bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mechanism and Regulation of the NLRP3 Inflammasome during Fibrosis
Authors: Artlett Carol M.
Published: April 2022

Fibrosis is often the end result of chronic inflammation. It is characterized by the excessive deposition of extracellular matrix. This leads to structural alterations in the tissue, causing permanent damage and organ dysfunction. Depending on the organ it effects, fibrosis can be a serious threat to human life. The molecular mechanism of fibrosis is still not fully understood, but the NLRP3 (NOD-, LRR- and pyrin–domain–containing protein 3) inflammasome appears to play a significant role in the pathogenesis of fibrotic disease. The NLRP3 inflammasome has been the most extensively studied inflammatory pathway to date. It is a crucial component of the innate immune system, and its activation mediates the secretion of interleukin (IL)-1β and IL-18. NLRP3 activation has been strongly linked with fibrosis and drives the differentiation of fibroblasts into myofibroblasts by the chronic upregulation of IL-1β and IL-18 and subsequent autocrine signaling that maintains an activated inflammasome. Both IL-1β and IL-18 are profibrotic, however IL-1β can have antifibrotic capabilities. NLRP3 responds to a plethora of different signals that have a common but unidentified unifying trigger. Even after 20 years of extensive investigation, regulation of the NLRP3 inflammasome is still not completely understood. However, what is known about NLRP3 is that its regulation and activation is complex and not only driven by various activators but controlled by numerous post-translational modifications. More recently, there has been an intensive attempt to discover NLRP3 inhibitors to treat chronic diseases. This review addresses the role of the NLRP3 inflammasome in fibrotic disorders across many different tissues. It discusses the relationships of various NLRP3 activators to fibrosis and covers different therapeutics that have been developed, or are currently in development, that directly target NLRP3 or its downstream products as treatments for fibrotic disorders.
Rapid Detection of Anti-SARS-CoV-2 Antibodies with a Screen-Printed Electrode Modified with a Spike Glycoprotein Epitope
Authors: Ameku Wilson A. , Provance David W. , Morel Carlos M. , De-Simone Salvatore G.
Published: April 2022

Background: The coronavirus disease of 2019 (COVID-19) is caused by an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was recognized in late 2019 and has since spread worldwide, leading to a pandemic with unprecedented health and financial consequences. There remains an enormous demand for new diagnostic methods that can deliver fast, low-cost, and easy-to-use confirmation of a SARS-CoV-2 infection. We have developed an affordable electrochemical biosensor for the rapid detection of serological immunoglobulin G (IgG) antibody in sera against the spike protein. Materials and Methods: A previously identified linear B-cell epitope (EP) specific to the SARS-CoV-2 spike glycoprotein and recognized by IgG in patient sera was selected for the target molecule. After synthesis, the EP was immobilized onto the surface of the working electrode of a commercially available screen-printed electrode (SPE). The capture of SARS-CoV-2-specific IgGs allowed the formation of an immunocomplex that was measured by square-wave voltammetry from its generation of hydroquinone (HQ). Results: An evaluation of the performance of the EP-based biosensor presented a selectivity and specificity for COVID-19 of 93% and 100%, respectively. No cross-reaction was observed to antibodies against other diseases that included Chagas disease, Chikungunya, Leishmaniosis, and Dengue. Differentiation of infected and non-infected individuals was possible even at a high dilution factor that decreased the required sample volumes to a few microliters. Conclusion: The final device proved suitable for diagnosing COVID-19 by assaying actual serum samples, and the results displayed good agreement with the molecular biology diagnoses. The flexibility to conjugate other EPs to SPEs suggests that this technology could be rapidly adapted to diagnose new variants of SARS-CoV-2 or other pathogens.
Hydrophobic Wafer-Scale High-Reproducibility SERS Sensor Based on Silicon Nanorods Arrays Decorated with Au Nanoparticles for Pesticide Residue Detection
Authors: Chen Fanhong , Zhao Yupeng , Zhang Shaoxun , Wei Shuhua , Ming Anjie , Mao Changhui
Published: April 2022

High sensitivity and reproducibility are highly desirable to a SERS sensor in diverse detection applications. Moreover, it is a great challenge to determine how to promote the target molecules to be more concentrated on the hotspots of the SERS substrate by engineering a surface with switching interfacial wettability. Along these lines, wafer-scale uniformly hydrophobic silicon nanorods arrays (SiNRs) decorated with Au nanoparticles were designed as the SERS substrate. Typically, the SERS substrate was fabricated by enforcing the polystyrene (PS) sphere self-assembly, as well as the plasma etching and the magnetron sputtering techniques. Consequently, the SERS substrate was treated by soaking within a n-dodecyl mercaptan (NDM) solution at different times in order to obtain adjustable wettabilities. By leveraging the electromagnetic enhancement resulted from the Au nanostructures and enrichment effect induced by the hydrophobicity, the SERS substrate is endowed with efficient SERS capabilities. During the detection of malachite green (MG), an ultralow relative standard deviation (RSD) 4.04–6.14% is achieved and the characteristic signal of 1172 cm−1 can be detected as low as 1 ng/mL. The proposed SiNRs’ structure presents outstanding SERS activity with sensitivity and reproducibility rendering thus an ideal candidate for potential application in analytical detection fields.
The Impact of Electroconvulsive Therapy on Negative Symptoms in Schizophrenia and Their Association with Clinical Outcomes
Authors: Tan Xiaowei , Martin Donel , Lee Jimmy , Tor Phern Chern
Published: April 2022

