II (an absolute 18% ‘gap’ from the 75% target). The likelihood of diagnosis at stage III/IV increased in older age, though variably by cancer site, being strongest for prostate and endometrial cancer. Increasing level of deprivation was associated with advanced stage at diagnosis for all sites except lung and renal cancer. There were, inconsistent in direction, sex inequalities for four cancers. Eliminating socio-demographic inequalities would translate to 61% of patients with the 10 studied cancers being diagnosed at stage I/II, reducing the gap from target to 14%.

Conclusions

Potential elimination of socio-demographic inequalities in stage at diagnosis would make a substantial, though partial, contribution to achieving stage shift targets. Earlier diagnosis strategies should additionally focus on the whole population and not only the high-risk socio-demographic groups.
Eye fluke infection changes diet composition in juvenile European perch (Perca fluviatilis)
Authors: Vivas Muñoz Jenny C. , Feld Christian K. , Hilt Sabine , Manfrin Alessandro , Nachev Milen , Köster Daniel , Jochmann Maik A. , Schmidt Torsten C. , Sures Bernd , Ziková Andrea , Knopf Klaus
Published: February 2021

Intraspecific diet specialization, usually driven by resource availability, competition and predation, is common in natural populations. However, the role of parasites on diet specialization of their hosts has rarely been studied. Eye flukes can impair vision ability of their hosts and have been associated with alterations of fish feeding behavior. Here it was assessed whether European perch (Perca fluviatilis) alter their diet composition as a consequence of infection with eye flukes. Young-of-the-year (YOY) perch from temperate Lake Müggelsee (Berlin, Germany) were sampled in two years, eye flukes counted and fish diet was evaluated using both stomach content and stable isotope analyses. Perch diet was dominated by zooplankton and benthic macroinvertebrates. Both methods indicated that with increasing eye fluke infection intensity fish had a more selective diet, feeding mainly on the benthic macroinvertebrateDikerogammarus villosus, while less intensively infected fish appeared to be generalist feeders showing no preference for any particular prey type. Our results show that infection with eye flukes can indirectly affect interaction of the host with lower trophic levels by altering the diet composition and highlight the underestimated role of parasites in food web studies.
Assessing the reliability of medicinal Dendrobium sequences in GenBank for botanical species identification
Authors: Wu Hoi-Yan , Chan Kwun-Tin , But Grace Wing-Chiu , Shaw Pang-Chui
Published: February 2021

DNA-based method is a promising tool in species identification and is widely used in various fields. DNA barcoding method has already been included in different pharmacopoeias for identification of medicinal materials or botanicals. Accuracy and validity of DNA-based methods rely on the accuracy and taxonomic reliability of the DNA sequences in the database to be compared against. Here we evaluated the annotation quality and taxonomic reliability of selected barcode loci (rbcL, matK, psbA-trnH, trnL-trnF and ITS) of 41 medicinal Dendrobium species downloaded from GenBank. Annotations of most accessions are incomplete. Only 53.06% of the 2041 accessions downloaded contain a reference to a voucher specimen. Only 31.60% and 4.8% of the entries are annotated with country of origin and collector or assessor, respectively. Taxonomic reliability of the sequences was evaluated by a Megablast search based on similarity to sequences submitted by other research groups. A small number of sequences (211, 7.14%) was regarded as highly doubted. Moreover, 10 out of 60 complete chloroplast genomes contain highly doubted sequences. Our findings suggest that sequences of GenBank should be used with caution for species-level identification. The scientific community should provide more important information regarding identity and traceability of the sample when they deposit sequences to public databases.
North Pacific warming shifts the juvenile range of a marine apex predator
Authors: Tanaka Kisei R. , Van Houtan Kyle S. , Mailander Eric , Dias Beatriz S. , Galginaitis Carol , O’Sullivan John , Lowe Christopher G. , Jorgensen Salvador J.
Published: February 2021

During the 2014–2016 North Pacific marine heatwave, unprecedented sightings of juvenile white sharks (Carcharodon carcharias) emerged in central California. These records contradicted the species established life history, where juveniles remain in warmer waters in the southern California Current. This spatial shift is significant as it creates potential conflicts with commercial fisheries, protected species conservation, and public safety concerns. Here, we integrate community science, photogrammetry, biologging, and mesoscale climate data to describe and explain this phenomenon. We find a dramatic increase in white sharks from 2014 to 2019 in Monterey Bay that was overwhelmingly comprised of juvenile sharks < 2.5 m in total body length. Next, we derived thermal preferences from 22 million tag measurements of 14 juvenile sharks and use this to map the cold limit of their range. Consistent with historical records, the position of this cold edge averaged 34° N from 1982 to 2013 but jumped to 38.5° during the 2014–2016 marine heat wave. In addition to a poleward shift, thermally suitable habitat for juvenile sharks declined 223.2 km2 year−1 from 1982 to 2019 and was lowest in 2015 at the peak of the heatwave. In addition to advancing the adaptive management of this apex marine predator, we discuss this opportunity to engage public on climate change through marine megafauna.
Purification of anti-glycoconjugate monoclonal antibodies using newly developed porous zirconia particles
Authors: Okuda Tetsuya , Kato Katsuya , Kitamura Masahiro , Kasahara Shinjiro
Published: February 2021

