bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibiting Transglutaminase 2 Mediates Kidney Fibrosis via Anti-Apoptosis
Authors: Moon Jong-Joo , Choi Yejin , Kim Kyu-Hyeon , Seo Areum , Kwon Soie , Kim Yong-Chul , Kim Dong-Ki , Kim Yon-Su , Yang Seung-Hee
Published: June 2022

Transglutaminase 2 (TG2) is a calcium-dependent transamidating acyltransferase enzyme of the protein-glutamine γ-glutamyltransferase family implicated in kidney injury. In this study, we identified associations between TG2 and chronic kidney disease (CKD) identified by visualizing TG2 in kidney biopsy samples derived from CKD patients using immunohistochemistry and measuring the plasma TG2 concentrations. Our study revealed a connection between TG2 and the pathological markers of kidney disease. We showed high plasma TG2 levels in samples from patients with advanced CKD. In addition, we observed an increase in TG2 expression in tissues concomitant with advanced CKD in human samples. Moreover, we investigated the effect of TG2 inhibition on kidney injury using cystamine, a well-known competitive inhibitor of TG2. TG2 inhibition reduced apoptosis and accumulation of extracellular molecules (ECM) such as fibronectin and pro-inflammatory cytokine IL-8. Collectively, the increased expression of TG2 that was observed in advanced CKD, hence inhibiting TG2 activity, could protect kidney cells from ECM molecule accumulation, apoptosis, and inflammatory responses, thereby preventing kidney fibrosis.
Extraction-Free Absolute Quantification of Circulating miRNAs by Chip-Based Digital PCR
Authors: D’Alessandra Yuri , Valerio Vincenza , Moschetta Donato , Massaiu Ilaria , Bozzi Michele , Conte Maddalena , Parisi Valentina , Ciccarelli Michele , Leosco Dario , Myasoedova Veronika A. , Poggio Paolo
Published: June 2022

Circulating microRNAs (miRNA) have been proposed as specific biomarkers for several diseases. Quantitative Real-Time PCR (RT-qPCR) is the gold standard technique currently used to evaluate miRNAs expression from different sources. In the last few years, digital PCR (dPCR) emerged as a complementary and accurate detection method. When dealing with gene expression, the first and most delicate step is nucleic-acid isolation. However, all currently available protocols for RNA extraction suffer from the variable loss of RNA species due to the chemicals and number of steps involved, from sample lysis to nucleic acid elution. Here, we evaluated a new process for the detection of circulating miRNAs, consisting of sample lysis followed by direct evaluation by dPCR in plasma from healthy donors and in the cardiovascular setting. Our results showed that dPCR is able to detect, with high accuracy, low-copy-number as well as highly expressed miRNAs in human plasma samples without the need for RNA extraction. Moreover, we assessed a known myocardial infarction-related miR-133a in acute myocardial infarct patients vs. healthy subjects. In conclusion, our results show the suitability of the extraction-free quantification of circulating miRNAs as disease markers by direct dPCR.
Complement Activation Profile in Myasthenia Gravis Patients: Perspectives for Tailoring Anti-Complement Therapy
Authors: Iacomino Nicola , Vanoli Fiammetta , Frangiamore Rita , Ballardini Marta , Scandiffio Letizia , Bortone Federica , Andreetta Francesca , Baggi Fulvio , Bernasconi Pia , Antozzi Carlo , Cavalcante Paola , Mantegazza Renato
Published: June 2022

The complement system plays a key role in myasthenia gravis (MG). Anti-complement drugs are emerging as effective therapies to treat anti-acetylcholine receptor (AChR) antibody-positive MG patients, though their usage is still limited by the high costs. Here, we searched for plasma complement proteins as indicators of complement activation status in AChR-MG patients, and potential biomarkers for tailoring anti-complement therapy in MG. Plasma was collected from AChR-MG and MuSK-MG patients, and healthy controls. Multiplex immunoassays and ELISA were used to quantify a panel of complement components (C1Q, C2, C3, C4, C5, Factor B, Factor H, MBL, and properdin) and activation products (C4b, C3b, C5a, and C5b-9), of classical, alternative and lectin pathways. C2 and C5 levels were significantly reduced, and C3, C3b, and C5a increased, in plasma of AChR-MG, but not MuSK-MG, patients compared to controls. This protein profile was indicative of complement activation. We obtained sensitivity and specificity performance results suggesting plasma C2, C3, C3b, and C5 as biomarkers for AChR-MG. Our findings reveal a plasma complement “C2, C3, C5, C3b, and C5a” profile associated with AChR-MG to be further investigated as a biomarker of complement activation status in AChR-MG patients, opening new perspectives for tailoring of anti-complement therapies to improve the disease treatment.
Mycelial Beehives of HIVEOPOLIS: Designing and Building Therapeutic Inner Nest Environments for Honeybees
Authors: Ilgun Asya , Schmickl Thomas
Published: June 2022