Objective: The treatment efficacy of electroconvulsive therapy (ECT) for negative symptoms amongst patients with schizophrenia remains unclear. In this study, we aim to examine the effects of ECT on negative symptoms in schizophrenia and their association with other clinical outcomes, including cognition and function. Methods: This is a retrospective data analysis of patients with schizophrenia/schizoaffective disorder treated with ECT at the Institute of Mental Health (IMH), Singapore, between January 2016 and December 2019. Clinical outcomes were assessed by the Brief Psychiatric Rating Scale (BPRS), the Montreal Cognitive Assessment (MoCA), and Global Assessment of Function (GAF). Changes in scores were compared with repeated measures analysis of variance. Sequential structural modelling was utilized to examine the pathway relationships between changes in negative symptoms, global functioning, and cognition functioning after ECT. Results: A total of 340 patients were analysed. Hence, 196 (57.6%), 53 (15.5%), and 91 (26.7%) showed improvements, no change, and deterioration in negative symptoms, respectively. ECT-induced improvement of negative symptoms was significantly associated with improvement of global functioning (direct effect correlation coefficient (r): −0.496; se: 0.152; p = 0.001) and cognition function (indirect effect r: −0.077; se: 0.037; p = 0.035). Moreover, having capacity to consent, more severe baseline negative symptoms, lithium prescription, and an indirect effect of voluntary admission status via consent capacity predicted ECT associated negative symptoms improvement. Conclusion: ECT is generally associated with improvements of negative symptoms in people with schizophrenia, which correlate with improvements of overall function. Possible novel clinical predictors of negative symptom improvement have been identified and will require further research and validation.
A Circuit Model for Working Memory Based on Hybrid Positive and Negative-Derivative Feedback Mechanism
Authors: Wei Hui , Jin Xiao , Su Zihao
Published: April 2022

Working memory (WM) plays an important role in cognitive activity. The WM system is used to temporarily store information in learning and decision-making. WM always functions in many aspects of daily life, such as the short-term memory of words, cell phone verification codes, and cell phone numbers. In young adults, studies have shown that a central memory store is limited to three to five meaningful items. Little is known about how WM functions at the microscopic neural level, but appropriate neural network computational models can help us gain a better understanding of it. In this study, we attempt to design a microscopic neural network model to explain the internal mechanism of WM. The performance of existing positive feedback models depends on the parameters of a synapse. We use a negative-derivative feedback mechanism to counteract the drift in persistent activity, making the hybrid positive and negative-derivative feedback (HPNF) model more robust to common disturbances. To fulfill the mechanism of WM at the neural circuit level, we construct two main neural networks based on the HPNF model: a memory-storage sub-network (the memory-storage sub-network is composed of several sets of neurons, so we call it “SET network”, or “SET” for short) with positive feedback and negative-derivative feedback and a storage distribution network (SDN) designed by combining SET for memory item storage and memory updating. The SET network is a neural information self-sustaining mechanism, which is robust to common disturbances; the SDN constructs a storage distribution network at the neural circuit level; the experimental results show that our network can fulfill the storage, association, updating, and forgetting of information at the level of neural circuits, and it can work in different individuals with little change in parameters.
Short-Term Memory for Auditory Temporal Patterns and Meaningless Sentences Predicts Learning of Foreign Word Forms
Authors: Service Elisabet , DeBorba Erin , Lopez-Cormier Angie , Horzum Meliha , Pape Daniel
Published: April 2022

The ability to accurately repeat meaningless nonwords or lists of spoken digits in correct order have been associated with vocabulary acquisition in both first and second language. Individual differences in these tasks are thought to depend on the phonological loop component of working memory. However, phonological working memory may itself depend on more elementary processes. We asked whether auditory non-verbal short-term memory (STM) for patterns in time supports immediate recall of speech-based sequences. Participants tapped temporal sequences consisting of short and long beeps and repeated nonsense sentences sounding like their native language or an unfamiliar language. As a language learning task, they also memorized familiar-word–foreign-word pairs. Word learning was directly predicted by nonsense sentence repetition accuracy. It was also predicted by temporal pattern STM. However, this association was mediated by performance on the repetition measure. We propose that STM for temporal patterns may reflect a component skill that provides the context signal necessary to encode order in phonological STM. It would be needed to support representation of the prosodic profile of language material, which allows syllables in words and words in sentences to be ordered and temporally grouped for short-term representation and long-term learning.
Predicting Math Ability Using Working Memory, Number Sense, and Neurophysiology in Children and Adults
Authors: van Bueren Nienke E. R. , van der Ven Sanne H. G. , Roelofs Karin , Cohen Kadosh Roi , Kroesbergen Evelyn H.
Published: April 2022