Here, we describe porous zirconia particles (PZPs) optimized for the purification of immunoglobulins. PZPs, with a pore size of approximately 10 nm, were designed to specifically interact with antibodies via surface modification with a phosphate functional group. A simple PZP purification method based on precipitation enabled efficient purification of mouse anti-glycosphingolipid globoside/Gb4Cer monoclonal IgM (κ-light chains) from hybridoma culture supernatants. Over 99% of contaminating proteins were removed by the PZP purification process, and approximately 50% of the IgM was recovered in the purified fraction after eluting the PZP-adsorbed antibodies with 100 mM phosphate buffer. Other IgG3 and IgM monoclonal antibodies that react with Gb4Cer or α2,6-sialyl LacNAc-modified glycoproteins could also be purified using PZPs and elution buffer at concentrations of 100–500 mM. All of the purified antibodies retained their antigen reactivity and specificity, indicating that PZP purification does not affect antibody function. As PZP purification is also suitable for purification of IgM consisting of λ-light chains and IgG derived from other mammalian species, it is expected to be applied to the purification of a variety of antibodies, including anti-glycoconjugate IgMs.
Identification of potential salivary biomarker panels for oral squamous cell carcinoma
Authors: Jain Anu , Kotimoole Chinmaya Narayana , Ghoshal Sushmita , Bakshi Jaimanti , Chatterjee Aditi , Prasad Thottethodi Subrahmanya Keshava , Pal Arnab
Published: February 2021

Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide with the maximum number of incidences and deaths reported from India. One of the major causes of poor survival rate associated with OSCC has been attributed to late presentation due to non-availability of a biomarker. Identification of early diagnostic biomarker will help in reducing the disease morbidity and mortality. We validated 12 salivary proteins using targeted proteomics, identified initially by relative quantification of salivary proteins on LC–MS, in OSCC patients and controls. Salivary AHSG (p = 0.0041**) and KRT6C (p = 0.002**) were upregulated in OSCC cases and AZGP1 (p ≤ 0.0001***), KLK1 (p = 0.006**) and BPIFB2 (p = 0.0061**) were downregulated. Regression modelling resulted in a significant risk prediction model (p < 0.0001***) consisting of AZGP1, AHSG and KRT6C for which ROC curve had AUC, sensitivity and specificity of 82.4%, 78% and 73.5% respectively for all OSCC cases and 87.9%, 87.5% and 73.5% respectively for late stage (T3/T4) OSCC. AZGP1, AHSG, KRT6C and BPIFB2 together resulted in ROC curve (p < 0.0001***) with AUC, sensitivity and specificity of 94%, 100% and 77.6% respectively for N0 cases while KRT6C and AZGP1 for N+ cases with ROC curve (p < 0.0001***) having AUC sensitivity and specificity of 76.8%, 73% and 69.4%. Our data aids in the identification of biomarker panels for the diagnosis of OSCC cases with a differential diagnosis between early and late-stage cases.
Enhanced light extraction efficiency and viewing angle characteristics of microcavity OLEDs by using a diffusion layer
Authors: Park Cheol Hwee , Kang Shin Woo , Jung Sun-Gyu , Lee Dong Jun , Park Young Wook , Ju Byeong-Kwon
Published: February 2021

The viewing angle characteristics and light extraction efficiency of organic light-emitting diodes (OLEDs) with a micro-cavity structure were enhanced. This was accomplished by inserting a diffusion layer composed of nano-sized structures of a transparent polymer poly(methyl methacrylate) (PMMA) combined with a zinc oxide (ZnO) semi-planarization layer with a high refractive index (n = 2.1) into the devices. The PMMA nanostructures were fabricated by employing a reactive ion etching (RIE) process. The height and density of the PMMA nanostructures were controlled by varying the speed at which the PMMA was spin-coated onto the substrate. The insertion of the diffusion layer into the micro-cavity OLEDs (MC-OLEDs) improved the external quantum efficiency (EQE) by as much as 17% when compared to that of a MC-OLED without a diffusion layer. Furthermore, adjustment of the viewing angle from 0° to 60° halved the peak shift distance of the electroluminescence (EL) spectra from 42 to 20 nm. Additionally, changing the viewing angle from 0° to 60° changed the color coordinate movement distance of the MC-OLED with the diffusion layer to 0.078, less than half of the distance of the MC-OLED without the diffusion layer (0.165).
Past landscape structure drives the functional assemblages of plants and birds
Authors: Lecoq Lucie , Ernoult Aude , Mony Cendrine
Published: February 2021