The perceptions and definitions of healthy indoor environments have changed significantly throughout architectural history. Today, molecular biology teaches us that microbes play important roles in human health, and that isolation from them puts not only us but also other inhabitants of urban landscapes, at risk. In order to provide an environment that makes honeybees more resilient to environmental changes, we aim for combining the thermal insulation functionality of mycelium materials with bioactive therapeutic properties within beehive constructions. By identifying mycelial fungi’s interactions with nest-related materials, using digital methods to design a hive structure, and engaging in additive manufacturing, we were able to develop a set of methods for designing and fabricating a fully grown hive. We propose two digital methods for modelling 3D scaffolds for micro-super organism co-occupation scenarios: “variable-offset” and “iterative-subtraction”, followed by two inoculation methods for the biofabrication of scaffolded fungal composites. The HIVEOPOLIS project aims to diversify and complexify urban ecological niches to make them more resilient to future game changers such as climate change. The combined functions of mycelium materials have the potential to provide a therapeutic environment for honeybees and, potentially, humans in the future.
Bioinspired Intelligence II
Authors: Crespo-Mariño Juan Luis , Segura-Castillo Andrés
Published: June 2022

Bioinspired intelligence methods are currently common approaches for both engineers and the scientists [...]
Enhanced Detection in Droplet Microfluidics by Acoustic Vortex Modulation of Particle Rings and Particle Clusters via Asymmetric Propagation of Surface Acoustic Waves
Authors: Liu Yukai , Ji Miaomiao , Yu Nanxin , Zhao Caiqin , Xue Gang , Fu Wenxiao , Qiao Xiaojun , Zhang Yichi , Chou Xiujian , Geng Wenping
Published: June 2022

As a basis for biometric and chemical analysis, issues of how to dilute or concentrate substances such as particles or cells to specific concentrations have long been of interest to researchers. In this study, travelling surface acoustic wave (TSAW)-based devices with three frequencies (99.1, 48.8, 20.4 MHz) have been used to capture the suspended Polystyrene (PS) microspheres of various sizes (5, 20, 40 μm) in sessile droplets, which are controlled by acoustic field-induced fluid vortex (acoustic vortex) and aggregate into clusters or rings with particles. These phenomena can be explained by the interaction of three forces, which are drag force caused by ASF, ARF caused by Leaky-SAW and varying centrifugal force. Eventually, a novel approach of free transition between the particle ring and cluster was approached via modulating the acoustic amplitude of TSAW. By this method, multilayer particles agglomerate with 20 μm wrapped around 40 μm and 20 μm wrapped around 5 μm can be obtained, which provides the possibility to dilute or concentrate the particles to a specific concentration.
A Proof-of-Concept Electrochemical Cytosensor Based on Chlamydomonas reinhardtii Functionalized Carbon Black Screen-Printed Electrodes: Detection of Escherichia coli in Wastewater as a Case Study
Authors: Antonacci Amina , Arduini Fabiana , Attaallah Raouia , Amine Aziz , Giardi Maria Teresa , Scognamiglio Viviana
Published: June 2022

Herein, we report a proof-of-concept algal cytosensor for the electrochemical quantification of bacteria in wastewater, exploiting the green photosynthetic alga Chlamydomonas reinhardtii immobilized on carbon black (CB) nanomodified screen-printed electrodes. The CB nanoparticles are used as nanomodifiers, as they are able to sense the oxygen produced by the algae and thus the current increases when algae are exposed to increasing concentrations of bacteria. The sensor was tested on both standard solutions and real wastewater samples for the detection Escherichia coli in a linear range of response from 100 to 2000 CFU/100 mL, showing a limit of detection of 92 CFU/100 mL, in agreement with the maximum E. coli concentration established by the Italian law for wastewater (less than 5000 CFU/100 mL). This bacterium was exploited as a case study target of the algal cytosensor to demonstrate its ability as an early warning analytical system to signal heavy loads of pathogens in waters leaving the wastewater treatment plants. Indeed, the cytosensor is not selective towards E. coli but it is capable of sensing all the bacteria that induce the algae oxygen evolution by exploiting the effect of their interaction. Other known toxicants, commonly present in wastewater, were also analyzed to test the cytosensor selectivity, with any significant effect, apart from atrazine, which is a specific target of the D1 protein of the Chlamydomonas photosystem II. However, the latter can also be detected by chlorophyll fluorescence simultaneously to the amperometric measurements. The matrix effect was evaluated, and the recovery values were calculated as 105 ± 8, 83 ± 7, and 88 ± 7% for 1000 CFU/100 mL of E. coli in Lignano, San Giorgio, and Pescara wastewater samples, respectively.
A Multi-Modal and Multi-Atlas Integrated Framework for Identification of Mild Cognitive Impairment
Authors: Long Zhuqing , Li Jie , Liao Haitao , Deng Li , Du Yukeng , Fan Jianghua , Li Xiaofeng , Miao Jichang , Qiu Shuang , Long Chaojie , Jing Bin
Published: June 2022