Previous work has shown relations between domain-general processes, domain-specific processes, and mathematical ability. However, the underlying neurophysiological effects of mathematical ability are less clear. Recent evidence highlighted the potential role of beta oscillations in mathematical ability. Here we investigate whether domain-general (working memory) and domain-specific (number sense) processes mediate the relation between resting-state beta oscillations and mathematical ability, and how this may differ as a function of development (children vs. adults). We compared a traditional analysis method normally used in EEG studies with a more recently developed parameterization method that separates periodic from aperiodic activity. Regardless of methods chosen, we found no support for mediation of working memory and number sense, neither for children nor for adults. However, we found subtle differences between the methods. Additionally, we showed that the traditional EEG analysis method conflates periodic activity with aperiodic activity; in addition, the latter is strongly related to mathematical ability and this relation differs between children and adults. At the cognitive level, our findings do not support previous suggestions of a mediation of working memory and number sense. At the neurophysiological level our findings suggest that aperiodic, rather than periodic, activity is linked to mathematical ability as a function of development.
Can Disruption of Basal Ganglia-Thalamocortical Circuit in Wilson Disease Be Associated with Juvenile Myoclonic Epilepsy Phenotype?
Authors: Rossi Jessica , Cavallieri Francesco , Giovannini Giada , Benuzzi Francesca , Ballotta Daniela , Vaudano Anna Elisabetta , Ferrara Francesca , Contardi Sara , Pietrangelo Antonello , Corradini Elena , Lui Fausta , Meletti Stefano
Published: April 2022

In this paper, we describe the multimodal MRI findings in a patient with Wilson disease and a seizure disorder, characterized by an electroclinical picture resembling juvenile myoclonic epilepsy. The brain structural MRI showed a deposition of ferromagnetic materials in the basal ganglia, with marked hypointensities in T2-weighted images of globus pallidus internus bilaterally. A resting-state fMRI study revealed increased functional connectivity in the patient, compared to control subjects, in the following networks: (1) between the primary motor cortex and several cortical regions, including the secondary somatosensory cortex and (2) between the globus pallidus and the thalamo-frontal network. These findings suggest that globus pallidus alterations, due to metal accumulation, can lead to a reduction in the normal globus pallidus inhibitory tone on the thalamo-(motor)-cortical pathway. This, in turn, can result in hyperconnectivity in the motor cortex circuitry, leading to myoclonus and tonic-clonic seizures. We suppose that, in this patient, Wilson disease generated a ‘lesion model’ of myoclonic epilepsy.
Fluorescence-Guided Surgery in Glioblastoma: 5-ALA, SF or Both? Differences between Fluorescent Dyes in 99 Consecutive Cases
Authors: Zeppa Pietro , De Marco Raffaele , Monticelli Matteo , Massara Armando , Bianconi Andrea , Di Perna Giuseppe , Greco Crasto Stefania , Cofano Fabio , Melcarne Antonio , Lanotte Michele Maria , Garbossa Diego
Published: April 2022

Background: Glioblastoma (GBM) is the most common primary brain tumor. The extent of resection (EOR) has been claimed as one of the most important prognostic factors. Fluorescent dyes aid surgeons in detecting a tumor’s borders. 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SF) are the most used. Only a few studies have directly compared these two fluorophores. Methods: A single center retrospective analysis of patients treated for GBM in the period between January 2018 and January 2021 was built to find any differences in terms of EOR, Karnofsky Performance Status (KPS), and overall survival (OS) on the use of 5-ALA, SF, or both. Results: Overall, 99 patients affected by isocitrate dehydrogenase (IDH) wild-type Glioblastoma were included. 5-ALA was administered to 40 patients, SF to 44, and both to 15. No statistically significant associations were identified between the fluorophore and EOR (p = 0.783) or postoperative KPS (p = 0.270). Survival analyses did not show a selective advantage for the use of a given fluorophore (p = 0.184), although there appears to be an advantageous trend associated with the concomitant use of both dyes, particularly after stratification by MGMT (p = 0.071). Conclusions: 5-Ala and SF are equally useful in achieving gross total resection of the enhancing tumor volume. The combination of both fluorophores could lead to an OS advantage.
Mean Stress Effect in High-Frequency Mechanical Impact (HFMI)-Treated Steel Road Bridges
Authors: Al-Karawi Hassan , Shams-Hakimi Poja , Al-Emrani Mohammad
Published: April 2022

High-frequency mechanical impact (HFMI) is a post-weld treatment method which substantially enhances the fatigue strength of steel weldments. As such, the method enables a more efficient design of bridges, where fatigue is often the governing limit state. Road bridges are typically trafficked by a large variety of lorries which generate load cycles with varying mean stresses and stress ranges. Unlike conventional welded details, the fatigue strength of HFMI-treated welds is known to be dependent on mean stress in addition to the stress range. The possibility of considering the mean stress effect via Eurocode’s fatigue load models (FLM3 and FLM4) was investigated in this paper. Moreover, a design method to take the mean stress effect into account was proposed by the authors in a previous work. However, the proposed design method was calibrated using limited traffic measurements in Sweden, and as such, may not be representative of the Swedish or European traffic. In this paper, larger data pools consisting of more than 873,000 and 446,000 lorries from Sweden and the Netherlands, respectively, were used to examine the validity of previous calibration in both countries. The comparison revealed no significant difference between the data pools with regards to the mean stress effect. Additionally, previous calibration provided the most conservative mean stress effect and was considered adequately representative for both countries. The proposed design method was further validated using four composite case study bridges. It was also found that the mean stress effect was mainly influenced by the self-weight, while variation in the mean stress due to traffic had a minor influence on the total mean stress effect. Furthermore, it was found that the mean stress effect could not be accurately or conservatively predicted using FLM3 or FLM4.
Governance Strategies for Informal Settlements in China: The Case of Guangzhou
Authors: Yang Jinkun , Cai Yayin , Ma Haitao , Weng Lisheng
Published: April 2022