Landscape structure is a major driver of biodiversity in agricultural landscapes. However, the response of biodiversity can be delayed after landscape changes. This study aimed to determine the effect of current and past landscape structure on plant and bird assemblages. We used a trait-based approach to understand their responses to landscape simplification and habitat fragmentation. We quantified landscape structure at three different years (1963, 1985, 2000) and sampled current plant and bird assemblages in twenty 1 km2landscape windows located along the Seine Valley (France). For each window, we calculated plant and bird species richness, Community Weighted Variance (CWV), and Community Weighted Mean (CWM) of five functional traits related to dispersal capacity, reproduction, and life-cycle. We detected non-random patterns of traits for both taxa. Plant and bird species richness was lower in simple landscapes. The functional variance of plant traits was higher in landscapes simple in configuration. Both plant and bird assemblages strongly responded to past landscapes, especially their traits related to reproduction and life-cycle. It suggests that landscapes of the Seine valley will face a functional extinction debt. Further research is needed to better predict the delayed response of biodiversity expected to occur after landscape structure changes.
Effects of ambient particulate matter on a reconstructed human corneal epithelium model
Authors: Ko Ryota , Hayashi Masahiko , Tanaka Miho , Okuda Tomoaki , Nishita-Hara Chiharu , Ozaki Hiroaki , Uchio Eiichi
Published: February 2021

We evaluated the effects of ambient particulate matter (PM) on the corneal epithelium using a reconstructed human corneal epithelium (HCE) model. We collected two PM size fractions [aerodynamic diameter smaller than 2.4 µm: PM0.3–2.4 and larger than 2.4 µm: PM>2.4] and exposed these tissues to PM concentrations of 1, 10, and 100 µg/mL for 24 h. After exposure, cell viability and interleukin (IL) IL-6 and IL-8 levels were determined, and haematoxylin and eosin and immunofluorescence staining of the zonula occludens-1 (ZO-1) were performed on tissue sections. In addition, the effects of a certified reference material of urban aerosols (UA; 100 µg/mL) were also examined as a reference. The viability of cells exposed to 100 μg/mL UA and PM>2.4 decreased to 76.2% ± 7.4 and 75.4% ± 16.1, respectively, whereas PM0.3–2.4 exposure had a limited effect on cell viability. These particles did not increase IL-6 and IL-8 levels significantly even though cell viability was decreased in 100 μg/mL UA and PM>2.4. ZO-1 expression was reduced in a dose-dependent manner in all groups. Reconstructed HCE could be used as an in vitro model to study the effects of environmental PM exposure on ocular surface cell viability and inflammation.
CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor
Authors: Ishizuka Masato , Harada Mutsuo , Nomura Seitaro , Ko Toshiyuki , Ikeda Yuichi , Guo Jiaxi , Bujo Satoshi , Yanagisawa-Murakami Haruka , Satoh Masahiro , Yamada Shintaro , Kumagai Hidetoshi , Motozawa Yoshihiro , Hara Hironori , Fujiwara Takayuki , Sato Tatsuyuki , Takeda Norifumi , Takeda Norihiko , Otsu Kinya , Morita Hiroyuki , Toko Haruhiro , Komuro Issei
Published: February 2021

Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
Sea surface temperature variability and ischemic heart disease outcomes among older adults
Authors: Majeed Haris , Moineddin Rahim , Booth Gillian L.
Published: February 2021

Ischemic heart disease (IHD) is one of the leading causes of death worldwide. While extreme summer surface air temperatures are thought to be a risk factor for IHD, it is unclear whether large-scale climate patterns also influence this risk. This multi-national population-based study investigated the association between summer Pacific and Atlantic sea surface temperature (SST) variability and annual acute myocardial infarction (AMI) or IHD event rates among older adults residing in North America and the United Kingdom. Overall, a shift from cool to warm phase of the El Niño Southern Oscillation (ENSO) was associated with reduced AMI admissions in western Canada (adjusted rate ratio [RR] 0.89; 95% CI, 0.80–0.99), where this climate pattern predominatly forces below-normal cloud cover and precipitation during summertime, and increased AMI deaths in western United States (RR 1.09; 95% CI, 1.04–1.15), where it forces increased cloud cover and precipitation. Whereas, the Atlantic Multidecadal Oscillation (AMO) during a strong positive phase was associated with reduced AMI admissions in eastern Canada (RR 0.93; 95% CI, 0.87–0.98) and increased IHD mortality during summer months in the United Kingdom (RR 1.08; 95% CI, 1.03–1.14). These findings suggest that SST variability can be used to predict changes in cardiovascular event rates in regions that are susceptible.