Background: Multi-modal neuroimaging with appropriate atlas is vital for effectively differentiating mild cognitive impairment (MCI) from healthy controls (HC). Methods: The resting-state functional magnetic resonance imaging (rs-fMRI) and structural MRI (sMRI) of 69 MCI patients and 61 HC subjects were collected. Then, the gray matter volumes obtained from the sMRI and Hurst exponent (HE) values calculated from rs-fMRI data in the Automated Anatomical Labeling (AAL-90), Brainnetome (BN-246), Harvard–Oxford (HOA-112) and AAL3-170 atlases were extracted, respectively. Next, these characteristics were selected with a minimal redundancy maximal relevance algorithm and a sequential feature collection method in single or multi-modalities, and only the optimal features were retained after this procedure. Lastly, the retained characteristics were served as the input features for the support vector machine (SVM)-based method to classify MCI patients, and the performance was estimated with a leave-one-out cross-validation (LOOCV). Results: Our proposed method obtained the best 92.00% accuracy, 94.92% specificity and 89.39% sensitivity with the sMRI in AAL-90 and the fMRI in HOA-112 atlas, which was much better than using the single-modal or single-atlas features. Conclusion: The results demonstrated that the multi-modal and multi-atlas integrated method could effectively recognize MCI patients, which could be extended into various neurological and neuropsychiatric diseases.
Comparing the Effect of Dexmedetomidine and Midazolam in Patients with Brain Injury
Authors: Huang Yanxia , Deng Yunxin , Zhang Renjing , Meng Mei , Chen Dechang
Published: June 2022

Background: Studies have shown that dexmedetomidine improves neurological function. Whether dexmedetomidine reduces mortality or improves quantitative electroencephalography (qEEG) among patients post-craniotomy remains unclear. Methods: This single-center randomized study was conducted prospectively from 1 January 2019 to 31 December 2020. Patients who were transferred to the ICU after craniotomy within 24 h were included. The analgesic was titrated to a Critical care Pain Observation Tool (CPOT) score ≤2, and the sedative was titrated to a Richmond Agitation–Sedation Scale (RASS) score ≤−3 for at least 24 h. The qEEG signals were collected by four electrodes (F3, T3, F4, and T4 according to the international 10/20 EEG electrode practice). The primary outcome was 28-day mortality and qEEG results on day 1 and day 3 after sedation. Results: One hundred and fifty-one patients were enrolled in this study, of whom 77 were in the dexmedetomidine group and 74 in the midazolam group. No significant difference was found between the two groups in mortality at 28 days (14.3% vs. 24.3%; p = 0.117) as well as in the theta/beta ratio (TBR), the delta/alpha ratio (DAR), and the (delta + theta)/(alpha + beta) ratio (DTABR) between the two groups on day 1 or day 3. However, both the TBR and the DTABR were significantly increased in the dexmedetomidine group. The DTABR in the midazolam group was significantly increased. The DAR was significantly increased on the right side in the dexmedetomidine group (20.4 (11.6–43.3) vs. 35.1 (16.7–65.0), p = 0.006) as well as on both sides in the midazolam group (Left: 19.5 (10.1–35.8) vs. 37.3 (19.3–75.7), p = 0.006; Right: 18.9 (10.1–52.3) vs. 39.8 (17.5–99.9), p = 0.002). Conclusion: Compared with midazolam, dexmedetomidine did not lead to a lower 28-day mortality or better qEEG results in brain injury patients after a craniotomy.
Correlation between Electrode Location and Anxiety Depression of Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease
Authors: Zhang Feng , Wang Feng , Xing Yu-Jing , Yang Man-Man , Wang Ji-Wei , Li Cong-Hui , Han Chun-Lei , Fan Shi-Ying , Gao Dong-Mei , Yang Chen , Zhang Jian-Guo , Meng Fan-Gang
Published: June 2022

Objectives: our group explored the correlation between postoperative coordinates of the electrode contacts, VTA, and anxiety and depression symptoms in Parkinson’s disease (PD) patients after subthalamic nucleus deep brain stimulation (STN-DBS). Methods: STN-DBS was conducted on PD patients (n = 57) for six months with follow-up. Clinical outcomes were explored using the unified Parkinson’s disease rating scale Part III (UPDRS-III), the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D) before and after surgery. At the Montreal Neurological Institute (MNI), the location of active contacts and the volume of tissue activated (VTA) were calculated. Results: patient evaluations took place preoperatively and follow-ups took place at 1 month, 3 months, and 6 months. The average patient improvement rates for HAM-A and HAM-D scores at the 6-month follow-up were 41.7% [interquartile range (IQR) 34.9%] and 37.5% (IQR 33.4%), respectively (both p < 0.001). In medication-off, there were negative correlations between the HAM-A improvement rate and the Z-axis coordinate of the active contact (left side: r = −0.308, p = 0.020; right side: r = −0.390, p = 0.003), and negative correlations between the HAM-D improvement rate and the Z-axis coordinate of the active contact (left side: r = −0.345, p = 0.009; right side: r = −0.521, p = 0.001). There were positive correlations between the HAM-A and HAM-D scores improvement rate at 6 months after surgery and bilateral VTA in the right STN limbic subregion (HAM-A: r = 0.314, p = 0.018; HAM-D: r = 0.321, p = 0.015). Conclusion: bilateral STN-DBS can improve anxiety and depression symptoms in PD patients. The closer the stimulation to the ventral limbic region of the STN, the more significant the improvement in anxiety and depression symptoms of PD patients.
The Luria-Nebraska Neuropsychological Battery Neuromotor Tasks: From Conventional to Image-Derived Measures
Authors: Corbo Daniele , Placidi Donatella , Gasparotti Roberto , Wright Robert , Smith Donald R. , Lucchini Roberto G. , Horton Megan K. , Colicino Elena
Published: June 2022