Informal settlements in developing countries have attracted widespread attention, and existing research is mainly concerned with the causes and evolution of informal settlements. However, few studies have focused on investigating the spatial governance strategies of informal settlements in order to understand the evolution of informal settlements in the context of institutional arrangements. The aim of this research is to develop a framework for the spatial governance of informal settlements to explain their causes. The research finds that informal settlements in China are influenced by an urban–rural dual land system in which the collective land ownership system means that villagers are ambiguous in their approach to land development. During rapid urbanization, villagers have adopted diverse land development strategies based on land rent incentives to attract capital investment and earn profits, which has led to the rapid spread of informal settlements.
Green Land Use Efficiency and Influencing Factors of Resource-Based Cities in the Yellow River Basin under Carbon Emission Constraints
Authors: Chen Meijing , Wang Qingri , Bai Zhongke , Shi Zeyu , Meng Peng , Hao Miao
Published: April 2022

Green and low-carbon strategies represent governance orientations for resource-based cities to respond to global changes and achieve sustainable development. Designating the Yellow River Basin (YRB), an important ecological functional area and an ecologically fragile area, as the research area, this study used the super-efficiency SBM model while considering undesirable outputs, including carbon emissions, to analyze green land use efficiency (GLUE) and its temporal and spatial differentiation, then used the Tobit regression model to analyze the influencing factors. The results were as follows: (1) The GLUE of the YRB presented a spatial pattern of “high in the west and low in the east”. (2) Overall, the efficiency values of all areas and types increased annually, but differences occurred in various areas and types of resource-based cities. (3) Overall, the efficiency values of the Yellow River Basin showed a “high-low” polarization. (4) Economic development and population growth factors substantially impacted the GLUE of resource-based cities in this region. It is concluded that increasing the efficiency improvement of low-efficiency regions or cities can improve regional GLUE. To ensure regional green and low-carbon transformation and development, it is essential to enhance urban economic vitality, promote an orderly population flow, and strive to improve social and public services.
Changing Landscape of Systemic Therapy in Biliary Tract Cancer
Authors: Woods Edward , Le Dat , Jakka Bharath Kumar , Manne Ashish
Published: April 2022

Biliary tract cancers (BTC) are often diagnosed at advanced stages and have a grave outcome due to limited systemic options. Gemcitabine and cisplatin combination (GC) has been the first-line standard for more than a decade. Second-line chemotherapy (CT) options are limited. Targeted therapy or TT (fibroblast growth factor 2 inhibitors or FGFR2, isocitrate dehydrogenase 1 or IDH-1, and neurotrophic tyrosine receptor kinase or NTRK gene fusions inhibitors) have had reasonable success, but <5% of total BTC patients are eligible for them. The use of immune checkpoint inhibitors (ICI) such as pembrolizumab is restricted to microsatellite instability high (MSI-H) patients in the first line. The success of the TOPAZ-1 trial (GC plus durvalumab) is promising, with numerous trials underway that might soon bring targeted therapy (pemigatinib and infrigatinib) and ICI combinations (with CT or TT in microsatellite stable cancers) in the first line. Newer targets and newer agents for established targets are being investigated, and this may change the BTC management landscape in the coming years from traditional CT to individualized therapy (TT) or ICI-centered combinations. The latter group may occupy major space in BTC management due to the paucity of targetable mutations and a greater toxicity profile.
Differences in the Active Endometrial Microbiota across Body Weight and Cancer in Humans and Mice
Authors: Kaakoush Nadeem O. , Olzomer Ellen M. , Kosasih Melidya , Martin Amy R. , Fargah Farokh , Lambie Neil , Susic Daniella , Hoehn Kyle L. , Farrell Rhonda , Byrne Frances L.
Published: April 2022

Obesity is a risk factor for endometrial cancer. The aim of this study was to determine whether actively replicating microbiota in the endometrium differ between obese vs. lean and cancer vs. benign states. We performed 16S rRNA amplicon sequencing on endometrial tissues from lean and obese women with and without endometrial cancer, and lean and obese mice. Results displayed human endometrial microbiota clustered into three community types (R = 0.363, p = 0.001). Lactobacillus was dominant in community type 1 (C1) while community type 2 (C2) had high levels of Proteobacteria and more cancer samples when compared to C1 (p = 0.007) and C3 (p = 0.0002). A significant increase in the prevalence of the C2 community type was observed across body mass index and cancer (χ2 = 14.24, p = 0.0002). The relative abundance of Lactobacillus was lower in cancer samples (p = 0.0043), and an OTU with 100% similarity to Lactobacillus iners was enriched in control samples (p = 0.0029). Mouse endometrial microbiota also clustered into three community types (R = 0.419, p = 0.001) which were not influenced by obesity. In conclusion, obesity and cancer are associated with community type prevalence in the human endometrium, and Lactobacillus abundance is associated with normal uterine histologies in humans and mice.
Skin Cancer-Associated S. aureus Strains Can Induce DNA Damage in Human Keratinocytes by Downregulating DNA Repair and Promoting Oxidative Stress
Authors: Krueger Annika , Mohamed Ahmed , Kolka Cathryn M. , Stoll Thomas , Zaugg Julian , Linedale Richard , Morrison Mark , Soyer H. Peter , Hugenholtz Philip , Frazer Ian H. , Hill Michelle M.
Published: April 2022

Actinic keratosis (AK) is a premalignant lesion, common on severely photodamaged skin, that can progress over time to cutaneous squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC, but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus can have cancer-promoting effects on skin cells, we performed RNA sequencing and shotgun proteomics on primary human keratinocytes after challenge with sterile culture supernatant (‘secretome’) from four S. aureus clinical strains isolated from AK and SCC. Secretomes of two of the S. aureus strains induced keratinocytes to overexpress biomarkers associated with skin carcinogenesis and upregulated the expression of enzymes linked to reduced skin barrier function. Further, these strains induced oxidative stress markers and all secretomes downregulated DNA repair mechanisms. Subsequent experiments on an expanded set of lesion-associated S. aureus strains confirmed that exposure to their secretomes led to increased oxidative stress and DNA damage in primary human keratinocytes. A significant correlation between the concentration of S. aureus phenol soluble modulin toxins in secretome and the secretome-induced level of oxidative stress and genotoxicity in keratinocytes was observed. Taken together, these data demonstrate that secreted compounds from lesion-associated clinical isolates of S. aureus can have cancer-promoting effects in keratinocytes that may be relevant to skin oncogenesis.
Potential of Inflammatory Protein Signatures for Enhanced Selection of People for Lung Cancer Screening
Authors: Bhardwaj Megha , Schöttker Ben , Holleczek Bernd , Benner Axel , Schrotz-King Petra , Brenner Hermann
Published: April 2022

Randomized trials have demonstrated a substantial reduction in lung cancer (LC) mortality by screening heavy smokers with low-dose computed tomography (LDCT). The aim of this study was to assess if and to what extent blood-based inflammatory protein biomarkers might enhance selection of those at highest risk for LC screening. Ever smoking participants were chosen from 9940 participants, aged 50–75 years, who were followed up with respect to LC incidence for 17 years in a prospective population-based cohort study conducted in Saarland, Germany. Using proximity extension assay, 92 inflammation protein biomarkers were measured in baseline plasma samples of ever smoking participants, including 172 incident LC cases and 285 randomly selected participants free of LC. Smoothly clipped absolute deviation (SCAD) penalized regression with 0.632+ bootstrap for correction of overoptimism was applied to derive an inflammation protein biomarker score (INS) and a combined INS-pack-years score in a training set, and algorithms were further evaluated in an independent validation set. Furthermore, the performances of nine LC risk prediction models individually and in combination with inflammatory plasma protein biomarkers for predicting LC incidence were comparatively evaluated. The combined INS-pack-years score predicted LC incidence with area under the curves (AUCs) of 0.811 and 0.782 in the training and the validation sets, respectively. The addition of inflammatory plasma protein biomarkers to established nine LC risk models increased the AUCs up to 0.121 and 0.070 among ever smoking participants from training and validation sets, respectively. Our results suggest that inflammatory protein biomarkers may have potential to improve the selection of people for LC screening and thereby enhance screening efficiency.
Opportunities for Participation in Randomized Controlled Trials for Patients with Multiple Myeloma: Trial Access Depends on Restrictive Eligibility Criteria and Patient Expectations
Authors: Boquoi Amelie , Rings Veronika , Mohring Annemarie , Savickaite Ingrida , Zukovs Romans , Strapatsas Judith , Nachtkamp Kathrin , Kobbe Guido , Germing Ulrich , Fenk Roland
Published: April 2022