Background: Sensorimotor difficulties significantly interfere with daily activities, and when undiagnosed in early life, they may increase the risk of later life cognitive and mental health disorders. Subtests from the Luria-Nebraska Neuropsychological Battery (LNNB) discriminate sensorimotor impairments predictive of sensorimotor dysfunction. However, scoring the LNNB sensorimotor assessment is highly subjective and time consuming, impeding the use of this task in epidemiologic studies. Aim: To train and validate a novel automated and image-derived scoring approach to the LNNB neuro-motor tasks for use in adolescents and young adults. Methods: We selected 46 adolescents (19.6 +/− 2.3 years, 48% male) enrolled in the prospective Public Health Impact of Metal Exposure (PHIME) study. We visually recorded the administration of five conventional sensorimotor LNNB tasks and developed automated scoring alternatives using a novel mathematical approach combining optic flow fields from recorded image sequences on a frame-by-frame basis. We then compared the conventional and image-derived LNNB task scores using Pearson’s correlations. Finally, we provided the accuracy of the novel scoring approach with Receiver Operating Characteristic (ROC) curves and the area under the ROC curves (AUC). Results: Image-derived LNNB task scores strongly correlated with conventional scores, which were assessed and confirmed by multiple administrators to limit subjectivity (Pearson’s correlation ≥ 0.70). The novel image-derived scoring approach discriminated participants with low motility (<mean population levels) with a specificity ranging from 70% to 83%, with 70% sensitivity. Conclusions: The novel image-derived LNNB task scores may contribute to the timely assessment of sensorimotor abilities and delays, and may also be effectively used in telemedicine.
Repetitive Transcranial Magnetic Stimulation of the Primary Motor Cortex beyond Motor Rehabilitation: A Review of the Current Evidence
Authors: Tomeh Abdulhameed , Yusof Khan Abdul Hanif Khan , Inche Mat Liyana Najwa , Basri Hamidon , Wan Sulaiman Wan Aliaa
Published: June 2022

Transcranial magnetic stimulation (TMS) has emerged as a novel technique to stimulate the human brain through the scalp. Over the years, identifying the optimal brain region and stimulation parameters has been a subject of debate in the literature on therapeutic uses of repetitive TMS (rTMS). Nevertheless, the primary motor cortex (M1) has been a conventional target for rTMS to treat motor symptoms, such as hemiplegia and spasticity, as it controls the voluntary movement of the body. However, with an expanding knowledge base of the M1 cortical and subcortical connections, M1-rTMS has shown a therapeutic efficacy that goes beyond the conventional motor rehabilitation to involve pain, headache, fatigue, dysphagia, speech and voice impairments, sleep disorders, cognitive dysfunction, disorders of consciousness, anxiety, depression, and bladder dysfunction. In this review, we summarize the latest evidence on using M1-rTMS to treat non-motor symptoms of diverse etiologies and discuss the potential mechanistic rationale behind the management of each of these symptoms.
A Novel Computational Approach for an Improved Expression of the Spectral Content in the Lower Atmospheric Boundary Layer
Authors: Potsis Theodore , Stathopoulos Ted
Published: June 2022

The paper presents an innovative methodology for the simulation of incoming wind conditions in computational domains that use large eddy simulation (LES) for the evaluation of wind loads on low-rise buildings. Simulating the atmospheric boundary layer has proven to be a challenging process for computational wind engineering, especially to correctly introduce the fluctuations in the high-frequency spectral domain. Experiments in the Concordia University Building Aerodynamics Laboratory were carried out to estimate the evolution of turbulence features in the along-wind direction of a generic profile. Virtual probes were placed inside the computational domain to match the location of those in the wind tunnel and compare mean speed values, turbulence intensity, integral length scales, and spectral content. Synthetic methods were applied for the incoming wind velocity to estimate their capacity to capture the evolution of these turbulence features in the streamwise direction. The inability of these synthetic methods to represent the spectral domain, particularly for heights of interest for low-rise buildings, was examined, and the so-called dynamic terrain method in which velocity time histories are extracted from wind tunnel measurements and reconstructed to fit certain statistical parameters was implemented. The proposed method represents the frequency domain’s spectral content with good agreement with the theoretical von Karman spectrum and the experimental results. Advantages of the method include time efficiency and relative simplicity, which makes it attractive to the practitioners for the design of a neutral atmospheric boundary layer respecting the turbulent wind characteristics.
Determination of Tensile Strength at Crack Initiation in Dynamic Brazilian Disc Test for Concrete-like Materials
Authors: Wang Jie , Tao Junlin
Published: June 2022

Concrete is a brittle material whose tensile strength is about one-tenth of its compressive strength. Tensile strength is a key parameter for concrete under impact loading. When a turning point occurs before peak load in the load–time curve from the dynamic Brazilian disc test, there is no basis for choosing the turning point or the peak load to calculate the tensile strength. The objective of this study is determining the crack initiation tensile stress at the turning point or the peak. The method contrasts the time duration from Digital image correlation (DIC) and the load–time curve from a split Hopkinson pressure bar (SHPB) system in order to obtain the load value when cracking first appears. The crack initiation tensile strength is less than the peak strength for concrete specimens with a turning point in the load–time curve. The crack initiation tensile strength is equal to the peak strength for concrete specimens without a turning point in the load–time curve. The proposed method is successfully applied to determine crack initiation of concrete specimens and obtain tensile strength at crack initiation of concrete specimens.
FEA Investigation of Elastic Buckling for Functionally Graded Material (FGM) Thin Plates with Different Hole Shapes under Uniaxial Loading
Authors: Elkafrawy Mohamed , Alashkar Adnan , Hawileh Rami , AlHamaydeh Mohammad
Published: June 2022