Randomized controlled trials (RCT) are the driver of therapeutic innovations. However, it has been frequently shown that less than 5% of adult cancer patients enroll in clinical trials, although 70% of patients are considered as being willing to participate. Barriers to trial participation have been extensively studied. Although there is evidence that trial participation correlates with improved survival and reduced mortality, the rate of participation has not changed substantially. We provide retrospective data from a single-center analysis of 411 patients with multiple myeloma (MM) who were treated at the University Hospital Duesseldorf in Germany between January 2014 and December 2016. Each patient was analyzed for the real-world possibility of participating in a clinical study, based on the inclusion and exclusion (I/E) criteria and the recruiting period of open studies. The overall rate of study participation was 19%. A total of 53% of NDMM patients were eligible for first-line studies (GMMG-HD6, LenaMain). Of these, 80% consented to enrolment (42% of all). In contrast, only 38% of the RRMM population was eligible (GMMG-Relapse, Castor, Tourmaline, Admyre). Of these, only 22% (7% of all) consented. This was confirmed by virtual analysis, showing that only 29% of all RRMM patients would have been eligible for six internationally recruiting trials leading to later drug approval. The majority of cases were rendered ineligible by only one I/E criterion. The most common criteria were study-specific (prior therapies or refractory disease to a specific drug), kidney disease, and previous malignancy, followed by internal, neurologic, and infectious disease. In summary, this single-center analysis showed that I/E criteria permit study participation for most NNDM patients, with a dramatic decrease in the RRMM population. This is aggravated by the fact that the willingness for study participation also significantly declines in RRMM. Thus, addressing patient expectations and priorities seems to be the most promising approach to increasing patient enrollment in clinical trials.
Tumor Microenvironment in Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: Interaction between Tumors and Immune Cells, and Potential Effects of Neuroendocrine Differentiation on the Tumor Microenvironment
Authors: Tsunokake Junichi , Fujishima Fumiyoshi , Watanabe Hirofumi , Sato Ikuro , Miura Koh , Sakamoto Kazuhiro , Suzuki Hiroyoshi , Sawai Takashi , Itakura Yuko , Hoshi Tatsuya , Kunimitsu Atsushi , Yamauchi Takuro , Akaishi Ryujiro , Ozawa Yohei , Fukutomi Toshiaki , Okamoto Hiroshi , Sato Chiaki , Taniyama Yusuke , Kamei Takashi , Sasano Hironobu
Published: April 2022

The tumor microenvironment is considered to play a pivotal role in various human malignancies. Neuroendocrine and non-neuroendocrine neoplasms are considered to have different tumor microenvironments. However, owing to differences in the systemic and/or local immune statuses, tumor microenvironments in different patients may be difficult to compare. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs), although rare, could be useful for exploring the effects of neuroendocrine differentiation on the tumor microenvironment, because both neuroendocrine and non-neuroendocrine components are present in the same tumor. Here, we examined 33 cases of histologically confirmed MiNENs and evaluated the influence of neuroendocrine differentiation on the tumor microenvironment by comparing tumor-infiltrating lymphocytes, tumor-associated macrophages, and other relevant factors in the two components the same tumor. The immunoreactivity of those examined above was evaluated quantitatively. The values of vasohibin-1-positive density (p < 0.0001) and immunoreactivity (p < 0.0001) (representing the neoangiogenesis status) were significantly higher in neuroendocrine as compared to non-neuroendocrine areas of the same tumors. In addition, the Foxp3/CD8 (p = 0.0717) and the PD-1/CD8 ratios (p = 0.0176) (representing tumor immunity suppression) tend to increase in neuroendocrine carcinomas. Immunoreactivity of CD163, a marker of M2-like macrophages, was also higher in the neuroendocrine areas. Our findings indicate that neuroendocrine and non-neuroendocrine tumors differ from each other with respect to the characteristics of both tumor cells and the tumor microenvironment.
Oncogenic Kras-Mediated Cytokine CCL15 Regulates Pancreatic Cancer Cell Migration and Invasion through ROS
Authors: Messex Justin , Adams Kiyah , Hawkins William , DeNardo David , Bardeesy Nabeel , Billadeau Daniel , Liou Geou-Yarh
Published: April 2022

Pancreatic ductal adenocarcinoma (PDAC) is well known for its high death rate due to prompt cancer metastasis caused by cancer cell migration and invasion within the early stages of its development. Here, we reveal a new function of cytokine CCL15, namely the upregulation of PDAC cell migration and invasion. We showed increased levels of CCL15 transcripts and protein expressions in human PDAC tissue samples, as well as in cultured cell lines. Furthermore, PDAC cells also expressed CCL15 receptors, including CCR1 and CCR3. Murine PDAC cell lines and tissues strengthened this finding. The manipulation of CCL15 in metastatic Panc-1 cells through CCL15 knockdown or CCL15 neutralization decreased Panc-1 cell motility and invasiveness. In addition, treating non-metastatic BxPC-3 cells with recombinant CCL15 accelerated the cell migration of BxPC-3. A reduction in the levels of reactive oxygen species (ROS) by either N-Acetyl-L-Cysteine treatment or p22phox knockdown led to a decrease in Panc-1 cell migration and a reversed effect on recombinant CCL15-promoted BxPC-3 cell movement. Importantly, the knockdown of oncogenic Kras in Panc-1 cells abolished CCL15 protein expression and impeded cell migration without affecting PDAC cell growth. Altogether, our work elucidates an additional molecular pathway of oncogenic Kras to promote PDAC metastasis through the upregulation of cell migration and invasion by the Kras downstream CCL15, a lesser-known cytokine within the cancer research field.
CD229 (Ly9) a Novel Biomarker for B-Cell Malignancies and Multiple Myeloma
Authors: Roncador Giovanna , Puñet-Ortiz Joan , Maestre Lorena , Rodríguez-Lobato Luis Gerardo , Jiménez Scherezade , Reyes-García Ana Isabel , García-González Álvaro , García Juan F. , Piris Miguel Ángel , Montes-Moreno Santiago , Rodríguez-Justo Manuel , Mena Mari-Pau , Fernández de Larrea Carlos , Engel Pablo
Published: April 2022

CD229 (Ly9) homophilic receptor, which belongs to the SLAM family of cell-surface molecules, is predominantly expressed on B and T cells. It acts as a signaling molecule, regulating lymphocyte homoeostasis and activation. Studies of CD229 function indicate that this receptor functions as a regulator of the development of marginal-zone B cells and other innate-like T and B lymphocytes. The expression on leukemias and lymphomas remains poorly understood due to the lack of CD229 monoclonal antibodies (mAb) for immunohistochemistry application (IHC). In this study, we used a new mAb against the cytoplasmic region of CD229 to study the expression of CD229 on normal tissues and B-cell malignancies, including multiple myeloma (MM), using tissue microarrays. We showed CD229 to be restricted to hematopoietic cells. It was strongly expressed in all cases of MM and in most marginal-zone lymphomas (MZL). Moderate CD229 expression was also found in chronic lymphocyte leukemia (CLL), follicular (FL), classic mantle-cell (MCL) and diffuse large B-cell lymphoma. Given the high expression on myeloma cells, we also analyzed for the presence of soluble CD229 in the sera of these patients. Serum levels of soluble CD229 (sCD229) at the time of diagnosis in MM patients could be useful as a prognostic biomarker. In conclusion, our results indicate that CD229 represents not only a useful biomarker but also an attractive therapeutic target.
Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Chan Daisy , Choi Horace , Lee Victor
Published: April 2022

(1) Background: We performed a meta-analysis to examine whether combined epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) and immune checkpoint inhibitor (ICI) increases treatment-related adverse events (trAEs) in advanced non-small cell lung cancer (NSCLC). (2) Methods: Articles from MEDLINE, EMBASE, and Cochrane databases were searched. Proportions and odds ratios (ORs) of the pooled incidence of overall and organ-specific trAEs in combination EGFR-TKI and ICI were compared to TKI monotherapy. (3) Results: Eight studies fulfilled our selection criteria. Any-grade organ-specific trAEs were more common in combination EGFR-TKI and ICI than TKI monotherapy (skin: OR = 1.19, p = 0.012; gastrointestinal tract: OR = 1.04, p = 0.790; ILD: OR = 1.28, p = 0.001). Grade ≥ 3 trAEs were also more frequent in combination treatment (skin: OR = 1.13, p = 0.082; gastrointestinal tract: OR = 1.13, p = 0.076; ILD: OR = 1.16, p = 0.003). (4) Conclusions: A higher proportion of grade ≥3 skin and gastrointestinal trAEs and ILDs was observed in combination TKI and ICI compared to TKI alone. Caution has to be taken when interpreting the results owing to the small number of studies included in this meta-analysis.
Malignant Superficial Mesenchymal Tumors in Children
Authors: Drabent Philippe , Fraitag Sylvie
Published: April 2022

Malignant superficial mesenchymal tumors are a very diverse group of neoplasms with few clinical and radiological discriminatory factors. Hence, some of these cancers are rarely suspected based on clinical and radiological grounds, others may be easily misdiagnosed, and the histological analysis of a biopsy or resection is central in the diagnostic process. In children, the age at presentation is a major element of the differential diagnosis. Some tumors have a very distinct epidemiology, while others may be seen at any age. More recently, the advances in molecular biology have greatly improved the diagnosis of mesenchymal tumors and new entities are still being described. In the present review, we provide an overview of the diversity of malignant superficial mesenchymal tumors in children, including new and/or rare entities. We discuss the important diagnostic features, be they clinical, histological, or molecular. Special attention was given to the genetic features of these tumors, particularly when they were helpful for the diagnosis or treatment.
PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives
Authors: Fuso Paola , Muratore Margherita , D’Angelo Tatiana , Paris Ida , Carbognin Luisa , Tiberi Giordana , Pavese Francesco , Duranti Simona , Orlandi Armando , Tortora Giampaolo , Scambia Giovanni , Fabi Alessandra
Published: April 2022

Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting.
7T HR FID-MRSI Compared to Amino Acid PET: Glutamine and Glycine as Promising Biomarkers in Brain Tumors
Authors: Hangel Gilbert , Lazen Philipp , Sharma Sukrit , Hristoska Barbara , Cadrien Cornelius , Furtner Julia , Rausch Ivo , Lipka Alexandra , Niess Eva , Hingerl Lukas , Motyka Stanislav , Gruber Stephan , Strasser Bernhard , Kiesel Barbara , Preusser Matthias , Roetzer-Pejrimovsky Thomas , Wöhrer Adelheid , Bogner Wolfgang , Widhalm Georg , Rössler Karl , Traub-Weidinger Tatjana , Trattnig Siegfried
Published: April 2022