In this paper, an investigation of linear eigenvalue buckling of functionally graded material (FGM) plates under uniaxial loading is carried out. The computer model is analyzed using the finite element (FE) package ABAQUS. An analysis is carried out to study the effect of the size and geometry of openings in the FGM plate on the critical buckling load. The circular, square, and diamond openings vary in size based on the ratio of the opening diameter to the width of the FGM plate. Moreover, the effect of the aspect ratio (width to thickness) of the FGM plate on the critical buckling load is examined. Further, the effect of the power law index on buckling behavior is investigated. The results show that the increase in the size of the opening and the aspect ratio reduces the critical buckling load of the FGM plate. Moreover, the lower the power law index, the higher the critical buckling load. The diamond shape opening shows the best performance in terms of the critical buckling load, and the effect of the plate thickness has a more significant influence on the critical buckling load of the FGM plate compared to the size of the opening.
A Systematic Review on FabLab Environments and Creativity: Implications for Design
Authors: Soomro Sohail Ahmed , Casakin Hernan , Georgiev Georgi V.
Published: June 2022

Fabrication laboratories (FabLabs) and makerspaces are used to transform ideas into tangible products. Used in a design–learning context, they can enhance cognitive and creative skills. Creativity is the pivotal ability to produce innovative outcomes in makerspaces, and several studies have attempted to understand the role of makerspaces and creativity in specific fields. However, a comprehensive study offering a holistic view of the contributions of the makerspaces as built environments that foster creativity is lacking. Therefore, we conducted a systematic literature review on FabLabs, makerspaces, and creativity to address this research gap. While the review was performed using five major databases, only peer reviewed journal articles were considered. The findings revealed that makerspaces help to develop person, product, physical, and social environments, as well as process aspects of creativity. Moreover, makerspaces induce problem solving, collaborative, and communication skills; they also offer appealing environments and technologies for developing creative solutions to real-life problems. We identified and analysed five major themes dealing with technical skills, technological and environmental elements, STEM learning, and skill development, and elaborated upon their importance for enhancing creativity in FabLab and makerspace environments.
Multimodal Approach of Optical Coherence Tomography and Raman Spectroscopy Can Improve Differentiating Benign and Malignant Skin Tumors in Animal Patients
Authors: Tamošiūnas Mindaugas , Čiževskis Oskars , Viškere Daira , Melderis Mikus , Rubins Uldis , Cugmas Blaž
Published: June 2022

As in humans, cancer is one of the leading causes of companion animal mortality. Up to 30% of all canine and feline neoplasms appear on the skin or directly under it. There are only a few available studies that have investigated pet tumors by biophotonics techniques. In this study, we acquired 1115 optical coherence tomography (OCT) images of canine and feline skin, lipomas, soft tissue sarcomas, and mast cell tumors ex vivo, which were subsequently used for automated machine vision analysis. The OCT images were analyzed using a scanning window with a size of 53 × 53 μm. The distributions of the standard deviation, mean, range, and coefficient of variation values were acquired for each image. These distributions were characterized by their mean, standard deviation, and median values, resulting in 12 parameters in total. Additionally, 1002 Raman spectral measurements were made on the same samples, and features were generated by integrating the intensity of the most prominent peaks. Linear discriminant analysis (LDA) was used for sample classification, and sensitivities/specificities were acquired by leave-one-out cross-validation. Three datasets were analyzed—OCT, Raman, and combined. The combined OCT and Raman data enabled the best sample differentiation with the sensitivities of 0.968, 1, and 0.939 and specificities of 0.956, 1, and 0.977 for skin, lipomas, and malignant tumors, respectively. Based on these results, we concluded that the proposed multimodal approach, combining Raman and OCT data, can accurately distinguish between malignant and benign tissues.
Computational Detection of Extraprostatic Extension of Prostate Cancer on Multiparametric MRI Using Deep Learning
Authors: Moroianu Ştefania L. , Bhattacharya Indrani , Seetharaman Arun , Shao Wei , Kunder Christian A. , Sharma Avishkar , Ghanouni Pejman , Fan Richard E. , Sonn Geoffrey A. , Rusu Mirabela
Published: June 2022