(1) Background: Recent developments in 7T magnetic resonance spectroscopic imaging (MRSI) made the acquisition of high-resolution metabolic images in clinically feasible measurement times possible. The amino acids glutamine (Gln) and glycine (Gly) were identified as potential neuro-oncological markers of importance. For the first time, we compared 7T MRSI to amino acid PET in a cohort of glioma patients. (2) Methods: In 24 patients, we co-registered 7T MRSI and routine PET and compared hotspot volumes of interest (VOI). We evaluated dice similarity coefficients (DSC), volume, center of intensity distance (CoI), median and threshold values for VOIs of PET and ratios of total choline (tCho), Gln, Gly, myo-inositol (Ins) to total N-acetylaspartate (tNAA) or total creatine (tCr). (3) Results: We found that Gln and Gly ratios generally resulted in a higher correspondence to PET than tCho. Using cutoffs of 1.6-times median values of a control region, DSCs to PET were 0.53 ± 0.36 for tCho/tNAA, 0.66 ± 0.40 for Gln/tNAA, 0.57 ± 0.36 for Gly/tNAA, and 0.38 ± 0.31 for Ins/tNAA. (4) Conclusions: Our 7T MRSI data corresponded better to PET than previous studies at lower fields. Our results for Gln and Gly highlight the importance of future research (e.g., using Gln PET tracers) into the role of both amino acids.
Combining TMEM Doorway Score and MenaCalc Score Improves the Prediction of Distant Recurrence Risk in HR+/HER2− Breast Cancer Patients
Authors: Ye Xianjun , Oktay Maja H. , Xue Xiaonan , Rohan Thomas E. , Ginter Paula S. , D’Alfonso Timothy , Kornaga Elizabeth N. , Morris Don G. , Entenberg David , Condeelis John S.
Published: April 2022

Purpose: to develop several digital pathology-based machine vision algorithms for combining TMEM and MenaCalc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. Methods: This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin-fixed paraffin-embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and MenaCalc (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and MenaCalc. Different ways of combining TMEM doorway and MenaCalc scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. Results: the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71–8.37), compared to 3.56 years (95% CI: 0.95–6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25–5.87) for the associated standalone MenaCalc analysis. Conclusions: combining TMEM doorway and MenaCalc scores as a new biomarker improves prognostication over that observed with TMEM doorway or MenaCalc Score alone in this cohort of 86 patients.
Phytocomplex of a Standardized Extract from Red Orange (Citrus sinensis L. Osbeck) against Photoaging
Authors: Tomasello Barbara , Malfa Giuseppe Antonio , Acquaviva Rosaria , La Mantia Alfonsina , Di Giacomo Claudia
Published: April 2022

Excessive exposure to solar radiation is associated with several deleterious effects on human skin. These effects vary from the occasional simple sunburn to conditions resulting from chronic exposure such as skin aging and cancers. Secondary metabolites from the plant kingdom, including phenolic compounds, show relevant photoprotective activities. In this study, we evaluated the potential photoprotective activity of a phytocomplex derived from three varieties of red orange (Citrus sinensis (L.) Osbeck). We used an in vitro model of skin photoaging on two human cell lines, evaluating the protective effects of the phytocomplex in the pathways involved in the response to damage induced by UVA-B. The antioxidant capacity of the extract was determined at the same time as evaluating its influence on the cellular redox state (ROS levels and total thiol groups). In addition, the potential protective action against DNA damage induced by UVA-B and the effects on mRNA and protein expression of collagen, elastin, MMP1, and MMP9 were investigated, including some inflammatory markers (TNF-α, IL-6, and total and phospho NFkB) by ELISA. The obtained results highlight the capacity of the extract to protect cells both from oxidative stress—preserving RSH (p < 0.05) content and reducing ROS (p < 0.01) levels—and from UVA-B-induced DNA damage. Furthermore, the phytocomplex is able to counteract harmful effects through the significant downregulation of proinflammatory markers (p < 0.05) and MMPs (p < 0.05) and by promoting the remodeling of the extracellular matrix through collagen and elastin expression. This allows the conclusion that red orange extract, with its strong antioxidant and photoprotective properties, represents a safe and effective option to prevent photoaging caused by UVA-B exposure.
B7-H4 Immune Checkpoint Protein Affects Viability and Targeted Therapy of Renal Cancer Cells
Authors: Emaldi Maite , Nunes-Xavier Caroline E.
Published: April 2022

Targeted therapy in combination with immune checkpoint inhibitors has been recently implemented in advanced or metastatic renal cancer treatment. However, many treated patients either do not respond or develop resistance to therapy, making alternative immune checkpoint-based immunotherapies of potential clinical benefit for specific groups of patients. In this study, we analyzed the global expression of B7 immune checkpoint family members (PD-L1, PD-L2, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7) in human renal cancer cells (Caki-1, A-498, and 786-O cell lines) upon treatment with clinically relevant targeted drugs, including tyrosine kinase inhibitors (Axitinib, Cabozantinib, and Lenvatinib) and mTOR inhibitors (Everolimus and Temsirolimus). Gene expression analysis by quantitative PCR revealed differential expression patterns of the B7 family members in renal cancer cell lines upon targeted drug treatments. B7-H4 gene expression was upregulated after treatment with various targeted drugs in Caki-1 and 786-O renal cancer cells. Knocking down the expression of B7-H4 by RNA interference (RNAi) using small interfering RNA (siRNA) decreased renal cancer cell viability and increased drug sensitivity. Our results suggest that B7-H4 expression is induced upon targeted therapy in renal cancer cells and highlight B7-H4 as an actionable immune checkpoint protein in combination with targeted therapy in advanced renal cancer cases resistant to current treatments.