The localization of extraprostatic extension (EPE), i.e., local spread of prostate cancer beyond the prostate capsular boundary, is important for risk stratification and surgical planning. However, the sensitivity of EPE detection by radiologists on MRI is low (57% on average). In this paper, we propose a method for computational detection of EPE on multiparametric MRI using deep learning. Ground truth labels of cancers and EPE were obtained in 123 patients (38 with EPE) by registering pre-surgical MRI with whole-mount digital histopathology images from radical prostatectomy. Our approach has two stages. First, we trained deep learning models using the MRI as input to generate cancer probability maps both inside and outside the prostate. Second, we built an image post-processing pipeline that generates predictions for EPE location based on the cancer probability maps and clinical knowledge. We used five-fold cross-validation to train our approach using data from 74 patients and tested it using data from an independent set of 49 patients. We compared two deep learning models for cancer detection: (i) UNet and (ii) the Correlated Signature Network for Indolent and Aggressive prostate cancer detection (CorrSigNIA). The best end-to-end model for EPE detection, which we call EPENet, was based on the CorrSigNIA cancer detection model. EPENet was successful at detecting cancers with extraprostatic extension, achieving a mean area under the receiver operator characteristic curve of 0.72 at the patient-level. On the test set, EPENet had 80.0% sensitivity and 28.2% specificity at the patient-level compared to 50.0% sensitivity and 76.9% specificity for the radiologists. To account for spatial location of predictions during evaluation, we also computed results at the sextant-level, where the prostate was divided into sextants according to standard systematic 12-core biopsy procedure. At the sextant-level, EPENet achieved mean sensitivity 61.1% and mean specificity 58.3%. Our approach has the potential to provide the location of extraprostatic extension using MRI alone, thus serving as an independent diagnostic aid to radiologists and facilitating treatment planning.
Influence of the Timing of Leptomeningeal Metastasis on the Outcome of EGFR-Mutant Lung Adenocarcinoma Patients and Predictors of Detectable EGFR Mutations in Cerebrospinal Fluid
Authors: Liao Pei-Ya , Ou Wei-Fan , Su Kang-Yi , Sun Ming-Hsi , Huang Chih-Mei , Chen Kun-Chieh , Hsu Kuo-Hsuan , Yu Sung-Liang , Huang Yen-Hsiang , Tseng Jeng-Sen , Yang Tsung-Ying , Chang Gee-Chen
Published: June 2022

Background: We aim to evaluate the influence of the timing of leptomeningeal metastasis (LM) occurrence on the outcome of EGFR-mutant lung adenocarcinoma and to explore the predictors of detectable EGFR mutation in the cerebrospinal fluid (CSF). Methods: EGFR-mutant lung adenocarcinoma patients with cytologically confirmed LM were included for analysis. EGFR mutation in CSF was detected by MALDI-TOF MS plus PNA. Results: A total of 43 patients was analyzed. Of them, 8 (18.6%) were diagnosed with LM prior to first-line EGFR-TKI treatment (early onset), while 35 patients (81.4%) developed LM after first-line EGFR-TKI treatment (late onset). Multivariate analysis suggested that both late-onset LM (aHR 0.31 (95% CI 0.10–0.94), p = 0.038) and a history of third-generation EGFR-TKI treatment (aHR 0.24 (95% CI 0.09–0.67), p = 0.006) independently predicted a favorable outcome. EGFR mutation detection sensitivity in CSF was 81.4%. The radiological burden of LM significantly correlated with CSF tumor cell counts (p = 0.013) with higher CSF tumor cell counts predicting a higher detection sensitivity of EGFR mutation (p = 0.042). Conclusions: Early onset LM was an independently poor prognostic factor. A higher radiological severity score of LM could predict higher tumor cell counts in CSF, which in turn were associated with a higher detection rate of EGFR mutation.
Protein Farnesylation on Nasopharyngeal Carcinoma, Molecular Background and Its Potential as a Therapeutic Target
Authors: Kobayashi Eiji , Kondo Satoru , Dochi Hirotomo , Moriyama-Kita Makiko , Hirai Nobuyuki , Komori Takeshi , Ueno Takayoshi , Nakanishi Yosuke , Hatano Miyako , Endo Kazuhira , Sugimoto Hisashi , Wakisaka Naohiro , Yoshizaki Tomokazu
Published: June 2022

Nasopharyngeal carcinoma (NPC) is one of the Epstein–Barr virus (EBV)-associated malignancies. NPC is highly metastatic compared to other head and neck carcinomas, and evidence has shown that the metastatic features of NPC are involved in EBV infection. The prognosis of advanced cases, especially those with distant metastasis, is still poor despite advancements in molecular research and its application to clinical settings. Thus, further advancement in basic and clinical research that may lead to novel therapeutic modalities is needed. Farnesylation is a lipid modification in the C-terminus of proteins. It enables proteins to attach to the lipid bilayer structure of cellular membranes. Farnesylation was initially identified as a key process of membrane association and activation of the RAS oncoprotein. Farnesylation is thus expected to be an ideal therapeutic target in anti-RAS therapy. Additionally, more and more molecular evidence has been reported, showing that proteins other than RAS are also farnesylated and have significant roles in cancer progression. However, although several clinical trials have been conducted in cancers with high rates of ras gene mutation, such as pancreatic carcinomas, the results were less favorable than anticipated. In contrast, favorable outcomes were reported in the results of a phase II trial on head and neck carcinoma. In this review, we provide an overview of the molecular pathogenesis of NPC in terms of the process of farnesylation and discuss the potential of anti-farnesylation therapy in the treatment of NPC.
APOBEC Alteration Contributes to Tumor Growth and Immune Escape in Pan-Cancer
Authors: Guo Honghong , Zhu Ling , Huang Lu , Sun Zhen , Zhang Hui , Nong Baoting , Xiong Yuanyan
Published: June 2022

The accumulating evidence demonstrates that the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. In particular, the APOBEC3 family was shown to induce tumor mutations by an aberrant DNA editing mechanism. However, knowledge regarding the reconstitution of the APOBEC family genes across cancer types is still lacking. Here, we systematically analyzed the molecular alterations, immuno-oncological features, and clinical relevance of the APOBEC family in pan-cancer. We found that APOBEC genes were widely and significantly differentially expressed between normal and cancer samples in 16 cancer types, and that their expression levels are significantly correlated with the prognostic value in 17 cancer types. Moreover, two patterns of APOBEC-mediated stratification with distinct immune characteristics were identified in different cancer types, respectively. In ACC, for example, the first pattern of APOBEC-mediated stratification was closely correlated with the phenotype of immune activation, which was characterized by a high immune score, increased infiltration of CD8 T cells, and higher survival. The other pattern of APOBEC-mediated stratification was closely correlated with the low-infiltration immune phenotype, which was characterized by a low immune score, lack of effective immune infiltration, and poorer survival. Further, we found the APOBEC-mediated pattern with low-infiltration immune was also highly associated with the advanced tumor subtype and the CIMP-high tumor subtype (CpG island hypermethylation). Patients with the APOBEC-mediated pattern with immune activation were more likely to have therapeutic advantages in ICB (immunological checkpoint blockade) treatment. Overall, our results provide a valuable resource that will be useful in guiding oncologic and therapeutic analyses of the role of APOBEC family in cancer.
Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives
Authors: Césaire Mathieu , Montanari Juliette , Curcio Hubert , Lerouge Delphine , Gervais Radj , Demontrond Pierre , Balosso Jacques , Chevalier François
Published: June 2022

Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.
A New Functional Screening Platform Identifies Colistin Sulfate as an Enhancer of Natural Killer Cell Cytotoxicity
Authors: Cortés-Kaplan Serena , Kurdieh Reem , Hasim Mohamed S. , Kaczmarek Shelby , Taha Zaid , Maznyi Glib , McComb Scott , Lee Seung-Hwan , Diallo Jean-Simon , Ardolino Michele
Published: June 2022

Due to their crucial role in tumor immunity, NK cells have quickly became a prime target for immunotherapies, with the adoptive transfer of NK cells and the use of NK cell engagers quickly moving to the clinical stage. On the other hand, only a few studies have focused on small molecule drugs capable of unleashing NK cells against cancer. In this context, repurposing small molecules is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we developed a new platform to screen small molecule compounds based on a high-throughput luciferase-release cytotoxicity assay. We tested 1200 FDA approved drugs from the Prestwick Chemical Library, to identify compounds that increase NK cells’ cytotoxic potential. We found that the antibiotic colistin sulfate increased the cytotoxicity of human NK cells towards cancer cells. The effect of colistin was short lived and was not observed when NK cells were pretreated with the drug, showing how NK cell activity was potentiated only when the compound was present at the time of recognition of cancer cells. Further studies are needed to uncover the mechanism of action and the pre-clinical efficacy of colistin sulfate in mouse cancer models.
Synthetic Vulnerabilities in the KRAS Pathway
Authors: Roman Marta , Hwang Elizabeth , Sweet-Cordero E. Alejandro
Published: June 2022

Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.
Real-World Treatments and Clinical Outcomes in Advanced NSCLC without Actionable Mutations after Introduction of Immunotherapy in Japan
Authors: Nokihara Hiroshi , Kijima Takashi , Yokoyama Toshihide , Kagamu Hiroshi , Suzuki Takuji , Mori Masahide , Santorelli Melissa L. , Taniguchi Kazuko , Kamitani Tetsu , Irisawa Masato , Kanda Kingo , Abe Machiko , Burke Thomas , Goto Yasushi
Published: June 2022

The aims of this study were to describe systemic treatment patterns and clinical outcomes for unresectable advanced/metastatic non-small-cell lung cancer (NSCLC) by first-line regimen type in real-world clinical settings in Japan after the introduction of first-line immune checkpoint inhibitor (ICI) monotherapy in 2017. Using retrospective chart review at 23 study sites, we identified patients ≥20 years old initiating first-line systemic therapy from 1 July 2017 to 20 December 2018, for unresectable stage IIIB/C or IV NSCLC; the data cutoff was 30 September 2019. Eligible patients had recorded programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) and no known actionable EGFR/ALK/ROS1/BRAF genomic alteration. Kaplan-Meier method was used to determine time-to-event endpoints. Of 1208 patients, 647 patients (54%) received platinum doublet, 463 (38%) received ICI monotherapy, and 98 (8%) received nonplatinum cytotoxic regimen as first-line therapy. PD-L1 TPS was ≥50%, 1–49% and <1% for 44%, 30%, and 25% of patients, respectively. Most patients with PD-L1 TPS ≥50% received ICI monotherapy (453/529; 86%). Excluding 26 patients with ECOG performance status of 3–4 from outcome analyses, the median patient follow-up was 11.3 months. With first-line platinum doublet, ICI monotherapy, and nonplatinum cytotoxic regimens, median overall survival (OS) was 16.3 months (95% CI, 14.0–20.1 months), not reached, and 14.4 months (95% CI, 10.3–21.2 months), respectively; 24-month OS was 40%, 58%, and 31%, respectively. Differences in OS relative to historical cohort data reported in Japan are consistent with improvement over time in real-world clinical outcomes for advanced NSCLC.
Influence of Beam Angle on Normal Tissue Complication Probability of Knowledge-Based Head and Neck Cancer Proton Planning
Authors: Hytönen Roni , Vanderstraeten Reynald , Dahele Max , Verbakel Wilko F. A. R.
Published: June 2022

Knowledge-based planning solutions have brought significant improvements in treatment planning. However, the performance of a proton-specific knowledge-based planning model in creating knowledge-based plans (KBPs) with beam angles differing from those used to train the model remains unexplored. We used a previously validated RapidPlanPT model and scripting to create nine KBPs, one with default and eight with altered beam angles, for 10 recent oropharynx cancer patients. The altered-angle plans were compared against the default-angle ones in terms of grade 2 dysphagia and xerostomia normal tissue complication probability (NTCP), mean doses of several organs at risk, and dose homogeneity index (HI). As KBP could be suboptimal, a proof of principle automatic iterative optimizer (AIO) was added with the aim of reducing the plan NTCP. There were no statistically significant differences in NTCP or HI between default- and altered-angle KBPs, and the altered-angle plans showed a <1% reduction in NTCP. AIO was able to reduce the sum of grade 2 NTCPs in 66/90 cases with mean a reduction of 3.5 ± 1.8%. While the altered-angle plans saw greater benefit from AIO, both default- and altered-angle plans could be improved, indicating that the KBP model alone was not completely optimal to achieve the lowest NTCP. Overall, the data showed that the model was robust to the various beam arrangements within the range described in this analysis.
Efficacy of Vinflunine for Patients with Metastatic Urothelial Cancer after Immune Checkpoint Inhibitor Pretreatment—A Retrospective Multicenter Analysis
Authors: Riedel Felix , Münker Mara , Roghmann Florian , Breyer Johannes , Schnabel Marco J. , Burger Maximilian , Sikic Danijel , Büttner Thomas , Ritter Manuel , Hiller Kiriaki , Wezel Felix , Bolenz Christian , Zengerling Friedemann
Published: June 2022

Background: Immune checkpoint inhibitors (ICI) are standard of care in patients with metastatic urothelial carcinoma (mUC) ineligible for cisplatin, and as second-line therapy after platinum-based chemotherapy. To date, few data exist about the efficacy of the former second-line chemotherapeutic agent vinflunine after the failure of sequential platinum-based chemotherapy and ICI treatment. The aim of this analysis was to examine the efficacy of vinflunine in a post-ICI third- or later-line setting. Methods: In this retrospective German multicenter study, data of mUC patients treated with vinflunine were reviewed in six centers between February 2010 and December 2021. All of the 105 included patients had radiologic progression after first-line platinum-based chemotherapy. The objective was to describe the efficacy of vinflunine in terms of overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and progression-free survival (PFS) for post-ICI and ICI-naïve patients, respectively. Results: In our cohort, 61 patients (58.1%) had preceding immunotherapy before vinflunine administration, and 44 patients (41.9%) were ICI-naïve. Patients with ICI pretreatment showed an ORR of 22.4% compared to 15.6% within ICI-naïve patients (p = 0.451), and CBR was 51.0% vs. 25.0% (p = 0.020), respectively. Post-ICI patients showed longer OS (8.78 vs. 5.72 months; p = 0.467) and longer PFS (3.09 vs. 2.14 months; p = 0.105). Conclusion: This analysis supports the sequential use of vinflunine in post-ICI patients since the vinca-alkaloid retains a measurable clinical activity in these heavily pretreated patients. The therapeutic benefit may be higher than demonstrated in previous studies.
Medium to Long-Term Clinical Outcomes of Spinal Metastasectomy
Authors: Kato Satoshi , Demura Satoru , Murakami Hideki , Shinmura Kazuya , Yokogawa Noriaki , Annen Ryohei , Kobayashi Motoya , Yamada Yohei , Nagatani Satoshi , Kawahara Norio , Tsuchiya Hiroyuki
Published: June 2022

The prolonged survival of metastatic cancer patients highlights the importance of the local control of spinal metastases, which reduce patient performance status. This retrospective study examined the medium to long-term outcomes of spinal metastasectomy by evaluating 124 patients who underwent metastasectomy for isolated spinal metastases (2006–2018) with a postoperative follow-up for a minimum of 3 years. The findings present information on patient demographics (i.e., performance status, location of non-spinal metastases, and history of systemic therapy) and postoperative outcomes, including perioperative complications, disease progression of non-operated metastases, and additional excisional surgeries. Additionally, postoperative survival, local tumor control in the operated spine, and maintenance of spinal reconstruction without instrumentation failure were determined using Kaplan–Meier analyses. The primary malignancy was kidney and thyroid cancer in 51 and 14 patients, respectively, low-grade sarcoma and lung cancer in 13 patients, breast cancer in 12 patients, and other malignancies in 21 patients. The 3-year and 5-year survival rates were 70% and 60%, respectively. We found that patients with thyroid cancer had the best survival results, with local tumor recurrence and instrumentation failure at 10% and 22%, respectively. These findings suggest that for certain patients with isolated and removable spine metastases, metastasectomy can improve function and survival.